The world is currently experiencing the largest isolation experiment in history. In an attempt to slow down the spread of the COVID-19 pandemic numerous countries across the world have been shutting down economies, education, and public life. Governments have mandated strict regulations of quarantine and social distancing in an unprecedented manner. The effects of these measures on brain, behavior, neuro-humoral and immunological responses in humans are largely unknown. Life science research for space exploration has a long history in using high-fidelity spaceflight analogs to better understand the effect of prolonged isolation and confinement on genes, molecules, cells, neural circuits, and physiological systems to behavior. We here propose to leverage the extensive experience and data from these studies and build a bridge between spaceflight research and clinical settings to foster transdisciplinary approaches to characterize the neurobehavioral effects on the immune system and vice versa. These approaches are expected to develop innovative and efficient health screening tools, diagnostic systems, and treatments to mitigate health risks associated with isolation and confinement on Earth and during future exploratory spaceflight missions. The brain’s susceptibility to SARS-CoV-2 could also be a potential risk factor for Alzheimer’s disease2. In addition to the clinical manifestations associated with COVID-19, physical distancing policies to control the spread of the diseases have led to large-scale and unprecedented social isolation across the globe. The prevalence of social isolation and loneliness in response to the COVID-19 pandemic is currently unclear, with estimates varying between 16 and 25%3. It is considered the greatest international biopsychosocial emergency the world has faced for a century4. Recent research reviewed the psychological implications of prolonged isolation and confinement associated with quarantine, reporting posttraumatic and acute stress symptoms, confusion, and anger in response to quarantaine5. The interventions to mitigate the negative effects on mental health and well-being include befriending schemes, individual and group therapies, various shared activity programs, social prescription by healthcare providers, and diverse strategies using information and communication technologies, but their effectiveness and relevance to different age groups remains to be determined3.Throughout history infectious diseases have been one of the greatest threats to global public health. Viruses have killed by far more humans than other disease, war or natural disaster. The outbreak of the novel Coronavirus SARS-CoV-2 shows that the risk of infectious diseases can rapidly put our health systems to the test and turn the world economy, education, and public life upside down. Research is just beginning to understand the full impact of the disease. There is increasing evidence that the current pandemic affects global health and well-being in many more ways than a respiratory disease, including the central nervous system and neurological diseases6. The “absence of environmental stimulation” is expected to account for sleep disruptions, impaired cognitive performance, negative affect, and interpersonal tension and conflict during exploratory spaceflight missions7. Space agencies and their human research programs have a long history of seeking to understand the effects of isolation and confinement on astronaut health and performance. Consequently, developing strategies to mitigate the risks of adverse behavioral conditions and psychiatric disorders associated with human spaceflight are of critical importance8. It may therefore not be surprising that the value of shared learnings from spaceflight during COVID-19 has been emphasized in numerous news reports and social media channels, providing anecdotal evidence for the parallelism of isolation and confinement in extreme environments and in the current pandemic11. Here, we summarize the opportunities of spaceflight analogs to accelerate (1) the understanding of the neurobehavioral and immunological consequences of social isolation during the COVID-19 pandemic, and (2) the development of innovative and efficient treatment strategies to mitigate adverse behavioral conditions.Reduced sensory stimulation and sensory monotony experienced in isolated, confined, and extreme (ICE) environments are also expected to be a major risk during future spaceflight exploratory class missions12, cardiovascular deconditioning13, renal stones and kidney dysfunction14. However, besides these physiological effects of microgravity and multiple environmental toxicants in space, the psychological stressors are exhaustive and additive: life in a tin can, lack of privacy, separation from friends and family, high workload, operational and interpersonal distress, dietary restrictions, noise, circadian disorders and sleep loss15. The development of adverse behavioral conditions and psychiatric disorders during future long-duration space missions (LDSM) are considered one of the most serious, but also least understood risks6. Isolation and confinement are significant contributors to these unmitigated risks, and can lead to mental health symptoms, impulse control deficits, workplace errors, and even increased mortality16.More than 50 years of research in space has revealed how the unique physiological conditions and stresses of space affect almost every biological system in all kingdoms of life; from plants, to bacteria, to humans. Man evolved in a world where Newton’s apple never fails to fall and at no stage did evolution prepare us for the eventuality that we may one day be exposed to life in zero gravity while confined in a hazardous environment. Spaceflight affects the entire human body. The lack of gravity results in considerable bone loss much akin to osteoporosis and muscle wasting7. The European Space Agency (ESA) early recognized the need to study the effects of isolation and confinement on mental well-being and performance to enable safe and successful spaceflight. Since the 1990s the European Space Agency (ESA) has been consistently sponsoring studies in isolated, controlled and confined analogs (ICC), starting with the 30-day campaign “Isolation Study for the European Manned Space Infrastructure” (ISEMSI) campaign in Bergen Norway in 199017, followed by the 60-day study “Experimental Campaign for the European Manned Space Infrastructure (EXEMSI) carried out at the German Aerospace Center (DLR) in Cologne, Germany in 199218. In 1994 ESA cooperated with the Institute of Biomedical Problems (IBMP) in Moscow, Russia, to further the understanding of the psychophysiological effects of isolation and confinement and extended the duration of the isolation period to 135 days in the “Human Behaviour in Extended Spaceflight” (HUBES)19 experiment, and up to 240 days  in the “Simulation of the Flight of the International Crew on Space Station” (SFINCSS) experiment. These studies lay the groundwork for the longest isolation experiment in history, i.e., the Mars500 study, which exposed six international crewmembers to 520 days of isolation and confinement in IBMP’s NEK facility in 201120. The success of the isolation studies at IBMP is now continued in close collaboration with NASA and ESA in a series of isolation studies as part of the “Scientific International Research in Unique Terrestrial Station” (SIRIUS) project21. In 2001 NASA started to simulate operations and test spacewalk techniques using a highly unique underwater habitat  with mission durations of up to three weeks22. Since 2013 NASA has also been supporting prolonged isolation studies using an analog habitat HI-SEAS  on the island of Hawaii23. More recently, NASA has been using its Human Exploration Research Analog (HERA) facility at Johnson Space Center to investigate the effects of isolation and confinement for up to 45 days24. Except for several Russian studies using the NEK complex21, and Chinese experiments in Chinese CELSS 25, laboratory-based isolation studies in isolated, controlled and confined analogs (ICC) have often been rather short in duration (<60 days). Submariners and Antarctic stations can provide excellent opportunities to study the effects of prolonged isolation and confinement in real extreme environments . Despite more than 80 Antarctic research stations, only very few qualify as high-fidelity analogs for space research. Suitable stations are characterized by a small crew sizes , extended mission duration of one year or longer, and include complex logistical operations with only limited or no rescue capabilities during the Antarctic winter.The beginning of the study of isolation and confinement can be marked by Polar expeditions, providing anecdotal evidence of the psychological and physiological challenges associated with prolonged isolation and confinement such as sleep disorders, mood disturbances, depression, anxiety, paranoia, and suicide26. A common denominator of perceived social isolation is that it translates to physiological stress responses via the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis. Loneliness has been shown to increase chronic sympathetic tone, oxidative stress, and HPA activation, and to decrease anti-inflammatory responses, and the expression of genes regulating glucocorticoid responses, ultimately leading to glucocorticoid resistance27.The complications associated with isolations and confinement depend on a plethora of factors including individual issues such as personality, coping strategies, psychological support, crew dynamics, and mission duration. Physical isolation may also not necessarily have any adverse effects per se. Physical isolation and perceived social isolation, the subjective distressed feeling of being alone or separated can be related, but physical isolation is not a sufficient condition for loneliness28. Both short- and long-term social isolation has been shown to reduce hippocampal long-term potentiation in rodents30. The dentate gyrus (DG) of the hippocampus is likely to play a key role in defining the impact of stress on hippocampal functioning. We recently published data on neuroendocrine and brain changes in response to Antarctic expeditions at the German Neumayer III station characterized by multiple stressors including environmental deprivation and prolonged physical and social isolation31. Our data demonstrated considerable decreases in dentate gyrus volume that were associated with changes in key neurotrophins such as brain-derived neurotrophic factor (BDNF). The reductions in dentate gyrus volume were also associated with lower cognitive performance in tests of spatial processing and the resolution of response conflicts test but there was no reduction in performance in other cognitive tests relying primarily on motor speed and attention, and manual dexterity. These data confirm the impact of environmental and social variation on hippocampal plasticity in humans32. The distinct changes of the dentate gyrus to environmental deprivation in comparison to other hippocampal subfields is similar to findings from animal models, suggesting a possible link between hippocampal neurogenesis, stress-induced behavioral changes, and environmental deprivation35. Furthermore, whole-brain analysis using voxel-based morphometry revealed significant decreases in gray matter volume of the right dorsolateral prefrontal cortex (DLPFC), and left orbitofrontal cortex (OFC) after the 14-month expedition31. THE DLPFC and the OFC are pivotal for executive control such as response inhibition, working memory and cognitive flexibility36, but also the generation of and regulation of emotion37. Projections between the hippocampus and orbitofrontal cortex (OFC), and to some extent also the DLPFC38, can foster cross-structural communication, and might interact to influence behavior39. Data from the ICC analog NEK also suggest decreases in white matter integrity of the right temporoparietal junction (TPJ) after prolonged isolation and confinement40. Whereas these data need to be interpreted cautiously because of their cross-sectional nature (reductions in white matter integrity were not reported within subjects over time), and a very small sample size, the results raise interesting questions about the effects of sensory deprivation on the brain during isolation and confinement that should be considered in future ICE/ICC experiments. The right TPJ integrates multisensory information and has been suggested to play a critical role for reorienting of attention, i.e., being able to respond quickly to unexpected events in the surroundings, and social processes41. We attribute these effects to both sensory deprivation as well as lack of diverse social interactions associated with the prolonged isolation and confinement. Together, these data suggest that prolonged isolation and confinement can have considerable, differential effects on brain structures involved in various complex cognitive controls including learning and memory formation, spatial navigation, self-control, planning, problem-solving, and emotional control. Notably, these data are characterized by considerable inter-individual differences in their response to social and environmental monotony. In addition, the recovery of these changes is currently unknown. The immune system could be a critical pathway in better understanding the specific neurobehavioral phenotypes. For instance, recent NASA funded research suggests that social isolation influences cytokine levels in the hippocampus42. The immune system is among the largest human organs and consists of more than four trillion cells. It affects every organ and influences almost every disease state from infection, to cancer, to cardiovascular disease and bone homeostasis. Most remarkable about the immune system is its adaptability to protect us rapidly and efficiently from the pathogenesis and progression of bacterial and viral infections. Using an orchestra of innate and adaptive response, it regulates a critical and delicate balance between health and disease. Any disruption of this equilibrium can lead to life threatening infections, autoimmune diseases, and cancer. Understanding this balance is vital to ensuring adequate immunity and health, which in a case of imbalance can lead to immune aging, viral reactivation, and hypersensitivities/allergies43.Two organ systems that are profoundly challenged by stress responses pertain to our host defense and our central control: the brain and the immune system. Stress can impact nearly any brain region, but one brain structure that is of particular importance is the hippocampus. The hippocampus plays a pivotal role in episodic memory formation, mapping spatial relationships and performing navigational tasks. Given the importance of visuospatial abilities during operations such as docking, landing, exploring and navigating in new environments and on planets with low gravity, it is imperative to understand the impact of spaceflight on spatial cognition and its neural basis. Because of the high density of corticosteroid receptors in the hippocampus it is not surprising that this brain region is very vulnerable to increased stress levels44, overwintering crews45 and participants voluntarily isolated and confined for the sake of research46, and also thereafter, when being re-exposed to everyday life again47. At the same this applies as much to people on Earth exposed to chronic emotional and physical stress—as it is happening right now around the world as a consequence of the COVID-19 pandemic. The parallels between social distancing and isolation and confinement and spaceflight analogs offer opportunities for shared learnings between these settings. For example, shedding of dormant herpes virus in saliva might be a very helpful surrogate marker of immune dysfunction. This could be internationally set and include many cases as clustered in different areas. Care points or pharmacies could enable data collections on a consensual basis. In addition, crowdsourcing could be supported by smart phone-based applications collecting self-reported data. An example is the EPB (European Polar Board)-ESA project ‘CHOICEe’ for the monitoring immune deficiencies after isolation48, and its potential applicability also in following the impact of infections with SARS-CoV-2 and the quarantine effects. A caveat of such epidemiological studies is often the lack of pre-pandemic reference data. Cross-sectional data from health controls including pre-mission data from spaceflight and spaceflight analogs can serve as a comparison for evaluating the effects of the COVID-19 pandemic. Data collected before the pandemic could be particularly valuable for establishing such a reference. For instance, the combination of self-reported data, medical records, biospecimen and neuroimaging collected during the previous 6 months prior to the COVID-19 pandemic and medical records could be considered either as a reference for between-subject comparisons or extended by follow up data collections, to foster a pre/post comparison within subjects. In particular, investigating brain morphological changes in a longitudinal manner could provide valuable information about the effects of social isolation on the brain plasticity, and verify the data we previously reported in response to prolonged isolation and confinement in extreme environments31. Further, future isolation and confinement studies of healthy individuals without a history of COVID-19 will remain a critical source for maximizing the synergies between spaceflight research and the clinical manifestations associated with social isolation.These gradual and inter-individual effects of psychological and environmental stressors are true for astronauts49. First, the “baking treatment” had crew members stay in front of the stove’s fire for several hours each day50. The radiant heat and light associated with the fire were expected to foster relaxation and restoration, and induce positive mood. Second, Cook requested the crew to take daily walks around the ship to engage in physical activity, which became known as the “mad-house promenade”50. About 100 years later, there is increasing scientific evidence about the role of exercise as a means of active release, enhancing brain structure and function, and improving cognitive performance52. Acute and chronic exercise has also been shown to improve innate and adaptive immunity54. Recent research highlights physical activity is an important clinical target to sustain and improve mental health during the current pandemic55.To mitigate the adverse health effects associated with isolation and confinement, innovative countermeasures are critically needed. This need was recognized as early as the one of the first Antarctic expeditions. The crew of the Belgian expedition “Belgica” led by Adrien de Gerlache de Gomery became the first to endure an Antarctic winter after being accidentally trapped among ice packs in the Bellinghausen Sea in 1898. Frederick Cook’s reports from that expedition can perhaps be considered as one of the observations of melancholy and depression observed during prolonged isolation and confinement. To counter these symptoms Cook prescribed two actions, which may be considered as one of first exercise and light interventions to treat depression6. They can foster a “virtual window”, i.e., exploring virtual worlds and induce a high degree of a first-person immersive experience of “being there”56, which has been suggested to be of central importance for eliciting restorative effects. The positive outcomes of exposure therapies in VR which include mood induction procedures58, stress reduction59, treatment of PTSD60, anxieties62 and pro-environmentalist behavior63 with immersive VR altogether have demonstrated the usefulness of this medium in changing our cognitive and emotional mechanisms. Currently, various projects sponsored by DLR, ESA, NASA and TRISH have been investigating the potential of VR as a countermeasure to mitigate sensory deprivation and social isolation. For instance, the NASA sponsored project “Hybrid Training - A Sensory Stimulation Countermeasure for Long Duration Space Exploration Missions” combines physical exercise with an interactive virtual environment to enhance sensory augmentation and stimulate brain plasticity during prolonged isolation and confinement64. The combination of VR technologies and physical exercise was also recently recognized as a promising coping strategy to promote health and wellness during COVID-1965. Former astronaut Jay C. Buckey and his team developed the Dartmouth PATH Program, a series of self-help tools designed by to relieve stress, improve mood, and maintain relationships during prolonged isolation and confinement associated with spaceflight. Ongoing research currently investigates whether the PATH Program also help people cope with the emotional stresses brought on by COVID-1967. Likewise, the NASA supported project ANSIBLE  delivered a multi-modal digital toolset that leverages virtual worlds to provide a space where humans and intelligent virtual agents can be companions, advisors, provided psychological support, and share experiences68. It is intended to virtually connect with their family, friends, and the ground crew to provide a sense of social consistency and permanence. Another digital resource to support astronauts during exploration class missions is the Crew Interactive MObile companioN (CIMON) project supported by DLR69. CIMON is a virtual voice-controlled interactive assistant that uses artificial intelligence to foster social interactions between humans and machines, and support astronauts during routine tasks. Such approaches could also directly translate to immunological benefits. It has become clear that the immune system is not autonomous and is not solely affected by pathogens alone. Instead how we feel, how we interact with others, the conditions in which we live all influence its function. This interaction between our social and emotional lives and the immune system take place via the central nervous system. Stress-sensitive neural systems and cells together with humoral pathways coordinate immune cell maturation, responsiveness and their interactions43. Recently, an international team of ESA, NASA and IBMP experts proposed a specific and personalized immune countermeasure prescription for prospective astronauts embarking on deep-space voyage70. The combination of different physical, medical and behavioral interventions including therapeutics, nutrient-enriched diets, regular exercise, adequate rest, and stress-relief could be expected to go beyond supporting immunologic responses by affecting other organ systems including the central nervous system. In particular, it is possible that the full synergistic potential of the proposed measures could be further enhanced by combining it with some of the behavioral strategies outlined above. Along these lines Data collected before the pandemic could be particularly valuable for establishing such a reference. For instance, the combination of self-reported data, medical records, biospecimen and neuroimaging collected during the previous 6 months prior to the COVID-19 pandemic and medical records could be considered either as a reference for between-subject comparisons or extended by follow up data collections, to foster a pre/post comparison within subjects. In particular, investigating brain morphological changes in a longitudinal manner could provide valuable information about the effects of social isolation on the brain plasticity, and verify the data we previously reported in response to prolonged isolation and confinement in extreme environments51. Further, future isolation and confinement studies of healthy individuals without a history of COVID-19 will remain a critical source for maximizing the synergies between spaceflight research and the clinical manifestations associated with social isolation.In addition to exercise, target-specific countermeasures will be needed to specifically address the risks associated with perceived social isolation and sensory deprivation. These could deliver similar restorative effects like the “baking treatment” during the Belgica expedition. Virtual reality (VR) technologies are likely to play an important role in meeting these requirements71. Likewise, given the specific requirements of spaceflight health monitoring technologies such as size, mass, ease of operation, and non-invasiveness, human spaceflight research programs can promote health technologies on Earth. An example is the application of a heat flux-based approach to non-invasively determine core body temperature at the head72. The technology was validated and tested in spaceflight analogs and on ISS74. The system is now available for patient monitoring in the clinical setting because temperature monitoring is critical for treating infections, detecting complications, and reducing postoperative mortality rates75. At the same emerging terrestrial biomedical research and technology development can accelerate the mitigation of risks associated with human spaceflight by providing promising new approaches, treatments, countermeasures or technologies that have practical application to spaceflight.Spaceflight-related research offers a variety of unique experimental approaches and designs that can foster basic research in life science and drive innovative medical and health-related applications Fig. . For ins76. Several space agencies have begun to address this need and developed initiatives to foster productive cross-disciplinary collaboration between universities, non-university institutions, companies, and governmental and international entities. For instance, the DLR initiatives INNOspace® Masters and Space2Health seek the development of innovative space technologies and services using expertise from various industries combined with existing technologies, services and applications from space for everyday life on Earth. It promotes both the commercialization and the initiation of “spin-in” (from non-space into a space sector) and “spin-off” (from space sectors into non-space) ideas. Likewise, ESA initiated several Business Incubation Centres (ESA BICs) to inspire and work with entrepreneurs to turn space-related business concepts and ideas into commercial start-up companies. Since its start in 2003 over 700 new companies have been launched throughout Europe transfer space technologies to various applications including medical care on Earth. Another approach has been fostered by NASA’s Human Research Program (HRP) by partnering with several external entities to accelerate the risk mitigation of future long-duration spaceflight missions. This also led to the launch of the Translational Research Institute for Space Health (TRISH), a consortium spearheaded by Baylor College of Medicine and includes the California Institute of Technology in Pasadena and Massachusetts Institute of Technology in Cambridge. TRISH closely collaborates with NASA to rapidly and effectively translate knowledge, methodologies, and technologies from laboratory experiments and clinical trials to point-of-care astronaut health and performance applications. The continuation and extension of these approaches is a key factor to help bridging the gap between experts in spaceflight life sciences, basic life science, and stakeholders in health technology innovation. This is particularly true for mitigating the risks of adverse behavioral conditions associated with isolation and confinement. Along this line TRISH has announced an “Industry Program 2020” grant call for industry and academic behavioral health experts to contribute towards the development of specific key areas of interest including novel anxiety and stress monitoring techniques, and unobtrusive health monitoring technologies. Similar to the OECD Council’s “Recommendation on Responsible Innovation in Neurotechnology” the TRISH program seeks to provide guidance at each step of the innovation process so that the benefits are maximized and risks minimized. This includes providing companies and pre-companies with (1) access to experts working in space health care and at NASA, (2) rapid technology maturation and de-risking, (3) preparation for transfer to commercial healthcare markets, and (4) pathways to government sales in the emerging space market.The full scope of the synergies between terrestrial and spaceflight applications remains to be uncovered. Recent reviews highlight the need to increase the awareness, training, and collaboration of the research community for revealing the true potential of applying these space technologies to global health settings“Facts are the air of scientists. Without them you can never fly” (Linus Pauling). That is why space agencies are taking research to the skies and are supporting innovative approaches to better understand how the human body copes with extreme conditions, and how this knowledge can be transferred to and benefit the people on Earth. Here we used the parallels of spaceflight analogs and the COVID-19 pandemic to illustrate the value of shared learnings for gaining a better understanding of the neurobehavioral and immunological implications of social isolation and how to mitigate related adverse health conditions. Since space research is addressing and increasingly influencing the traditional fields of medicine including neurobiology, clinical immunology, and public health of an aging society, this pandemic, the re-entry to normal life and its aftermath should strengthen current inter- and transdisciplinary collaborative research initiatives between space life sciences, basic biomedical science, clinical applications, and industrial stakeholders to mitigate the negative effects of physical and social isolation in health and disease. Such collaborative research initiatives combined with historic data from spaceflight analogs could lead to a better understanding of the cause and effects of social distancing and quarantine on health and mental well-being. They can also provide the basis to develop innovative and efficient health screening tools, diagnostic systems, and personalized treatments to mitigate health risks associated with isolation and confinement. Partnerships between space agencies, non-space funding bodies, academic institutions and companies will continue to play an important role to translate research from Space to Earth and scale it effectively.


Background: Despite strong evidence for supervised pelvic floor muscle training (PFMT) for women with urinary incontinence (UI), and weight loss and exercise for overweight and obese women with UI, implementation literature on these combined interventions is limited. This paper aimed to describe the rigorous and systematic processes involved in the collaborative development, implementation, refinement and evaluation of a novel, holistic 12 week exercise training and healthy eating group program (ATHENA) for overweight and obese women with UI. Methods/Design: This intervention description paper is part of a larger mixed-methods feasibility study of implementing the ATHENA intervention within a physiotherapy service at a public hospital in Australia. The collaborative intervention design had input from clinicians, researchers and a consumer representative. Results: The intervention involved four evidence-based components—(1) supervised PFMT; (2) general exercise training; (3) pelvic health education; and (4) healthy eating education—delivered face to face over a 12 week period. Supporting resources developed included a Facilitator’s Guide and Participant Workbook. Conclusion: ATHENA is an evidence-based, multifaceted, group-based intervention targeting exercise training and healthy eating for management of UI for overweight and obese women. The structured development process and transparency of intervention content and resources aims to enhance practical application and success in future studies. Urinary incontinence (UI) is the occurrence of involuntary loss of urine . It affeEvidence-based clinical practice guidelines for the conservative management of UI recommend intensive, supervised pelvic floor muscle training (PFMT) as first-line treatment for women with UI ,13. ThisIt is challenging for Australian health services to provide the level of care stipulated in clinical practice guidelines to patients with UI. This may largely be due to an ageing population, high rates of overweight and obesity, and public health services operating at capacity with increasing numbers of UI referrals. An audit of our hospital’s urogynaecology waitlist found a significant increase (139%) in new referrals per month from 2016 to 2017, highlighting the increasing demand for continence service provision. Furthermore, an audit of the Women’s Health Physiotherapy (WHP) service identified that over half of new patients with pelvic floor conditions were overweight or obese. Usual care for these patients consisted of one-on-one consultations with physiotherapists and the prescription of a home-based PFMT program, but did not include the combined weight management and PFMT approach, or the frequency of supervised PFMT recommended by evidenced-based clinical practice guidelines, thus highlighting a clear evidence–practice gap. In order to deliver care conforming with evidence-based guidelines, an innovative approach that was feasible, effective, and sustainable to be integrated into the WHP service within existing resources was required. As stated earlier, a multicomponent intervention, incorporating several of the strategies recommended by guidelines, may be an efficient and effective way to manage UI among overweight and obese women, who make up the majority of patients presenting to the WHP service. Furthermore, a group-based program may promote behaviour modification and increase adherence to treatment, through provision of mutual support, information sharing, and peer motivation . It may an exercise training and healthy eating group program (ATHENA), for overweight/obese women with UI—in order to manage the increasing demand for continence service provision. ATHENA is the product of translating evidence-based clinical practice guidelines for UI into usual practice in a feasible, effective and sustainable way, within the resources and budget of the health service. Given that research translation is a complex process, we are providing this detailed description of the ATHENA program’s development to give a real-world example of how this process can occur in practice, with limited resources. This brings important insights to the field of knowledge translation (KT) and to health services research more broadly, given behaviour change interventions are only described in detail 5–30% of the time and that adequate description of interventions is key for their further development and scale up [As such, our team has developed a novel, multifaceted, group-based lifestyle intervention with both physiotherapy and dietary components—scale up . Thorougscale up , which iscale up . As the This holistic, group-based intervention may be effective in promoting behavioural exercise and dietary changes for weight loss whilst providing regular, supervised PFMT for overweight and obese women with UI. It may also be an efficient way to deliver the care recommended by clinical practice guidelines, by using a group-based approach ,24. WhilThe current study describes the rigorous and systematic processes undertaken to collaboratively develop, implement, refine, and evaluate the ATHENA intervention for overweight and obese women with UI. This paper is part of a mixed-methods feasibility study that was conducted within the WHP service at a large, public, tertiary hospital in Queensland, Australia. This study was approved by relevant hospital (reference number: HREC/2018/QGC/46582) and university  Human Research Ethics Committees.The development of the ATHENA intervention required an innovative approach to translate evidence-based UI guidelines into routine clinical practice. An integrated knowledge translation (research co-production)  approachThe ATHENA intervention and supporting clinician and participant resources were developed by the research co-production team; and human resources, equipment and consumables were secured via consultation with and support from key stakeholders , Assistant Director of Physiotherapy (Outpatients) and Allied Health Research Team) over a three-month period in October–December 2018.A multidisciplinary research team was formed in October 2018, including physiotherapists, dietitians, allied health research fellows and a health consumer. This team worked together on all aspects of intervention development, implementation and refinement. Three skilled physiotherapists  with extensive clinical experience and training in continence and women’s health, who were appropriately positioned in the WHP service, designed recruitment procedures and intervention strategies for women with UI . Three dietitians were also members of the research team, including a clinical dietitian experienced in nutrition education and weight loss who practiced in the physiotherapy outpatient clinic (NB); and two academic dietitians, one experienced in group-based weight loss interventions (LR); and one allied health research fellow with consumer engagement and implementation research experience (SR). A second allied health research fellow with a background in speech pathology and research co-production who had previous experience in research in the WHP service (KW) and a health consumer who had personal experience with both UI and the WHP service (HT) were also part of the research co-production team.a; (2) general exercise training (for weight loss)b; (3) pelvic health educationc; and (4) healthy eating educationb .Evidence-based guidelines recommend intensive, supervised PFMT for 8–12 weeks ; and weiThe exercise component of the ATHENA intervention  was held in the physiotherapy outpatient gym for one hour on a weekly basis. The research physiotherapists selected a range of general exercises in the format of high-intensity interval training, with the aim to increase confidence and meaningful participation in physical activity during the ATHENA intervention and for practice at home. The supervised PFMT component was based on training principles of muscle physiology, with functional training incorporating PFMT with increases in intrabdominal pressure and general exercise.The healthy eating and pelvic health education components were delivered in a private room near the gym for an hour immediately following the PFMT and general exercise training. The healthy eating education was adapted from the evidence-based Healthy Eating and Lifestyle Program (HELP) , which fAll aspects of the intervention were delivered by clinicians via open discussion, guided by learning outcomes outlined in the Facilitator’s Manual see  and reflPhysical resources required to deliver the intervention included (1) infrastructure: gym space with rails, chairs, towels, surface cleaning and first aid equipment, water fountain, and music; and a private room with whiteboard, chairs and table; (2) equipment: pelvic anatomy models and diagrams, food consumption models, and exercise equipment ; and (3) consumables: stationery, printouts of Participant Workbooks and other resources . To implement the intervention, the following human resources were required: ATHENA coordinator (1 h/week); physiotherapist (2 h/week); dietitian (1 h/week); and administrative officer (1 h/week).The establishment of the intervention team was finalised in December 2018. The ATHENA coordinator ensured that all administrative processes were completed correctly  and that clinicians delivering weekly ATHENA sessions were orientated and organised. Lead researcher, ZH, was the ATHENA coordinator for the first four months (January–April 2019), followed by LS for the remaining months (May–December 2019). Physiotherapists on the research team  and in WHP service recruited participants and delivered the physiotherapy intervention components: PFMT, general exercise training and pelvic health education . The dietitian working in the physiotherapy outpatient clinic (NB) was seconded one hour/week to the WHP service to deliver the dietetic component. Leave cover was provided by the academic dietitians  for dietetic components, and by physiotherapists working in the WHP service for physiotherapy components. Consistency in delivering physiotherapy and dietetic education sessions was achieved through development of, and training on, the Facilitator’s Guide . All cliThe ATHENA intervention was implemented in the existing WHP service in January 2019 at the study hospital. Intervention sessions ran weekly (Tuesday 10 am–12 pm) during the study period (January–December 2019).2) were eligible to participate. Exclusion criteria included contra-indications for exercise , pregnancy, <3 months post-natal, and being unable to provide informed consent . Physiotherapists screened patients for eligibility within their usual WHP clinics. Patients who met eligibility criteria were given a brief explanation of this study and asked for verbal consent for the research team to contact them. Those who agreed to be contacted were provided with the Participant Information and Consent Form and the ATHENA Promotional Brochure. One week later, an ATHENA coordinator  phoned potential participants to provide more information about the ATHENA study and intervention, and to answer any questions. Patients who chose to participate were enrolled in this study and booked into an ATHENA session, to which they were instructed to bring their signed consent form.Participants were recruited consecutively from January to October 2019 from the WHP service. Women accessing the hospital’s WHP service who were aged ≥18 years, diagnosed with UI and considered overweight or obese . If participants missed an education topic, they could attend the next one offered in four weeks’ time; and were also able to repeat education topics if they wished. The supervised PFMT and general exercise training ran on a weekly basis for the entire 12 weeks (minimum attendance: four weeks of exercise training components). There were no more than ten participants at each ATHENA session to allow for adequate supervision of PFMT and general exercise training.Fortnightly debriefing and evaluation of intervention delivery processes were completed during the period January–February 2019 by members of the research co-production team, with most feedback coming from the consumer co-investigator (HT), who had attended some ATHENA sessions. This resulted in minor revisions to intervention resources and delivery processes to ensure they met participants’ needs. After the initial eight weeks of the intervention implementation there were no further changes to allow consistency in intervention delivery.The intervention was implemented and evaluated concurrently using a hybrid implementation-effectiveness design , which aThe ATHENA intervention consisted of four components, as described in detail below. For successful implementation, these four components were supported by the Facilitator’s Guide  and PartThe first component of ATHENA aimed to meet evidence-based clinical practice guidelines  that recThe second component of the intervention aimed to increase participation in meaningful physical activity to assist with weight loss as recommended by clinical practice guidelines . The genThe third component of the intervention aimed to increase participants’ knowledge on different pelvic health topics, through open-forum group education and discussion. This is an integral aspect of the intervention, as knowledge about the function of pelvic floor muscles and their activation has been shown to reduce symptoms of pelvic floor muscle dysfunction and improve quality of life . Pelvic The fourth and final component of the intervention aimed to improve healthy eating behaviours and complemented the general exercise training component to achieve non-surgical weight loss to reduce UI (as recommended for overweight and obese women ). This cThis paper describes the development, implementation, refinement and evaluation of ATHENA, a novel exercise training and healthy eating group program for overweight and obese women with UI. The ATHENA intervention was developed to facilitate the translation of evidence-based clinical practice guidelines  into usuThe success of the ATHENA intervention’s development was largely attributed to the rigorous co-production/integrated KT approach underpinned by high quality, evidence-based clinical practice guidelines. The varied expertise of and collaboration between members of the research team allowed for pragmatic integration of recommendations into practice, within an existing hospital service. The inclusion of both clinician and academic researchers on the study team, who had content expertise in physiotherapy and dietary interventions, and experience in research co-production and KT, was vital to success. The inclusion of highly skilled continence and women’s health physiotherapists who worked within the health service (and hence had a broad understanding of study context) ensured the intervention was relevant to the target population and feasible to deliver within the health service’s existing resources. Having consumer co-investigator (HT) involvement throughout the research process provided a unique ‘insider perspective’ to the consumer experience of intervention content and delivery. This co-production approach is recognized to produce interventions that are likely to be relevant and acceptable to end users , potentiThe delivery style adopted was key to participants’ understanding of and involvement in the intervention; and reflected principles of patient participation in care. Patients who take ownership and are actively involved in their own care have been found to have improved health outcomes and higher satisfaction with care ,38. SahlEducational components of ATHENA also took into consideration participants’ health literacy, another important aspect of patient-centered care. Health literacy is a broad term that encompasses how people access, understand and use health information . People This intervention description paper provides an example of how to co-develop and implement a multidisciplinary exercise and health eating group intervention for overweight and obese women with UI into an existing health service. While the development process was fairly resource intensive, the resultant intervention may lead to cost savings in the future, through more efficient health service delivery and better patient outcomes (if ATHENA is shown to be effective). For example, Lamb and colleagues identified that the average cost of continence treatment provision was £53.37 per participant for individual treatment and £7.73 per group participant (group size approximately ten women) in the United Kingdom’s public health system. With the increasing prevalence and demand on health services to manage UI and obesity, future cost-effectiveness studies of the ATHENA intervention are of importance.While we plan to publish our findings on ATHENA’s effectiveness for improving UI and weight among overweight/obese women at our health service, its evaluation in other settings is warranted. Future studies should report on any adaptations made to ATHENA and how implementation occurs, to assist interpretation of findings. Research should also be undertaken to determine the longer-term effects of ATHENA, including whether patients are able to maintain their lifestyle changes. If proven effective, ATHENA could be adopted in other Australian health services and perhaps more broadly, potentially benefiting patients  and health services (through efficient and effective service delivery).As outlined previously, a clear evidence–practice gap existed for a holistic, multifaceted, group-based intervention for treating UI in overweight/obese women ,20. Deta


Reliable benchmarking in Lean healthcare requires widely relevant and applicable domains for outcome metrics and careful attention to contextual levels. These levels have been poorly defined and no framework to facilitate performance benchmarking exists.We systematically searched the Pubmed, Scopus, and Web of Science databases to identify original articles reporting benchmarking on different contextual levels in Lean healthcare and critically appraised the articles. Scarcity and heterogeneity of articles prevented quantitative meta-analyses. We developed a new, widely applicable conceptual framework for benchmarking drawing on the principles of ten commonly used healthcare quality frameworks and four value statements, and suggest an agenda for future research on benchmarking in Lean healthcare.We identified 22 articles on benchmarking in Lean healthcare on 4 contextual levels: intra-organizational (6 articles), regional (4), national (10), and international (2). We further categorized the articles by the domains in the proposed conceptual framework: patients (6), employed and affiliated staff (2), costs (2), and service provision (16). After critical appraisal, only one fifth of the articles were categorized as high quality.When making evidence-informed decisions based on current scarce literature on benchmarking in healthcare, leaders and managers should carefully consider the influence of context. The proposed conceptual framework may facilitate performance benchmarking and spreading best practices in Lean healthcare. Future research on benchmarking in Lean healthcare should include international benchmarking, defining essential factors influencing Lean initiatives on different levels of context; patient-centered benchmarking; and system-level benchmarking with a balanced set of outcomes and quality measures. The healthcare sector worldwide is undergoing a major transformation driven by the pressures to reduce the rate of growth in healthcare spending, balance supply and demand, and improve health outcomes . In induIn an attempt to address the above challenges, many healthcare organizations have adopted transformational performance improvement initiatives such as the Lean management system. Originally developed at Toyota beginning in the 1950’s, it has since spread to service industries including healthcare. In healthcare, the definition of Lean and the approach to Lean implementation are highly variable. We define Lean in healthcare as a management philosophy emphasizing patient focus, respect for people, eliminating waste and striving for excellence by engaging staff in continuous improvement and problem solving through a set of practices and tools such as A3 thinking, daily huddles, visual management, 5S , and the PDSA (plan-do-study-act) cycle.Attention to local context has been recognized as an important factor in Lean healthcare transformation sustainability, and it has been suggested that a uniform approach does not work in all contexts , 5. The The narrowest definition of context includes only intra-organizational factors such as teamwork, change resistance, ability to bridge silos, transparency, leadership commitment, communication, resources, people engagement, and empowerment , 8. The Regional factors affecting the context around Lean healthcare transformation may include geographical characteristics, market concentration and local economy, interrelations of healthcare organizations, local customs and public expectations, ethnic diversity, local authorities, and regional funding for Lean initiatives. For example, in Canada, several provinces have mandated all health regions to participate in Lean , and OntThe structures of the national healthcare system, the national healthcare funding model, and major stakeholders such as insurance companies play a major role in shaping the national landscape for Lean healthcare transformation. Furthermore, issues related to legislation and policies may influence the flexibility of task reallocation and serve as an inhibitor . Labor uThere is a fourth contextual level that transcends national borders. Independent of previously described factors such as the national healthcare system model, the healthcare industry around the world has common characteristics that differentiate it from other fields such as manufacturing . One limThe underlying assumption of performance benchmarking is that the organizations have shared objectives represented by measurable outcomes. Following Camp, we define benchmarking as “…the search for the best industry practices which will lead to exceptional performance through the implementation of these best practices” . In LeanThere is a call for cross-comparative research to assess possible cultural influences on Lean implementation. In their comprehensive review on Lean in healthcare, D’Andreamatteo and coworkers conclude that there are few cross-comparative and multi-site analyses, and identify the need for more research concerning different countries to allow an appreciation of the extent of using Lean in healthcare and a better evaluation of possible cultural influences . No framIn this first attempt to address the challenges of cross-comparative research in Lean healthcare, we identified two equally important dimensions as prerequisites for reliable and meaningful performance benchmarking: clearly defined contextual level and a universally relevant, applicable, and balanced set of domains for benchmarking. We asked three research questions:On which of the context levels and outcomes has benchmarking been used in Lean healthcare?What outcome domains are applicable and relevant for benchmarking the performance of Lean healthcare organizations operating in different contexts?Based on the extent to which different contexts and outcome domains have been used to benchmark Lean initiatives, what should be the agenda for future Lean benchmarking research in healthcare?We aim to address the first question by conducting a systematic review of current literature on benchmarking Lean in healthcare and identifying the levels of cultural context reported. Uncovering the similarities in widely used healthcare quality frameworks and value statements, we address the second question by developing a conceptual framework with a widely applicable and balanced set of outcome and quality domains and examine the articles identified through the systematic review using this novel framework. Informed by the contextual levels and outcome domains used in the articles identified through the systematic review, we identify major gaps in the existing research and propose a future research agenda that would fill those gaps and provide actionable results to the international Lean healthcare audience. Figure The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) and the associated checklist was used . On Octo AND (Lean OR “Toyota Production System” OR “Robust Process Improvement”) AND (benchmarking OR compare OR comparison) NOT (obesity) NOT (adipose).The terms “obesity” and “adipose” were used for excluding articles using the term “Lean” in the context of nutrition status or weight.To be considered, the articles had to be published in English, publicly available, and peer reviewed. Furthermore, the articles had to fulfill the following predefined criteria: (1) the study was set in a hospital or healthcare context, (2) compared original data from two or more units or organizations, (3) reported using Lean methods such as those described previously in our definition of Lean, and (4) reported benchmarked outcomes in the context of Lean. The articles identified through the initial search and additional articles from reference lists went through three rounds of review: title screening, abstract review, and full text review. The review was performed by two authors (AJ and ER) independently. All disagreements were resolved through further review and discussion and, if required, with a tie-breaking vote by a third author (JB).The methodological quality and risk of bias assessment was done at the study level for each included article using the Critical Appraisal Skills Programme (CASP) and the Specialist Unit for Review Evidence (SURE) checklists to ensure a standardized assessment across the studies –41. BothFinally, we reviewed the literature to identify commonly used healthcare quality frameworks and value statements, and performed a detailed content analysis of their key elements. We then used a bottom-up approach to reveal shared domains emerging from their principles to develop a conceptual framework, which we used to further explore the articles identified through the systematic review.The initial search yielded a total of 960 articles: 159, 279, and 522 articles in Pubmed, Scopus, and Web of Science respectively. The authors identified an additional 22 articles through article reference lists. After removing 94 duplicates, the remaining 888 articles first went through title screening, and the abstracts of 209 articles were reviewed to determine if they met the pre-determined inclusion criteria. A total of 38 articles were selected for full text review, from which 22 articles fulfilling the criteria were identified and thus included in the final review. The two original reviewers (AJ and ER) reached agreement in all cases and no tie-breaking vote by the third author (JB) was necessary. Figure We assessed the methodological quality and risk of bias in the 22 included articles using the CASP and SURE checklists, categorizing the overall quality of the articles as low (4 articles) –46, inteWe examined the 22 articles using two different categorizations: first, the level of context and second, the reported outcome domains. The most commonly used level of context was national level (10 articles) –57, 63. We identified six studies that reported benchmarking in the context of Lean management on the intra-organizational level Table  43, 44,, 60, 61.The description of contextual factors varied across the studies. All six studies provided the geographical location (country and/or region) and general organizational setting of the study , 60, 61.A total of four studies reported regional-level benchmarking in Lean healthcare Table  45, 49,, 62. ThrAll four studies provided details on the location and, to a variable degree, the organizational characteristics of the study sites , 50, 62.Ten studies used benchmarking in Lean healthcare on a national level Table  31, 46,–57, 63. All ten studies defined the location –54, 63 aAll ten studies referred to culture-related and contextual issues in the discussion. Five studies identified the general associations of organizational culture and context with outcomes , 57, 63.Only two studies reported benchmarking in Lean healthcare on the international level Table  58, 59], 5958, 5The other study benchmarked the operations of three Lean eye hospitals in the UK, the US and the Netherlands, addressing six Lean aspects . The autThe above review revealed a wide variation and a lack of consistency in the selection of outcome measures among the benchmarking studies. To address this issue, we integrated the overarching themes of 10 quality frameworks  and fourWe classified the 22 articles identified through the systematic review according to the benchmarked outcomes using the proposed conceptual framework and the four levels of context identified through the literature Table . UnsurprIn the critical appraisal, four of the seven articles that benchmarked clinical outcomes were categorized as intermediate , 52, 55 The two studies that benchmarked patient experience were both categorized as intermediate overall quality and represented the national level of context , 56. HowTwo studies using the employee perspectives on Lean for benchmarking were categorized as intermediate , 54 and One study benchmarked the costs on the national level of context  and one Of the five studies benchmarking access, one was categorized as low  ,three aThere were a total of 14 articles that benchmarked process measures. Nine were categorized as intermediate , 58, 59,Only one study used benchmarking measures related to continuous improvement represented by the daily management system index, and strategic perspective represented by the Lean leadership commitment index, both subdomains of service provision. The overLean is a set of organizational principles, practices, and problem-solving tools designed for improving quality and processes. The existing literature on benchmarking in Lean healthcare is surprisingly scarce considering the relatively widespread adoption of Lean in healthcare organizations, and is dominated by results from the US much like Lean-related literature in healthcare in general . FurtherThe context is an important factor to consider in healthcare Lean transformation. Each healthcare organization is inevitably influenced by factors on all four levels of context, and these factors should be recognized and addressed when benchmarking is used; the greater the geographic distance between the benchmarked organizations, the more complex the differences in the context. Identifying the levels of context facilitates a comprehensive approach to help with better understanding the validity of the benchmarking results.No consensus on the dimensions of performance measurement and benchmarking in Lean healthcare exists. Our proposed conceptual framework identifies the outcome domains based on the values and quality frameworks shared by most healthcare organizations to guide measuring performance and quality in Lean healthcare and facilitate benchmarking. Additionally, the framework could facilitate establishing a balanced set of benchmarking measures reflecting all outcome domains for each level of context.For leaders and managers our findings suggest that there is some benchmarking research that identifies contextual factors affecting Lean performance that they can use in making decisions about Lean adoption and implementation. But that research is generally limited both in terms of the levels of context addressed in any given study and the types of performance outcomes for which any context is reported. Hence, caution and in-house assessments of contextual factors and their possible effects on Lean will be important.For researchers, our findings reveal gaps in current research that should be addressed in future studies to increase the likelihood that decisions about Lean adoption and implementation will be better informed with evidence about the potential effects of context. Based on our findings, we suggest the following directions for a future research agenda:Research on international level benchmarking in Lean healthcare.Categorizing the included articles by the level of context indicates that despite the growing interest in transformational performance improvement among nearly all countries, benchmarking has rarely been used beyond the national level. Only two of the studies reported international benchmarking, both in distinct clinical subspecialties. The worldwide use of Lean methodology to transform healthcare highlights the need to address the complexities of international benchmarking to expand knowledge in the field.(b)Essential factors on different levels of context influencing the results of Lean initiatives.The characteristics of the context reported in existing studies are highly variable and the influence of contextual factors beyond the intra-organizational level was discussed in only one study. Less than one third of the included articles indicated additional resources allocated to the Lean initiative, yet their potential impact on the results was not discussed in depth. Thus, further work is necessary to identify the most essential characteristics of context to enhance the generalizability and applicability of benchmarking results to other countries, regions, and organizations.(c)Patient-centered benchmarking in Lean healthcare.The previously recognized need to tie Lean process improvement efforts to the ultimate goals of healthcare  is also (d)System level research using a balanced set of outcome and quality measures.The large number of studies using benchmarking measures primarily reflecting processes compared to studies using benchmarking measures reflecting access may also be an indicator of the low maturity of Lean implementation in the healthcare sector. The focus is still primarily on production and intra-organizational processes whereas fewer studies have taken a broader perspective on service provision at the system level beyond the scope of a single organization. Time is the single most frequently used measure for benchmarking in Lean healthcare. Time, while easy to measure and an indicator of patient flow and throughput, cannot adequately measure costs or the quality of care. For a more balanced approach, some of the studies used additional measures such as readmission rates. Most of the studies reported benchmarking measures from only one or two outcome domains. None of the studies used measures from all four main domains and, in particular, studies on benchmarking the subdomains of continuous improvement or strategic perspective are rare, highlighting the need for future studies with a balanced set of benchmarking measures.Our systematic review has two main strengths. First, it is based on relatively broad literature search criteria to increase the likelihood of capturing relevant articles. Second, our pre-defined inclusion criteria intentionally allowed a range of study designs, providing as comprehensive an understanding of the existing literature as possible. Furthermore, we conducted a critical appraisal of all included studies and indicate the results in the review text and tables, but did not exclude any articles from the review even if the overall quality was categorized as low.This systematic review also has limitations. Despite the broad search criteria, we may have missed some articles that used some other terms for benchmarking. To decrease the likelihood, we added the words “compare” and “comparison” to the search strategy. We also cannot discount publication bias, which may have influenced the results of our systematic review. Due to the broad search and inclusion criteria the study designs and outcomes were highly variable. Together with the low overall number of studies, this prevented a meta-analysis of the results.Lean empowers frontline staff to eliminate waste and to continuously improve through standard work and problem solving. Studies on benchmarking in Lean healthcare are scarce and mostly limited to intra-organizational, regional, and national levels of context. The most commonly used benchmarking measures represent the domain of service provision, particularly process outcome metrics, and studies with fully balanced sets of benchmarking measures are lacking. Leaders and managers should pay careful attention to the limited extent of information on contextual factors when making evidence-informed decisions based on current Lean healthcare benchmarking literature. The proposed conceptual framework defining the outcome domains emerging from widely used quality frameworks and value statements may facilitate performance benchmarking and spreading best practices in Lean healthcare. Future research in Lean healthcare benchmarking should include international benchmarking, defining essential factors influencing Lean initiatives on different levels of context, patient-centered benchmarking, and system-level benchmarking with a balanced set of outcomes and quality measures.


Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference . Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.CRD42019157236).PROSPERO (ID:  The acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome of rapid-onset pulmonary failure characterized by a dysregulated inflammatory response that results in severe respiratory failure and the need for mechanical ventilation . AlthougThe clinical and biological heterogeneity within syndromes such as sepsis ARDS makes it essential to identify more homogeneous subphenotypes when investigating potential therapies , 5. TherThe retrospective analysis of data from two large multicenter RCTs   has firsTranslation of basic research findings to clinical practice remains daunting because of the heterogeneity and complexity of ARDS . A substWe hypothesize that ARDS subphenotypes may exist among preclinical ARDS studies and that they may have distinct treatment response to select therapies.To test this hypothesis, we designed a systematic review and meta-analysis of controlled preclinical trials in experimental, − in vivo  and ex vivo (human lung preparation) -, models of ARDS. The primary goal of the review is to compare the key features of preclinical ARDS, as defined by the American Thoracic Society (ATS) consensus conference  , in lungThe systematic review and meta-analysis protocol originated from discussions between our team of translational research scientists , information system specialists , a statistical and methodologist (BP), and the European Society of Intensive Care Medicine (ESICM) Translational Biology Group of the Acute Respiratory Failure section. The protocol was registered on PROSPERO (ID: CRD42019157236) in December 2019.We will include controlled comparative studies (randomized and non-randomized) of preclinical acute lung injury/ARDS published from 2009 to 2019 that evaluate the efficacy and safety outcomes of a number of predefined therapies  pathway, anticoagulants, and halogenated agents). In order to collect sufficient data to test our hypotheses, it was decided a priori to include only studies in which at least two features, out of the four key features of preclinical ARDS proposed by the 2011 Official ATS Workshop Report , are assWe will include preclinical in vivo animal and ex vivo human models of experimentally induced acute lung injury that mimic at least some aspects of the pathophysiology of humans with ARDS according to the ATS consensus criteria . The incPreclinical intervention groups will include animals and ex vivo human lungs from studies that examine the therapeutic use of stem cells (and their derived microvesicles), fibroblast growth factors, IL-2, IL-10, beta-agonists, corticosteroids, RAGE modulators, anticoagulants, and halogenated agents such as isoflurane, sevoflurane, and desflurane  to fraction of inspired oxygen (FiO2) ratio. These quantitative features and measurements are summarized in Table These include histological evidence of tissue injury , alteration of the alveolar-capillary barrier , measures of the inflammatory response in the lung , and measures of physiological dysfunction such as the alveolar-arterial gradient of oxygen concentration and the partial pressure of arterial oxygen .Search strategies and equation of searching have been developed and tested with the help of two librarians using the Peer Review of Electronic Search Strategies (PRESS) template . The full text of all potentially eligible studies will be retrieved and reviewed for eligibility. Disagreements between reviewers will be resolved by consensus or by a third member of the systematic review team (JA). Reasons for exclusion of potentially eligible studies will be recorded to enable a transparent selection process and to be in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines developed for proper reporting of clinical systematic reviews . The PreData will be extracted by four members  of the research team and collected into standardized, pilot-tested forms using REDCap electronic data capture tools hosted at CHU Clermont-Ferrand . REDCap The risk of bias will be evaluated by two reviewers  for each included preclinical study. Since no validated and standardized risk of bias checklist exists for preclinical studies, we will describe the biases of the included studies using the Cochrane risk of bias assessment  and the We will also record features that will facilitate judgements of construct validity and external validity . ConstruWe will describe the quality of reporting of the included preclinical studies using the elements of the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. The ARRIVE guidelines were developed to enhance the transparent and comprehensive reporting of research methods and results for in vivo animal experiments .This study does not require ethical approval. Data collected through this systematic review will be managed by the ESICM Translational Biology Group and made available upon reasonable request. The results of this systematic review will be presented at relevant conferences and published in a peer-reviewed journal.2 [Statistical analyses will be performed using Stata , Comprehensive Meta-Analysis , and Mplus  software2 , which wThen, meta-regression will be conducted, with covariates determined according to the aforementioned analyses and to clinical and/or biological relevance, and methodological issues such as the categories of time from ARDS induction. Particular attention will be paid to the study of multicollinearity and interactions between covariates 1) studying the relationships between the covariates and 2) evaluating the impact of adding or removing variables to or from the multivariable model. Whenever possible in appropriate data, latent class analyses will be carried out to identify subphenotypes within experimental models of ARDS, associated with distinct outcomes and differential responses to therapy. Statistical analyses will be conducted including all controlled comparative studies, with the type of study considered as stratification variable (randomized and non-randomized).When the number of studies and sample size will permit, analyses will be performed by study type. Several subgroup analyses to examine preclinical heterogeneity will be conducted on the primary endpoint. These analyses will include “clinical”/biological features  causes major alveolar inflammation profiles, it remains unknown whether these models might have reliable value to represent clinical subphenotypes of higher inflammation and of higher degree of lung epithelial injury, respectively [The results of this systematic review and meta-analysis will inform translational and clinical scientists, researchers, and clinicians internationally regarding the existing preclinical evidence for subphenotypes among preclinical, in vivo or ex vivo models of ARDS. Such data will be crucial to confirm the potential of personalized ARDS medicine , 8, 46, Our review is timely since there is an increasing amount of research dedicated to the identification of ARDS subphenotypes, their underlying mechanisms, and their potential responsive treats , 48–52. In a broader perspective, we also hope this review will increase our knowledge on, and identify challenges and barriers related to, the conduct of preclinical ARDS studies. Ultimately, it will also inform and enrich future preclinical and clinical precision, subphenotype-based, research that should aid the translation of novel therapies for ARDS.Additional file 1. Representative Search Strategy.Additional file 2. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) checklist.


Child stunting and linear growth faltering have declined over the past few decades and several countries have made exemplary progress.To synthesize findings from mixed methods studies of exemplar countries to provide guidance on how to accelerate reduction in child stunting.1) a series of descriptive analyses of cross-sectional data from demographic and health surveys and multiple indicator cluster surveys; 2) multivariable analysis of quantitative drivers of change in linear growth; 3) interviews and focus groups with national experts and community stakeholders and mothers; and 4) a review of policy and program evolution related to nutrition.We did a qualitative and quantitative synthesis of findings from existing literature and 5 exemplar country studies . Methodology included 4 broad research activities: Several countries have dramatically reduced child stunting prevalence, with or without closing geographical, economic, and other population inequalities. Countries made progress through interventions from within and outside the health sector, and despite significant heterogeneity and differences in context, contributions were comparable from health and nutrition sectors (40% of change) and other sectors (50%), previously called nutrition-specific and -sensitive strategies. Improvements in maternal education, maternal nutrition, maternal and newborn care, and reductions in fertility/reduced interpregnancy intervals were strong contributors to change. A roadmap to reducing child stunting at scale includes several steps related to diagnostics, stakeholder consultations, and implementing direct and indirect nutrition interventions related to the health sector and nonhealth sector .Our results show that child stunting reduction is possible even in diverse and challenging contexts. We propose that our framework of organizing nutrition interventions as direct/indirect and inside/outside the health sector should be considered when mapping causal pathways of child stunting and planning interventions and strategies to accelerate stunting reduction to achieve the 2030 Sustainable Development Goals. The global prevalence of childhood linear growth retardation, commonly measured as stunting, has declined over the last decades, but remains unacceptably high. In most cases, such growth failure is seen in the wake of persistent and widespread poverty, chronic undernutrition, and adverse environmental exposures. The bulk of linear growth faltering seen in children aged <5 y occurs within 1000 d after conception . It can Lancet series have highlighted the importance of optimizing childhood nutrition for survival  stunting reduction  . Determi1) review the current burden, trends, and distribution of child stunting prevalence in exemplar countries; 2) contrast key basic, underlying, and immediate drivers of child stunting reduction across exemplar countries; 3) undertake an assessment of policy and programmatic investments across exemplars; 4) propose a framework for categorizing drivers of change; and 5) suggest a roadmap for national or subnational efforts to reduce child stunting at scale.In an effort to expand, strengthen, and contribute to the current knowledge base, this article consolidates findings from our series of systematic mixed-methods exemplar case studies with the aim of providing summative guidance on how to accelerate reductions in national stunting prevalence in order to achieve our WHA and SDG targets. Exemplar countries are those that have an outsized reduction in stunting prevalence in a 15–20-y period relative to economic growth (as defined earlier in the “Methods” article of this supplement)  and inclData and evidence for this article were drawn from our country case studies that were undertaken using mixed methods as described in Paper 2 of this series . As deta1) a series of descriptive analyses of cross-sectional data; 2) a deterministic analysis of quantitative drivers of change in linear growth; 3) country-level stakeholder interviews; 4) a review of policy and program evolution over the time period of study; and 5) an integrative analysis of insights from these 4 core research activities.The final set of methods included: z-scores (HAZ) and under-5 child stunting prevalence (HAZ < −2 SD of the WHO growth reference standards). Using cross-sectional data, we examined stunting prevalence geospatial patterns and inequalities by key dimensions . Kernel density plots of child HAZ scores were examined to understand the population HAZ shifts over time. Child age compared with HAZ growth trajectories (Victora curves) were fitted using smoothed polynomial regressions to study stunting risk at birth and how the growth faltering process changes with age.A series of descriptive analyses were undertaken to explore levels, distributions, and trends in the main outcomes examined, that is, child height-for-age Using household survey datasets  and various country-level administrative data sources, we assembled cross-sectional panels into a pseudo-cohort design to study multivariable quantitative drivers of child stunting reduction in each country using Oaxaca–Blinder decomposition methods and linear mixed-effects regression with a difference-in-difference design.We conducted in-depth interviews with national experts from within and outside the health sector (10–20 participants in each country), in-depth interviews with community-level stakeholders (10–15 participants), and focus group discussions with mothers in communities (2–4 focus groups in each country with 10–15 participants each) to understand the macro  and micro  factors that contributed to stunting reduction.A comprehensive review of programs/policies/strategies/laws/legislation adopted from the 1990s (or earlier) to 2018 from within and outside the health sector was undertaken to identify key national investments and efforts that each country adopted to reduce stunting at scale. Detailed methods for this review are included in Paper 2 of this series .Results from each research activity were analyzed iteratively and shared with technical experts, research partners, and research leads to develop a strong evidence-based narrative of stunting reduction drivers for exemplar countries. The conceptual framework for improved nutrition proposed by UNICEF  and adapStunting prevalence baselines in exemplar countries generally cluster into 2 groups .Supplemental Figure 1 for HAZ kernel density plots) in exemplar countries, suggesting that child growth faltering is reducing at a national level. Examining kurtosis is useful to measure outliers in the data, with higher values indicating fewer outliers (or fewer children in the tails of the HAZ distribution). Kurtosis increased notably over time in Peru and Kyrgyz Republic, suggesting a potential reduction in HAZ inequalities (fewer children in the tails of the distribution) whereas in Senegal, Ethiopia, and Nepal it stayed about the same or even increased. Of course, reduced kurtosis could also indicate better measurement or precision around anthropometry metrics over time, and the difference is difficult to ascertain from HAZ kernel density curves alone . Our equity analysis of stunting prevalence provides further insights into inequalities. Stunting prevalence reduced for all wealth quintiles in Peru (with only the poorest lagging behind) from 2000 to 2016, whereas in Kyrgyz Republic the >20% point gap between the richest and poorest in 1997 became negligible in 2014 . This indicates that newborns became substantially larger at birth over this time, and could be indicative of improvements in maternal nutritional status  and maternal and newborn care. Peru and Senegal did not make progress in reducing the birth disadvantage. Flattening of the Victora curve between 0 and 6 mo was observed in all countries over time, and could be related to better breastfeeding practices and overall environment for the baby. For children aged 6–23 mo, Peru and Senegal had dramatic flattening of the HAZ curve over time , which suggests that major stunting drivers in these 2 countries could be related to improvements in disease prevention and management, better dietary practices, and improved household environment. Ethiopia, Nepal, and Kyrgyz Republic made comparatively fewer gains in this age group.Child HAZ compared with age curve analysis  to identify gaps and priorities for different intervention packages and delivery strategies in the health/nutrition sector.Phase II involves strengthening of delivery systems and implementation of scaled-up actions identified through the iterative process in Phase I in both the health and nutrition sectors and nonhealth sectors. Although we have rank ordered interventions in our framework, each country's adoption of these should depend on its baseline situation, existing status of relevant policies and programs, logistics, capacities, and finances. In addition, policies that shape the broader household and community environment for improvements in child growth require attention such as the extent and nature of economic and agricultural growth, education, and sanitation, with a front and center focus on achieving social equity in these areas. Finally community engagement and buy-in seems critical in many ways. Together, actions across these areas have the potential to accelerate improvements in child growth.Supplemental Table 2) and found no major issues in missingness, response mismatch, or digit preference in the included surveys.This summary article, focused on drivers and initiatives for reducing child stunting at scale, has analyzed global evidence of stunting determinants from LMICs, in-depth case studies from 5 exemplar countries, and the existing nutrition literature base. We found that improvements in child growth faltering and reductions in stunting were related to investments from both within and outside the health sector; we note that ∼40% of the impact came from direct and indirect health-related nutrition strategies, 50% from other sectoral strategies, and 10% was unexplained. Notably, improvements in maternal nutrition, maternal education, broad maternal and child health care, and fertility practices yielded some of the greatest gains. However, given differences in context and baseline status of some countries, the relative contribution of various components and the percentage explained by decomposition varied somewhat. In addition, the impact of food security and improved dietary practices (including complementary feeding practices) could be understated in our findings due to limitations in data availability and quality. Lastly, accurate serial coverage data for most direct health sector nutrition interventions  were generally lacking. Taken together, all such observational analyses are subject to ecological fallacies, and hence the relative contribution of various factors to improvements in stunting must be viewed as illustrative and associational rather than deterministic. Additionally, this study did not discuss findings from control or counterfactual countries  though a second phase of the exemplars project is currently examining large-population countries  with the aim of assessing these subnational trends and policy environments more robustly. The quality of anthropometry measures continues to be a challenges in survey datasets; we have examined key metrics of height, weight, and age quality in exemplar country survey datasets  should be considered when mapping child stunting causal pathways and planning interventions and strategies to accelerate stunting reduction to achieve the 2030 SDGs. Our road map of diagnostics coupled with intervention prioritization could provide a valuable foundation for stunting reduction investment cases at national or regional scales. In addition, we call for a better coordination of the various efforts to understand drivers of nutrition change in a country, and accelerated efforts to undertake these analyses where they have not been done.Many aspects of the analysis are dependent on the proxy data that we have on hand as opposed to direct measures of constructs. To illustrate, the interface of maternal and newborn nutrition and its relation to epigenetic factors and fetal growth is well recognized . HoweverOur exercise was also somewhat limited in that we did not have sufficient longitudinal information on population micronutrient status as well as concurrent stunting and wasting , 31. FutAs highlighted throughout this supplement, the specific drivers of reductions in national-level stunting prevalence for individual countries vary. However, there exist a set of key determinants that must be addressed with policy change and programmatic action to drive further progress on reducing stunting, optimizing child growth and development, and, ultimately, achieving 2030 SDG health and nutrition targets. The opportunities and ambitions to scale up actions in high-burden countries must be matched with financing needs, as assessed by the World Bank, and optimizing available resources (Optima Nutrition) so as to manage expectations of impact. Other collections of country case studies on the key drivers of improved nutrition, such as the “Stories of change in nutrition” , have hinqaa153_Supplemental_FileClick here for additional data file.