We summarize content from the opening thematic session of the 20th anniversary meeting for Biomechanics and Neural Control of Movement (BANCOM). Scientific discoveries from the past 20 years of research are covered, highlighting the impacts of rapid technological, computational, and financial growth on motor control research. We discuss spinal-level communication mechanisms, relationships between muscle structure and function, and direct cortical movement representations that can be decoded in the control of neuroprostheses. In addition to summarizing the rich scientific ideas shared during the session, we reflect on research infrastructure and capacity that contributed to progress in the field, and outline unresolved issues and remaining open questions. At the 20th anniversary meeting for Biomechanics and Neural Control of Movement (BANCOM), the opening thematic session was chaired by Dr. Fay Horak . Presentations and discussions covered insights from 20 years of research in the field of motor control, delivered by Drs. Zev Rymer (Rehabilitation Institute of Chicago), Andy Biewener (Harvard University), Andy Schwartz (University of Pittsburgh), and Daofen Chen . Presentation themes included the impact of technological advancements on motor control research, unresolved issues in muscle biology and neurophysiology, and changes in the scientific funding landscape. This brief review summarizes content presented by each speaker, along with discussions from the audience.Considerable changes have occurred in the fields of biomechanics and motor control over the past 20 years, changes made possible by rapid technological advances in computing power and memory along with reduced physical size of biotechnology hardware. Because of these changes, research approaches have been reshaped and new questions have emerged. Previously, motor control research was constrained to laboratory-based assessments of individual neurons, muscles or joints, captured from low sample sizes. In the past, reliance on large, expensive, external recording devices, such as optical motion capture systems, understandably limited the feasibility of large-scale, multivariate research. Today, whole-body kinematic recordings using body-worn inertial measurement units, wireless electromyography (EMG), electroencephalography (EEG), and functional near infrared spectroscopy (fNIRS) systems, and electrode arrays for neural network recordings are increasingly commonplace. Alongside these technical leaps, sociocultural bounds have expanded research inclusion, as evidenced in the representation of speakers at the 2016 BANCOM meeting. In contrast to the 1996 meeting, which included three invited female speakers, 13 women were included as speakers in 2016. Such advancements will continue to shape our scientific landscape, driving innovation through new technologies and perspectives.Although considerable progress has been made in the field of biomechanics and motor control over the past 20 years, there remains unfinished business on many fronts. Many tasks were halted because of technical obstacles that led to redirected research questions, though in some instances, loose ends have remained due to perceptions that remaining problems have already been solved. For example, a notable open question remains: “What do muscle spindle receptors sense?” We know that muscle spindles regulate muscle contraction by responding to changes in muscle length via changes in joint angle. However, the elaborate nature and more complex sensory function of these organs cannot be overstated. Matthews and Stein  revealedOverlap in the anatomical locations of alpha and gamma motoneurons in the ventral horn of the spinal cord is well-established , 4. TheiA variety of physiological motor control systems exist that appear to have emerged under evolutionary pressures . Nerve fThe manner in which reference errors from muscle spindles are used to make adaptive adjustments at the level of the brain nevertheless remains incompletely understood. Muscle spindle discharge rates routinely increase during muscle lengthening, but also during shortening, especially when shortening is slow and against an inertial load. In each case, increased afferent activity has been attributed to the detection of movement irregularities that allow reflexive corrections .Further insight into the role of muscle spindles in detecting joint movements has come from studies examining perceived movements during muscle vibration , 12–15. Understanding functional relationships between muscle spindle afferents and central motor control has consequences for neurological disorders. Spasticity is a known syndrome of stroke, multiple sclerosis, spinal cord injury, and central nervous system lesions, characterized by slow voluntary movements, exaggerated tendon reflexes, and muscle hypertonia expressed by rigid muscles with velocity-dependent stretch resistance . Muscle Uncovering relationships between nervous system structure and function remains a considerable basic science challenge. Among the progress made in understanding the neural control of movement over the past 20 years is the dissection of spinal networks that control locomotion. Most notably, locomotor networks have revealed a distinct modular organization, where output from numerous integrated supraspinal areas interact with neuron assemblies located in the spinal cord to produce locomotor patterns and rhythms . DespiteDetailing interactions between upstream motor commands and spinal locomotor networks remains unresolved. Previously, motor maps charted functional relationships between motor cortical areas and muscles associated with specific joint movements. Although more complex than simple topographic cortical representations of muscle activations, the motor cortex depicts limb movements . ContempAmong the challenges faced in understanding motor control mechanisms is the need for in vivo muscle function examinations during complex motor tasks. To this end, we summarize recent findings across muscles and species, including interactions among muscle properties and neural reflexes during motor learning and task execution, with an emphasis on locomotion.Studies examining in vivo muscle function have revealed time-varying force-velocity and force-length relationships. Neural recruitment interacts with muscle activation patterns to regulate muscle force, length, and work, which affect the cost of force generation. Tendon stretch has been outlined as a key element for reducing locomotor energy cost, therefore muscle architecture and physiology combine with tendon geometry for specific functions . ChangesUnder concentric conditions, muscles shorten to produce mechanical work, maximizing power in movements such as climbing and jumping. During hopping and running, muscles may contract nearly isometrically, undergoing small length changes and performing little work while producing large forces. Reduced energy cost is therefore achieved by recovering elastic energy from tendon stretch, as well as by reducing the recruited volume of muscle needed to generate force . In contBiomechanical observations during locomotion have uncovered much about the basic principles of locomotor control. In vivo observations have revealed that neuromechanical interactions among intrinsic muscle contractile properties, reflex feedback and feed-forward control are key to stabilizing rapid movements. Comparative research has therefore been carried out across species, demonstrating fundamental underlying similarities. Many studies have relied on the simple spring-mass model for explaining dynamic energy fluctuations of the body’s center of mass, based on a ‘spring-loaded inverted pendulum’ , 25. BecLocomotion speed also plays a role in the ability of higher brain centers to maintain stability. At fast speeds, spinal sensorimotor circuits must work in concert with the biomechanical properties of the musculoskeletal system to maintain stability due to transmission delays from higher level neural control centers .Although overground locomotion has been studied in a number of species, comparative muscle function has also been evaluated in bird flight, which further underscores relationships between muscle-tendon design and function. During flight, the pectoralis muscle of the pigeon undergoes isometric or eccentric strain in late upstroke, enhancing force development, before shortening over substantial length during downstroke and performing work . The lonObstacle avoidance strategies in running guinea fowl indeed suggest that locomotor stability when moving across uneven terrain is maintained using a combination of feedforward adjustments and reflex feedback to tune leg impedance . BecauseWith the growing use of musculoskeletal modeling and neuromuscular simulation to study normal and pathological gait, there is a need for improved muscle models. Wakeling  demonstrBeyond the need for improved muscle models for calculating in vivo muscle loads, examining the role of cortical circuits in motor skill learning and task execution is critical for understanding more complex features of the neural control of movement. Neuroanatomical approaches that relate isolated brain regions to specific behaviors assume direct relationships between structure and function. Increasingly, however, research examining transient perturbations of specific neural circuits uncovers interconnections within the brain that can compensate to recover learned motor tasks . The abiBehavioral studies examining motor variability in humans and animals provide another window into motor control processes. Motor variability has been used to measure motor learning, revealing higher levels of task-relevant variability in early skill acquisition . Trial-tThe manner in which the brain controls movement has remained a central basic science question over the past 20 years of motor control research. Technological and computational advancements over the past decades have enabled many new discoveries in this area of research. Circa the 1996 BANCOM meeting, single unit recordings from the motor cortex of monkeys allowed hundreds of action potentials to be measured extracellularly. When analyzed as a population, relationships between cortical firing rates and movement velocity were uncovered, demonstrating that movement velocity was continuously encoded in motor cortex and could be extracted as a spatiotemporal trajectory –45. ContThe last 20 years of research into the cortical control of arm and hand movement has emphasized the idea of population coding. Rather than each neuron coding for one particular parameter (e.g. contraction of a specific muscle), it has become clear that each neuron encodes multiple movement parameters simultaneously. If all of these parameters are together encoded as a single firing rate, predicting all of the parameter values from an individual neuron would not be possible. Because these parameters may be weakly but redundantly represented in these individual neurons, a de-multiplexing or decoding algorithm, using a population of the firing rates recorded from many individual neural units can be used to extract consistent predictions of their values. In a series of experiments –51, GeorExtracting the neural representations of movement has been made possible by multichannel microelectrode arrays implanted in the motor cortex of primates, and, more recently, humans. Commonly-used microelectrode arrays that enable long-term recordings include the planar Michigan silicon probe with multiple recording sites per probe  and the simultaneously to produce graceful, coordinated reach, grasp, and placement of objects in tasks exemplifying those that occur in acts of daily living [More recent work has shown how the high-performance Modular Prosthetic Limb can be controlled as a neural prosthetic device. A paralyzed woman implanted with intracortical microelectrode arrays in her motor cortex was able to control this device using 10 degrees-of-freedom. She was able to control 3D arm displacement, 3D wrist orientation, and four dimensions of hand shape y living . Using ty living .Advancements in the area of neuroprostheses will continue to occur on several fronts. Robotic limbs that supply full manual dexterity and somatosensory feedback are in development, along with advanced neural decoding algorithms applied in real time. The ability to control the compliance or impedance of the robot effector is an active area of research and its development is essential for dexterous object manipulation. Intracortical microelectrode arrays have shown to be capable of recording signals from which high-fidelity, many degree-of-freedom arm and hand control signals can be robustly extracted. The information contained in these signals is much greater than that found in the mixed neuron recordings provided by ECOG or EEG. Intracortical recordings are often faulted for the limited duration (months to years) in which reliable single-units can be isolated from the recordings. However, even though the number of isolatable single units may decrease, multi-unit recordings persist almost indefinitely. High-fidelity control signals can also be extracted from these multi-unit recordings . In addiAlthough further work is needed to enable real world functionality for neuroprostheses, considerable progress has been achieved by harnessing the results from years of basic research describing the relation between cortical activity and movement. This fundamental knowledge has forged new paths for applied research, underscoring the importance of basic science research in generating bottom up growth.National Institutes of Health (NIH) saw its budget doubled. This significant funding increase was timely for mushrooming biomedical engineering departments in major research institutions across the US, launching many biomechanics, motor control, and rehabilitation research focused graduate programs. Established funding programs relevant to the field of biomechanics and neural control of movement at the NIH dramatically increased the number of funded applications, including those at the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Furthermore, the newly legislated and formed National Center for Medical Rehabilitation Research (NCMRR) and the National Institute of Biomedical Imaging and Biomedical Engineering (NIBIB) made additional resources available, and were active in joining the growing critical mass of NIH funding programs focused on developing scientific initiatives with various funding mechanisms essential in building research capacity in the area of biomechanics and neural control of movement. Of all the NIH programs that promoted research funding in this area, the NINDS Neuroprosthesis Program is widely considered to have played a critical role in effectively boosting support for cutting-edge and risk-taking innovative research. Importantly, many efforts were made through special research contract mechanisms, which proved to be effective for addressing challenges associated with an initial lack of expert representation in the competitive NIH peer-review process of unsolicited proposals, particularly in the neural interface field that was still in its adolescence. Other special funding programs that played pivotal and sustained roles for the growth of this field include the NIH-NSF  joint Collaborative Research in Computational Neuroscience (CRCNS) and the Bioengineering Research Partnership/Grant programs (BRP/BRG).Advances in computing power and micro-electromechanical systems have indeed been a key driving force behind the growth of biomechanics and neural control of movement as a significant field. Increases in both human and financial resources, however, have also grown in recent decades, which have expanded research capacity. The emergence and maturation of biomedical engineering as an academic discipline has not only provided additional intellectual drive and analytical approaches to tackle fundamental movement control research questions, but has also provided a highly skilled research workforce that is capable of taking full advantage of newly available tools. At the same time, a desire for achieving clinical autonomy and evidence-based practices further enabled the emergence of clinical rehabilitation as an applied research area. The two forces formed an unprecedented synergy, and created new opportunities for clinical research. In North America, early research clusters of critical mass played a critical role for incubating and nurturing a nascent but growing research capacity in biomechanics and neural control of movement. Most critically, in a 5-years period following the 1996 BANCOM meeting (1998-2003), the US Department of Veterans Affairs (VA), the National Science Foundation (NSF), and the National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR), all played significant roles in facilitating the development of early research clusters, mostly through their training and center grants. Special funding programs aimed at addressing the need for protection and care of warfighters at the US Department of Defense (DoD) and DARPA accelerated the pace for innovative translational efforts aimed at restoring, maintaining, and enhancing mobility, as well as other biomechanical and sensorimotor capabilities of warfighters using biologically inspired systems for defense technologies. This surge in research capacity has been transformative for the field, reflected not only in the increasing number of funded investigators, but also in topic diversity generated from multidisciplinary collaborations. As a result of a 3-4 fold surge in the number of NIH applications in the area of biomechanics and neural control of movement in the years following the NIH budget doubling, the NIH Center for Scientific Review (CSR) expanded review panels to accommodate new peer-review demands. These additional review needs were implemented first through ad hoc special emphasis panels (SEPs) and then through specially chartered and themed study sections. Most notably, the Motor Function and Speech Research (MFSR) and the Musculoskeletal Rehabilitation Sciences (MRS) study sections evolved during that time, in addition to the already existing Sensorimotor Integration (SMI) panel, which together conducted reviews for significant portion of the investigator-initiated proposals submitted to NIH. Currently, the SMI, MFSR, and MRS remain the most significant study sections concentrated on proposals themes related to biomechanics and movement control, with an increasing proportion of applications in this area also being reviewed by other panels with expertise in cognitive, disease mechanisms, or technological development components. Serving now as the formalized review channel for applications in this program area, these CSR panels not only reflect robust growth, but also symbolize an emerged identity for a branch of science that was ready in both breadth and depth to compete with other scientific areas for research support from a common NIH resource pool for investigator-initiated proposals. This increase has been steady over the years, even after the NIH budget stalled and then flattened since the mid-2000s. The growth of this multidisciplinary domain coupled with a shared desire to understand neural control of human movement and a shared interest in addressing clinically relevant movement problems was well represented by many of the young BANCOM attendees in 1996. These investigators later became part of the significant cohort of applicants to take advantage of the NIH’s well-established peer-reviewed system with well defined and consistent review criteria [In addition to the NIH, several other mission-specific federal funding programs, including those at the criteria , competirenewable research project grant of its kind for unsolicited proposals across the entire research funding ecosystem.From the perspective of sustainability for any scientific area, having a critical mass of NIH R01 funded investigators is essential, as the funding mechanism is considered to be the only Moving forward, it is essential to maintain a broad and balanced portfolio of basic, translational, population, and clinical research for achieving expected outcomes and public health benefits. Because uncovering the structure and function of the brain remains a substantial basic science challenge, it is particularly critical to continue vigorous support in our pursuit of fundamental knowledge . The NIHLike many other scientific research areas, the field of biomechanics and neural control of movement must rely on an iterative process from basic, translational, to clinical studies, as well as reverse-translation for mechanistic insights using animal models . Being iGiven the migration and evolution of research capacity over the past decades, an ideal academic home for the field of biomechanics and neural control of movement may vary from institution to institution, depending on overall institutional strength and research focus. Nevertheless, in-depth training in fundamental systems neuroscience and human physiology are essential elements for training programs studying human sensorimotor control, nurturing a regenerative process for basic science ideas, be they based in biomedical engineering, kinesiology, or rehabilitation science. In a time of budget constraints and evolving landscape for the academic research enterprise, it is crucial for current and future research capacity growth to be maintained or focused particularly on research addressing basic and fundamental questions, so that the entire field studying biomechanics and neural control of movement can continue to be robust and resilient , 85.In this review, we summarized many scientific discoveries from the past 20 years of research in the field of biomechanics and neural control of movement. Rapid technological, computational, and financial growth have led to the development of fundamental scientific knowledge in the context of communication mechanisms at the level of the spinal cord, relationships between muscle structure and function, and direct cortical representations of movement that can be decoded to control neuroprostheses. Despite the depth and breadth of these discoveries, unresolved questions remain, particularly surrounding the manner in which various levels of the nervous system interact to produce and control movement. The need to generate more testable hypotheses in uncovering the neural basis of movement control therefore becomes clear. Academic challenges in training the next generation of motor control scientists to include a firm background in basic neuroscience, as well as translational and clinical expertise, will hopefully be resolved over the next 20 years. Although an incomplete synopsis of two decades of biomechanics and neural control of movement research, we hope this review provides insight into the rich scientific ideas shared in the opening thematic session of BANCOM 2016.


Accidents and acute medical events at workplaces are unfortunately not rare events—the International Labour Organization (ILO) estimates that 313 million people are injured and 350.000 are killed in work-related accidents annually .The Emergency Preparedness and Response in Occupational Health (EPROH) scientific committee was developed as part of the International Commission on Occupational Health (ICOH)  to raise–Every worker worldwide should have access to first aid, rescue, and emergency care in case of accidents and acute medical events.–Compliant with “ICOH policy”–In the “Seoul Statement (June 2015) on the development of Occupational Health and Safety for All”–and approved by ICOH, it is stated that Occupational Health and Safety includes prevention of physical and mental diseases and injuries inclusive of first aid .–Influenced by the model of the chain of survival, where response and care are linked to preparedness, multidisciplinary cooperation between occupational/safety professionals, on the one side, and emergency responders/volunteers, on the other side, will harmonize first aid and emergency care approaches worldwide .Its work is guided by the following principles:The EPROH committee follows Evidence Based Medicine principles and undertakes literature review, practice networking, and surveys, including workers’ expectations to develop recommendation for prevention, first aid treatment, and additional care within the field of occupational health. All potential conflicts of interest are mandatorily stated and reviewed.To review the existing knowledge about emergency response, we started to look for the best evidence from research and performed systematic reviews on some aspects of regulation, procedures, and training in first aid, including effectiveness of automated external defibrillators in workplaces , 7. ConsEmergency Plans and ProceduresThese plans and procedures range from daily care to exceptional emergency care situations. They have to respond to risks by the way of an appropriate assessment, taking into account local legislation, cultural and organizational specific policies, economic background, number of employees, contractors, and local emergency medical services (EMS) systems. These plans and procedures must include:○Medical supplies and equipment—such as first aid kits, automatic external defibrillators (AEDs), drugs for emergency care, respirators, portable medical equipment, tele-medical equipment, appropriate personal protective equipment (PPE) for medical staff, ambulances, and additional vehicles as needed.○Infrastructure—e.g., field clinics, first aid stations, and muster points.○Human resources—minimal number of first aiders, paramedics, nurses, and doctors as well as distribution of work shifts.○Organizational plans—including alarm plans, plans of installations, means of communication, plans for maintenance of medical equipment and replacement of medical goods, and development of “emergency medical guidelines” on medical care and “fact sheets” on chemicals employed.○Cooperation with other internal/external rescue and public/private services , and EMS systems incl. medevac procedures. In case of disaster, plan to accept external assistance of occupational health services, including human resources.○Provision for mass casualties and disaster care.Preparedness and Training○Occupational health provisions for emergency care providers—such as immunizations, training aimed at site-specific risks, PPE, and access to specific health promotion programs.○Training plans to build and maintain skills and competencies—including first aid courses, training for medical staff, medical emergency drills, and cooperation with internal and external rescue teams and other care providers.○Audit procedures—including plans for internal and external audits to ensure quality and continuous improvement.○Communication lines—internal and external, including media info and contacts.○Refresher courses and compulsory « long life learning » during the working time.Prevention of emergencies and follow-up○Risk assessment: medical emergency care needs at workplaces should be identified through a thorough risk assessment. This includes physical, chemical, ergonomic, work organization, and environmental influence factors, such as climate and epidemic problems. This assessment must take into account local emergency response characteristics such as time for EMS to reach the scene and time to reach medical facilities by any means of transportation, such as by road, sea, air, and so on.○Surveillance system based on risk assessment and adverse health effects to trigger an alert response in case of a potential emergency occurred.○Psychosocial care—debriefing preparedness sessions should address both involved employees and medical staff if needed. This will provide opportunities to gain access to trained psychological resources in case of unexpected need.○Special follow-up of responders as needed.○Use of reporting tools and lessons learned.Taking into account the title of our group “Emergency Preparedness and Response in Occupational Health,” we clarified the scope of our group. We aim to be involved in practice, training, and research on:All of these elements are linked together for the purpose of improving workers’ health and safety from those injured to responders Figure . We willEach worker should benefit in case of a medical emergency, work related or not, minor or major, from an optimal response delivered by the company until emergency medical services (EMS) arrive on scene.Minimum response plans for every workplace include information about initial management and EMS contact information. The duty of the employer is to deliver initial care until EMS arrives to handle the case.Information about initial care in case of emergency must also include a procedure for contacting other rescue services when EMS is not available such as fire departments, law enforcement, or other first responders.First aid must be encouraged, and several steps may be identified:○Minimum traceable information made available to all workers with description of the company’s procedures in case of emergency.○Basic Life Support responses based on International First Aid/International Liaison Committee on Resuscitation (ILCOR) recommendations, with modules adapted for specific company risks.○Refresher courses during the working time.Advanced Life Support when available, either incorporated in the company or sub-contracted to other bodies.Occupational health and safety professionals will have to develop procedures that detail responses to emergencies, from minor events to major disasters, including alert systems. The written procedures should be based on initial symptoms and adapted to the company-specific situation and shared between professionals and signed by them, and reevaluated regularly.As needed, emergency providers should be followed up regularly by an occupational specialist for extended intervals after an event, on a regular basis and sometimes for a prolonged period of time. In addition to fitness for work, specific training should focus on information about chemical, physical, biological, and psychological hazards and risks. Regular simulation sessions and drills should be a mandatory component of the training.In case of mass casualties/disaster incidents, reasonable but rapid communication aimed at professionals and volunteers, on the one side, and media, on the other side, must be released by involved companies, assisted by occupational professionals.Public policies should help companies to implement such programs of prevention and response to emergencies in occupational settings. Financial discounts of insurance, special offers for best prevention, or other incentive programs should be encouraged.Evaluation should be performed at least every 5 year.We are emphasizing the importance of business continuity plan. OH can support for making this plan.To improve the dramatic situation of workplace fatalities and accidents/events, EPROH experts have developed the following general position statement:This position statement emphasizes the importance of having a general position statement on the multiple aspects of emergency preparedness and response in occupational settings for every worker.Previous surveys and reports highlighted the difference of general organization of Health and Work systems, mostly on the important question related on “who are in charge in Emergency Preparedness and Response in Occupational Health”: is it companies itself, the government or community, or nobodies. Then, this general position statement should be adapted locally with the help of national societies in charge of emergency response and occupational health and safety. Subcontracting companies involved in first aid, rescue and care in occupational setting should comply with these requirements and adapt their own procedures to avoid discrepancies.Additional research and global harmonization is needed for emergency preparedness and response in occupational settings. The current level of evidence is limited, mostly based on practice experience and workers expectations, with few global recommendations. The difference of regulation in nations, in workplaces—such as from the size of the company, its activity, and financial capacity, environment, and emergency response capacity, makes harmonization challenging.However, this general position statement should be applied in every country with the help of national societies in charge of emergency response in occupational settings or other relevant not-for-profit organizations. It is a first step in the long road of improving general worker health with the help of everyone.Emergency Preparedness and Response in Occupational Health (EPROH) scientific committee: Nicholas Aigbovo; Fathi Ben Larbi; Nick Copper; Maurits De Ridder; Dorothy Dingwiza; Félix Enrique Echevarria Reymer; Ahmed El Makaty; Babacar Fall; Wahida Farah; Mame Diarra Faye; Diana Gagliardi; Todd Hamel; Philippe Havette; Richard Heron; Mouloud Kalaai; Margaret Kitt; Tatsuhiko Kubo; Roberto Lucchini; Ashish Mittal; Horatiu Moldovan; Akiba Okon; Anna Ozguler; Bruno Papaleo; Kumar Selva; Promila Sharma; Mukhtar Syed Aamir; Styliani Tziaferi; Paula Viapiana; Koji Wada; Joy Wilson; Barthelemy Wognin.All authors had substantial contributions to the conception and interpretation of the work. Investigator list (EPROH scientific committee) includes all active participants of the group. All authors gave final approval of the version submitted.No conflict of interest .


Noncommunicable diseases are the leading cause of death and disability worldwide. Initiatives that advance the prevention and control of noncommunicable diseases support the goals of global health security in several ways. First, in addressing health needs that typically require long-term care, these programs can strengthen health delivery and health monitoring systems, which can serve as necessary platforms for emergency preparedness in low-resource environments. Second, by improving population health, the programs might help to reduce susceptibility to infectious outbreaks. Finally, in aiming to reduce the economic burden associated with premature illness and death from noncommunicable diseases, these initiatives contribute to the objectives of international development, thereby helping to improve overall country capacity for emergency response. The first cohort of infants with Zika virus–related birth defects was reported in 2015 in Brazil, where >4,000 cases of infant microcephaly were documented by the end of that year  country capacity for rapid response to emerging contagions (emergency preparedness), and 2) the strength of ongoing activities to support the underlying population health . In this example, the interconnectedness between these 2 factors was highlighted by the contribution of the existing primary care infrastructure to the success of the Zika emergency response. Brazil’s public health system, ordinarily set up for routine care rather than emergent outbreak containment, enabled the documentation of new cases of the not-yet-identified infection, and an existing surveillance platform, the Notifiable Diseases Information System, facilitated identification of the epidemic by tracking confirmed Zika cases and their birth defect consequences   advances a 3-pronged approach to prevention and control by strengthening surveillance, expanding the evidence base, and enhancing workforce capacity . The proThe Standardized Hypertension Treatment and Prevention project promotes the use of the following evidence-based tools and practices: 1) standardized treatment protocols, 2) team-based care, 3) access to a core set of medications, 4) registries for patient monitoring, 5) patient empowerment, 6) community engagement, 7) policy interventions, and 8) sodium reduction counseling. This project is being piloted in 2 countries. In Barbados, the focus is to improve patient care in 2 publicly funded clinics; in Malawi, the project is designed to enhance 2 HIV clinics funded by the US President’s Emergency Plan for AIDS Relief.To support governments in strengthening CVD prevention and control, the World Health Organization (WHO), CDC, and other partners launched the Global Hearts Initiative to promote a set of evidence-based interventions that, when used together, can have a major impact on improving global heart health. These interventions include prevention approaches for tobacco control and standardized protocols for CVD management at the primary healthcare level  are country-owned programs that strengthen national capacity in epidemiology, surveillance, and outbreak response, including those related to NCDs. Through dedicated curriculum and mentorship, FETP has helped develop expertise within ministries of health in chronic disease surveillance and response, including cardiovascular disease, toxicology, nutrition, tobacco, cancer, injury, and maternal and child health/birth defects. Initial surveillance efforts to first detect and then confirm a causal link between Zika infection and Guillain-Barré syndrome and microcephaly through cohort and case-control studies were led by FETP residents and graduates in Brazil and Colombia. In other locations, FETP residents have led investigations into risk factors for virus-related cancers ; current practices related to cervical cancer screening; and the interplay between chronic and infectious disease, such as smoking and tuberculosis. FETP work in nutrition has assisted in emergency famine response, preventing infectious disease outbreaks in displaced persons camps.The goals of this program are to assess the feasibility, quality, and validity of nationally representative mobile phone surveys; implement NCD mobile phone surveys in 10 countries and support face-to-face WHO STEPwise Approach to Surveillance Surveys in 6 overlapping countries; and compare findings from the 2 data collection methods. These surveys will be implemented by participating countries and ministries of health in collaboration with relevant ministries of information and technology, national statistical offices, and telecommunication operators. A course to improve the use of locally available data, entitled Data to Policy, is providing skills in economic evaluation, burden measurement, and impact modeling to develop policy briefs, covering both infectious  and noninfectious  topics.CDC is working with the International Agency for Research on Cancer of the WHO and other partners to establish 6 regional support centers (hubs) that provide training and assistance to cancer registries around the world. CDC supports these centers in Asia and sub-Saharan Africa and is working with partners to develop a regional hub in the Caribbean. Because little is known about the costs of setting up cancer registries in LMICs, CDC has piloted a cost assessment tool in many of its partner countries. The tool estimates the resources required to operate and improve cancer registries, including funding for the registries, how much it costs to register a cancer case, and factors that affect the efficiency of cancer registries  project —to reduce micronutrient deficiencies among children https://www.ghsagenda.org/) is an international effort to prioritize action for global health security. It aims to support the goals of the 2005 International Health Regulations, which strives to increase country capacity for addressing health threats including but not limited to those of infectious origin  (s origin .The relevance of current NCD-related activities to GHSA goals can be illustrated by the potential contributions of ongoing programs such as the Global Hearts Initiative, FETP, and Data for Health. Global Hearts can serve GHSA objectives of threat detection by establishing a mechanism for real-time surveillance and medical workforce development and can support avenues for emergency response by strengthening medication supply chains. Alternative survey methods, such as the mobile phone–based Data for Health initiative, can provide insight into the possibility of using innovative approaches to disease surveillance and detection, especially in low-resource environments where traditional surveillance methods might be too slow or expensive. FETPs can enhance local detection capabilities by training district, regional, and national medical and surveillance personnel in recognizing and preventing emerging threats to health security alongside noncommunicable conditions.Incorporating NCD control strategies alongside and within ongoing GHSA efforts for infectious disease control in LMICs can offer a long-term path for a resilient health infrastructure that can respond well both in normal times and during health emergencies. Specific GHSA goals in developing countries can be strengthened by investment in NCD programs like Global Hearts, which can bolster pathways for population outreach, and FETP, which can produce cadres of public health workers.The growing epidemiologic and infrastructural overlap between NCDs and infectious diseases has motivated increased consideration of NCDs as a component of global health security. Most recently, global resources for NCD prevention and care have increased (


Several anthropogenic activities including mining, modern agricultural practices, and industrialization have long-term detrimental effect on our environment. All these factors lead to increase in heavy metal concentration in soil, water, and air. Soil contamination with heavy metals cause several environmental problems and imparts toxic effect on plant as well as animals. In response to these adverse conditions, plants evolve complex molecular and physiological mechanisms for better adaptability, tolerance, and survival. Nowadays conventional breeding and transgenic technology are being used for development of metal stress resistant varieties which, however, are time consuming and labor intensive. Interestingly the use of microbes as an alternate technology for improving metal tolerance of plants is gaining momentum recently. The use of these beneficial microorganisms is considered as one of the most promising methods for safe crop-management practices. Interaction of plants with soil microorganisms can play a vital role in acclimatizing plants to metalliferous environments, and can thus be explored to improve microbe-assisted metal tolerance. Plant-associated microbes decrease metal accumulation in plant tissues and also help to reduce metal bioavailability in soil through various mechanisms. Nowadays, a novel phytobacterial strategy, i.e., genetically transformed bacteria has been used to increase remediation of heavy metals and stress tolerance in plants. This review takes into account our current state of knowledge of the harmful effects of heavy metal stress, the signaling responses to metal stress, and the role of plant-associated microbes in metal stress tolerance. The review also highlights the challenges and opportunities in this continued area of research on plant–microbe–metal interaction. It can affect soil, flora, and fauna health by contaminations from leaded fuels, dust, old lead plumbing pipes, various industrial sites, or even old orchard sites in production where lead arsenate is used . Pb2+ is2 fixation , inorganic (Hg2+), associated with ions , and organic (CH3-Hg) but in agricultural soils the ionic form is predominant (Hg2+)  . Increasr plants . At loweisorders . Bindingn plants . Addition plants . Mercurin plants .Arabidopsis, Brassica, and Lycopersicum revealed role of several transcription factors (TFs) such as bHLH, bZIP, AP2/ERF, and DREB under heavy metal stress . Several kinases and phosphatases relay the stress signals that further leads to gene expression of various TFs and synthesis of metal-detoxifying peptides , CaM-like proteins, calcineurin B-like proteins (CBLs), and Ca2+-dependent protein kinases (CDPKs) exist in plants that sense, decode, and convey the alterations in cytosolic Ca2+ concentration for the stress response (2+ activates antioxidant enzymes and provides tolerance against Cr stress (Medicago sativa (OsMAPK2 and myelin basic protein (MBP) kinase gene in rice  under salt stress indicating the induction of MAPKs signaling in presence of PGPR in plants .Remediation of heavy metals is necessary for the protection and conservation of the environment . For thethe cell . Here weBacillus, Pseudomonas, Streptomyces, and Methylobacterium have the potential to improve growth and production of crops by reducing the detrimental effects of heavy metals  mainly in a reduction process and also in a sorption process  are also one of the most prominent soil microorganisms. They establish direct physical link between soil and plant roots which increase root surface area facilitating nutrient absorption by the plants . AM fungHeavy metal contamination and remediation has received considerable attention in today’s world owing to the fact that several heavy metals cannot be degraded and hence persist in the soil. Several strategies have been successfully applied to generate plants which are able to grow in metal contaminated soils and accumulate or tolerate metal stress. Use of microbial approach for heavy metal tolerance and remediation is an eco-friendly and economic approach. Since the plant heavy metal uptake and tolerance depend on various factors, interactions between plant and microbes can play an important role in successful survival and growth of plants in contaminated soils. Plant growth promoting microbes also assist plant growth by changing bioavailability of heavy metal. These beneficial effects exhibited by microbes, together with the suggested interrelationship between heavy metal tolerance and plant growth promoting ability, indicates that their exploitation in remediating metal contaminated soils might have significant potential in near future. In spite of these practices, genetically engineered microbes also have been used for remediation processes. Undoubtedly these engineered microbes have greater remediation potential but their impact on ecosystems needs to be elucidated before commercialization. Despite several findings to date, various steps of regulatory networks via plant-associated microbes in heavy metal stress are still unknown, and more investigations need to be done for unraveling the cross-talk among soil-microbe and metal interaction in different crops. Additionally, synergistic action of plant and microbe and their mechanism for metal mobilization, transformation, and detoxification should also be studied. Further monitoring and managing microbial heavy metal remediation requires the characterization of the fate and behavior of the compounds of interest in the environment. However, at present, it is difficult to understand the environmental impacts of various metals mostly as a consequence of insufficient information being available about them. Thus this highlights the importance of a consistent link between research and development for the assessment and treatment of emerging metal pollutants and the tools, equipment and knowhow that contributes toward the fulfillment of these challenges.ST and CL wrote and reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


QUALICOPC is an international survey of primary care performance. QUALICOPC data have been used in several studies, yet the representativeness of the Canadian QUALICOPC survey is unknown, potentially limiting the generalizability of findings. This study examined the representativeness of QUALICOPC physician and patient respondents in Ontario using health administrative data.This representativeness study linked QUALICOPC physician and patient respondents in Ontario to health administrative databases at the Institute for Clinical Evaluative Sciences. Physician respondents were compared to other physicians in their practice group and all Ontario primary care physicians on demographic and practice characteristics. Patient respondents were compared to other patients rostered to their primary care physicians, patients rostered to their physicians’ practice groups, and a random sample of Ontario residents on sociodemographic characteristics, morbidity, and health care utilization. Standardized differences were calculated to compare the distribution of characteristics across cohorts.QUALICOPC physician respondents included a higher proportion of younger, female physicians and Canadian medical graduates compared to other Ontario primary care physicians. A higher proportion of physician respondents practiced in Family Health Team models, compared to the provincial proportion for primary care physicians. QUALICOPC patient respondents were more likely to be older and female, with significantly higher levels of morbidity and health care utilization, compared with the other patient groups examined. However, when looking at the QUALICOPC physicians’ whole rosters, rather than just the patient survey respondents, the practice profiles were similar to those of the other physicians in their practice groups and Ontario patients in general.Comparisons revealed some differences in responding physicians’ demographic and practice characteristics, as well as differences in responding patients’ characteristics compared to the other patient groups tested, which may have resulted from the visit-based sampling strategy. Ontario QUALICOPC physicians had similar practice profiles as compared to non-participating physicians, providing some evidence that the participating practices are representative of other non-participating practices, and patients selected by visit-based sampling may also be representative of visiting patients in other practices. Those using QUALICOPC data should understand this limited representativeness when generalizing results, and consider the potential for bias in their analyses.The online version of this article (10.1186/s12875-018-0767-9) contains supplementary material, which is available to authorized users. Ongoing primary care reform in Canada and around the world has spurred a need for comprehensive and meaningful measurement of primary care performance . This isSurveys are an important source of information in health services research, policy, and planning. However, physician surveys often have low response rates, which may introduce concern about their validity and representativeness . While rThere is limited research exploring nonresponse bias in primary care patient surveys. Some studies have found that patient surveys have potential for biased results due to method of survey administration –17. One The Quality and Costs of Primary Care study (QUALICOPC) is a multi-national study on primary care performance investigating quality, equity, and costs of primary care in 34 countries worldwide , 19. DetWhile QUALICOPC represents the largest study on quality, organization, and patient values and experiences in primary care in Canada, limited resources were available for provider recruitment and response rates for physicians across the country were generally low, ranging from 2% in British Columbia to 21% in Nova Scotia [To what extent are the QUALICOPC physician respondents representative of i) the physicians in their practice group, and ii) other primary care physicians in Ontario?To what extent are the QUALICOPC patient respondents representative of i) the patients in their physicians’ rosters, ii) the patients in their physicians’ groups’ rosters, and iii) the general Ontario population?The objective of the current study was to examine the representativeness of QUALICOPC physician and patient respondents in Ontario by answering the following questions:This representativeness study linked a database of QUALICOPC survey respondents to health administrative databases held at the Institute for Clinical Evaluative Sciences (ICES). Data holdings at ICES include a number of databases with information on providers and patients, such as physician billings, hospital inpatient and emergency room care, and census data , 21. UniOf the 1698 patients who completed the QUALICOPC patient experience survey, 1225 (72%) consented to linkage to health administrative databases using their health card numbers. We then identified the other patients in their physicians’ rosters, as well as the other patients in their physicians’ practice groups’ rosters. We included patients who were formally or virtually rostered to the primary care physicians; formally rostered patients had signed an enrollment form while virtually rostered patients were those who saw a particular physician for the majority of their visits over the previous year. Finally, in order to construct a provincially representative sample of patients for comparison, we also determined a 10% simple random sample of all patients in Ontario aged 18 and older with a valid health card number.The physician cohorts were compared on demographic characteristics, including sex, age, years since graduation, and whether they were Canadian medical graduates. They were also compared on type of primary care practice model they were practicing in, and roster size. The patient cohorts were compared on sociodemographic characteristics, including sex, age, material deprivation, and rurality, as well as morbidity and health care utilization, including primary care visits, emergency department visits, and acute care hospitalizations. These variables are commonly found to vary among respondents and nonrespondents in other studies. Furthermore, these variables may be related to primary care performance and patient experience, and are thus important to examine in the context of a primary care performance survey , 18.Demographic and practice information for physicians was derived from the ICES Physician Database (IPDB) and Client Agency Program Enrolment (CAPE) tables. Primary care models were also derived from CAPE, and classified according to type of practice (solo vs. group) and remuneration: solo physicians (including enhanced fee for service and fee for service), group enhanced fee for service , group capitated , and group capitated with an allied health team . Family Health Network and Other group models were not included in the analysis as they each had fewer than 6 physician respondents in the QUALICOPC. See Additional file Demographic information for patients, including age, sex, and postal code, was derived from the Registered Person’s Database (RPDB). Health care utilization was derived from the National Ambulatory Care Reporting System (NACRS), the Canadian Institute of Health Information Discharge Abstract Database (CIHI-DAD), and the Ontario Health Insurance Plan (OHIP).Rurality of the patients was measured using the Rurality Index of Ontario (RIO), a scale which assigns a number score between 0 and 100 using postal codes and an algorithm which takes into account population density and travel times to referral centres. RIO scores of 0–9 were considered urban, 10–39 as suburban, and 40 or greater as rural .Material deprivation of the patients was measured using the Canadian Marginalization Index, which is derived geographically from census data and includes measures such as proportion of the population without a high school diploma, proportion of households living in dwellings that are in need of major repair, and proportion of the population above the age of 15 who are unemployed .To account for the morbidity burden of the patients, resource utilization bands (RUBs) were used. RUBs are part of the Johns Hopkins Adjusted Clinical Groups Casemix system and are derived from hospitalization and primary care visit records. RUBs range from 0  to 5 (very high users) . The preThe standardized difference, also known as effect size, was calculated to compare the means and proportions of variables across the physician and patient comparison groups. The standardized difference was selected as it is not as sensitive to large sample sizes, such as those in our study, as traditional significance tests and it also provides information about the relative magnitude of differences between groups . ConsistData from 175 physician QUALICOPC respondents were compared to 2507 physicians in the same practice groups, and 9758 Ontario primary care physicians  from the comparison groups, even though they were not eligible to participate in the QUALICOPC.We only examined the representativeness of the Ontario subset of the Canadian QUALICOPC respondents. Physician recruitment methods varied slightly between provinces; therefore, the generalizability of the physician component of this study is certain only in the province of Ontario . The patThe physician respondents of the Ontario QUALICOPC differed slightly from their practice groups, and to a larger extent from other Ontario primary care physicians with respect to most of the characteristics studied. Visit-based sampling may have led to a biased patient respondent sample, in which the patient respondents of the Ontario QUALICOPC tended to be older, sicker, and more likely to be female than the other patient groups. However, despite these differences, Ontario QUALICOPC physician respondents had similar rosters overall compared to their practice groups and the general population.These results will have implications for studies relying on QUALICOPC data as well as other primary care surveys. Those using QUALICOPC data should understand the limited representativeness of the respondents, and consider the potential for bias in their analyses. While physician and patient-level results are not representative of the entire Ontario population, the participating practices may be representative of other non-participating practices, and the patients selected by visit-based sampling may also be representative of visiting patients in other practices. Future primary care surveys are encouraged to consider consistent recruitment and sampling strategies across jurisdictions if possible, and to consider integrating measurement of nonresponse bias into survey protocols. We have demonstrated one method of assessing sample representativeness using administrative data, which could be used regardless of the sampling methodology selected.Additional file 1:Primary Care Models. Summary of primary care models in Ontario including composition and characteristics, physician compensation type, and whether patient enrolment is required. (DOCX 14 kb)


Malnutrition in elderly patients is a common condition. Nevertheless, there is evidence on specific risk factors and problems of malnutrition in geriatric patients with neurological diseases. In this review, we summarize recent knowledge on malnutrition in different neurological diseases with a focus on elderly patients. This overview also provides strategies for a more specific and profound assessment of neurogeriatric patients to improve identification and treatment of malnutrition. Early and consequent treatment of malnutrition can lead to a decreased progression of the neurological disease and to a better quality of life in geriatric patients. An important and yet under-recognized geriatric syndrome is malnutrition. Although a widely accepted definition of malnutrition that adequately reflects its pathophysiology and its consequences is still lacking, the most relevant and recognized elements in the definition of malnutrition comprise the In clinical practice, the nutritional intake may be compromised in settings of: (1) pure chronic starvation without inflammation , (2) conditions with sustained mild inflammation , and (3) acute disease with significant inflammation which elevates resting energy expenditure   <20–22 is usually regarded as indicator for malnutrition in geriatric patients /22 cm  and calf-circumference below 31 cm are sensitive indicators of malnutrition and easily applicable , not affected by non-nutritional factors, and normalize through nutritional therapy  recommends three scores for screening malnutrition. The Malnutrition Universal Screening Tool (MUST) uses BMI, history of unexplained weight loss and acute illness effect  from 1619 participants of greater age, baseline weight, female gender, higher baseline disease severity assessed by Unified Parkinson Disease Rating Scale (UPDRS) scores, greater postural instability, difficulty in eating and drinking, lower cognitive scores, and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly difficulties such as swallowing, dyskinesia, depression, constipation, and nausea/vomiting were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients  patients with acute stroke are at a high risk for developing malnutrition. The National Institute for Health and Care Excellence (NICE) guideline states the necessity of screening and assessing all acute stroke patients for swallowing problems by appropriately trained staff before being given any oral food, fluid or medication  is higher in the elderly than in other adults. This is caused by an increased prevalence of epilepsy, neuropathic pain and behavioral disorders associated with dementia, for which AEDs are frequently administered. Extensive use of AEDs accounts for adverse drug reactions and contributes to the high frequency of untoward drug effects Lackner, . Since, Nutritional problems have also been found to be associated with multiple sclerosis (MS). Although it is reasonable to expect that due to the nature of MS  malnutrition is associated with MS, the prevalence of malnutrition in elderly MS patients is currently unknown , vascular dementia (25%), Lewy body dementia (15%), and frontotemporal dementia  have to be specifically addressed. The therapeutic goals in geriatric patients do not fundamentally differ from those for younger patients, but are weighted differently. While in younger patients the reduction of morbidity and mortality is of importance, the preservation of function, independence and quality of life are the focus in geriatric patients  felbamate, topiramate, zonisamide; (2) cardiovascular drugs ; (3) psychiatric drugs , and (4) non-steroidal anti-inflammatory agents (Landi et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Population structure, spatial diffusion, and climatic conditions mediate the spatiotemporal spread of seasonal influenza in temperate regions. However, much of our knowledge of these dynamics stems from a few well-studied countries, such as the United States (US), and the extent to which this applies in different demographic and climatic environments is not fully understood. Using novel data from Norway, Sweden, and Denmark, we applied wavelet analysis and non-parametric spatial statistics to explore the spatiotemporal dynamics of influenza transmission at regional and international scales. We found the timing and amplitude of epidemics were highly synchronized both within and between countries, despite the geographical isolation of many areas in our study. Within Norway, this synchrony was most strongly modulated by population size, confirming previous findings that hierarchical spread between larger populations underlies seasonal influenza dynamics at regional levels. However, we found no such association when comparing across countries, suggesting that other factors become important at the international scale. Finally, to frame our results within a wider global context, we compared our findings from Norway to those from the US. After correcting for differences in geographic scale, we unexpectedly found higher levels of synchrony in Norway, despite its smaller population size. We hypothesize that this greater synchrony may be driven by more favorable and spatially uniform climatic conditions, although there are other likely factors we were unable to consider (such as reduced variation in school term times and differences in population movements). Overall, our results highlight the importance of comparing influenza spread at different spatial scales and across diverse geographic regions in order to better understand the complex mechanisms underlying disease dynamics. Influenza is a respiratory infection of serious public health concern, with over three million cases of severe influenza-associated illness reported globally each year . In tempNorway is situated in Northern Europe, a temperate region near the Arctic Circle, and provides a novel environment to explore spatial patterns of influenza spread. Firstly, Norway is the longest country in Europe in terms of latitudinal range, with an extremely heterogeneous population distribution. Over 80% of inhabitants live in urban areas around the south and central coasts, whereas the northern regions are more sparsely populated and geographically isolated. One may therefore expect a strong spatial signature in influenza epidemics, driven by preferential spread between large and well-connected southern cities such as Oslo and Bergen .On the other hand, underlying climatic variables, such as humidity and temperature, may modify these patterns in unexpected ways –13. For In addition to influenza spread within Norway, fluid population movements between neighboring countries underscore the importance of considering spread across a wider geographic scale . For insIn this paper we first explore patterns of influenza spread in Norway using spatially rich data from the national sentinel surveillance system. We then investigate the role of geographic, demographic, and climatic factors in mediating these patterns, and incorporate data from Sweden and Denmark to extrapolate our findings across a wider geographic scale. Finally, we use the US as a demographically and climatically diverse temperate region with which to assess the generalizability of our results. To address discrepancies in geographic scale between Norway and the US, we develop a novel approach of partitioning the latter into geographical transects of comparable size to Norway. Our results highlight the importance of comparing influenza spread across different geographic regions if the dynamics of this pervasive disease are to be fully understood.Influenza data for Norway were obtained from the Norwegian sentinel surveillance system  and contain weekly reports of influenza-like illness (ILI) cases for 16 consecutive influenza seasons, from 1998–2014. Such sentinel data have been shown to provide reliable estimates of influenza activity across Norway and the wider European region . ILI casThe Danish data were obtained from the Danish sentinel surveillance system (Statens Serum Institut) and contain weekly ILI cases reported by approximately 140 GPs from 2001–2014. Similar to Norway, the data indicate the municipality and region  in which each GP is located. The Swedish data were obtained from the Swedish virological surveillance system  and consist of weekly positive confirmed cases of influenza from 2001–2015. These are reported by up to 27 laboratories across the country, and contain information on the county in which each laboratory is located. The majority of samples are processed in the county in which the corresponding case originated, and thus the data are assumed to be spatially representative. To coincide with peak influenza transmission, reporting in all three countries typically extends from week 40 of each year to week 20 of the following year. Notable exceptions were the pandemic seasons of 2009/10 and 2010/11 for which reporting continued year-round. The spatial boundaries of all municipalities and counties within each country are depicted in The US data were obtained from IMS Health  electronic medical claims records and have been described previously , 20, 21.In brief, for Norwegian municipalities we obtained publicly available information on population sizes, latitude and longitude coordinates, altitude landscapes, flow of passengers traveling between Norwegian airports, and daily temperature and specific humidity records . We alsoTo explore fine-scale spatiotemporal patterns of transmission within Norway, the ILI incidence data were aggregated at the municipality-level. Although weekly ILI records are often normalized by the weekly number of GP visits, we excluded this step as the latter data were unavailable for the first period of our study (1998–2003). Comparative analyses of the ILI and normalized ILI time-series from 2004–2014 produced qualitatively similar results and so we do not expect this omission to impact our conclusions. Of the 428 municipalities in Norway, 165 were originally represented in the data. To account for low sample sizes we removed 29 that failed a conservative Box-Pierce white noise test or had more than two seasons with less than ten total cases reported  22]. Th. Th22]. To analyze synchrony in epidemic timing, wavelet phase-angles were also reconstructed from the 136 ILI time-series. Following standard procedures, each series was first padded with zeros to the nearest power of two, then log-transformed and standardized to reduce variability and noise obscuring the underlying periodic features , 23. TheSynchrony in epidemic amplitudes (or timing) between each pair of municipalities was measured as the correlation between each respective pair of ILI (or phase) trajectories. The average phase difference between each pair of phase trajectories was employed as a supplemental measure of synchrony in timing , 26. RegFinally, to test the relationship between epidemic synchrony and a wider range of predictor variables, we also performed Mantel and partial Mantel tests with Spearman correlations , 28–30. To explore patterns of transmission across national borders, the above analyses were repeated with additional data from Denmark and Sweden. Weekly time-series were aggregated by county from 2001–2014 in accordance with the common spatiotemporal resolution of the data. Of the resulting 45 time-series, eight failed our low sample size tests and were discarded from further analysis see . The disFinally, to compare our findings with those from a demographically and climatically diverse temperate region, the sncf analyses were repeated with the US ILI data and corresponding phase-angle trajectories. Two approaches were used to reconstruct the US phase-angles: 1) by using the original year-round ILI data; and 2) by first removing weeks 21–39 of each year to mimic the temporal distribution of sampling in Norway. Comparing these approaches enabled us to assess the impact of the unsampled weeks on our estimates of synchrony in Norway. To control for spatiotemporal resolution, the Norwegian data were aggregated by county from 2002–2009. To control for differences in the geographic scale of each country, we developed an algorithm to partition the contiguous US into an array of distinct transects of similar size and shape to Norway , distance and temperature , and altitude and population size . Moreover, we found that all municipalities are highly correlated with respect to their temperature and humidity time-series . This suggests a substantial degree of spatial homogeneity in climatic conditions.Using Mantel tests we found that distance, population size, temperature, and specific humidity conditions are all moderately associated with synchrony in epidemic amplitudes and timing  or not (1). This binary variable was the most strongly associated predictor, and was the only variable to remain significant whilst controlling for all other predictors , whereas in summer amplitudes are more similar . Removing the summer weeks then removes the most correlated part of the time-series and thus causes synchrony to decrease. In contrast, variation in phase-angles should be greatest before epidemics begin to take off, when the underlying periodic signal is most obscured (i.e. near the transition between summer and winter). Removing this period would then increase correlation, and thus estimates of synchrony.Partitioning the abridged US data into transects of similar size to Norway allowed us to compare synchrony between these countries whilst controlling for differences in sampling and geographic scale. We expected larger population sizes in the US transects to have a stronger synchronizing effect on influenza epidemics. Instead, we found that amplitude and phase synchrony were indiscriminately higher in Norway. One reason for this may be the lower mean and variance of Norwegian climatic conditions . For exaAnother caveat to our transect analysis is that the partitioning algorithm likely only captures a subset of all possible US transects. In addition, the coarse state-level resolution of the algorithm may have facilitated disproportionate representation of expansive and well-connected states in the central and southern regions. Therefore, although the transects we identified collectively spanned the entire country and included a range of population sizes and climatic conditions, we cannot guarantee that the resulting synchrony distribution is fully representative. Future work could explore this problem further by comparing both countries at finer spatial resolutions. This would allow more flexible partitioning of transect boundaries and greater sampling of irregular coastal and northern regions.Additional caveats to note concern the type of data used in this study. Firstly, as the majority of our data are GP diagnosed cases of ILI, they may also include misclassified cases of other wintertime respiratory diseases, such as respiratory syncytial virus. However, sentinel ILI data are a robust indictor of influenza activity in Europe , and if Thirdly, our analyses do not differentiate influenza cases by strain or subtype and thus cannot account for patterns of spatial spread that may be caused by concurrent circulation of multiple strains , 41. ForUsing rich data from Norway, Sweden, and Denmark we characterized the spatial spread of influenza at different spatial resolutions and geographic scales. Although we found high degrees of epidemic synchrony, further comparison with the US suggested these estimates may be partly confounded by discontinuous temporal sampling. National surveillance systems are diverse with respect to sampling procedures, and our results highlight the challenges in analyzing influenza spread across regions where such differences are present. Nevertheless, important insights can be gained from careful studies that take sampling practices into account. In particular, future mechanistic models could be used to compare different sampling procedures and test their impact on the above analyses. Finally, incorporating data from the US enabled the comparison of influenza spread in two very different regions of the Northern Hemisphere. Contrary to expectations, US epidemics were less synchronized than those in Norway, demonstrating that further study of diverse environmental and demographic settings is needed to better understand the key mechanisms underlying influenza spread.S1 TextDetails of additional covariate data and statistical methods referenced in the main text.(PDF)Click here for additional data file.S1 TableMantel and partial Mantel tests using Spearman correlations to detect associations between the amplitude and phase synchrony of Norwegian municipalities and a number of additional predictor variables.(PDF)Click here for additional data file.S2 TableMantel and partial Mantel tests using Spearman correlations to detect associations between the phase synchrony of Norwegian, Swedish, and Danish counties and a number of predictor variables.(PDF)Click here for additional data file.S3 TableMantel and partial Mantel tests using Spearman correlations to detect associations between the phase synchrony of Norwegian, Swedish, and Danish counties and a number of predictor variables (using downsampled Norwegian and Danish data).(PDF)Click here for additional data file.S4 TableMantel and partial Mantel tests using Spearman correlations to detect associations between the phase synchrony of Norwegian and Danish counties and a number of predictor variables (after excluding the Swedish data).(PDF)Click here for additional data file.S1 FigMunicipality-level measures of population size (A), specific humidity (B), temperature (C), altitude (D), and airline travel (E). For details on how these data were obtained, see (PDF)Click here for additional data file.S2 FigCounty-level measures of population size (A), vapor pressure (B), and temperature (C). For details on how these data were obtained, see (PDF)Click here for additional data file.S3 FigNorwegian ILI time-series that were removed from our analysis due to failure of a Box-Pierce white noise test or the presence of at least two seasons with less than ten cases reported.(PDF)Click here for additional data file.S4 FigNorwegian ILI time-series that were used in all municipality-level analyses. Each row represents a distinct municipality, and these are ordered from top to bottom by decreasing latitude. Blank regions represent weeks for which we do not have data.(PDF)Click here for additional data file.S5 FigNorwegian, Swedish, and Danish county time-series. Red trajectories indicate that the data were removed from further analysis due to failure of a Box-Pierce white noise test or the presence of at least two seasons with less than ten cases reported; series that were kept for further analysis are depicted with blue trajectories. The background color of each plot indicates the country in which each county is located.(PDF)Click here for additional data file.S6 FigAverage phase differences between each Norwegian municipality and Oslo. Oslo is indicated by the black square and the area surrounding the capital is enlarged in the inset box for clarity. A positive (negative) phase difference indicates epidemics tend to follow (precede) those in Oslo.(PDF)Click here for additional data file.S7 FigColors indicate the average center of mass of epidemics  for each Norwegian, Swedish, and Danish county; counties for which data were discarded are shown in white. Oslo is indicated by the black square.(PDF)Click here for additional data file.S8 FigColors indicate the correlation in phase-angles (A) and the average phase difference (B) between each county and Oslo (marked by the black square); counties for which data were discarded are shown in white.(PDF)Click here for additional data file.S9 FigStates in blue were those included in each transect.(PDF)Click here for additional data file.S10 FigEach state is colored according to the proportion of transects in which it is included.(PDF)Click here for additional data file.S11 FigMean and standard deviation of city humidity conditions (measured as vapor pressure) (A), population size (B), and temperature (C) within each US transect; red points indicate the corresponding values across Norwegian counties.(PDF)Click here for additional data file.S12 FigTop: blue states on the map were those included in the transect. Bottom: Spatial non-parametric correlation function comparing synchrony between the US transect (blue) and Norway (purple) for (A) ILI trajectories and (B) phase-angle trajectories. Solid lines represent the average synchrony across all regions, dashed lines depict the predicted relationship between synchrony and distance, and shaded regions are the 95% confidence intervals.(PDF)Click here for additional data file.S13 FigAverage synchrony estimates for 84 US transects obtained by applying the spatial non-parametric correlation function to the abridged data of (A) ILI trajectories and (B) phase-angle trajectories. Points mark transect centroids and colors represent the corresponding synchrony estimate. Inset panels show the distribution of transect synchrony estimates; the estimate for Norway is marked by the dashed line.(PDF)Click here for additional data file.S14 FigSpatial non-parametric correlation function for municipalities in Norway with (purple) and without (blue) the inclusion of the 2009/10 pandemic for (A) ILI trajectories and (B) phase-angle trajectories. Solid lines represent the average synchrony across all regions; dashed lines depict the predicted relationship between synchrony and distance; and shaded regions are the 95% confidence intervals.(PDF)Click here for additional data file.


CArdiac Rasopathy NETwork (CARNET), collaborated in this multicentric, observational, retrospective data analysis and collection. In this study, clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Cardiac defects, crude mortality, survival rate of patients with 1) hypertrophic cardiomyopathy (HCM) and age <2 years or young adults; 2) individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations; 3) biventricular obstruction and PTPN11 mutations; 4) Costello syndrome or cardiofaciocutaneous syndrome were analysed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. In particular, with this Data In Brief (DIB) paper, the authors aim to report specific statistic highlights of the multivariable regression analysis that was used to assess the impact of mutated genes on number of interventions and overall prognosis.A comprehensive description of morbidity and mortality in patients affected by mutations in genes encoding for signal transducers of the RAS-MAPK cascade (RASopathies) was performed in our study recently published in the International Journal of Cardiology. Seven European cardiac centres participating to the  Specifications TableValue of the data•Rasopathy syndromes are a well known entity and specific genotype-cardiac phenotype correlation have been established. Limited information is available on genotype, phenotype and clinical/surgical cardiac outcomes in these patients, thus more data need to be collected and analysed.•The large cohort recently published in the related research article provides specific information on cardiac morbidity and mortality about RASopathies. In this study the authors demonstrated that cardiac mortality is relatively uncommon in these disorders and that in specific subsets of patients, risk factors for surgical mortality or sudden death can be observed.•Statistical correlations reported in tables and figures of the present DIB paper focus in details on genes description for each syndrome, genetic testing, mortality rate and surgical re-intervention.•Defining the worse cardiac phenotype spectrum will be essential to target specific treatment phenotype/gene/mutation-specific in patient affected with RASopathies. This knowledge also allow to optimize the counselling for family and for patients affected by these genetic disorders.1–––In –Additional supplementary tables: the relation between morbility and genetic mutation, syndromes and cardiac defects is reported. Data were presented as median and range, mean±standard deviation (SD), or percentages and CI, as appropriate. These supplementary tables better explain some correlations observed in Data shared consist in peculiar details and explanation of methods and techniques of the statistical analysis of patients’ reports and overall data. Moreover, we have correlated patients and parameters in the following figures and tables.2The cardiac defects that were taken into account in the analyses were selected based on the clinical impact of each single defect on the natural history of disease We investigated all relevant gene mutations present in our population, but given the rarity of most genetic defects in RASophaties, we decided to focus on mutations of BRAF, PTPN11, RAF1 and SOS1. Especially, when plotting the results of the analyses, we reported only the results relative to this subset of genes in order to increase clarity and interpretability.We performed a number of inferential analyses using multivariable regression models.The models were chosen according to the type of dependent variable investigated.Poisson regression was used to study the association between mutated genes and the number of procedures received by each patient with a cardiac defect (interpreted as a count variable), adjusting for sex, presence of PS, HCM, AVC or OHD, and natural logarithm of years of follow-up, to take into account the length of the follow up for each subject. Through Poisson regression, we investigated the association of each syndrome with the number of interventions, adjusting for sex, type of heart defect and length of follow up (transformed as above), and association between presence of PS, HCM, AVC and OHD, and the number of interventions, correcting for sex, gene, and length of follow up (transformed as above).Regression analyses were performed using a Bayesian regularization approach with a non-informative prior with a Cauchy distribution, which allows for more stable estimates in case of unbalanced class distribution or perfect/quasi-perfect predictor-outcome separation, avoiding the production of extreme estimates which are probable to be random fluctuation, therefore improving reproducibility of results Kaplan-Meier (KM) curves were used to describe the incidental risk of intervention and mortality, stratified by time, for each mutated gene, syndrome and heart defect; 95% confidence intervals (95% CI) are shown for the cumulative survival KM plots. In the population of subjects with heart defects, Cox proportional hazards models were used to assess the effect of having a mutated gene, a syndrome or a specific heart defect on the risk of intervention, respectively adjusting for sex and heart defect, sex and heart defect, sex and gene.Variability of the estimates was assessed by applying a non-parametric bootstrap analysis with 5000 repetitions in order to be more robust in presence of non-normal distributions of the investigated effects, which is a common situation when facing complex, multifactorial phenomena Standardized effect sizes (sES), defined as the ratio between mean and SD of the bootstrap distributions of the predictors, were reported to assess the inferential strength of each predictor on the outcomes .Accuracy of the estimates is reported as bias-corrected and accelerated bootstrap 95% Confidence Intervals (BCa 95% CIs) A relationship was considered significant when the BCa 95% CIs were either greater or smaller than the null effect. For each analysis, we took into account only subjects for whom the considered variables were present. The actual number of subjects that entered in each analysis is reported in each table.We purposely decided not to report p-values since we believe this statistic can lead to a superficial if not mislead interpretation of research results We also report the sES in order to provide a further synthetic statistic which join precision and strength of an effect, giving an approximate degree of inferential importance without misleading probabilistic implications. Many share our criticism of p value, therefore we decided to avoid using it in this publication.