Parkinson's disease and stress, psychological stress, mental stress, and chronic stress resulted in 11 articles that met inclusion criteria. The results revealed significant associations between psychological stress and increased motor symptom severity and loss of dopamine-producing neurons in animal models of PD and between psychological stress and increased symptom severity and poorer health outcomes in human subjects with PD. Further research is needed to fully elucidate the underlying biological mechanisms responsible for these relationships, for the ultimate purpose of designing targeted interventions that may modify the disease trajectory.Parkinson's disease (PD) is characterized by complex symptoms and medication-induced motor complications that fluctuate in onset, severity, responsiveness to treatment, and disability. The unpredictable and debilitating nature of PD and the inability to halt or slow disease progression may result in psychological stress. Psychological stress may exacerbate biological mechanisms believed to contribute to neuronal loss in PD and lead to poorer symptom and health outcomes. The purpose of this integrated review is to summarize and appraise animal and human research studies focused on biological mechanisms, symptom, and health outcomes of psychological stress in PD. A search of the electronic databases PubMed/Medline and CINAHL from 1980 to the present using the key words Parkinson's disease (PD) is characterized by complex symptom patterns that fluctuate in onset, severity, responsiveness to treatment, and associated level of disability. The classic motor symptoms of tremor, rigidity, bradykinesia, and postural instability are compounded by nonmotor symptoms such as depression, cognitive impairments, sleep disturbances, fatigue, pain, and autonomic dysfunction. Many of these nonmotor symptoms respond poorly to available treatment options and significantly contribute to poorer quality of life and increased functional disability . Early iThe unpredictable and debilitating nature of the symptoms associated with PD combined with the inability to halt or slow disease progression has the potential to result in psychological stress. Psychological stress is a complex phenomenon that involves cognitive, emotional, behavioral, and biological responses to events or experiences that are perceived as threatening . An indiBiological responses of the neuroendocrine and immune systems represent plausible mechanisms that may explain relationships between psychological stress and poorer symptom and health outcomes. A complex network of bidirectional links between the neuroendocrine and immune systems serve as major regulatory mechanisms for mounting effective biological responses to psychological stress . The hypBased upon work in non-PD animal models, a number of underlying biological mechanisms have been implicated in stress-induced neuroinflammation, oxidative stress, and neuronal loss to include microglial activation, upregulation of proinflammatory cytokines, transcription factors, and isoenzymes, increased production of reactive oxygen species (ROS), and imbalances in the production of ROS and antioxidant reduction. α), interleukin-1 (IL-1), and interleukin-6 (IL-6), proinflammatory cytokines that have been implicated in oxidative stress and apoptosis within the central nervous system [The upregulation of proinflammatory cytokines and transcription factors may further perpetuate stress-induced neuroinflammation and oxidative stress within the central nervous system. Cytokines play an important role in stimulating and coordinating the cellular interactions necessary for mounting effective immune responses to infection, injury, and disease . Psychols system –29. Prois system , 31, whis system , 32. Acts system . While Cs system , 34, 35.Stress-induced oxidative mechanisms have also been associated with neuronal loss within the central nervous system. Oxidation, and the subsequent production of ROS, occurs normally throughout the body as a result of aerobic metabolism. The greatest concentrations of ROS are found within mitochondria, the main site of adenosine triphosphate (ATP) production . Under nβ, IL-6, TNF-α, and IFN-γ) [κB pathways [Stress-induced dysregulation of the neuroendocrine and immune systems may play an important role in symptom and health outcomes in PD. While the exact cause remains unknown, progressive loss of dopaminergic neurons within the substantia nigra pars compacta (SNc) and nondopaminergic neurons within the central, peripheral, and autonomic nervous systems are believed to contribute to symptom and disease progression . As bried IFN-γ) , 46, 47,pathways , 48, incpathways  and NDAPpathways , and incpathways –53. As s Parkinson's disease and stress, psychological stress, mental stress, and chronic stress. A total of 221 articles were identified (n = 171) or caregiver stress (n = 9) in PD. Full-text review and assessment for inclusion criteria was conducted on the remaining 21 articles. An additional 15 articles were excluded, the majority of which were literature reviews and involved biological mechanisms of psychological stress in non-PD animal models or case-studies that did not involve the induction of psychological stress and/or quantify psychological stress levels. The remaining six articles met the above identified inclusion criteria and were included in this review. An additional five articles were identified after a manual review of the references cited in the included articles and excluded articles that underwent a full-text review. A total of eleven articles met the inclusion criteria and were included in this review.An integrated review was conducted to examine human and animal research studies that focused on biological mechanisms and symptom and health outcomes of psychological stress in PD. A title search of the electronic databases PubMed/Medline and CINAHL was conducted from 1980 to the present using the key wordsentified . ArticleOf the 11 studies included in this review, seven examined biological mechanisms of psychological stress that contribute to pathophysiological processes and symptom outcomes in animal models of PD –61. In cα-synuclein, a misfolded protein complex that is recognized as a pathological hallmark of PD. All of the animal studies included in this review examined symptom outcomes specific to the motor manifestations of PD [Seven of the studies included in this review examined biological mechanisms and symptom outcomes of psychological stress in animal models of PD –61. Healns of PD –61. Onlyns of PD . In addins of PD . These sα-synuclein, which plays a major role in the development and progression of PD. While no significant changes were identified in locomotion, activity, and anhedonia in the stress or MPTP/p groups, greater behavioral changes in all parameters were identified in the MPTP/p followed by stress group. Cumulatively, these findings provide important evidence to suggest that psychological stress may contribute to biological mechanisms, symptom outcomes, and disease progression in PD.Using a MPTP/probenecid (MPTP/p) animal model of PD, researchers examined the effects of chronic mild psychological stress on biological mechanisms involving DA and 5-HT levels and the expression of dopaminergic markers of the nigrostriatal (substantia nigra and striatum) and nonnigrostriatal  systems and symptom outcomes specific to depression . SymptomIn a 6-OHDA animal model of PD, researchers examined the effects of chronic variable psychological stress on biological mechanisms involving DA as measured by TH cell counts and motor symptom outcomes . SubjectIn a 6-OHDA animal model of PD, researchers examined the effects of restraint stress and corticosterone administration on biological mechanisms associated with dopaminergic neurodegeneration and motor symptom outcomes . The resUsing a 6-OHDA animal model of PD, researchers examined the effects of psychological stress on the neuroprotective effects of voluntary exercise to include motor symptom outcomes as measured by rotational behavior and biological mechanisms associated with dopaminergic neurodegeneration . SubjectIn a 6-OHDA animal model of PD, researchers examined the extent to which motor symptom outcomes as measured by akinetic and cataleptic behaviors and biological mechanisms specific to DA concentrations were affected by psychological stress . BiologiIn a MPTP animal model of PD, researchers examined the effects of immersion immobilization stress on motor symptom outcomes associated with locomotor activity and biological mechanisms involving DA content, metabolites (DOPAC and HVA), and indices (DOPAC + HVA/DA) . SubjectFinally, in a 6-OHDA animal model of PD, researchers examined the effects of psychological stress on biological mechanisms involving DA and norepinephrine that may contribute to motor symptom outcomes of akinesia . The resα-synuclein [Collectively, these studies suggest important relationships exist between psychological stress and biological mechanisms that contribute to pathophysiological processes and symptom outcomes in animal models of PD. Specifically, significant relationships have been demonstrated between psychological stress and increased motor symptom severity –61 and dynuclein . One stuynuclein . HoweverThe remaining four studies in this review examined symptom and health outcomes of psychological stress that may modify the illness trajectory in human subjects with PD –65. Thren = 29) and controls (n = 27), researchers examined the effects of psychological stress on biological mechanisms of autonomic dysfunction, specifically SSR [In subjects with PD  [n = 105) cited being in a stressful situation as a significant trigger of FoG.In a cross-sectional study, researchers examined factors that influence symptom outcomes of FoG in subjects with PD (n = 130) . FoG, a n = 19) and matched controls (n = 19), researchers examined the effects of psychological stress on symptom outcomes, specifically goal directed movements and hedonic responsiveness [In subjects with PD (siveness . Impairen = 3075) to include symptom and health outcomes of psychological stress [In a cross-sectional study, researchers examined patterns of psychological problems in subjects with PD (l stress . ClusterThese studies provide preliminary evidence to support relationships between psychological stress and poorer symptom and health outcomes in individuals with PD. Significant relationships were demonstrated between psychological stress and symptom outcomes to include increased FoG , decreasα-synuclein, increased neurodegeneration of dopaminergic neurons as indicated by increased Fluoro-Jade positive cells and GFAP in the SNc, and decreased 5-HT levels. These findings suggest the induction of psychological stress in animal models of PD contributes to poorer motor symptom outcomes by exacerbating underlying pathogenic features associated with PD.This integrated review supports the notion that psychological stress affects biological mechanisms and symptom and health outcomes in PD. Evidence in animal models has demonstrated that significant relationships exist between psychological stress and poorer symptom outcomes to include increased motor symptom severity and behaviors associated with depression. Significant relationships have also been demonstrated between psychological stress and biological mechanisms involving biomarkers of dopamine production and metabolism, serotonin, and dopaminergic neurodegeneration. Specifically, the evidence suggests psychological stress in animal models of PD results in greater DA depletions in the nigrostriatal and nonnigrostriatal systems, exaggerated expression of nigrostriatal and nonnigrostriatal Preliminary evidence also exists to suggest psychological stress may play a role in symptom and health outcomes in individuals with PD. In human subjects with PD, evidence supports relationships between psychological stress and increased symptom severity and poorer health outcomes. Significant relationships have been demonstrated between psychological stress and poorer symptom outcomes to include increased FoG, depressive moods, sleep disturbances, anxiety, sexual problems, and communication difficulties and decreased hedonic responsiveness. Greater levels of psychological stress have also been associated with poorer health outcomes such as difficulty coping with PD, poorer social relationships, less enjoyment of life, and the need for more social support. Evidence is lacking regarding underlying biological mechanisms of psychological stress that contribute to these findings in human subjects with PD.Cumulatively, the studies included in this review provide evidence of the potential importance of psychological stress to biological mechanisms and symptom and health outcomes in PD. It should be noted however that many of the reviewed studies demonstrated limitations that may affect the validity and generalizability of these findings. These limitations include issues associated with translating experimental outcomes in animal models to human populations, key differences in the primary outcomes examined, methods for inducing psychological stress, and underlying stress paradigms and study design and methodologies issues.A number of limitations exist when attempting to translate outcomes of animal experimentation to human populations. Routine laboratory procedures and conditions, such as artificial and restricted housing environments, noise, human handling, and contagious anxiety, have been associated with elevations in stress-related biomarkers, factors that may confound experimental results , 67. TheKey differences were identified in the primary outcomes examined in the reviewed studies. The majority of the animal studies included in this review focused on the effects of psychological stress on biological mechanisms that may contribute to pathophysiological processes in PD whereas the studies involving human subjects focused on the effects of psychological stress on symptom and health outcomes that may modify the illness trajectory. Extreme caution should be exercised when attempting to extrapolate biological outcomes in animal models as a means of explaining factors that modify symptom and health outcomes in those living with PD. As such, this highlights the need for additional research that focuses on biological mechanisms of psychological stress specific to underlying pathophysiological processes that may modify symptom and health outcomes in human populations with PD.Important differences were demonstrated in the manner in which psychological stress was induced in animal models of and human subjects with PD. In the reviewed studies, the induction of psychological stress in individuals with PD involved performing strenuous mental tasks , 64. In Key differences in acute versus chronic stress paradigms are important to consider when evaluating the studies included in this review. The underlying stress paradigms in the majority of the reviewed studies focused on the implementation of acute psychological stressors that varied in timing and type so as to limit predictability –62, 64. A number of design and methodological issues were identified in the reviewed studies. For instance, between-subject procedural variability , the intAs this review has demonstrated, significant gaps exist in our understanding of biological mechanisms and symptom and health outcomes of psychological stress in individuals living with PD. Much of what is currently known about biological mechanisms and symptom outcomes of psychological stress in PD has been conducted in animal models of PD and/or predicated on research in non-PD animal models. While important, this knowledge may not adequately reflect these constructs in individuals living with the disease, particularly given the multifaceted nature of stress in human populations and similarities in key pathogenic features of PD that may be exacerbated by underlying biological mechanisms of psychological stress. As a result, additional research is needed in order to further elucidate underlying biological mechanisms and symptom and health outcomes of psychological stress in PD. Psychoneuroimmunological frameworks provide an important opportunity for gaining insight into plausible biological mechanisms of the neuroendocrine and immune systems that may contribute to stress-induced neuroinflammation, oxidative stress, and loss of dopaminergic neurons in PD, which may lead to poorer symptom and health outcomes . RigorouHealthcare providers need to be aware of multifaceted factors that may contribute to symptom and health outcomes in PD. Given the progressive and unpredictable nature of PD, individuals living with the disease must cope with and adapt to a variety of stressors over a protracted period of time. The cumulative costs of psychological stressors may further exacerbate pathogenic mechanisms in PD thereby perpetuating neuronal loss within the central nervous system. Consideration of these factors in the design of future research studies as well as the clinical care of individuals with PD represents an important opportunity to improve symptom and health outcomes in those living with the disease.


Bone regeneration is a complex process requiring highly orchestrated interactions between different cells and signals to form new mineralized tissue. Blood vessels serve as a structural template, around which bone development takes place, and also bring together the key elements for bone homeostasis into the osteogenic microenvironment, including minerals, growth factors and osteogenic progenitor cells. Vascular endothelial growth factor (VEGF) is the master regulator of vascular growth and it is required for effective coupling of angiogenesis and osteogenesis during both skeletal development and postnatal bone repair. Here, we will review the current state of knowledge on the molecular cross-talk between angiogenesis and osteogenesis. In particular, we will focus on the role of VEGF in coupling these two processes and how VEGF dose can control the outcome, addressing in particular: (1) the direct influence of VEGF on osteogenic differentiation of mesenchymal progenitors; (2) the angiocrine functions of endothelium to regulate osteoprogenitors; (3) the role of immune cells, e.g., myeloid cells and osteoclast precursors, recruited by VEGF to the osteogenic microenvironment. Finally, we will discuss emerging strategies, based on the current biological understanding, to ensure rapid vascularization and efficient bone formation in regenerative medicine. Bone regeneration entails a complex series of biological events, with the interplay of different cell types and the orchestration of several intracellular and extracellular signaling pathways. Bone health requires vascular control since blood vessels are key regulators for bone homeostasis, both providing nutrients and minerals and serving as structural templates for bone development  A is one of the most important regulators of angiogenesis and it is critical for both bone development and regeneration. In these processes VEGF has a dual role, acting both on endothelial cells to promote their migration and proliferation, and stimulating osteogenesis through the regulation of osteogenic growth factors  signaling upregulates the transcription factor Runx2, which kickstarts the expression of specific proteins, like BSP, osteocalcin, and osteopontin, necessary to produce mineralized matrix  increased the deposition of mineralized extracellular matrix (ECM), while overexpression of sFLT-1, a secreted blocker of VEGF, reduced mineralization ; type L, which are an extension of type H vessels, form sinusoidal vessels within the hematopoietic bone cavity and are less strongly positive for CD31 and Endomucin (CD31loEmcnlo). Type-H endothelium displays high proliferative activity and secretes factors that regulate osteoblast function and chondrocyte proliferation  class of molecules has been described to both regulate VEGF-induced angiogenesis and bone homeostasis. The Semaphorin family includes eight subclasses of glycoproteins originally described as axon guidance molecules during neuronal development  , promote smooth muscle cell recruitment and arteriogenesis by TGF-β1 and PDGF-BB secretion during VEGF-induced angiogenesis (Zacchigna et al., in vivo and optimized delivery ensured normal, stable, and functional angiogenesis over a 500-fold dose range and improved perfusion of ischemic tissues. In a conceptually different strategy, a recombinant fibronectin fragment was engineered to contain the natural binding sites for fibrin, integrins, and growth factors (Martino et al., The equilibrium between VEGF-triggered angiogenesis, osteogenesis and bone resorption is clearly key to engineer vascularized bone. The design of rational strategies, to fully exploit the potency of VEGF as an angiogenic regulator and at the same time to ensure robust bone formation, should take in consideration this complex cross-talk. Several clinical conditions require replacement of the damaged or lost bone tissue due to trauma or surgery, or also in idiopathic conditions such as avascular necrosis of the lunate, scaphoid, and talus bones, where endogenous bone repair is insufficient. Several regenerative medicine approaches have been investigated to restore vascularization and promote bone regeneration, including combinations of biomaterials with angiogenic growth factors and/or genetically modified progenitors. More recently, protein engineering approaches have enabled the generation of natural matrices decorated with bound growth factors that are presented to cells in their physiological context during bone repair (Martino et al., Vascular endothelial growth factor has a critical role in bone development and postnatal bone repair (Maharaj and D’Amore, AG, AB, and NDM wrote and revised the manuscript. MGB and AL wrote the manuscript. DJS revised 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.


The Practitioner Research and Collaboration Initiative (PRACI) is an innovative, multi-modality practice-based research network (PBRN) that represents fourteen complementary medicine (CM) professions across Australia. It is the largest known PBRN for complementary healthcare in the world and was launched in 2015. The purpose of this paper is to provide an update on the progress of the PRACI project, including a description of the characteristics of PRACI members in order to facilitate further sub-studies through the PRACI PBRN.A CM workforce survey was distributed electronically to CM practitioners across fourteen disciplines, throughout Australia. Practitioners electing to become a member of PRACI were registered on the PBRN database. The database was interrogated and the data analysed to described sociodemographic characteristics, practice characteristics, professional qualification and practice interest of PRACI members.Foundational members of PRACI were found to be predominately female (76.2%) and middle-aged (82.5%). Members were primarily located in urban settings (82.5%) across the Eastern seaboard of Australia (82.5%), with few working remotely. The main modalities represented include massage therapists (58.5%), naturopaths (26.4%) and nutritionists (14.4%). The primary area of clinical interest for PRACI members were general health and well-being (75.4%), musculoskeletal complaints (72%) and pain management (62.6%).PRACI provides an important infrastructure for complementary healthcare research in Australia and its success relies on CM practitioners being involved in the research being conducted through the PBRN. The aim of this database is to ensure that the research conducted through PRACI is rigorous, robust, clinically relevant and reflects the diversity of clinical practice amongst CM practitioners in Australia. The practice-based research network (PBRN) is a research infrastructure that has been growing in popularity globally since the 1960s . A PBRN The regulatory landscape in Australia for the complementary medicine professions is largely reliant on self-regulation by professional associations, with acupuncturists and Chinese herbalists being one of the few CM professions controlled through statutory registration . In the The Practitioner Research and Collaboration Initiative (PRACI) is an innovative, multi-modality PBRN that represents fourteen complementary medicine (CM) professions across Australia. The establishment and design of PRACI were reported in detail in 2014  and thisA secondary analysis of the characteristics of practitioner members of the PRACI network based upon their responses to the survey used to establish the initial PRACI database.The aim of the paper is to describe the characteristics of members of PRACI including sociodemographic characteristics, practice characteristics, professional qualification and practice interest, to highlight opportunities for further sub-studies through the PRACI PBRN.All CM practitioners from targeted professions , reflexologists, Western herbalists and yoga practitioners) were invited to join the PRACI network. Completion of a baseline workforce survey was required before individual practitioners could elect to become a member of PRACI.The PRACI database of members was established from all practitioners who completed a CM workforce survey in 2015 and elected to join the network. The questions of the baseline survey were designed to capture key information linked to each PRACI member and enable effective administration of future sub-studies through PRACI. The survey contained 19 items covering practitioner demographics and practice characteristics.Questions regarding the socio-demographic characteristics of participants, such as age and gender, were included. Practitioners were also asked to provide information about the number of years since completing their first qualification in complementary health care. The survey included questions about the professional qualifications of practitioners. Respondents were grouped into professional categories based on their reported qualifications .Respondents were asked to provide information about the location of their clinical practice/s. This included the State or Territory in which they practised , as well as the category of their practice locality . Respondents were also asked to identify areas of practice interest in line with a wide range of common health specialities .The baseline workforce survey was distributed electronically through over 20 national professional associations, social media , national conferences and organisations  whose client-base targeted the fourteen included professions. The survey was promoted multiple times through each organisation to maximise participation. The survey was administered between January and November 2015 using the SurveyGizmo platform.Raw data was extracted from SurveyGizmo to a Microsoft Excel spreadsheet and imported into Stata 14 statistical software for analysis. Binary variables for each professional group were developed to allow for practitioners to be allocated to multiple professional groups in line with their qualifications. Similarly, binary variables were developed for the location of practice to ensure practitioners with multiple practice locations were appropriately reflected in the data. Frequencies and percentages were calculated for variables of interest for all respondents as well as for individual professional groups. In addition, associations between key demographic characteristics of PRACI members and the wider CM workforce was determined through chi-squared tests.The baseline survey was completed by 1264 practitioners of whom 764 agreed to join the PRACI PBRN, reflecting a 60% conversion rate. The exact response rate of either the baseline survey or the PRACI membership could not be calculated due to the absence of reliable national workforce numbers, due in part to an absence of registration of the professions included in PRACI , or the age of work that has been done relating to professions in PRACI  of PRACI members operate a clinic based in an urban location, with a smaller proportion reporting clinical practices based in rural , remote  and very remote  localities.The location of PRACI members’ clinical services is presented in Table n = 175; 22.9%) and 20 or more  years ago, and also between members who qualified 10 to 14 years  or less than 5 years  ago. The least prevalent group of members based upon years since qualification are those that graduated 5 to 9 years ago .There is a fairly even proportional representation of PRACI members based upon the years since their first qualification in complementary health care , naturopathy , nutrition , and reflexology . PRACI also includes members with qualifications in acupuncture , Western herbal medicine , myotherapy , aromatherapy , homeopathy , Chinese herbal medicine , Bowen therapy , kinesiology , yoga , and Ayurveda .The specific professional groups within which PRACI members are registered are presented in Table n = 576; 75.4%) and musculoskeletal conditions . A substantial number of practitioners also report a special interest in pain management , digestive disorders , women’s health , and mental health issues . The least common areas of special interest are paediatrics , renal conditions , and gerontology  , musculoskeletal conditions  and women’s health issues . The areas least commonly identified as practice special interests include gerontology , renal conditions , sports performance , oncology , and weight loss . The majority of practitioners in PRACI with acupuncture qualifications are situated in urban settings  within Queensland , New South Wales  and Victoria .Amongst practitioners with acupuncture qualifications, the most common areas of practice interest are pain management  and musculoskeletal conditions . Aromatherapists report gerontology , paediatrics , and ear, nose and throat conditions  as practice areas they are least frequently interested in. Almost half of the aromatherapist members of PRACI practice in Queensland , with a substantial proportion practicing in Victoria  or New South Wales . Most aromatherapists practice in an urban location , with only one in five  based in a rural, remote or very remote setting.The most common areas of practice interest for aromatherapists are general health and wellbeing (n = 3) identify a focus in all areas of practice interest except complex and chronic disease , endocrine health , gerontology , paediatrics , renal conditions , sports performance  and oncology . Clinical practice localities of the ayurvedic members of PRACI include Australian Capital Territory (n = 1), New South Wales (n = 1), Queensland (n = 1) and Victoria (n = 1). These practices are primarily located in urban locations (n = 3).All ayurvedic practitioners  and general health and wellbeing  are most frequently identified by Bowen therapists as an area of interest in their practice. Bowen therapists are least likely to identify gerontology , renal health , ear, nose and throat conditions  and oncology  as an area of practice interest. Bowen therapist members of PRACI report practice locations in mostly urban  settings across Victoria , Queensland , New South Wales  and Western Australia  and Tasmania .Musculoskeletal conditions , women’s health , digestive disorders , and musculoskeletal conditions  are commonly identified as an area of practice interest by practitioners with a Chinese herbal medicine qualification. Gerontology  and renal health  are identified as a practice interest area for Chinese herbal medicine practitioners least frequently. Practitioners with Chinese herbal medicine qualifications report practice locations in all States  but not in the Territories. Practices for this group were primarily located in urban settings , and to a lesser extent, rural settings .Pain management , digestive disorders , allergies and sensitivities , complex and chronic diseases , and mental health  as an area of practice interest. Gerontology  and sports performance  are reported least frequently as an area of practice interest by homeopaths. The practices of homeopaths are predominantly located in the States of New South Wales , Queensland  and Victoria . The homeopaths in PRACI most commonly identify their practice as being located in an urban setting , with few situated in a rural  or remote  location.A substantial number of homeopaths list women’s health , pain management , and musculoskeletal conditions  most commonly as areas of practice interest. Least common areas of practice interest amongst kinesiologists are oncology , gerontology , and renal health . Kinesiologists most commonly report practice locations in Victoria  although a substantial number practice in Queensland , and New South Wales . Practices in Western Australia , South Australia , and Tasmania  are less common. The majority of kinesiologists’ practice locations are reported in the urban setting , followed by the rural setting .Kinesiologists report general health and wellbeing , general health and wellbeing , and pain management . Gerontology , renal health , and paediatrics  are least commonly reported. While all States and Territories have massage therapists as members of PRACI, the majority of massage therapists in PRACI have a practice location in Victoria , Queensland , and New South Wales . The massage therapists practice primarily in an urban location , and to a lesser extent, in a rural location .The most commonly identified areas of practice interest for massage therapists are musculoskeletal conditions  and pain management . Least common areas of practice interest amongst the PRACI myotherapists are renal health , gerontology , and paediatrics . More than half of the myotherapists have their practice located in Victoria  although a number are also situated in Queensland  and New South Wales . Whilst the majority of myotherapist members of PRACI practice in an urban location , one in five also report practising in a rural setting .The areas of particular practice interest for myotherapists are musculoskeletal conditions , women’s health  and general health and wellbeing  as areas of practice interest. Least common is gerontology , renal health  and sports performance . A similar number of naturopaths who are members of PRACI practice in Victoria  and New South Wales , with slightly lower numbers reported in Queensland  and less again in other States and Territories. The PRACI naturopaths report practicing mostly in urban  and rural  settings.Naturopaths most commonly report digestive disorders , general health and wellbeing  and women’s health . Gerontology , renal health  and oncology  are reported least frequently by nutritionists as areas of practice interest. The highest number of nutritionists who are members of PRACI are located in New South Wales , Queensland  and Victoria , with PRACI nutritionists primarily practicing in urban  and rural locations .The most frequently cited areas of practice interest for nutritionists are digestive disorders , musculoskeletal conditions , and women’s health  are listed as areas of practice interest amongst the majority of reflexologists, whereas gerontology , paediatrics  and renal health  are listed as areas of practice interest by smaller numbers of PRACI reflexologists. The practice locations of reflexologists involved in the PRACI network are reported in all States and Territories except Northern Territory, with the highest number occurring in Queensland , Victoria , and Western Australia . The majority of PRACI reflexologists describe their practice setting as urban  or rural .General health and wellbeing , women’s health , and general health and wellbeing  are all practice interest areas commonly identified by PRACI Western herbal medicine practitioners. In contrast, gerontology , oncology , renal health  and sports  are least commonly identified as areas of practice interest amongst the PRACI Western herbal medicine practitioners. Over half of Western herbal medicine practitioners list their practice location as either New South Wales  or Queensland , although a substantial number are located in Victoria , South Australia  and Western Australia . Most Western herbal medicine practitioners describe their practice as being located in an urban setting , with only 19% (n = 18) located rurally.Digestive disorders , women’s health , mental health  and musculoskeletal conditions  as areas of practice interest. Gerontology  and paediatrics  are least frequently reported by yoga practitioners as an area of practice interest. Yoga practitioners are located in all States and Territories, although the highest numbers are in New South Wales , Victoria , Western Australia , and Queensland . These practitioners describe their practices as mostly situated across urban  and rural  settings.Yoga practitioners who are members of PRACI most frequently report general health and wellbeing . It also has a high level of representativeness based on existing workforce data and has the capacity to support a diverse range of research designs as sub-studies. For this reason, PRACI is expected to make a significant contribution to CM research in Australia and throughout the world. Our aim is to ensure that the research conducted through PRACI is rigorous, robust, clinically relevant and reflects the diversity of clinical practice amongst CM practitioners in Australia.PRACI is a new and innovative resource for CM research. It represents the largest CM practice-based research network in the world based on the total number of included professional groups (


Unhealthy food behaviours, influences Beyond personal control and Environmental influences) had direct and indirect associations with three weight control methods factors, named: Healthy habits, Eat less, sit less, and Dieting. Middle class food providers in the study regions share public health views of obesity causation and personal weight control. These findings could inform public health and food policies, and the design of public health interventions and communications. Further research is required among lower socio economic status (SES) populations.The rise of the middle classes in developing countries and the associated epidemiological transition raises the importance of assessing this population group’s awareness of the causes of obesity and effective weight control strategies in order to develop effective health promotion strategies. The study aimed to examine the perceptions of the causes of obesity and weight control strategies held by middle class household food providers in Melbourne, Singapore, Shanghai, Indonesia and Vietnam. An online survey was conducted in late 2013, early 2014 among 3945 respondents. Information about body weight concerns, perceived causes of obesity, effectiveness of weight control methods, demographics, self-reported height and weight, and personal values was elicited. Confirmatory factor analyses (CFA) derived nine reliable factors which were used in structural equation modelling (SEM). Two thirds of respondents were trying to change their body weight, of them, 71% were trying to lose weight. The CFA and SEM showed that demographics, region of residence, personal values and perceptions of the causes of obesity ( Public health policies have been proposed to deal with the high prevalence of obesity, ranging from mass education programs to regulation of marketing and advertising ,2. The uSince much of human physical activity and food intake is strongly influenced by the household environment , the houDemographic characteristics: Older people tend to be more concerned about food and health issues than younger people ,10,11,12Body Mass Index status: People who are overweight or obese might be expected to have greater reason than others to consider the causes of obesity as well as methods to control body weight. In terms of attribution theory, their greater involvement suggests that as “actors” they may be more likely than slimmer people to attribute obesity to external causes beyond their personal control .Personal value orientations: These are generally associated with attitudes and opinions . For exaLevels of economic development: In regions undergoing rapid economic and epidemiologic transitions , the expPerceptions of effective weight control strategies: The perceived causes of obesity may influence perceptions of effective ways to control body weight. For example, those who believe environmental influences are mainly responsible for obesity might see environmental changes as the most effective ways to maintain a healthy body weight. Identification of food providers’ support for valid effective weight control activities could be used to develop supporting obesity prevention policies.Generally, food providers’ views of the causes of obesity have been little studied. In our previous work, we showed that the Australian public held sophisticated views of the causes and prevention of children’s obesity . These iIn summary, our aims were to examine the perceived causes of obesity among middle class people in five regions at different stages of economic development, and to examine their associations with demographics, body weight, personal values, economic development and perceptions of personal effective weight control methods. We proposed a conceptual model  based onDuring December 2013 and January 2014, a detailed online survey (The Families and Food Survey) was conducted among approximately 800 household food providers in each of Indonesia, Melbourne, Shanghai, Singapore and Vietnam, by Global Market (GMI), an online market research company. This company maintains databases of volunteers who are rewarded by points for survey participation, the points being redeemable for small monetary payments. The main inclusion criteria were that respondents had to be household food providers, over 18 years and approximately 40 per cent were to be men to reflect possible changes in family food provisioning.Ethics permission for the study was granted by the Deakin University Health Ethics Advisory Group (HEAG 2013-163). The survey questionnaire was translated into Vietnamese, Bahasa Indonesia and Chinese by GMI. These translations were then checked by nationals of these countries  and any culturally sensitive or misleading phrases were reworded. Prospective respondents were drawn from the GMI databases in the five regions. They were sent an email inviting them to take part in the survey.The questionnaire included an extensive list of questions about household food issues. Responses to the following sets of questions are reported in this paper. • Self-reported height and weightRespondents reported their height (in cm) and their weight (in kg) and these were converted into body mass indices . BMI bas• Demographic characteristicsDetails were elicited of the respondents’ age, gender, marital status , and, highest level of education . The number of children in the household was elicited for the 0–5, 5–12, 13–18 year age groups. In addition, the city or country of residence was dummy coded into four binary variables using Melbourne as the reference group.• Household ownership of electronic communication and entertainment devicesRespondents were asked to indicate the numbers of electronic communication  and entertainment devices  in their households. The numbers of entertainment devices and communication devices that people owned were calculated .• Concern about body weightAre you concerned about your weight at the moment? They could respond: Not at all (1); A little concerned (2); Somewhat concerned (3); or Very concerned (4).Respondents were asked: Then they were asked: Are you trying to do anything about your weight? Are you trying to lose weight? and, Have you heard of the Body Mass Index (BMI)? They could answer: No (1); or Yes (2) to each of these questions .• Perceived causes of obesityWhat do you think are the main causes of obesity? In this and the next two sets of questions, five-point Likert scales were used . The order of items was rotated across respondents. It should be stressed that respondents were asked about the causes of obesity in general, not specifically about children’s or adult obesity.Thirteen items were taken from our previous study of the perceived causes of children’s obesity  Table 3. Respond• Perceived effectiveness of weight control strategiesHow effective are the following actions that individuals can take to maintain a healthy body weight? A list of 23 possible actions was presented in rotated order , dummy coded regions of residence and BMI were used as independent variables. BMI was standardised with a mean of zero and standard deviation of 1.SPSS 22  and MpluFifty-seven per cent of the respondents were female; the mean age was 35.72 (SD 11.23) years . Sixty pFewer than half of the respondents were a little concerned or unconcerned about their body weight; 17.4% were very concerned. Greatest concern (“somewhat” plus “very”) was seen among respondents from Singapore and Vietnam . Least cThere was much agreement between the respondents in the different countries although there were some major differences . Item coUnhealthy food behaviour: About 80% indicated that overconsumption of sugar sweetened beverages (SSB), eating oversized servings of food, and regular consumption of fast foods were causes of obesity, though respondents in Vietnam rated these (and other causes) lower than respondents in other countries. Beyond personal control: “Lack of awareness of the dangers of obesity” was cited most by Indonesians and least by Melbournians. “Poor availability of healthy foods” was indicated least by the Vietnamese respondents. “Lack of physical activity opportunities” was indicated most by people in Shanghai and least by Melbourne respondents. Genetic causation of obesity was most endorsed by Singaporeans and least by Vietnamese.Environmental influences: Modern technology and the promotion of unhealthy foods was blamed most by respondents in Melbourne, Singapore and Shanghai, and least by those in Indonesia and Vietnam. The low cost of unhealthy foods was endorsed least by the Vietnamese and most by the Melbournians. Healthy habits, Eat less, sit less and Dieting , Security-conformity-tradition , age , female gender , number of e-entertainment devices owned , and Environmental influences  but negatively linked to being Indonesian , Singaporean , or Vietnamese  (vs. Melbournian). Dieting was positively associated with Healthy habits , Security-conformity-tradition , Self-oriented hedonism , being Indonesian  or Vietnamese  (vs. Melbournian), and Beyond personal control  but negatively related to Equality-nature . Healthy habits were positively associated with Unhealthy food behaviour , female gender , Equality-nature , being Vietnamese  (vs. Melbournian) and Environmental influences  but negatively related to being Singaporean  (vs. Melbournian).Unhealthy food behaviour was directly and positively related to female gender , Equality-nature , being Indonesian  (vs. Melbournian), and Environmental influences  but negatively associated with number of children aged between 0 and 5 years  and Self-oriented-hedonism . Beyond personal control was positively associated with Security-conformity-tradition , being Shanghainese , Indonesian , Singaporean , or Vietnamese  (vs. Melbournian), and Environmental influences .Environmental influences were positively linked to Security-conformity-tradition  and education  but negatively related to being Shanghainese , Indonesian , or Vietnamese  (vs. Melbournian).Unhealthy food behaviour , Environmental influences , and Eat less, sit less  and related to Beyond personal control , and Healthy habits . However, these significant bivariate relationships are not evident in the multivariate model.On a bivariate level, the standardized BMI was associated with It is clear from the high levels of home ownership, education and ownership of electronic devices that most of the respondents can be regarded as “middle-class” with considerable purchasing power. Our findings are complex but there are at least five clear themes which have relevance for obesity prevention in the Asia Pacific region. First, there were many similarities between the regions. Concern with body weight and interest in losing weight was high in these middle class respondents. This is similar to survey findings from the US, the UK and other “Western” countries . The moBeyond personal control factor (Melbournians scoring lower than the others) but no difference was seen between Melbournians and Singaporeans on the Environmental influence factor. In contrast the Melbournians scored more highly on Environmental influences than Indonesian, Shanghainese and Vietnamese respondents. This may be related to the media coverage of industry’s role in the causation of obesity in Australia. There was only partial support for the role of e-entertainment and computer ownership which were weakly associated with Self-oriented hedonism and Equality-nature and thence with several perceived causal and effectiveness factors.Second, there were also major national differences. These tended to be consistent, with exceptions, with our economic development hypothesis. Respondents in developed economies, Melbournians and Singaporeans tended to share similar views of many topics, and those in developing economies, particularly the Vietnamese and Shanghainese respondents, held differing views. However, other cultural factors appear to have influenced the findings such as the greater opposition to the promotion of alcoholic drinks in Indonesia which has a large Muslim population. The Vietnamese respondents understated most of the perceived causes of obesity. This may be because obesity is a new phenomenon in Vietnam and people have had little time to become familiar with it. Lack of awareness of obesity was reported most by Indonesian respondents and least by Melbournians. The divide between Melbourne and the other regions is most apparent in the SEM . There wEnvironmental influences was negatively associated with Unhealthy food behaviour, positively with Healthy habits and Eat less, sit less. Since causal perceptions are likely to be malleable, they provide the opportunity for awareness raising communications to bring about changes in the perceived effectiveness of a number of weight control strategies thus affecting readiness to change. Individual outcome factors like Dieting can be examined to determine their aetiology to identify foci for communication programs.Third, causal perceptions predicted effectiveness strategies, e.g., Security-conformity-tradition and Equality-nature played major mediating roles between the stable demographic factors and the perceptual factors. From a health promotion perspective, they could be used to segment the respondents to identify perceptual and other characteristics which could be the foci of communication programs [Security- conformity-tradition and Equality-nature values) resist the adoption of consumerist practices like soft drink consumption could be tested. Certainly the interests of these people in the common good should be supported by health and food policies. Finally, as expected, Self-oriented Hedonism was associated with lesser emphasis on Unhealthy food behaviour causes and more with Dieting as an effective form of weight control.Fourth, the three derived values factors are similar to the three main segments postulated in Schwartz’s values taxonomy . Their rprograms . In furtHealthy habits and Eat less, sit less. More novel was the positive relationship between higher education and Environmental influences and the weak, negative relationship between Unhealthy food behaviour and the presence of children under 5 years. Food providers with children in this age group tended to dismiss the consumption of oversized servings of foods, sugar sweetened drinks and fast food as causes of obesity. This requires further confirmation and explanation but it suggests that public health messages about these products may need to be communicated more effectively to parents and caregivers. The other relationships with causal and effectiveness factors were mediated by the personal values factors. Finally, contrary to our expectations, food providers’ BMI was unrelated to any of the examined factors in the SEM, even though BMI was significantly correlated with these factors at the bivariate level. That is, these particular obesity beliefs appeared to be independent of weight status.Fifth, demographics played only small roles in the SEM. However, the findings were consistent with earlier research ,15,16,17We have shown in this paper that members of the middle class in the five countries have sophisticated views about the causes and individual responses to overweight and obesity. The question that arises is whether the public health policies in these countries are congruent with the respondents’ views? In developed countries such as Australia and Singapore, obesity and non-communicable diseases have been on public health agenda for many years and many health promotion activities have been designed to address the issue. In contrast, Indonesia, Vietnam, and China, are still dealing with under nutrition and stunting whilst also experiencing rapid increases in obesity and non-communicable diseases, particularly in urban areas. This double burden of disease has been well described in the nutrition literature . HoweverThis exploratory study has several limitations. First, although the online survey administration was a good way to reach middle class respondents, the final samples are highly skewed to middle class, highly educated, well off respondents. It is possible that the high purchasing power of the respondents may enable them to purchase healthier, less energy dense foods than people from less well off backgrounds  thus infThe findings show that middle class food providers in the Asia Pacific Region are concerned with body weight and share public health advocates’ views about the causes of obesity and personal ways to control body weight. The findings can inform public health and food policies, and the identification of mediating values and perceptual variables could aid the design of health interventions and communications in the region. Further research is required among lower SES populations.


Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large-scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%–20% of all AIDS-related deaths , 4.PLOS Neglected Tropical Diseases (PLOS NTDs) as a neglected tropical disease (NTD), it is listed in the G-Finder report, as it disproportionately affects people in low- and middle-income countries (LMICs), with market failure evident for existing essential antifungal medicines and an urgent need for new, effective, and less toxic medicines. PLOS NTDs defines NTDs as a “group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of LMICs” ), placing it in the bottom tier of neglected diseases, receiving support essentially from 3 public health funders: United States National Institutes of Health (NIH), United Kingdom Medical Research Council (MRC), and Australian National Health and Medical Research Council [line.asp ). In adddex.html ). Oral f3), which is recommended by the WHO and the President's Emergency Plan for AIDS Relief (PEPFAR), combined with preemptive antifungal treatment can prevent or detect at an early stage a significant proportion of cryptococcal meningitis cases, as the antigen can be detected in blood for weeks to months prior to the development of clinical disease. There are sensitive and specific CrAg lateral flow assays (CrAg LFAs) that can be used for diagnosis either in the laboratory or at the point of care. The strategy is highly cost-effective and has recently shown a mortality benefit when combined with increased adherence support and early detection of tuberculosis (TB) [Despite the challenges, 2 strategies for the control and treatment of cryptococcal meningitis exist that together could make a significant impact: screen-and-treat programs for CrAg and delivery of short-course improved therapies . CrAg scsis (TB) , 44. AltWith regard to treatment, optimized, sustainable regimens using existing antifungal medicines, drug development, and testing of repurposed drugs could significantly reduce the case fatality rate. Simplified treatment regimens consisting of short-course combination amphotericin B therapy and a purely oral combination of fluconazole and 5-FC are currently being tested in African LMICs with results expected in 2017 . Liposomal formulations of amphotericin B offer a far better-tolerated alternative to traditional formulations. The AMBITION-cm trial is comparing the efficacy of 1 high dose of liposomal amphotericin in combination with fluconazole for HIV-associated cryptococcal meningitis . A few intermittent doses could prove cost-effective if hospital admission duration was reduced, and there is precedent for efforts to increase access. In September 2016, Gilead extended a donation program to the WHO to make an additional 380,000 vials of liposomal amphotericin available at cost to continue treating patients with visceral leishmaniasis over 5 years [C. neoformans, with good central nervous system penetration and synergy with fluconazole [Repurposing of established drugs has also been applied to the search for new medicines . This apconazole . Both drLastly, raised intracranial pressure affects approximately one third of patients, and managing this common, debilitating, life-threatening complication improves patient outcomes , 48. HowWhilst debate continues as to whether cryptococcal meningitis should be listed as an NTD, affected persons in LMICs remain neglected, with opportunities missed to both prevent disease and provide effective treatment to reduce mortality. Stating that increased ART coverage alone will obviate the problem of HIV-associated cryptococcal meningitis in LMICs is not tenable; the evidence, with striking data from Botswana of ongoing cryptococcal meningitis cases despite excellent ART coverage, shows that this has not been the case to date . PatientPLOS NTDs, UNITAID, The Global Fund, and WHO to declare cryptococcal meningitis an NTD and press for urgent funding and policy drives to target optimisation and rollout of CrAg-screening programs, access to 5-FC and liposomal amphotericin B, and new drug development.In 2013, the Cryptococcal Meningitis Action Group (CryptoMAG) was formed to improve access to diagnostic tests and essential antifungal medicines and to disseminate clinical best practices for treatment and prevention in LMICs. The debate over whether or not cryptococcal disease is an NTD detracts from cryptococcal meningitis being both HIV related and also urgently needing the interventions  from which NTDs benefit. We therefore call on the global health community,


Life is mechanobiological: mechanical stimuli play a pivotal role in the formation of structurally and functionally appropriate body templates through mechanobiologically-driven cellular and tissue re/modeling. The body responds to mechanical stimuli engendered through physical movement in an integrated fashion, internalizing and transferring forces from organ, through tissue and cellular length scales. In the context of rehabilitation and therapeutic outcomes, such mechanical stimuli are referred to as mechanotherapy. Physical therapists use mechanotherapy and mechanical interventions, e.g., exercise therapy and manual mobilizations, to restore function and treat disease and/or injury. While the effect of directed movement, such as in physical therapy, is well documented at the length scale of the body and its organs, a number of recent studies implicate its integral effect in modulating cellular behavior and subsequent tissue adaptation. Yet the link between movement biomechanics, physical therapy, and subsequent cellular and tissue mechanoadaptation is not well established in the literature. Here we review mechanoadaptation in the context of physical therapy, from organ to cell scale mechanotransduction and cell to organ scale extracellular matrix genesis and re/modeling. We suggest that physical therapy can be developed to harness the mechanosensitivity of cells and tissues, enabling prescriptive definition of physical and mechanical interventions to enhance tissue genesis, healing, and rehabilitation. Exogenous  and endogenous  mechanical stimuli literally shape the body's unfolding template during development, as well during growth and re-/modeling of the body's tissues and organs throughout life Figure 1. These Physical movement and/or mechanical interventions propagate mechanical stimuli from the length scale of the organismal system (body) to its cellular inhabitants. Mechanotherapy refers to such mechanical stimuli in the context of promoting healing, tissue repair and rehabilitation, i.e., “any intervention that introduces mechanical forces with the goal of altering molecular pathways and inducing a cellular response that enhances tissue growth, modeling, remodeling, and/or repair”  focuses primarily on force transfer and mechanoadaptation of musculoskeletal tissues, before describing recent examples of mechanotherapy-based interventions and future directions in the field.Physical therapists use exercise therapy and manual therapy to restore function and reduce pain to treat disease and/or injury. Although physical therapy implies the use of physical approaches or movements to treat the body, the opportunity to foster an interactive discourse between human biomechanics and physical therapy has not yet been realized. In a Pubmed “Title/Abstract” search where the terms “biomechanics” and “physical therapy” was entered, there was evidence supporting the importance of exercise therapy and mobilizations to joint rehabilitation, but incomplete evidence linking biomechanics theory to therapeutic outcomes. To bridge the gap between engineering biomechanics and clinical physical therapy, here we describe physical movement in the context of joint biomechanics and draw upon the literature to demonstrate how force distribution in the body can be altered through exercise and/or manual therapy. The aim is to facilitate healing and/or target specific mechanoadaptations to foster healthy balance of forces to prevent future injuries and maximize wellbeing. While the former is specific to physical therapy in a clinical context, the latter expands well beyond physical therapy to exercise physiology and its health benefits throughout life  and manual therapy (passive physiologic and accessory joint movements) . The forces involved with motion are transferred through the body via rotational and translational dynamics, which generate moments about joints, i.e., joint torques  and amplitude of joint mobilization amongst clinicians treating knee osteoarthritis, it was found that intra-clinician consistency was excellent but inter-clinician consistency was moderate  of varying mechanical properties and tissue architectures. As the main structural components of the musculoskeletal system, muscles, and connective tissues are particularly relevant for tissue-level mechanotransduction. The mechanical properties of muscle and connective tissues are dependent on their cellular and extracellular matrix components, including interstitial fluid  actuates joint torque and hence movement. Muscle is the greatest contributor to joint support, stability, force generation, forward propulsion, and shock absorbance  and/or deviatoric stresses on cells , the osteocyte and the red blood cell (RBC). These cells in particular provide an interesting study in contrasts, e.g., between the unspecialized cell which itself serves as a sensor and actuator of mechanical stimuli and mechanoadaptation, respectively, and the ultra specialized adherent (osteocyte) and perfectly motile (RBC) cell exhibiting specialized structures to transduce mechanical stimuli  than terminally differentiated (mature) cells, such as osteocytes and chondrocytes (circa 1–2 kPa)  and the extracellular matrix. The organization of the actin, tubulin, and intermediate fibers between the cell membrane and the nuclear membrane itself exhibits anisotropy, which provides a further means by which shape and volume changing stresses can direct changes in nuclear shape and volume , whether imbued via vibrations or oscillations, increase the anabolic potential of bone tissue. This mode of mechanotherapy has been shown to increase both trabecular and cortical bone mass density in patients with bone fractures after 6–12 months of treatment. The same studies combined low magnitude with high frequency loading, as tissues are biologically sensitive to high frequency events. Low magnitude-high frequency (LMHF) stimuli improved trabecular bone mass density by 34%  provides a non-invasive technique to deliver dynamic pressure to tissues of the skin and muscle. In a rat model of functional disuse, DHS was used, alternating 30 mmHg of static and 30 mmHg of dynamic, DHS was used, alternating 30 mmHg of static and 30 mmHg of dynamic loading to the muscle tissue surrounding the tibiae. Following this loading regimen, DHS stimulated tibiae exhibited an 83% increase in bone volume and 190% greater bone apposition rate in comparison to their non-stimulated counterparts  and extracorporeal shock wave therapy (ESWT) have garnered much interest of late. These therapies play a putative role in the modulation of natural inflammatory pathways, growth factor upregulation and protein synthesis  and the physical properties of their synthesized matrix, which are manifested as tissue structures. Theoretically, mechanical stimuli can be “controlled” at physiological levels that encourage and stimulate constructive tissue adaptation and remodeling through engineering of physical therapy and exercise protocols. By directing loading regimens to specific sites, and having an understanding of the mechanotransduction and mechanobiological response across these length and time scales, physical therapy can be used to expedite healing and rehabilitation throughout life. In the future, exercise therapies, manual mobilizations and other physical modalities used in physical therapy may be tailored to facilitate (i) the recruitment, migration and targeted lineage commitment of stem cells, (ii) expedited tissue genesis, and (iii) optimal remodeling such that healed tissues meet or exceed their native mechanical strength.This article was written and edited by the coauthors, JN, MK, SK, and MKT.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.


Although the Lao People’s Democratic Republic (Lao PDR) is comparatively small landlocked country with patterns of both in- and out-migration, its human migration situation has been poorly studied. This is despite all of the country’s 18 provinces sharing both official and unofficial border checkpoints with neighboring countries. Economic reforms in the last decade have seen a gradual increase in the promotion of foreign investment, and main towns and transportation networks have been expanding thus offering new opportunities for livelihoods and economic activities.In the last decade, there has also been a significant reduction of reported malaria cases in Lao PDR and while this is an important prerequisite for eliminating malaria in the country, malaria outbreaks reported in the last four years suggest that population mobility, particularly in the south, is an important factor challenging current control efforts.Bolder investment in social sector spending should be geared towards improving health service provision and utilization, ensuring equitable access to primary health care  through efforts to achieve universal health coverage targets. This should be extended to populations that are mobile and migrants. The local government plays a critical role in supporting policy and enforcement issues related to private sector project development in the provinces. Cross-border initiatives with neighboring countries, especially in terms of data sharing, surveillance, and response, is essential. Mechanisms to engage the private sector, especially the informal private sector, needs to be explored within the context of existing regulations and laws. Existing and new interventions for outdoor transmission of malaria, especially in forest settings, for high-risk groups including short- and long-term forest workers and their families, mobile and migrant populations, as well as the military must be combined into integrated packages with innovative delivery mechanisms through social marketing approaches. This should happen at multiple points in the mobility pathway and involve the private sector rather than being fully reliant on the national malaria vertical programThis article based on the review of existing literature from abstracts and full texts, includes published, peer-reviewed English language literature sourced through PubMed and grey literature sources through Google and Google Scholar. The review included also case reports, sector reports, conference proceedings, research reports, epidemiology studies, qualitative studies, and census reports in both Lao and English languages. The authors used the search terms: malaria and mobile populations, malaria control program and elimination, health system performance, malaria outbreak, Lao PDR; and included articles published until June 2015.The online version of this article (doi:10.1186/s40249-017-0283-5) contains supplementary material, which is available to authorized users. Please see Additional file Malaria transmission varies across the different ecological zones of Lao People’s Democratic Republic (Lao PDR). The majority of high transmission areas are hilly, forested areas in the southern part of the country where the majority of people are employed in forest-related occupations . Lower rPopulation groups at risk of acquiring malaria in endemic areas of Lao PDR include both static and mobile populations . The malLao PDR’s economy grew to 8.1% in 2013 resulting in the World Bank declaring that the country has a fast-growing economy. There has been an average 7% gross domestic product growth over the last two decades, the highest growth rate in Southeast Asia. The country’s population is projected to increase by 27% from 6.4 million in 2010 to 8.8 million in 2030, and it is predicted to achieve its long-term goal of graduating from its ‘least developed country’ status by 2020 . While iRural infrastructure development may bring non-immune people into endemic areas , and incAlthough all 18 provinces of Lao PDR are bordered with GMS countries, the out-migration patterns are not significantly higher near the borders highlighting that geographical proximity of other countries does not seem to be the most crucial factor stimulating out-bound migration . The higThe main network for health care provision remains the public system with government owned and managed provincial and district hospitals and health centers/clinics. At the village level, there are large numbers of village health volunteers (VHVs), members of community health committees, and traditional birth attendants (TBAs). Members of community health committees and village  committees are characterized by various health center management arrangements, health promotion activities, and communicable disease prevention campaigns, and are usually linked with staff from their local health centers.In the period of 2009–2010, there were 53 676 local community members involved in health activities, of whom 14 812 were VHVs, 6 128 were TBAs, 1 222 were traditional healers, and 31 514 were members of village health committees . Since 2In 2012, malaria reporting forms were redesigned to simplify the process and improve the MIS. This resulted in some enhancement in the accuracy and timeliness of reporting due to the introduction of a cloud-based reporting system . In 2015In Champasak, southern Lao PDR, the therapeutic efficacy of artemether/lumefantrine  has been unaffected and cure rates have remained high since 2005. However, a trial conducted in two of the province’s districts in 2013 reported that 22.2% of the patients treated with artemether/lumefantrine were still parasitemic on day 3 after treatment, with the presence of K13 mutations in the circulating parasite population. This confirmed the emergence of artemisinin resistance in southern Lao PDR . These rPlasmodium vivax currently accounts for almost 50% of the malaria cases in southern Lao PDR and ongoing pilot studies in three sites to inform a nationwide introduction of primaquine is expected to be a core strategy to prevent the relapse of P. vivax infections while also acting as a radical cure for P. falciparum. If scaled up nationally, this could be the single most important factor for reducing transmission among returning mobile workers from the south, many of whom have repeated infections in a given year .After a 2005 drug use survey  revealedWhile notable attempts have been made since 2012 by the national program to address coverage of MMPs with LLINs, long-lasting insecticide-treated hammocks (LLIHs), and mosquito repellents, high-risk groups that do not have fixed addresses, families that are newly settled in a village, and forest goers in areas of new settlements are missed during the formal mass distribution. A recent survey in the south of Lao PDR, albeit limited in its sampling, revealed that 82% of MMPs used conventional and hammock untreated nets purchased from the market, while only 16% used LLINs distributed free of charge as part of the program. In addition, 26% preferred using mosquito coils, lotion, or spray repellents . This suThe Laotian military has yet to be fully engaged in terms of malaria prevention and case management despite the fact that it is a high‐risk mobile population. Whilst positive attempts have been made to collaborate and coordinate with the Ministry of Defense (MoD) by the Center for Malariology, Parasitology, and Entomology (CMPE), a systematic programmatic and integrated approach for incorporating the military malaria control program into the national strategy is lacking. Efforts have been made to provide army doctors and medics with up‐to‐date training covering the current national guidelines, case management, prevention strategies, and the provision of insecticides. There is now also mutual interest to explore options around insecticide-treated uniforms and repellents, and establish a memorandum of agreement between MoH and MoD to address the problem of malaria among soldiers, including the sharing of information on malaria morbidity and mortality .Health service provision is constrained by serious weaknesses relating to human resources for health. Key issues include limited numbers of qualified health workers, inappropriate distribution of qualified staff among geographic and health system levels, low and underfunded salaries, lack of incentives , and inadequate reimbursement of costs leading to poor morale and low productivity among staff. Towards the end of 2013, the quota for the health workforce was increased by 4 000 but most of these workers were deployed in cities and urban centers, thus resulting in little support for malaria services in remote areas [Malaria elimination requires skillful staff in health facilities at all levels, however, the facilities that treat malaria currently are understaffed, which compromises the ability of the malaria program to detect and respond to outbreaks. The contrasting epidemiological dynamics between the northern and southern regions with an unequal human resource distribution within the vertical malaria program poses an even greater layer of complexity in being able to efficiently provide protection to the highest risk groups, including forest workers and soldiers .Numerous laws exist to safeguard the health and welfare of workers , 29 inclIn 2009, the government agreed to allow the formation of Lao non-governmental organizations (NGOs). This decision was believed to encourage the creation of a stronger civil society  and to cMember countries committed to adopting the World Health Assembly Resolution WHA68.2 on the WHO Global Technical Strategy for Malaria 2016–2030 and the GMS elimination strategy 2015–2030 in May 2015. The Lao PDR’s 2015–2020 National Strategy for Malaria Control and Elimination outlines the strategies to progressively roll out the elimination of all species of malaria in selected provinces. Lao PDR’s prime minister has also signed the Declaration to Eliminate Malaria by 2030 in the Association of South East Asian Nations (ASEAN) Region at the 9th East Asia Summit. Although the challenges are numerous, the outlook is optimistic if efforts are made on a few critical fronts.Firstly, bolder investment in social sector spending should be geared towards improving health service provision and utilization , ensurinSecondly, although the current population movement to forested areas and development projects is economically and financially driven and cannot be entirely stopped, in parallel with efforts to increase access through innovative strategies considering the mobility patterns and preferred access to health services of MMPs, enforcement of existing regulations should be accelerated to protect the workers and local populations living in these outbreak areas. In the short term, a multisector provincial action plan needs to be developed with the involvement of relevant agencies in agriculture, forestry, labor, energy and mining, as well as local community organizations, local authorities, and the military. A prerogative of the provincial governor should be to mandate all companies and project developers registered with the province to appoint focal point/s for health-related issues. A relook on agreements and in particular the possibility of channeling tax revenues collected from private companies on land use and forestry-related activities towards health-related activities, including malaria control and its elimination, should be explored. The Provincial Health Department, in turn, could ensure all health investment in the province is aligned with a provincial health integration plan. At a higher level, the MoH should create a subcommittee within the National Emerging Infectious Diseases Coordinating Office (NEIDCO) established under the prime minister’s office to oversee local government authorities to support policy and enforcement issues related to private sector project development in the provinces.Thirdly, malaria elimination strategies will require cross-border cooperation with Lao PDR’s neighboring countries. Introduction of bilingual malaria patient cards that contain essential malaria information to be shown at any health care facility supported by SMS or mHealth platforms  will conFourthly, the engagement with the private sector would be essential, especially in the timely and effective implementation of health and environmental impact assessments, with private sector companies engaged in development and extractive industries . This enFifthly, the Lao malaria control program currently largely relies on LLINs and, in cases of outbreaks, indoor residual spray , 3. EvidSixthly, while acknowledging that timely access to malaria information and treatment, and availability of preventive and treatment services is of utmost importance to malaria control and elimination, some interventions need to be specifically tailored to the particular circumstances of these non-homogenous populations. These should factor in pathways of movement, seasonality and timing of departure, transit, and arrival of high‐risk groups including short‐ and long‐term forest workers, their accompanying families, MMPs, and the military. This needs to be done in collaboration with a broader involvement of civil society, local NGOs, and indeed by direct representation of people affected by malaria in in ensuring ‘MMP sensitive’ approaches and interventions are adopted depending on the mobility context and the acceptance of the population


Shibani Pati and Todd Rasmussen summarize progress in preclinical research on cellular therapeutics for traumatic injury and its sequelae and discuss prospects for clinical translation. Trauma is the leading cause of death for individuals between the ages of 1–44 worldwide.–4 There A novel, emerging area of investigation that has generated considerable interest is the potential use of cellular therapies (CT) to prevent secondary injury and promote repair of injured tissue in trauma. Blood trIn recent years, largely spurred by interest and investment from the US military’s trauma injury research program, the field of cellular therapeutics and regenerative medicine has grown rapidly. CT have been investigated preclinically and clinically for applications in trauma. AlthoughA multitude of cell types derived from a variety of tissues are currently under preclinical and clinical investigation for applications in trauma. CT fall into 2 main categories of cell types: adult multipotent cells and pluripotent embryonic stem cells (ESCs). Induced pluripotent stem cells (IPSCs) are a third cell group that are derived from de-differentiated adult cells. Adult muMechanistically, cell-based therapies have been shown to improve outcomes in preclinical studies of trauma-related conditions characterized by uncontrolled inflammation, vascular compromise, and aberrant coagulation: a pathophysiological triad known as the endotheliopathy of trauma (EOT). CT mechanisms of action include the following: (1) producing soluble factors that regulate the EOT  through anti-inflammatory and cell-protective effects , (2) repIdentifying which cohort of trauma patients would most likely benefit from CT and which endpoints are best matched to the mechanism of action defined for the particular cell type under investigation is critical to developing successful clinical trials. In terms of mortality, there are 3 main cohorts of patients defined by time postinjury. In the first 2 hours after injury, approximately 25% of the deaths that occur are secondary to hemorrhage.. There iPreclinical studies in animal models have provided insight on the potential of various CT and their mechanisms of action, but no single model can fully recapitulate the complex heterogeneity of the disease. While research is advancing in multiple areas of clinical investigation, including orthopedic trauma and wound healing , we focuNeurotrauma remains a significant public health concern in both civilian and military populations worldwide. AlthoughSCI involves a myriad of adverse processes that are potential therapeutic targets for CT. These include increased oxidative stress, inflammation, demyelination, blood–spinal cord barrier permeability, increasing cavity lesion size, glial scarring, and decreased neural connectivity.,37 Cell In the category of organ failure, CT using bone marrow–derived MSCs have been investigated extensively for ARDS. ,24,42 PrChallenges remain with regard to the translation of CT into practice. For example, the assessment of which cell types and cell sources are most likely to improve outcomes of severe injury is still in its early stages. Additionally, research and development is needed to characterize different processing methods, doses, route, and timing of administration. Advances in each of these categories are needed to inform the effective design and conduct of clinical studies. Another critical area of development is the reliable production of clinical-grade cells in sufficient quantities for trials and eventual licensure. A fact underscoring the relatively nascent state of clinical work in this area is the absence of a Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved, commercially-derived CT for trauma or critical care medicine, but even if FDA or EMA clearance were to be obtained for any of the MSC-based therapies, current sources of clinical-grade cells would probably not be sufficient to meet demand. Optimal methods to support large-scale cell expansion and processing of the various cell products is still in development. Each cell type requires its own specific conditions for optimal growth, which may also be disease application–dependent.Regulatory challenges also exist for CT. The regulatory roadmap is still under development at European and US regulatory agencies.–48 RegulFinally, adequate and reliable sources of medical research funding are required to support preclinical and human subject research. In the US, some states have started agencies, such as the California Institute of Regenerative Medicine (CIRM), that aim to support regenerative medicine research efforts. The National Institutes of Health (NIH) and the DOD have also embarked on specific endeavors to support foundational, applied, and clinical study of CT for the treatment of trauma-related conditions. Although injury is a leading cause of death and disability in the US, research funding for this condition and investigation of therapies focused on mitigating its impact are low in comparison to the support aimed at cancer and infectious and cardiovascular diseases .Increasing awareness of the promise of CT, and the impossibility of developing a single drug to address the heterogeneous states of trauma and injury, led the DOD to initiate a “state of the science” meeting in 2015 [