The Community Oriented Substance Use Programme (COSUP) is the first publicly funded, community-based programmatic response to the use of illegal substances in South Africa. It is founded on a systems thinking, public health and clinical care harm reduction approach.To describe the critical components, key issues and accomplishments in the initiation and delivery of evidence-based, community-oriented, substance-use health and care services.The Community Oriented Substance Use Programme is implemented by the University of Pretoria in four of seven Tshwane Metropolitan Municipality regions.Quantitative and qualitative data were extracted and triangulated from plans, reports, minutes and other documents.Between 2016 and 2019, COSUP engaged in national and local policy and guidelines development. In Tshwane, it created practical working relations with 169 organisations and institutions and set up 17 service sites. These provide counselling, linkage to care and opioid substitution therapy services to 1513 adults (median age of 30 years), most of whom are male (90%), with similar proportions of clients who smoke (51%) or inject (49%) heroin. It also offers needle and syringe services (approximately 17 000 needles distributed/month) and has built human resource capacity in harm reduction among staff, clients and personnel in partner organisations.The Community Oriented Substance Use Programme offers an evidence-based, public-health informed, feasible alternative to an abstinence-based approach to substance use. However, to translate the programme’s achievements into sustainable outcomes at scale requires health system integration; generalist, patient-centred care; affordable medication in a comprehensive package of harm reduction services; multisectoral partnerships; systematic, continuous capacity development; financial investment; and sustained political commitment. It is the first publicly funded, community-based programmatic response to the use of unregulated drugs in SA. In the last half of 2015, cannabis, heroin, cocaine and methcathinone were the most common primary substances of use among patients registered at substance use treatment centres in Gauteng .5 COSUP is founded on a systems thinking, harm reduction approach to public health and clinical care.6 It seeks to provide a continuum of evidence-based, substance-use services that are integrated into the delivery of community-oriented primary care (COPC).7 The core service package includes physical, mental and substance use screenings, assessments, brief interventions and referrals; harm reduction counselling; opioid substitution therapy (OST)6 The HIV and tuberculosis (TB) screening has been integrated into the package, and viral hepatitis testing is conducted where laboratory services and resources allow. Treatment of HIV, TB and HCV infections is provided in partnership with the available health services.In a significant break with prohibitionist and abstinence-focused assumptions and practices that have yielded poor outcomes,8 Because of this, the programme also has developed and proactively applied a number of processes and organisational measures to counter the moral and political opposition to harm reduction programmes and to engage policy reform.9Like all healthcare interventions that involve novel approaches and new practices and procedures, COSUP engages actively in capacity development. Responses to unregulated drug use are shrouded in prejudice and fear of contagion, as well as ignorance and uncertainty, much like TB in the 19th century and HIV in the twentieth century.10 to designing and implementing the different elements of the programme.The Community Oriented Substance Use Programme was initiated in mid-2016 with the signing of a 3-year service level agreement between the City of Tshwane and the University of Pretoria. Understood as a test of concept, the programme has adopted a staggered start, adaptive planning approachImplementation began with mapping the people and organisations involved in substance use management in Tshwane. Over the 3 years, through workshops, meetings and community forums across the city, COSUP was able to identify potential partners and develop practical working relations with workers and administrators from 169 health, law enforcement, social service, housing, social justice and other organisations and institutions. Essential to the effectiveness of the intervention, this work is ongoing and takes time and effort, not least of all because many participants come schooled in the ‘common sense’ of abstinence and are strongly opposed to harm reduction as an approach to substance use management.Community Oriented Substance Use Programme service sites have been phased in over the 3 years. Seven were set up and running by June 2017. By mid-2019 there were 17 functional and viable sites available to clients in Tshwane. Twelve included drop-in centres that provided access to ablution facilities, nutrition, computers, other psychosocial services and/or safe spaces to socialise.n = 10) operate within or from the premises of non-profit and faith-based organisations. Five sites are in public health facilities. Of these, three are in primary healthcare clinics, one of which is jointly run by the University of Pretoria and two are on hospital premises, where they assist with inpatient care of people with substance use problems in the presence of co-morbidities. The remaining two sites operate in private healthcare practices.The initial idea of setting up sites in public health service facilities proved challenging to realise in many instances. Much like in the early years of HIV treatment provision, space constraints, bureaucracy, stigma and public safety concerns forced COSUP to establish most sites outside the public primary healthcare facilities. The majority , staff supervisors (n = 2) and researchers (n = 3 part-time). Between three and five family physicians and a professional nurse provide clinical oversight and support across the sites. At each site, there is a service team of up to seven staff members, comprising a social worker, a mid-level medical practitioner, clinical associate and one or more peer educators who are recruited from the community of people who use drugs. Some teams also include one or more community health workers (CHWs) who work in the government district health system. Data capturers (n = 10) support several sites. A schematic representation of the staffing is included in The Community Oriented Substance Use Programme project and service teams were created parallel to and during the process of site identification and set-up. The project team ‘Backoffice’ comprises project managers, partner liaison and support staff . To screen for the presence and assess the risks of substance use and to provide linked brief interventions,From the start of service delivery, screening results have been used to select the services offered clients, including brief interventions, risk reduction strategies, support for better practices, self-regulation, OST, individual psychotherapy, harm reduction counselling, practical support, psychosocial group therapy and referral for acute or chronic medical treatment. Testing services for HIV infections were included from the second year of the programme, and people diagnosed with HIV infection were referred to other providers for treatment. The patient management system was initially designed to focus on OST and efforts are ongoing to better capture information around HIV and TB testing and the HIV and TB treatment cascades.The programme helped create 19 community advisory groups to ensure person-centredness, equity and inclusivity. Community advisory groups provide a voluntary forum for staff, clients and other stakeholders to meet to identify and respond to issues and problems that arise from the programme, or the context in which it operates. The purpose and frequency of meetings vary across the sites, as their functionality depends on participant interest and needs.The Community Oriented Substance Use Programme has also responded to endemic social issues arising from homelessness, the need for livelihoods and family conflict and disruption. These all require society-wide interventions and are critical to harm reduction outcomes. Although the programme works with the Tshwane Leadership Foundation, Sediba Hope, the University of Pretoria’s Community Engagement and other partner organisations to secure transitional shelter and develop the skills and work readiness of clients, satisfactorily addressing these issues is beyond the immediate scope of the current programme.8 Although well understood by the programme, there has been a failure to allocate funding for their provision, and system constraints have meant that neither methadone nor buprenorphine, the medications used to treat heroin dependence, are on SA’s Essential Medicines List (EML) for maintenance .11Accessible OST and needle and syringe services are fundamental to the success of the sites, service delivery and effective patient care.The process to obtain methadone on the EML is at an advanced stage and COSUP has been used as the practical example for both the need and the possibility to implement OST at scale.n = 34) through approved reallocation of a limited amount of programme funds. It was also able to provide OST to another 86 who could afford to pay out of pocket. As seen in other South African settings,11 during that year, the unaffordability of methadone led to threefold lower retention among clients who self-funded their treatment compared with those whose treatment was funded by COSUP. There was a general drop-off in engagement with the other services offered to heroin-dependent people at sites. And like elsewhere,12 the out-of-pocket payment cost led to sub-optimal dosing as well as a reduction in the duration and protective benefits against overdosing among those who are able to pay. At the end of the programme’s third year, 5861 people had used a COSUP service at least once. A total of 1513 (26%), mostly male , services users were started on OST. With a median age of 30 years (interquartile range: 26–34), 744 (49.2%) injected and 769 (51.8%) smoked heroin. More than half (57%) of OST clients were retained for at least 6 months. Although this rate is similar to OST retention rates in other low- and middle-income settings, it continues to be adversely influenced by the fact that OST is neither free nor affordable.10 Other factors contributing to loss to follow-up were suboptimal methadone dose, residing outside of the city centre and injecting heroin.In terms of OST, COSUP was granted permission to procure methadone from the private sector in May 2017 and 120 clients were initiated on OST in June. At the cost of approximately R2400 (US$160) per month per person for the recommended dose, COSUP could provide only free OST to a few clients , Lawyers for Human Rights, Tshwane Leadership Foundation, Tshwane District Hospital and the University of Pretoria’s Community Engagement, to address common concerns for safety, security and well-being. The programme has also supported capacity development, especially within law enforcement. Community Oriented Substance Use Programme staff members have proactively sensitised police around the need for harm reduction and developed the police’s understanding of this approach through regular meetings and workshops as well as specific interventions. For example, ‘sports is our gang’ soccer and netball-friendly tournaments provided the opportunity for mixed teams of players from local police stations and COSUP clients to participate in a 2-day competition. At a critical, if more mundane service level, SAPS has started to call on COSUP staff to assist with getting health and care services to people in their custody. Community Oriented Substance Use Programme and its partners engage with SAPS when their programme staff or clients are wrongfully treated, threatened or attacked. Amongst other things, COSUP integrates stigma mitigationIn 2019, to assist the City of Tshwane to fulfil its municipal mandate, COSUP supported the re-establishment of regional drug action committees by helping with planning, monitoring and evaluation of the committees through the development of standard operating procedures and training.The Community Oriented Substance Use Programme is developing #Learning@COSUP. It uses a capability approach through which learning becomes an ongoing process involving clients, families, staff and leadership. The programme began by training doctors, clinical associates, social workers and peers newly recruited into the team. It mobilised available expertise in harm reduction, substance use disorder management, community-orientated primary care and learning. Individual and team competencies were developed and grown over time through work-integrated learning that involved practice, weekly team meetings to review issues in service delivery and capacity development around the meaning of non-stigmatising service delivery and client agency, as well as OST and needle and syringe service provision.Also, the programme provided in situ training for social development, police and healthcare professionals and workers, including doctors, nurses, allied health professionals and CHWs. In the hospital setting this has meant guiding doctors on OST prescribing, training ward staff on harm reduction, the importance of OST provision and adherence, stigmatisation and linkage to care.Apart from the skills provided to clients to manage their substance use more safely, COSUP enabled 800 clients to participate in life skills, work readiness and other skills development programmes offered by partners. About half of those trained were able to find some form of formal, albeit temporary, employment.Through COSUP it has also been possible to support the integration of harm reduction principles and evidence-based substance use treatment services into medical and social worker professional education. At the University of Pretoria undergraduate level, harm reduction and exposure to substance use services are now included in medical student rotations in first, fourth and fifth years as well as in the orientation, ethics and research methods courses of clinical associate and social work students. Identifying, understanding and responding to harmful substance use are also included in postgraduate medical registrar training and are a focus of research for several honour’s, master’s and doctoral students in social work and family medicine.Overall, COSUP has grown the competency base in substance use service delivery by using a harm reduction approach. With more than 3000 student contacts, this intervention has put SA at the forefront of substance use curriculum reform in the region. It has also stimulated growing academic and practical interest in researching and responding to harmful substance use across the academic complex.A summary of COSUP outputs and factors influencing the project is included in BOX 1Summary of Community Oriented Substance Use Programme outputs and factors influencing implementation.Project outputs (2016–2019):Programme implemented in four regions of Tshwane17 sites established, and fostered relationships with 169 organisations, employing 121 people and engaging more than 3000 students19 community advisory groups established5861 people accessed COSUP services and 1513 people initiated onto OST±17 000 needles and syringes distributed monthlyProgress towards integration of a mobile phone application, electronic patient management system and an electronic ASSIST platformInformed national OST guidelines and implementation planCOSUP, Community Oriented Substance Use Programme; OST, opioid substitution therapy.The Community Oriented Substance Use Programme is a harm reduction, community-oriented, primary healthcare, systems approach to substance use. In its short existence, the programme has shown that it is feasible to respond to harmful substance use in a way that improves the health and well-being of people who use drugs, encourages service cooperation around substance use and improves role players’ understanding of the systemic issues that make managing and responding to substance use so complex without the singular focus on abstinence.Implementing COSUP has helped distil critical issues that need addressing to make it sustainable and scalable. Key among these include ensuring:core healthcare service deliverables – system integration and generalist, patient-centred careaffordable medication in a comprehensive package of harm reduction services that includes OST and needle and syringe servicesmultiple partner involvement across services and sectors to meet the many-sided needs of patients, clients, families and communities and to find and share ways of responding cooperatively to inevitable systemic disorder and unpredictabilitysystematic, continuous human resource capacity development in harm reduction and community oriented health and care service deliveryfinancial investment in a harm reduction programmatic response to substance usesustained political commitment so that the investment is realised in positive health and social outcomesclear and significant change from the war on drugs towards a human rights approach including diversion programmes from the law-enforcing sector.


Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment. Bone and muscle are both tissues of mesodermal origin that together with joints constitute the musculoskeletal functional unit to facilitate the locomotion of the organism, which is guided by the central nervous system and the neuronal networks and their neuromuscular junctions. Both tissues provide a highly flexible system of adaptation as a response to the variability of physical forces generated through gravity and environmental conditions. This influences tissue structures from development throughout adult life using similar principles of both tissue formation and repair/regeneration. Evolution has provided multiple pathways for the mutual interaction of muscle and bone in order to adapt the stability of the skeleton and muscle to the forces needed for locomotion and environmental challenges. Recent information indicates that the reciprocity of mechanochemical interaction is extremely dynamic, including the cellular, the tissue, and the organismic level ,2,3,4. IIn pathology and in aging, accumulating cell and tissue damage can alter the delicate balance of adaptive maintenance and regeneration and may cause disease and degenerative conditions. This review summarizes knowledge about the principles of mutual interactions of muscle and bone, where physics and biochemistry/cell biology get integrated and adjust to each other according to environmental needs. It also highlights the common effectors of these interactions and the secondary response, which sustains a dynamic reciprocity of adaptation. Connective tissues physically joining muscle and bone, especially tendons and ligaments, naturally play a critical role in this interaction, as addressed in a recent review article in detail .Due to gravity on earth, organisms must adapt their constitution to extrinsic physical forces from the beginning. Mobile forms of life in addition generate intrinsic forces when moving. Human beings developed the capacity of locomotion during evolution and adapted to the daily needs for hunting and gathering, which required climbing trees and hills but also running on plain territory. In modern societies, exercise and sports have largely replaced the ancient motivations of locomotion. The physical forces generated in the context of motion are extremely variable from very low to high impact. The variability of impact on the different levels of cell/cell, cell/tissue, and tissue/tissue interaction ranges from 0.1 to 100 kPa from development to adult life and produces a complex interactive network of physics and biochemistry involving both muscle and bone ,6,7,8.Mechanical stimuli can be transmitted through deformation (stretching and compression) and/or shear strain applied by fluids that pass by. The former prevail in muscle while bone strongly (but not exclusively) responds to fluid flow in the osteocyte canalicular network . MechanoThe physical mechanisms of applying mechanical forces on living organisms such as gravity and active muscle contraction have recently been complemented by technically applied forces generated by external vibrations of different amplitudes and frequencies. Two different modes of operation exist: one type of vibration plates uses the alternating vibration, which provokes reactive muscle contractions up to around 30 Hz with variable amplitudes. The other device type applies low-amplitude/high-frequency vibration without alternation. Both types of machines have been introduced commercially and partly ahead of scientific evaluation. However, the evidence-based knowledge has been increased during the last decade. There is no doubt that external mechanical vibration may variably substitute for gravity and add up to active muscle contraction both in space missions and as dedicated types of exercise. Vibration certainly can also elicit cellular responses, which may be beneficial in terms of inducing and maintaining muscle hypertrophy and elevated bone mass under conditions of disuse or unloading in simulated microgravity ,13,14. NAt the cellular level, the reciprocity of continuous challenge and adaptation has provoked the statement that “virtually every step of cell and tissue biology depends upon mechanochemical events” as made by researchers who mainly deal with principles of cell migration . The lasCellular deformations induce adaptive signaling that provides adequate function, fulfilling the actual environmental needs/challenges. ,24,25,26Mechanotransduction even involves the nuclear envelope and nuclear pore structures as an upcoming new field of mechanobiological coupling, where deformations are followed by changes in the passage of molecules in and out of the nucleus and also changes in chromatin packing and architecture ,31. A reMany molecular mechanisms of mechanosensing and mechanotransduction are common pathways for muscle and bone. Focal adhesion kinases, integrin-related adhesion, or Hippo/Yap/Taz signaling (Yes-associated protein (YAP); transcriptional coactivator with PDZ-binding motif (TAZ)) are just a few examples that recently have been characterized ,33. SpecCaenorhabditis elegans degenerins and the mammalian epithelial Na+ channels), transient receptor potential (TRP) channels, L-type (osteoblasts) and T-type (osteocytes) voltage sensitive calcium channels (VSCC), Annexin V voltage-gated calcium channels (VGCC), and Piezo-type mechanosensitive ion channel component (Piezo 1 and 2). Mechanical stimulation enhances calcium flux into the cell , the cytoskeleton, lipid rafts, ion channels, and in addition by the primary cilium. With slight variability concerning differential channel expression, virtually all bone cells express the necessary tools, including the primary cilium. The evidence for the relevance of fluid flow and deflection of primary cilia comes from in vitro studies but also from knockout (KO) mouse experiments that impair primary cilia development, but there is still some debate about the contributions and their molecular mechanisms related to primary cilia in mechanotransduction elicited by fluid flow ,37,38,39iewed in ), and thmothers against decapentaplegic”) as a means of mechanotransduction is also related to the cilium, since the receptor BMPIIR is located at the basal body of the cilium, and activated BMP signaling can be blocked by abolishing cilium expression. In bone, the primary cilium appears to be an important mediator of gravity and consecutive osteogenic response, because in simulated microgravity, the cilium gradually shrinks and inhibition of this shrinkage using cytochalasin D maintains osteoblast differentiation capacity (reviewed in [The primary cilium is a unique subcellular organelle composed of nine (+0) axonema structures B. It cariewed in ). In musiewed in .The downstream molecular mechanisms for signal transduction after sensing mechanical stress via the primary cilium are very much in analogy to the molecular mechanisms induced by deformation strain. On the other hand, the internal space of the cilium appears to be a separate and regulated space that sends and receives its own signals. These are mediated by the second messenger signals as well as polypeptide phosphorylation cascades, and the cilium receives and sends vesicles along a tubulin-related trafficking pathway toward the nucleus ,22,43,44Mechanisms of mechanotransduction show vivid cross-talk with each other on their way to the nucleus and induce changes in the activation and nucleotropy of transcription factors. Consecutively transcription factor (TF)-responsive DNA elements and promoter regions get activated to modulate gene transcription that may be called “mechanoresponsive”, because the nucleotropy of respective TFs responds to strain and/or fluid flow. Such mechanoresponsive elements and promoter constructs have been analyzed and characterized by promoter bashing experiments using reporter gene constructs under the control of the iterative deletion of promoter sequences. Using cyclic stretching experiments, we investigated the mechanoresponse of the promoter of the matricellular growth factor cysteine-rich angiogenic inducer 61 (CYR61/CCN1) in human telomerase-immortalized mesenchymal stem cells . Others Besides communication via physical forces/mechanosensing/adaptation mechanisms, the systemic humoral organ communication is one more classical way to interact. Secreted proteins and signaling molecules are the basis of mutual interaction between muscle and bone both in a paracrine and also an endocrine setting. This involves also other organ systems such as the central nervous system, metabolism, and putatively the whole organism. Complex interaction patterns integrate muscle and bone into such organismic interactions that still need to be unraveled in the sense of a systems biology network analysis.Secreted cell and tissue products mediate autoregulation as well as paracrine and endocrine communication between cells, tissues, and organs. A considerable part of secretory products forms the ECM and associated matricellular factors, whose adaptation is part of the mechanochemical coupling process.Secreted products from muscle have been named myokines or exerkines (when stimulated by exercise), while products derived from bone have been called osteokines, (osteo)blastokines, or (osteo)clastokines in analogy to cytokines. Many of these products are members of huge cytokine families, but also, other growth and differentiation factors may transmit signals between muscle and bone. They are mainly related to tissue regeneration and modeling/remodeling but they also represent mediators of important metabolic functions ,60,61,62Ions and non-peptide small molecule signaling systems often supply the microenvironment to regulate intercellular communication. Prominent examples involved in tissue regeneration and mechanosensing/mechanotransduction in bone and muscle are prostaglandins, NO, sphingosines, and ATP, and its dephosphorylation-related products that fuel into purinergic signaling. Physical forces through muscular activity or vibration induce the cellular secretion of ATP and sphingosines, which are tightly involved in osteoblast, osteoclast, and osteocyte activity ,63,64,65Both muscle and bone have recently been referred to as “endocrine organs” in several publications and reviews. In general, the secretion of polypeptides can follow the constitutive secretory pathway (CSP) or the regulated secretory pathway (RSP). While the former requires secretory signal peptide sequences, classical endocrine signaling requires the production of large secretory vesicles packed with preformed protein and the rapid release upon defined signals ,51 FiguC. There Recently, extracellular vesicles (EVs) have been described as important mediators of mutual interactions both in the microenvironment and at a distance. EVs are fundamentally different from secretory vesicles that carry hormones and are involved in endocrine regulatory networks C. EVs caBone-specific secreted products can influence the formation, maintenance, and regeneration of muscle and other tissues. Many bone regulating signal transducers such as transforming growth factor β (TGFβ) and the ligands of the wnt pathway are usually thought to act more locally, but wnt3a can influence myoblast differentiation and might also act at a certain distance  The mostOsteocalcin  is a γ-carboxylated product of osteoblasts involved in bone mineralization and metabolic control, but also in brain development and male fertility. The degree of vitamin K-dependent γ-carboxylation of osteocalcin determines its activity in insulin sensitizing and muscular glucose uptake, where undercarboxylated or uncarboxylated osteocalcin is the most active. The injection of uncarboxylated osteocalcin in mice rescued their exercise capacity and rescued the age-associated loss of muscle mass (reviewed in . G proteSclerostin (SOST) is a very potent inhibitor of osteogenic wnt signaling and appears to be rather specific to osteocytes. Recent evidence links high SOST serum levels in Korean sarcopenic women with appendicular skeletal muscle mass . ExercisGlucocorticoids (GC) might be a common and potentially pathologic regulatory link between muscle and bone regeneration, since FGF-2 rescues both the deleterious effects of GC on myostatin and SOST expression . MembersHypoxia may increase the amounts of vesicles released. Various signaling compounds may also influence the respective niches of osteocytes and myocytes in response to mechanical cues, and such paracrine effects can also be transduced via vesicle fusion ,60,61,86Focusing on muscle secretory products, Bente Pedersen and her group were the first to thoroughly describe IL-6 as a putative endocrine product of muscle in response to exercise (reviewed in ) as wellThe constitutive secretome of muscle (and bone cells) represents the integrated response to mechanical strain and systemic modulators. Due to less invasive accessibility, we have more information on muscle tissue compared to bone, at least in humans. Studies exploiting muscle biopsies ahead and after exercise found an enhanced transcription of characteristic target genes. The resulting changes of muscle secretomes induced by exercise occur with a decent delay to allow de novo protein synthesis, inducing a moderately fast adaptation and (re)modeling response. One example is the immediate rise of muscle insulin-like growth factor 1 (IGF-1) mRNA after an exercise bout and the significant rise of peripheral blood IGF-1 protein levels after 24 h (not yet significant after 2 h) post exercise, which was gone after 48 h . IGF-1 aSeminal work on the muscle cell secretory transcriptome and proteome was published in 2012 by Le Bihan et al. and Terry et al ,90 ThreeThere is evidence from genome-wide association studies that pleiotropic genes may both regulate bone and muscle homoeostasis as recently reviewed . Both poGoing back to a shared developmental origin of muscle and bone, many parallels can be found in effector mechanisms driving tissue maintenance and regeneration respectively, as discussed in the following sections.Muscle and bone are derived from common precursors during development, indicating a close relationship and interaction. Mesoderm (from ancient Greek μεσοσ and δερμα “between the skin”) develops from the epithelial germ layers via epithelial–mesenchymal transition (EMT), where cells disengage from tightly adherent tissue assemblies, acquire migratory capacity, and give rise to what is histologically called “mesenchyme”. This population of embryonic cells is ill-defined in terms of stemness and multipotency, but there is high plausibility that these precursors can give rise to any mesenchyme-derived tissue type including e.g., bone, cartilage, muscle, tendon, ligament, and fat tissue ,99,100. When acquiring migratory capacity, mesenchyme-derived cells sense forces, respond to forces, and generate forces. The dynamic plasticity of adhesion systems and the developing cytoskeleton enables cells to migrate and provides mechanochemical interactions already at the cell–cell and cell–tissue interaction level, creating extremely complex interaction patterns ,106.Joint structures as important features of the musculoskeletal functional unit develop under the influence of respective core signaling cascades of osteogenic, chondrogenic, and ligamentogenic pathways. This process is fundamentally influenced by mechanical forces already in utero, directed by movement of the fetus ,101. In In conclusion, there is convincing evidence that during development, the interaction between physics and biology is boosted by EMT and the acquisition of migratory capacity, and every step of interaction causes and supports biological consequences in terms of lineage commitment and maturation. This early interaction via physical forces is certainly accompanied by humoral interactions; however, these are only partially unraveled in these early stages of development.As discussed above, already very early in in skeletal development, there is evidence for an important role of mechanical forces in addition to other physical cues and soluble morphogens in controlling cellular fate determinations, patterning, and tissue development ,46,110. Bone formation or modeling can be induced de novo in adult organisms by changing the impact of physical forces in everyday life such as changes of muscle forces exerted by exercise-induced hypertrophy or by changes in body weight. Modeling describes the  independent activity of osteoblasts without or with only minimal osteoclast resorptive activity, just adding more mineralized tissue in response to e.g., physical forces through strain and fluid flow. The molecular cascade that follows high-impact strain to bone obviously resembles endochondral bone formation .Almost any osteogenic pathway can be modulated by mechanical stimuli. Above all, the PTH1R signaling cascade is especially sensitive to mechanical loading. Anabolic PTH1R signals elicited through bone anabolic treatment using intermittent 1-34 PTH (teriparatide) are almost ineffective under conditions of unloading . BesidesBone formation and bone resorption are both part of the adaptive refinement and remodeling processes, which are mechanically guided and where both osteoblasts and osteoclasts respond to physical forces ,118. CouNext to mechanical stimuli, early bone regeneration is also associated with the secretion of proinflammatory factors showing again many parallels to the muscle regeneration mechanisms discussed below. It is supported by a proinflammatory reaction initiated by platelets in case of injury (platelet-derived growth factor (PDGF) and cytokine signaling) and/or by TLR 2 and 4 and their ligands such as SAA1 and SAA2 or cell fragments and DNA. This initiates a cascade of cytokines involving e.g., IL-1, IL-6, IL-8, and other proinflammatory polypeptides as well as Wnt5A as part of the non-canonical osteogenic Wnt pathway  derive from. The orchestrating network transcription factor is paired box gene 3 (Pax3), which is the core transcription factor that initiates myogenic signaling through the family of myogenic regulatory factors (MRF), which includes MyoD, myogenin, Myf5, and MRF4. The complex myogenic differentiation process is also co-regulated by in part very specific miRNAs. Specific reviews on this process have recently been published elsewhere, but some important aspects shall be recalled in the context of muscle and bone interaction ,129,130.Very much in analogy with bone and probably many other tissues, the initial phase of regeneration is governed by intrinsic inflammatory signals and is further induced by cells of the innate immune system, e.g. sequentially recruited neutrophils and resident macrophages. Cytokines already known from bone regeneration such as IL-1, 6, and 8 are involved in innate immune cell recruitment until the secretion of anti-inflammatory cytokines such as IL-10 and TGFβ1 introduce the anti-inflammatory phase of regeneration where tissue resident macrophages become important ,133.Notch signaling is also a crucial pathway for postnatal muscle regeneration. Muscle fibers express Notch receptors and their ligands, Delta-like ligand  and Jagged . Notch signaling in muscle follows the classical way of binding of ligand to the receptor, the intracellular cleavage of Notch by ADAM and γ-Secretase proteases, and the release of Notch intracellular domain (NICD) to the nucleus. After nuclear translocation, NICD binds the repressor RBPJ , which is active in chromatin remodeling. Upon binding to NICD, RBPJ recruits chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins. As a consequence of the resulting derepression, downstream Notch target genes are activated such as the transcription factors HeyL, Hes1, and Hesr1/3. This appears to be also relevant in the context of the involvement of epigenetic events where Notch signaling possibly provides links to these important upcoming fields see . The relSatellite cells, located between the basement membrane and plasmalemma of the muscle fiber, are the principal muscle stem cells that organize muscle regeneration after injury. However, there are some other populations that substantially contribute to regeneration such as the Sca1+/CD34+ fibro-adipogenic progenitors (FAPs) residing in the muscle interstitium. Following injury, satellite cells re-enter the cell cycle and proliferate to give rise to myoblasts that differentiate and fuse to restore the damaged fiber or generate myofibers de novo, while FAPs support their amplification and fusion. Pharmacological inhibition of the latter impairs their regeneration efficiency. FAPs also harbor fibroblast differentiation capacity that in pathology may contribute to fibrosis and degeneration . RecentlOverall, very much in analogy to bone regeneration, also muscle regeneration starts with an inflammatory reaction that activates the myofiber-specific amplification and differentiation process and ends up in tissue remodeling according to mechanical challenge. A condition described as fatty infiltration or degeneration in muscle through disuse and chronic inflammatory processes represents an important feature in pathology to further unravel and target also pathological interactions between both tissues and their respective mechanisms of maintenance and remodeling see also .Cells of both the innate and the adaptive immune system are intricately involved in the efficient regeneration in both muscle and bone ,137.Restorative macrophages even orchestrate the interaction between myogenic cells and endothelial precursors during muscle regeneration. Interestingly, the main signaling molecules involved were apelin (APLN), oncostatin M (OSM), and periostin (POSTN), which are also important for bone regeneration . In addiEndothelial cells (EC) are essential for tissue regeneration. For bone, it has been demonstrated that endothelial specification strongly contributes to microarchitectural structures—for example, cortical versus trabecular bone. Moreover, there is again an important contribution of Notch signaling since the process of endothelium specification and its mutual interaction with osteogenesis is Notch dependent ,149,150.Overall, tissue regeneration appears to be a teamwork that requires the interactions of several cell populations including tissue-specific precursors, immune cells, and endothelial precursors, whereby also the latter seem to be tissue specific, and this applies to both muscle and bone .Epigenetic changes are part of the physiological tissue responses on mechanical stimulation and pathology, but they may also fundamentally change and often impair the response patterns. The general feature of epigenetic regulation, the regulation of DNA domain accessibility for transcription factors (TFs), is shaped by high-order chromatin interactions. However, some recent observations indicate that some TFs actively contribute to the modeling of DNA architecture, as it was reported for MyoD. This TF can obviously change nuclear architecture to dominantly set up the muscle cell differentiation program even in a preformed environment through cooperation with the architectural protein CTCF (CCCTC-binding factor) . IntriguIn conclusion, there are basically two systems to mutually communicate between muscle and bone where physics and biochemistry meet. Physical forces exerted by physical load, muscle activity (contraction and relaxation), and fluid flow are translated into biochemical signals and the biology of cells and tissues. The primary biological response to physical cues changes the receiving biological system, and in consequence, the secondary response is different until homeostasis is achieved, while decreasing physical challenge causes tissue degradation in both compartments. This is the basis for a continuum of reciprocity that is even more complex, since cells and organisms can generate resistive and propulsive forces, especially in the context of migration and locomotion. A highly complex but also very economic system of adaptation models the living organism according to environmental changes. Having said this, it becomes evident that the same regulatory mechanisms are very sensitive to malfunction and the development of disease if the conditions of life are rapidly escaping millions of years of evolution and are rapidly changing such as “unnecessarily” long life spans or an exuberance of nutrients without the necessity of moving for their retrieval. It is not possible to provide an in-depth review of any pathology in the context of muscle and bone interaction, but the following two sections will look at two aspects of interaction that appear to be important in the context of development of osteoporosis and sarcopenia, namely chronic inflammation and unloading.Muscle and bone in concerted action with joint and ligament structures represent the musculoskeletal functional unit. Many disease entities point toward a strong interaction of the formation, maintenance, and remodeling of all components through the interaction of individual pathologies. Single component diseases are widespread, as it is the case for osteoporosis, sarcopenia, osteoarthritis, and degenerative tendon disease. It is beyond the scope of this review to describe all aspects of interaction. When focusing on muscle and bone, the most obvious mechanisms that trigger diseases in both compartments are unloading and chronic inflammation, which will be discussed in the following sections for translational perspectives.Disuse in the sense of low mobility-related or mechanical unloading is discussed as one of the most predominant problems in modern societies, although in young people, such effects are not (yet) found to be very prominent ,165. YetChronic inflammation can be both a cause and consequence of disuse and atrophy in muscle and bone. It impairs mechanotransduction and triggers the production of inhibitors of regeneration in both compartments, namely myostatin, activin, SOST, and DKK-1 under various clinical conditions. Apart from chronic inflammatory rheumatic and intestinal diseases, so-called subclinical inflammation is also a driver of tissue-related “inflammaging”. This form of inflammation can seriously impair tissue regeneration on several levels and in several segments. While inflammation is an essential part of the initial phase of tissue regeneration, the failure of timely resolution through anti-inflammatory cytokines is key for these roadblocks and it also drives aging and the manifestations of an inflammatory senescence-associated phenotype (SASP) ,109,177.Dual x-ray absorptiometry (DXA) and bioimpedance analysis (BIA) are widely and easy-to-use techniques to quantify body composition . The forIn clinical routine, the preferred method is semi-quantitative assessment of muscle and adipose tissue area or volume from T1 weighted MR images, which show very good contrast between these two tissues see .With MR Dixon sequences that generate so-called fat and water fraction images  bottom , the fatComputed tomography is an alternative 3D modality for muscle imaging . SimilarCurrently, there are no guidelines by which imaging parameter(s) should be quantified to address a given muscle composition question. For example, whether IMAT or muscle FF are more sensitive, parameters or whether the FF of all or of specific muscles should be measured. In the context of osteoporosis muscles, in addition to the thigh and hip region, paraspinal muscles are of great interest in order to describe the muscular compartments around bones affected by so-called major osteoporotic fractures. Comparative studies are still missing.The concept of bone muscle interaction should have an impact on osteoporotic fracture. In men, a decrease in subcutaneous fat thickness increased hip fracture risk independent of area bone mineral density (BMD) , but in Interestingly, the combination of soft tissue parameters discriminated hip fractures as well as a combination of trabecular BMD and cortical thickness, documenting a strong interaction between muscle and bone structure using fatty infiltration and other soft tissue architectural parameters as surrogate parameters. The multimodality imaging of CT and MR or the combination of different MR sequences including the integration of T2 imaging for the quantification of inflammation along with the development of sophisticated image processing and analysis techniques will further advance our understanding of muscle composition as surrogates for actual power and fatty infiltration-based inflammatory activity and their impact on bone density, architecture, and fracture resistance.Muscle and bone interact in order to provide adaptive modeling and remodeling mechanisms in an environment that is physically challenging. Both tissues sense mechanical strain, transduce biochemical signals in response, and mutually influence the respective tissue architecture to balance muscle power and fracture resistance. Ongoing intense research activity dissects the molecular mechanisms that transform physics into biochemistry and cell biology. It is physical strain that strongly modulates the biology of cells along their lineage commitment and maturation as well as the hypertrophy versus atrophy of tissues according to physical challenge. Physical strain is transformed into a multitude of biochemical signals that causes modeling or remodeling until a new state of homeostasis is reached as long as the physical input remains in a steady state. Decreasing physical input leads to muscle atrophy and bone loss, as is most impressively documented under zero-G in space missions. We are beginning to understand the mechanisms of regulation, but we do not yet exactly know where the borders to pathology begin, which stimulus hurts cells, and which one stimulates adaptive remodeling. We need more research in this area to define the borders between benefit and harm both in everyday life and in sports activities. Backflashes from unusual unloading situations as well as from pathologic inhibitory conditions such as those in chronic inflammation indicate that deficient mechanotransduction is both a driver and a consequence of degenerative diseases such as osteoporosis, sarcopenia, and chronic degenerative tendon conditions. Continuous adaptive remodeling appears to be the key to delay aging-associated degeneration; hence, exercise and locomotion in concerted interaction between muscle and bone are core phenomena of health maintenance in higher organisms. Epigenetics is strongly involved in aging phenomena, and recent research indicates that both positive exercise and training effects and also exercise resistance and degeneration can be modulated by epigenetic mechanisms. As we get older, such conditions prevail and the dissection of the molecular mechanisms behind will allow for more targeted prevention and intervention in the future.


The North American Mitochondrial Disease Consortium (NAMDC) comprises a network of 17 clinical centers with a mission to conduct translational research on mitochondrial diseases. NAMDC is a part of the Rare Disease Clinical Research Network (RDCRN) and is funded by the National Institutes of Health. To foster its mission, NAMDC has implemented a comprehensive Mitochondrial Disease Clinical Registry (hereafter NAMDC Registry), collected biosamples deposited into the NAMDC Biorepository, defined phenotypes and genotypes of specific disorders, collected natural history data, identified outcome measures, characterized safety and long-term toxicity and efficacy of promising therapies, and trained young investigators interested in patient-oriented research in mitochondrial disease.www.umdf.org). All clinical research in NAMDC depends on the participation of mitochondrial disease patients. Since individual mitochondrial disorders are often extremely rare, major communication and recruitment efforts are required. Therefore, NAMDC has forged a very close partnership with the premier patient advocacy group for mitochondrial diseases in North America, the United Mitochondrial Disease Foundation (UMDF).Research conducted by NAMDC is built on the foundation of the Clinical Registry. Data within the registry are encrypted and maintained in a centralized database at Columbia University Medical Center. In addition to clinical data, NAMDC has established a mitochondrial disease biorepository, collecting DNA, plasma, cell, and tissue samples. Specimens are assigned coded identifiers in compliance with all relevant regulatory entities and with emerging NIH guidelines for biorepositories. NAMDC funds two pilot projects each year. Pilot grants are small grants typically supporting an early stage concept to obtain preliminary data. Pilot grants must enhance and address major issues in mitochondrial medicine and specific areas of need for the field and for the successful outcome of NAMDC. The grant selection process is facilitated by input from multiple stakeholders including patient organizations and the strategic leadership of NAMDC. To train new mitochondrial disease investigators, NAMDC has established a Fellowship Program which offers a unique training opportunity to senior postdoctoral clinical fellows. The fellowship includes a 6-month period of intensive training in clinical trial methodology through the Clinical Research Enhancement through Supplemental Training program and equivalent programs at the other sites, along with rotations up to 3 months each to two additional consortium sites where a rich and varied training experience is provided. Nine core educational sites participate in this training program, each offering a summer grant program in mitochondrial medicine funded by our NAMDC partner the United Mitochondrial Disease Foundation (www.namdc.org), a NAMDC biorepository housed at the Mayo Clinic in Rochester, MN, and essential diagnostic guidelines for consensus research. In addition, eight clinical studies have been initiated and the NAMDC fellowship program has been actively training the next generation of mitochondrial disease clinical investigators, of which six have completed the program and remain actively involved in mitochondrial disease research.The NAMDC Registry has confirmed the clinical and genetical heterogeneity of mitochondrial diseases due to primary mutations in mitochondrial DNA or nuclear DNA. During the 8 years of this NIH-U54 grant, this consortium, acting in close collaboration with a patient advocacy group, the UMDF, has effectively addressed these complex diseases. NAMDC has expanded a powerful patient registry with more than 1600 patients enrolled to date, a website for education and recruitment of patients (The NAMDC Patient Registry and Biorepository is actively facilitating mitochondrial disease research, and accelerating progress in the understanding and treatment of mitochondrial diseases. Mitochondrial diseases due to OxPhos defects and caused by mutations in either the mitochondrial or the nuclear genome are an exceptionally heterogeneous group of disorders. Some are confined to the central or peripheral nervous system  but most are multisystemic. Although clinical severity varies, often within families or within cohorts of patients harboring the same pathogenic mutation, by and large these are progressive and often crippling disorders, causing weakness, exercise intolerance, fatigue, ataxia, seizures, mental retardation, dementia, hearing loss, blindness, parkinsonism, strokes, peripheral neuropathies, and premature death. Because of the clinical heterogeneity and the frequent multisystemic involvement, mitochondrial diseases present formidable diagnostic challenges. When accurately diagnosed, they pose even more formidable therapeutic difficulties, as there are very few disease-modifying therapies, and symptomatic therapies, often only anecdotally reported, and are only partially effective.There is a vibrant international research community engaged in the study of the mechanisms and clinical characterization of mitochondrial diseases and the search for better treatments. However, since there is a large number of distinct mitochondrial diseases, each with relatively low incidence, it has been difficult to assemble sufficiently large datasets or patient groups for research studies and clinical trials.The North American Mitochondrial Disease Consortium (NAMDC) was established to create a network of clinicians and clinical investigators in North America who follow sizeable numbers of patients with mitochondrial diseases and are interested in mitochondrial research. These “centers of excellence” collaborate with each other and with participating patients to collect vital information and conduct research on mitochondrial diseases. At present, NAMDC is collaborating with some of the leading researchers within the mitochondrial community at 17 academic institutions in United States and Canada .By allowing researchers to aggregate patient data and biological samples from across all member sites, NAMDC eases some of the difficulties associated with studying these rare and diverse diseases. NAMDC is facilitating a number of clinical trials and natural history studies that would otherwise not be feasible due to insufficient sample size.To join NAMDC, clinical investigators with expertise in mitochondrial diseases are required to submit an official request to the consortium’s Principal Investigator and Program Manager explaining how the new site will enhance the ability of the consortium to meet its goals and the commitment to comply will all data standards and study accountability as outlined in the RDRN Policies, Procedures, and Standards. The NAMDC Executive Committee then reviews the request and, if it is approved, forwards it to the Rare Disease Clinical Research Network (RDCRN) Board for final approval. At a minimum, NAMDC sites are required to fully participate in our Registry and Biorepository recruitment; to participate in other consortium activities, including monthly NAMDC and NAMDC Fellowship meetings; and to agree to abide by our research requirements and compliance goals.To collect information about the wide spectrum of mitochondrial diseases, NAMDC has designed and implemented a comprehensive NAMDC Mitochondrial Disease Clinical Registry that gathers baseline clinical, biochemical, and molecular genetic data and tracks the natural histories of the patients through the NAMDC Clinical Longitudinal study. All data in the NAMDC Registry are handled in a strictly confidential manner. All data are stored in encrypted databases, and all communications of data are password-protected and encrypted. Patient identifiers are stored separately from clinical data and are made available only to authorized users.www.namdc.org) provides a patient-friendly platform that includes passcode access, online screening, electronic consent, and data capture for enrollment of eligible patients who reside far from any of the NAMDC participating sites and/or have difficulties traveling to the sites due to their disabilities.Patient enrollment may occur in person at one of the NAMDC member sites or through the Remote Recruitment program streamlined through the NAMDC Clinical Coordinating Center at Columbia University. The web-based remote enrollment  Core in Rochester, Minnesota. Participation in the Biorepository is optional.The NAMDC Clinical Registry, Research Diagnostic Criteria, and Biorepository are three pillars that form a strong foundation for multi-center collaborative mitochondrial disease research. The NAMDC registry includes a data-mining tool to facilitate access to de-identified data among NAMDC investigators as well as a consortium-style Master Service Agreement that allows transfer of de-identified biosamples among NAMDC sites, and to other external entities upon the appropriate approval.The Pilot Project Program is an important component of NAMDC, and supports 1–2 pilot projects annually. NAMDC pilot projects focus on biomarkers, diagnosis, natural history, and treatment of mitochondrial diseases. Thus, projects must be human subject studies, i.e., include patients, human cells, tissues, or body fluid samples. Pilot grants are often a first step for junior investigators, for whom the grant application is frequently the first formal funding application. The Pilot Core provides multiple mentoring steps for junior investigators including feedback on initial proposals , throughout the grant development process, and during project implementation. Mentoring is done by the NAMDC PI, Statistical PI, Pilot Core PI, local site PI, NAMDC Clinical Liaison, and additional collaborators as needed.The NAMDC Pilot Program Committee is responsible for reviewing the pilot/new project proposals. Applicants for Pilot Projects must be NAMDC members. The NAMDC Pilot Project Committee recommends funding decisions that best meet the needs and priorities of the consortium and encourage its growth. Selection for funding is based upon information from written peer review and from the NAMDC PIs following oral presentation at the annual Face-to-Face meeting. Following the recommendation by the Pilot Program Committee, the NAMDC Executive Committee makes the ultimate decision as to what pilot/new projects are funded with input from the RDCRN and approval from the NIH officers. Multicenter studies are prioritized over single-site study projects. Applicants apply for funding for projects that occur during the 12-month window of the NAMDC yearly cycle of NIH funding. This means that applicants apply for projects that will be carried out from 1 September to 31 August of the following year. Grantees are expected to submit a brief quarterly report, a preliminary report presentation at the annual Face-to-Face meeting, and a final report within two months of the conclusion of the grant.There is a severe shortage of physicians trained to diagnose and treat pediatric and adult patients with mitochondrial disease. The NAMDC Career Enhancement Program is designed to provide training in rare disease with a focus on mitochondrial medicine. The program consists of the following components:The NAMDC Fellowship Program, which offers a unique training opportunity to senior postdoctoral clinical fellows to move on to the attending/assistant professor level in an academic setting as well-trained clinician scientists. The focus is on translational medicine, teaching of diagnostic expertise, and the development of clinical trials expertise. NAMDC aims to train the first of a new generation of clinician scientists who will be well equipped to move promising new treatments for mitochondrial disease into the clinical arena. Nine training sites are collaborating in this program. These sites - Columbia, San Diego, Seattle, Cleveland, Hamilton, CHOP, Baylor, University of Colorado, and Mayo Clinic - are all leading institutions in the field of mitochondrial medicine. World-renowned faculty are to be found at each site. Fellows participate in RDCRN training courses where they present a summary of their work.The fellowship program is unified by telemedicine conferences led by the NAMDC Career Enhancement PI and involves all consortium sites with monthly video webinar conferencing. These conferences are well attended by faculty, students, and NIH representatives. RDCRN trainees are also invited to participate.A Career Enhancement program is being developed to include: (1) a didactic core lecture series on Clinical Trial readiness to be available as an online lecture series; (2) the directors of the 10 Career Enhancement Sites to post a comprehensive series of lectures on management of mitochondrial disease; and (3) the Mitochondrial Medicine Society to develop a series of organ-specific mitochondrial disease lectures to be CME-certified by the United Mitochondrial Disease Foundation (UMDF) and made available online.Funds provided by the UMDF will be used to attract young physicians, medical students, MD/PhD students, and recent graduates heading to medical school and the field of mitochondrial medicine. A committee of Site Directors and UMDF grant reviewers will review proposals. In addition, an annual retreat will take place on the day following the UMDF annual meeting where the awardees and the NAMDC fellow can interact with and present their work to the Site Directors.etc.), set the long-term strategic goals for the Consortium, and define the terms and rules by which the Consortium interacts with outside entities .The Administrative Core of NAMDC provides critical organizational and strategic support to assure the overall success of the Program in accordance with NIH RDCRN program objectives. As the central hub and coordinating center for all NAMDC projects, the Administrative Core manages the interactions between multiple academic departments and between the Consortium and external organizations and institutions. The Core has an Overall Program Director/Principal Investigator, a Statistical Principal Investigator, a Clinical Team Liaison, a Bioinformatician, and an Administrative Coordinator, with ultimate responsibility for the Program’s scientific, clinical research, and training/educational operations. The NAMDC Executive Committee (EC) consists of these individuals plus the Chairs of the seven NAMDC Standing Committees , two NIH Representatives, and one Patient Advocacy Group representative. The EC meets regularly to assess the progress of NAMDC programs  recently expanded for remote enrollment in Latin America (www.namdc.org/sp); and (3) an external website coordinated with RDCRN to publicly communicate NAMDC’s mission and the availability of training opportunities and core services (https://www.rarediseasesnetwork.org/cms/namdc/).The Administrative Core also maintains three independent websites: (1) an internal website to manage internal documents and communications with NAMDC sites; (2) a patient remote enrollment website . A data-mining tool has been programmed to allow NAMDC site investigators to perform data queries for internal use. NAMDC is expanding the Registry to collect natural history data on all enrolled patients with select diseases. Additionally, the NAMDC Biorepository currently holds more than 330 biological samples as well as a virtual fibroblast of 185 cell lines. A Central IRB at Columbia University Medical Center has been established for this program.NAMDC is part of the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institute of Health (NIH U54NS078059). NAMDC has established a network of 17 clinical centers of excellence to improve the diagnosis, natural history, and treatment of mitochondrial diseases . NAMDC s–4, and others are in progress. The awarded projects focus on development of biomarkers, improving diagnostic tools, characterizing natural history, and testing therapies for mitochondrial diseases [To date, nine pilot projects have been awarded. Some of them have been completed and publisheddiseases .The NAMDC Fellowship program has been highly successful with monthly webinar meetings and didactic training of six fellows. The first three trainees who completed the program have obtained faculty positions and are active mitochondrial disease clinician investigators. The three latest trainees are continuing their clinical training within the field of neurogenetics.–8. In addition, a survey of NAMDC investigators regarding the NAMDC Research Diagnostic Criteria has been completed and the results have contributed to the refinement of the NAMDC Diagnostic Criteria.In addition to the pilot studies, five patient surveys have been assessed through the NAMDC Registry: (1) attitudes of women carrying mitochondrial DNA mutations and healthy egg donors regarding oocyte nuclear transfer to prevent transmission of mtDNA disease; (2) nutritional supplement use in mitochondrial disease; (3) cardiovascular events in patients with metabolic diseases on chronic carnitine supplementation; (4) motivations and barriers for participation in clinical trials by individuals with mitochondrial diseases; and (5) the diagnostic odyssey of mitochondrial disease patients. Results of four of the five completed surveys have been publishedMitochondrial diseases are challenging because they may be the most diverse human disorders at every level: clinical, biochemical, and genetic. Some are confined to the nervous system but most are multi-systemic, often affecting the brain, heart, liver, skeletal muscle, kidney, endocrine, and respiratory systems. Although severity varies, largely these are progressive and often crippling disorders. They frequently cause weakness, exercise intolerance, fatigue, seizures, mental retardation, dementia, hearing loss, blindness, and premature death.. Given this heterogeneity of mitochondrial disorders, it is essential to apply common, agreed-upon standards to the diagnosis and classification of patients. Further, given the variety of clinical and biochemical phenotypes, effective research on any given subset depends on aggregating relatively large numbers of patients.The challenge lies in the extraordinary clinical spectrum of mitochondrial diseases, which all too often leads practitioners to either underdiagnose (“what is this complex disorder?”) or to overdiagnose . The diagnostic difficulty is reflected in the diagnostic odyssey encountered by patients; in our survey study utilizing the RDCRN Contact Registry, subjects reported seeing, on average, more than eight clinicians before being given the diagnosis of mitochondrial diseaseThese exigencies make clear that two prerequisites are necessary before effective clinical research can take place: (1) a clinical patient registry/longitudinal study to evaluate and expedite subsequent research with available patients; and (2) uniform diagnostic criteria for mitochondrial diseases. NAMDC was established with the goal of addressing these essential elements. After 8 years of continuous support of a U54 RDCRN cooperative agreement, NAMDC has built a basic infrastructure, established a robust clinical registry, expanded the NAMDC Biorepository, plans to implement a registry-wide Natural History study for more common mitochondrial disorders, continues support of pilot projects, and plans to expand the career enhancement program to train new mitochondrial disease investigators. Furthermore, NAMDC plans to collaborate in the international data-harmonization efforts aiming to provide users with access to a comparable view of data from global mitochondrial registries. As NIH funding of projects has a finite lifespan, NAMDC leadership is implementing innovative and cost-effective alternatives such as remote enrollment and is assembling a patchwork of funding sources by ensuring industrial support and strategic collaboration with the UMDF non-for-profit enterprise. Through this approach, NAMDC aims to build a critical infrastructure and performance level to support a resource-efficient and sustainable plan for future mitochondrial disease research in North America and in collaboration with international partners.supplementary materials


Linear multiple regression was used to determine the interactive effects of subjective religiosity and reported police abuse on Black American adolescent boys. Higher reports of subjective religiosity were associated with lower depressive symptomatology. Reports of police abuse were associated with lower public regard beliefs (belief that society views Black Americans less favorably). Results highlight the impact experiencing police abuse has on Black adolescent boys and we conclude with implications, areas for future research and intervention points.State sanctioned violence aimed at Black individuals and communities is an issue that has pervaded American history and society since before the establishment of the United States. For Black males, anticipating and preparing for involuntary police contact, unfortunately, is an inevitable part of life. The purpose of this study is to examine the impact of reports of police abuse on mental health and perceived racial out-group perceptions and the protective role of religiosity among a nationally representative sample of Black American adolescent boys (M The criminalization of and subsequent state sanctioned violence aimed at Black individuals and communities is a social issue that has permeated American society since the establishment of the United States . From slIn 40 interviews with Black males aged 13 to 19, Brunson found that cumulative mistreatment was so common that respondents came to anticipate police abuse as a common occurrence in policing . SubsequDespite these circumstances, mechanisms may be activated to combat the adverse effects on psychological well-being as a result of negative police contact. Religiosity, in particular, may play a buffering role against the adverse effects and out-group perceptions of those who have experienced police abuse, particularly among Black youth during some of the most formative years in adolescent development. The role of religion in addressing mental health among minority adolescents, however, is complex. When Rose and colleagues explored the role of religion in connection to the mental health of Caribbean Black adolescents they found that involvement in organized religious activities was positively related to coping and self-esteem but negatively related to depression and attending religious service was not related to any mental health domains . QualitaA meta-analysis of the factors associated with officers’ decision to use force finds that the characteristics of the individual targeted by police abuse plays an important role in the likelihood of police use of force. Specifically, minorities, males, and/or individuals from economic disadvantage were most likely to experience police use of force . Recent Recent empirical work on police abuse found that, when compared to Whites, Blacks are more likely to be fatally shot by law enforcement . While sRed Record, which systematically tracked accounts of lynching reported in the Chicago Tribune [Empirical pursuits exploring police violence have suffered from challenges around its operationalization both historically and presently. For example, during the 1800s, the U.S. lacked any sort of nationally mandated tracking of lynching victims. As a result, the sociological and journalistic work of Ida B. Wells uncovered the occurrence and prevalence of lynching, as made evident in her development of the  Tribune . Present Tribune . Nonethe Tribune ,25.Racial identity is one’s attitude, beliefs and self-concept regarding the meaning and significance they ascribe to their racial group membership . FurtherResearch shows that endorsement of a healthy racial identity is associated with more positive mental health outcomes . ResearcThus, we extend the racial identity literature by examining how reports of police abuse among Black American boys impact public regard beliefs . For instance, Sellers and colleagues  found thThe compounding effect of police abuse only further exacerbates health and mental health challenges. A large body of work exploring the adverse effects of aggressive policing highlights the ways these encounters are associated with several mental health challenges ,39. ReseAnother study exploring associations between police abuse and psychological distress among the NSAL adult sample find that African Americans were more likely to report hallucinations compared to Caribbean Black adults . AdditioThere is a growing body of work exploring mental health outcomes for Black youth using the National Survey of American Life (NSAL-A) adolescent sample exploring issues around perceived discrimination and psychological distress ,47, withCompared to other adolescents, African American adolescents are the most religious group in the United States, as indicated by prayer frequency and importance of religion . Butler-Guiding this study is the Integrative Model for the Study of Developmental Competencies of Minority Children, which argues that there are sociocultural processes influencing the developmental processes of adolescents of color . The modDue to the vast reports of racial profiling  and poliData for this analysis are from the National Survey of American Life—Adolescent Supplement (NSAL-A), a nationally representative household survey estimating prevalence, frequency, and comorbidity of DSM-IV disorders among 1170 African American and Caribbean adolescents ages 13–17 connected to adult households from the National Survey of American Life (NSAL) adult sample. The NSAL adult sample was part of the National Institute of Mental Health (NIMH) Collaborative Psychiatric Epidemiology Survey (CPES) which consists of the NSAL, the National Comorbidity Survey Replication (NCS-R), and the National Latino and Asian American Study (NLAAS) . AdditioInformed consent and assent was obtained from both the adolescent’s legal guardian and the adolescent. Most of the adolescent interviews were conducted face-to-face using a computer-assisted instrument in their homes, while other interviews were either conducted on the phone or partially (approximately 18% face-to-face or phone interview). Overall, interviews lasted 1 h with an overall response rate of 80.6% (80.4% for African Americans and 83.5% for Caribbean Blacks).Demographic. Annual household income , race (0 = African American & 1 = Caribbean Black), and adolescent ages were included.Police Abuse. Police abuse was measured using a dichotomous variable (1 = Yes and 0 = No) in response the question “have you ever been abused by the police?”.Subjective Religiosity. Subjective religiosity was measured with two items: “How important is religion in your life?” and “How important is prayer when you deal with stressful situations?” Item responses ranged from 1 = very important to 4 = not important at all. Responses were reverse scored and averaged so that higher scores on the scale reflected higher religiosity beliefs. Internal consistency for the scale is 0.71.Mental Health. Depressive symptomatology was measured using an abbreviated 12-item version of the Center for Epidemiologic Studies Depression (CESD) Scale [D) Scale ,66. The D) Scale ,66. ItemD) Scale  was usedRacial Identity Beliefs. Racial identity beliefs are comprised of seven subscales of the Multidimensional Inventory of Black Identity scale containing three domains of African American racial identity including ideology, centrality, public and private regard [e regard . For theMPLUS 7.3 was used to conduct the analyses because of the complex design-based estimates of variance. The weighted data were used. The NSAL-A sample is a stratified and clustered sampling design. Full-Information Maximum Likelihood (FIML) estimation was used to account for missing data. Approximately 71% of the sample was African American and 29% were Caribbean Black adolescent boys. We used linear multiple regression analyses for multivariable data. In the model, reports of police abuse (1 = yes and 0 = no), subjective religiosity, and the subjective religiosity x police abuse interaction were the main predictors in the model. Depressive symptomatology, perceived stress, and public regard were the outcomes and adolescent age, household income, and race (0 = African American and 1 = Caribbean Black) were covariates in the model.r = −0.15, p < 0.10), and family income was statistically negatively associated with perceived stress  (Sample descriptive statistics and correlations are presented in  < 0.10) . AdditioLinear regression analyses were performed to examine the demographics , independent variables (reported police abuse and subjective religiosity), and the interaction effect of subjective religiosity x reported police abuse on the mental health and public regard beliefs of Black American boys. All of the variables were simultaneously entered into the model to examine the impact on three outcome variables: depression, public regard beliefs, and perceived stress. B = −0.010; SE = 0.002, p = 0.001). In model 2, after controlling for the covariates, household income  and reported police abuse  was associated with public regard beliefs. More specifically, Black American boys who reported being abused by the police felt that society did not view them favorably in comparison to those who did not report being abused by the police. In model 3, controlling for covariates, reported household income  was associated with perceived stress. Black American boys reporting higher household income was associated with lower levels of perceived stress. Finally, the subjective religiosity x police abuse interaction for models 1 to 3 was not statistically significant for depressive symptomatology, public regard, or perceived stress.In model 1, controlling for the covariates , subjective religiosity was associated with lower reports of depressive symptomatology  and public regard beliefs among Black American adolescent boys and the role of subjective religiosity in buffering against the negative effects of police abuse. We posited that among adolescent Black American boys, experiencing police abuse would negatively impact psychological well-being and public regard beliefs and that subjective religiosity would buffer against the negative effects of police abuse. Our findings are provided in the following sections, and overall show partial support of our hypothesis.Our hypothesis that experiencing police abuse impacts depressive symptomatology was not supported; however, our hypothesis that subjective religiosity would be associated with lower depressive symptomatology was supported. More specifically, findings did reveal that, overall, subjective religiosity was associated with lower levels of depressive symptomatology. This particular finding highlights how the specific construct of religion may reduce negative mental health outcomes and aligns with prior work that finds associations between religiosity and healthy psychological well-being ,49.Our findings also corroborate previous work on the important role of subjective religiosity in the lives of Black Americans ,69,70. TIn support of our hypothesis that police abuse would impact the public regard beliefs of Black American adolescent boys, the results showed lower levels of public regard  among Black American adolescent boys who were abused by the police. These particular findings highlight the complexity of the lived experiences of minority youth and contribute to the variations found in empirical work regarding the within-group differences among minority groups relative to police contact. For example, while some studies have found that foreign-born participants tend to hold more favorable views of the police when compared to U.S.-born participants ,72, otheLastly, we found that higher household income was associated with Black American boys perceiving that others in society viewed their racial group less favorably. We speculate that because of Black American boys’ racialized status within the U.S., higher socioeconomic status does not protect them from negative racial encounters and experiences. For instance, recent research has found that higher SES does not protect Black men against depression  and thatOur hypothesis that experiencing police abuse and subjective religiosity would impact levels of perceived stress was not supported. However, we found that socioeconomic status played a key role as Black American adolescent boys from households with higher incomes reported lower levels of perceived stress. This finding contributes to earlier work indicating that low-income Black youth reported higher levels of psychological distress . UnemploA limitation of the study is that the National Survey of American Life Adolescent Supplement was collected from 2001 to 2004. While it is possible that the experiences of youth abused by the police and associated effects of religiosity and mental health may vary from the experiences of minority youth presently, many of these challenges may still remain. Another limitation is the low occurrence of police abuse among the adolescent youth in the sample (26%). We suspect that this smaller sample size might be due to the phrasing of the question , which highlights the challenges around how police abuse is operationalized empirically. Measuring police abuse faces similar challenges to those faced by intimate partner violence (IPV) research with respect to what should be included in the definition of IPV, from physical to emotional and psychological abuse . The strAdditionally, the cross-sectional design of the NSAL-A limits an aspect of our study’s aim to explore the impact of police abuse on the developmental processes of adolescents over time. This design also makes it difficult to discern the trajectory of mental health over time with regards the psychological well-being of Black American adolescents who have experienced police abuse. Place matters, especially with respect to the effects and prevalence of negative police encounters. Neighborhood indicators of social cohesion, social disorder, and level of quality of community-police relations in a neighborhood may have shed important light on the psychological well-being outcomes particularly among minority adolescents and their interactions with local law enforcement.Several implications arose from this study. First, research on trauma and brain development continues to emerge, pointing to the specific ways trauma can affect brain development, particularly when trauma occurs early in life . Future Our findings also highlight how punitive responses by institutions aimed at minorities do not operate in a vacuum. Differential treatment of youth is widely known in educational institutions, perpetrated through School Resource Officers (SROs)  and zeroAdditionally, a meta-analysis examining the role of racial identity and academic achievement found a small but significant effect size linking racial identity with academic achievement . Recent Additionally, more longitudinal research is needed to understand how police interactions impact Black American boys’ developmental competencies and self-perceptions over time. Black American adolescent boys who reported police abuse in the current study perceived that society held more negative views about their racial group membership which may impact other areas of development such as perceived self-worth. Future research is needed that deploys mixed methodologies to understand the lived experiences of Black American boys relative to interactive effects of law enforcement, religiosity, and the role of additional support mechanisms . More specifically, qualitative research is warranted to better understand the affective meaning of these negative encounters with the police and its impact on Black American boys’ sense of self.Halgunseth and colleagues found variation in the significance of religious beliefs and practices of African American parents on their children, with mothers’ religious beliefs being linked to the beliefs of both their sons and daughters and found that fathers’ religious beliefs were only linked to sons’ religious beliefs . HoweverThe null finding related to police abuse, perceived stress, and depressive symptomatology, compared to the statistically significant association found between public regard and reported police abuse could be due to barriers Black Americans face with respect to mental health. Specifically, Thompson and colleagues found that stigma, costs, cultural misunderstanding, and trust were major barriers among African Americans seeking mental health services . AdditioPolice abuse involving minorities, particularly Black men, has been a haunting feature of U.S. history. These issues have once again caught national attention most recently with death of George Floyd, Breanna Taylor and countless others prompting global protests, recognitions by police organizations of the historical mistreatment by the police of minorities , and nat


Research in Adult Protective Services suffers from the problems of small sample size, low completion rates, and poor data quality. To address the “small sample size” issue, data were generated on 1,472 elder abuse cases over six months in California using the Identification, Services and Outcomes (ISO) Matrix. The problem of poor data quality was addressed by testing psychometric properties of Short-Forms on each type of abuse. Good reliability and predictive validity were found for all measures except those that were very rare. Finally, even shorter Mini-Forms were developed and tested in order to contribute to improved completion rates. Mini-Form results were mixed, and some will require further research on their reliability and validity, as well as examination of their ability to improve completion rates. Ongoing adoption by two California counties and the State of Montana demonstrate sustainability and increasing sample sizes using the ISO Matrix for research and practice.