The objective of this review is to describe the evolution of lung tissue-derived diploid progenitor cell applications, ranging from historical biotechnological substrate functions for vaccine production and testing to current investigations around potential therapeutic use in respiratory tract regenerative medicine. Such cell types  were extensively studied since the 1960s and have been continuously used over five decades as safe and sustainable industrial vaccine substrates. Recent research and development efforts around diploid progenitor lung cells  consist in qualification for potential use as optimal and renewed vaccine production substrates and, alternatively, for potential therapeutic applications in respiratory tract regenerative medicine. Potentially effective, safe, and sustainable cell therapy approaches for the management of inflammatory lung diseases or affections and related symptoms  using local homologous allogeneic cell-based or cell-derived product administrations are considered. Overall, lung tissue-derived progenitor cells isolated and produced under good manufacturing practices (GMP) may be used with high versatility. They can either act as key industrial platforms optimally conforming to specific pharmacopoeial requirements or as active pharmaceutical ingredients (API) for potentially effective promotion of lung tissue repair or regeneration. Vast historical experience has been gathered around industrial use of diploid progenitor cell sources  as vaccine substrates since the 1960s, when developmental cell biology studies served as a basis for optimization of biological starting material selection ,5,6,7. DOptimized methodological aspects concerning tissue procurement and processing for progenitor cell isolation were the foundations of recent work on cutaneous and musculoskeletal cell therapies ,48,49,50The present narrative review compiles and discusses the potential and highly polyvalent valorization pathways to be considered for robust lung tissue-derived diploid progenitor cell sources. Such pathways comprise the recognition of specific cell sources by central health authorities as qualified and suitable vaccine production substrates or the appropriate registration of cell sources as active pharmaceutical ingredients (API) for the promotion of damaged lung tissue repair or regeneration. Overall, evolutive methodological and process-based aspects of diploid progenitor cell sourcing, cell bank establishment, and cell bank exploitation are summarized in this review. These elements are discussed in view of identifying gaps and potential optimization solutions available for the establishment of safe and sustainable biological material supply chains in modern biotechnological manufacturing processes and/or in translational regenerative medicine. The inclusion of primary diploid cell sources in industrial manufacturing settings was prompted by the considerable material needs in the field of vaccine development and production during the second half of the twentieth century . The gen6 doses of vaccine [In 1929, it was demonstrated that the generation of virus material for eventual vaccine development and production was dependent upon the presence of viable host cells when tissue explants from hen kidneys were used as viral propagation tools . Several vaccine . Further vaccine . Therefo vaccine ,55,56,57In the 1950s and 1960s, collaborations between the Wistar Institute  and the Karolinska Institute  constituted an advanced platform for prenatal tissue procurement and primary cell type establishment . The oriSubsequently, property rights over the cell sources of interest  constituted the object of lengthy legal disputes, with the epicenter set on Hayflick himself . Indeed,In parallel to the American developments of human primary diploid cell sources, similar proceedings were undertaken in 1966 by Dr. Jacobs in the United Kingdom under the auspices of the Medical Research Council (MRC). A most notable cell type was the MRC-5 source, originally isolated from lung tissue donated at 14 weeks of gestation  ,59,60,61Due to the optimal qualification of human diploid cell sources as vaccine substrates and despite the considerable sustainability of such derived cell banks, a major bottleneck is currently arising with the transiently high activity in the vaccine industry and the aging of the original cell sources developed in the 1960s  . While oDrastic differences characterize the context in which original tissue procurement occurred in the 1960s and occurs today. They pertain mainly to quality-driven processes for material handling and ethical considerations centered on specificities of research on human subjects and donor consent. While modern technical workflows, detailed in ad hoc legal frameworks and guidance documents, may be interpreted as highly restrictive as compared to historical methods, modern safety prerequisites are critical in ensuring an acceptable overall quality level of materials serving for therapeutic product manufacture ,67,68,69In addition to ethical aspects of diploid cell source establishment, the evolution of cell culture methods and related tools, in particular, have contributed to the optimization of material processing and ensurance of adequate specific safety or quality levels. Notably, progress in material science has allowed for the transition from obsolete glass contact-process consumables  to single-use polymeric CE-marked devices, or transition from animal-sourced raw and ancillary materials  to defined synthetic equivalents  70,71,7,73,74. SA third point of interest to mention in view of illustrating the drastic differences between historic and modern processes related to cell sourcing resides in the tumorigenicity testing methodology of primary cell types, a critical parameter of cell source safety characterization and qualification. Specifically, such testing was carried out in terminal phase cancer patients in the 1930s, a practice that would be disregarded in modern medical practice . ThereafA major discussion point with fundamental and applied moral implications around the use of diploid cells and vaccines in general has emerged, voiced notably by religious scholars in remarkable publications centered on the nature of the original biological starting material  ,13,14,15® CCL-171™) and WI-38 cell type , as mentioned previously [The main characteristics that have enabled and favored the industrial adoption of human diploid cells pertain to sustainability, stability, and robustness for application in selected manufacturing processes. Notable examples of non-transformed diploid cells, originally isolated in the 1960s from prenatal lung tissue, are the MRC-5 cell type  have been developed and proposed for pharmaceutical uses toward the end of the twentieth century. The PER.C6 cell line was developed from prenatal retinoblasts , which were immortalized by plasmid transfection of adenovirus type 5 . This cell line has been primarily used for manufacturing of adenovirus vectors for gene therapy and of developmental stage vaccines for diverse pathologies caused by the Ebola virus, influenza viruses, the Japanese encephalitis virus, and HIV. A considerable technical advantage of PER.C6 cells consists in the ability to proliferate in adherent culture vessels or in suspension in serum-free media, meeting requirements for both European and US regulatory bodies . Such fl7 cells/test-animal to induce tumorigenicity), additional steps are also required in purification workflows if these cells are utilized in vaccine production. Specifically, vaccine manufacturers may use the HEK-293 cell line for well-defined activities in three different stages as follows:Development stages: to identify optimal mechanisms and processes to be used in product manufacture.Confirmation stage: to assure that optimal mechanisms and processes may be tangibly transposed to product manufacture.Production stage: to validate the use in the actual manufacturing system of the final product formula.An alternative modified cell line, the HEK-293, originally isolated from human embryonic kidney tissue, was developed and extensively used in diverse applications in medicinal product development due to a high propensity toward transfection. HEK-293 cells have been under recent public scrutiny due to the intensive use in COVID-19 vaccine development efforts . Indeed,To provide recent examples of currently developed and approved vaccines, it is important to note that the respective Pfizer and Moderna COVID-19 vaccine developers and manufacturers used such cell lines during the development and confirmation stages but not in the actual production of the final vaccine formulation. In contrast, the Johnson and Johnson/Janssen COVID-19 vaccine was developed and is currently produced with an adenovirus carrier, where the virus vector is efficiently produced using the easily transfected PER.C6 cells. Flaviviridae) and vaccinia  [Alternative substrates for viral propagation are embryonated chicken eggs, which are widely used in industrial manufacturing processes. In this model, viral materials are inoculated into the allantoic cavity for propagation. This method was used since the 1940s for the propagation of many viruses, including mumps, polio, rabies, and certain veterinary vaccine viruses. Specifically, eggs provided an alternative substrate to mammalian brain tissue, which bore the potential of inducing allergic encephalitis from non-virus antigens. Furthermore, primary chicken cells/tissues were historically and importantly used for attenuated viral strain production such as yellow fever  . Technicviridae) . Overallviridae) . https://rumble.com/vclsch-jp2mri-ethical-and-cutting-edge-covid-19-vaccine-research.html, accessed on 20 July 2021).A major area of investigation for optimized substrate elaboration resided in the development and use of continuous cell lines, defined as immortal cells, which maintain the karyology of the original starting tissue. While some cell lines have been immortalized by described mechanisms , other commonly used cell lines  are still being further characterized for elucidation of the immortalization mechanism. Therefore, the latter may be used in medicinal product manufacturing processes, but vaccine product manufacturers need to demonstrate that the final product does not contain any oncogenic agents . Such cell lines have been historically used for inactivated poliovirus vaccine and inactivated rabies vaccine production. The Vero cells, developed from African green monkeys in 1962 , presented the advantage of not being tumorigenic within certain passages, being adventitious agent-free, and could be used for the propagation of different viruses used in the manufacture of existing vaccines  . StartinEvolutive risk-benefit analyses of continuous cell lines used as substrates, mediated by specific biotechnological advances , have allowed for the appropriate safety characterization and qualification of MDCK cells for influenza vaccines and PER.C6 cells in vectored vaccines. A critical parameter for cell substrate selection is the quality and safety of the finished product for the intended human therapeutic application. Therefore, residual cellular DNA in vaccine products would present a potential iatrogenic risk in the case of tumorigenic cell substrate use. Thus, it is necessary to determine the presence and quantity of residual substrate DNA  in a quantitative assay to measure both infectivity and oncogenic activities of said residues .Despite the high sustainability and stability of the original diploid cell banks established in the 1960s, specific technical problems have arisen as even the best cryopreservation storage practices have not made the preserved vial impervious to the effects of time. With the example of the MRC-5 cell source, the importance of the historic use of such cells has been brought to the attention of the World Health Organization (WHO) for sustainable exploitation of the remaining materials. Therefore, the original PDL 7 stock  established in 1966 was recently renewed over concerns of deteriorating quality of original glass ampoules and related stability or biosafety risks . The MRCIn parallel to the renewal of seed stocks of existing cell types, current efforts are also allocated toward the establishment of novel cell types within modern legal workflows and technical capabilities ,47,48,50Despite numerous advantages of such modern approaches , high inertia exists within manufacturer and regulatory circles with regard to the homologation of novel cell types. A noteworthy example of modern diploid cell type establishment is the Chinese Walvax-2, derived from prenatal lung tissue and proposed in 2015  as a qualified substrate for viral material propagation [For the isolation and establishment of the Walvax-2 cell source, the original methods of Hayflick  were replicated . AlthougOverall, vast opportunities for vaccine substrate renewal exist and have been underlined by current shortages, themselves exacerbated by the COVID-19 pandemic. Novel diploid cell sources have been developed, similar to historically used materials, with prenatal and perinatal tissues . In particular, based on the large available data on human diploid progenitor cell GMP banking in Switzerland for therapeutic material sourcing, high interest is currently set locally on specific cell types  for candidacy as novel and robust cell source establishment . Indeed,Organ donations have become central in many advances to medicine and are therefore regulated under strictly defined programs. In Switzerland, the specific legal framework in transplantation medicine is of potentially high interest to devise programs that clearly define procurement and usage of human tissues for establishing primary diploid cell sources .The Swiss Constitution provides that the Federal Council may fully elaborate laws concerning research on human beings  and transplantation medicine . In Switzerland, women may undergo voluntary interruptions of pregnancy without being penalized by criminal law until twelve weeks  and at later stages of gestation if attested by a medical doctor in the possibility of physical danger or deep distress  . ImportaSpecific safety procedures are then established, specifying sequential serological testing of the donor at the time of donation and after an appropriate period in order to exclude sero-conversion for specified pathogens. During this period , the established cryopreserved cell stocks are quarantined, as out-of-specification test results from the repeated pathogen screening or retraction of the donor with regard to the inclusion of materials in the transplantation program would warrant the destruction of established stocks. As regards ethical and legal oversight, the devising and execution of the transplantation program must be submitted to appropriate controls  and defined in framework documents . Therefore, it is important to note several major differences  in processes and regulations for human research, ethical issues, and informed consent obtention in the context of diploid cell sourcing .The evolution pertaining to organ donation traceability and safety since the 1960s demonstrates the importance of tissue sourcing and specifically for fully informed consent obtention within applicable legal frameworks. Specifically devised transplantation programs and biobanks assure that material and information traceability is ensured, with appropriate ethical review and oversight levels, and that full informed consent is available . For optimal technology development and overall quality assurance, interdisciplinary approaches for organ donation and processing are warranted. Lawyers may help to interpret regulatory issues of organ donations and biological material use; biologists may select the appropriate cell source and process technical specifications; bioengineers may choose delivery and tissue engineering designs or preservation conditions; medical doctors may perform donor screening and informed consent documentation .Various musculoskeletal and related soft-tissue diploid progenitor cell types have been studied over the past two decades, and dermal cells  have been successfully implemented in clinical use ,26,33. MThe most notable effects of PBB applications have been the reduced tissue scarring following recovery, with excellent structural and functional skin barrier restoration ,44. AddiVarious technical methodologies for lung tissue-derived progenitor cell isolation and culture initiation may be adopted , whereas the official context or framework for tissue sourcing and procurement should be adequately defined , as described previously . 6 to 107 cells to be preserved [2 and 37 °C incubation) are sufficient for initiation of adherent lung tissue-derived progenitor cell cultures in vitro. Following strict procedures and controlled access to materials and information, prenatal lung tissue samples are anonymously yet traceably obtained for subsequent bioprocessing, ensuring optimal quality and safety of progeny cell sources. Technical specificities of lung progenitors place such cell sources at the forefront of potential therapeutic material candidates for regenerative medicine applications. Indeed, rapid establishment and extensive cell banking capabilities practically negate the need for repeated organ donations, as attested by the industrial use of the MRC-5 cell type, for example, which has lasted over fifty years thus far following a single tissue donation . Thereforeserved . StandarDue to the high robustness and extensive proliferative potential of primary progenitor cells, such sources may be used in industrial-scale cell banking campaigns under good manufacturing practice (GMP) requirements . For an Cultured diploid progenitor cells may be considered as optimal biological sources presenting potentially vast therapeutic utility in the domain of inflammatory lung diseases and control of symptoms thereof . Due to Therefore, similar to other domains of regenerative medicine, the origin and processing of the considered therapeutic cellular materials are often limiting factors in the effective development of novel therapies or products, mainly due to safety, consistency, sustainability, or manufacturing cost issues ,97,98,99Based on the vast translational experience with skin-derived progenitors and their various putative in vivo therapeutic modulatory effects, a similar homologous cell therapy approach could be employed using lung tissue-derived progenitors for the local management of inflammatory lung diseases and related symptoms . VariousDue to the fact that human therapeutic lung tissue-derived progenitors have undergone substantial manipulation , final cell-based products may be considered as standardized transplants and/or (combined) advanced therapy medicinal products (ATMP) from a regulatory point of view, depending on the specific formulation and processing applied ,64,65. IThe exact mechanism of action of therapeutic progenitors has not yet been exactly elucidated but probably relies on some form of synergistic paracrine or trophic modulation of patient target tissues by multiple cellular components  . Based oTherefore, further studies are necessary in preclinical and clinical settings to better characterize the in vivo effects of therapeutic lung-derived progenitors or derivatives thereof, as abundant research in the neighboring field of stem cells has evidenced preponderant roles of cell secretomes or sub-cellular vesicles in mechanisms of repair and/or regeneration ,89. SuchIn addition to the qualification of modern lung tissue-derived progenitor cell sources as vaccine substrates, optimization of regulatory aspects of potential direct therapeutic uses thereof is of equal high interest. In this sense, homologation of the cell source in an appropriate form would enhance the transparency and safety levels pertaining to the API of considered investigational medicinal products. From a technical standpoint, the use of standardized progenitor cells or cell derivatives as APIs has significant advantages, notably in terms of traceability and consistency. Due to the extensive expansion potential of selected primary cells, an individual cell type may be thoroughly tested and fully qualified in terms of safety, similarly to MRC-5 or WI-38 cells, which are recognized as safe  by pharmacopeias, without the necessity for repeated testing . This asWith regard to cell source homologation or optimization of regulatory statuses, three pathways are considered herein, namely the creation of pharmacopeial monographs , the creation of a cell and tissue monograph, or the registration of specific cell sources as WHO reference cell banks. Firstly, the inclusion of a cell monograph in a pharmacopeia at a supranational level  would enable the facilitated prescription of cell-based preparations in hospital settings, for example, with the setting of adequate technical and quality specifications. A recent example of a cell monograph introduced in the European Pharmacopoeia is the monograph 2323, “Human hematopoietic stem cells”, which may serve as a basis for the elaboration of adequate texts relative to lung tissue-derived progenitor cells of appropriate quality. Secondly, a cell and tissue monograph may be considered, as set forth in the “Guide to the quality and safety of tissues and cells for human application” of the EDQM, with a similar definition of technical specifications and quality attributes of considered cell APIs or products, once the clinical experience is gathered . ThirdlySpecifically, the criteria to be met for the possible inclusion of cell banks in the WHO reference cell bank system are presented in Based on the technical specificities of primary diploid progenitor cell types and the historic experience around the safe industrial and clinical uses, it is currently of high interest to further investigate lung tissue-derived progenitor cell sources for developing novel cell therapy products or biotechnological substrates. The high demand for adequate and renewed cell substrates was illustrated with the current pandemic context and the extensive needs of the vaccine industry. Furthermore, increasing numbers of patients presenting inflammatory or degenerative lung tissue affections prompt the development of novel and effective therapeutic products, among which cell-based or cell-derived solutions. Overall, it is expected that lung tissue-derived progenitors produced under good manufacturing practices may be used with high versatility, either as key industrial platforms conforming to specific pharmacopeial requirements or as active pharmaceutical ingredients in advanced therapy medicinal products or standardized transplants. Both approaches are highly interesting and potentially valuable in current and continued struggles against the COVID-19 pandemic, with potential contributions to industrial development efforts and tangible support in global clinical challenges around patient therapeutic management.


Spinal cord injury (SCI) is a complex neurological condition caused by trauma, inflammation, and other diseases, which often leads to permanent changes in strength and sensory function below the injured site. Changes in the microenvironment and secondary injuries continue to pose challenges for nerve repair and recovery after SCI. Recently, there has been progress in the treatment of SCI with the use of scaffolds for neural tissue engineering. Polymeric fibers fabricated by electrospinning have been increasingly used in SCI therapy owing to their biocompatibility, complex porous structure, high porosity, and large specific surface area. Polymer fibers simulate natural extracellular matrix of the nerve fiber and guide axon growth. Moreover, multiple channels of polymer fiber simulate the bundle of nerves. Polymer fibers with porous structure can be used as carriers loaded with drugs, nerve growth factors and cells. As conductive fibers, polymer fibers have electrical stimulation of nerve function. This paper reviews the fabrication, characterization, and application in SCI therapy of polymeric fibers, as well as potential challenges and future perspectives regarding their application. Spinal cord injury (SCI) is considered as the main type of central nervous system (CNS) injury, which may lead to paraplegia or quadriplegia and affect the quality of life of patients . There aIn recent decades, the application of scaffold-based neural tissue engineering technology has been widely studied for the treatment of SCI . Seed ceTo date, many different types of polymeric fibers have been used as scaffolds for neural tissue engineering. Polymeric fibers can be produced by a variety of processes such as electrospinning , phase s2+ influx activates caspases and some enzymes involved in the decomposition of cytoproteins, resulting in cell apoptosis  (PGA), polycaprolactone (PCL), poly (lactic acid) (PLA), and poly (lactic acid-co-glycolic acid) (PLGA), for the treatment of SCI. A variety of natural polymers such as collagen and gelatin have also been extensively studied . Fibers Biocompatibility is the crucial property of fiber scaffolds in tissue engineering. The implanted fiber scaffolds are foreign substances to the spinal cord, which may cause immune rejection reaction and thus reduce their efficacy . TherefoThe function of polymeric fiber scaffold depends on its geometry. Electrospun nanofiber scaffolds have high specific surface area , porous Electrospinning fibers can be used to deliver therapeutic drugs. Local and sustained release of therapeutic drugs integrated into biomaterial scaffolds has been used to promote nerve regeneration or reduce secondary injury after SCI. Drugs are typically implanted into these scaffolds by embedding the polymer matrix in the manufacturing process or by attaching molecules to the surface of the fiber. Drugs are typically implanted into these scaffolds in two ways: one is to embed the polymer matrix during the manufacturing process, the other is to attach molecules to the surface of the fiber . The simMany polymeric fibers have been used in SCI, including natural polymeric fibers, synthetic polymeric fibers, and polymers containing mixtures of natural and synthetic components .Natural polymeric fibers, such as collagen, gelatin, elastin, chitosan and fibroin, have been used to prepare scaffolds. Owing to their biocompatibility, biodegradability, and beneficial effects on cell adhesion and survival, natural polymeric fibers have been widely used to develop various forms of regenerative scaffolds for SCI repair .Collagen is a ubiquitous protein in the human body and because of its biocompatibility and biodegradability, it is a suitable natural polymer scaffold material for SCI repair . Naturalin vitro sustained release when modified with a neurotrophin-3 (NT-3)/fibroin complex  the mechanism of differentiation of stem cells into different cell phenotypes; 3) the degradative speed of polymeric fiber scaffolds were kept up with nervous tissue regeneration; and 4) local release curve of drugs loaded on polymeric fiber scaffolds.Currently, in addition to polymeric fiber scaffolds, stem cells and bioactive molecules play an important role in neural tissue engineering. Combination therapy with polymeric fiber scaffolds, stem cells and bioactive molecules is a promising direction for the treatment of SCI. Neural tissue engineering of SCI needs to be further studied in-depth, primarily including the following aspects: 1) the biocompatibility of polymeric fiber scaffolds, stem cells and nerve tissues In conclusion, polymeric fibers have great potential as scaffolds in neural tissue engineering for the treatment of SCI. We believe that the application of polymeric fiber scaffolds in the treatment of SCI will eventually achieve good clinical results.


There are 5.8 million Americans living with Alzheimer’s disease, but currently there is no cure or effective treatment. Alzheimer’s disease and related dementias (ADRD) are characterized by cognitive decline, but patients also have behavioral symptoms and functional decline. Understanding the gamut of risk and prognostic factors for ADRD and those associated with the task of caring for these patients is layered. The National Health and Aging Trends Study (NHATS) and the sister National Study of Caregiving (NSOC) are excellent resources to investigate layers of ADRD incidence, progression, and caregiving in the population. NHATS is a nationally representative sample of Medicare beneficiaries aged 65 and older. Since 2011, annual in-person interviews have collected data in many areas, including health, environment, wellbeing, cognition, and function. NSOC has been conducted at three timepoints corresponding with NHATS rounds and collects detailed data on caregivers, including information on care activities, caregiver burden, and caregiver wellbeing. This symposium illustrates the broad range of ADRD research questions that can be probed using NHATS/NSOC data. The session begins with a presentation the association between caregiver burden and ADRD patient cognitive outcomes. The second presentation examines the role of physical performance as a predictor of developing ADRD. The third presentation investigates the role of dual sensory impairment – both hearing and vision impairment – on dementia incidence. The session concludes with an examination of whether hearing impairment among dementia patients is associated with different caregiving needs.


The pharmaceutical industry is currently trying to develop new bioactive compounds to inactivate both enveloped and non-enveloped viruses for therapeutic purposes. Consequently, microalgal and macroalgal bioactive compounds are being explored by pharmaceutical, as well as biotechnology and food industries. In this review, we show how compounds produced by algae include important candidates for viral control applications. We discuss their mechanisms of action and activity against enveloped and non-enveloped viruses, including those causing infections by enteric, parenteral, and respiratory routes. Indeed, algal products have potential in human and animal medicine. Many significant zoonotic pathogens are viruses and they have substantial infection-related impacts on public health worldwide. Non-enveloped enteric viruses are persistent in the environment , resisting pH ranges of up to 3 to 9, temperature variations, and radiation . Such viEnteric and respiratory viruses present enormous challenges both for human and animal medicine, and there is therefore a need for new antiviral solutions for fighting viruses with their worldwide economic and social consequences. Recent respiratory viral epidemics such as the worldwide outbreaks of swine flu, avian flu, and coronavirus has increased interest in the development of antiviral drugs . ExploriMacroalgae are a phylogenetically artificial group of multicellular, macroscopic, eukaryotic, photoautotrophic organisms, mostly benthic (many being commonly known as seaweed), which are classified into three large groups: Chlorophyta , Rhodophyta , and Phaeophyceae  .The components of macroalgae vary from simple to complex compounds, including polysaccharides , phenolics and phlorotannins , protein and peptides , lipids, terpenoids and steroids , vitamins and minerals . Freshwain vitro and in vivo. However, their potential is still underexplored by the pharmaceutical industry, and only 9% of medicines of natural origin come from algae , involving solvents to extract soluble constituents from a solid or semisolid matrix. The downside of this method is its long extraction time and high solvent consumption . Other rObtention of compounds of interest from marine macroalgae and microalgae involves the following major steps: (1) collection and taxonomic identification of samples; (2) drying; (3) extraction through the use of solvent; (4) filtration and concentration by evaporation .2 in a layer in a 96-well plate, and applying serial dilutions of compounds of interest. After 7 days of incubation, viable cells are revealed by using chemicals such as sulphorhodamine B and tetrazolium dye 3--2,5-diphenyltetrazolium bromide (MTT)  .Antiviral assays identify compounds that for example inhibit viral replication. Such assays generally involve placing viruses in contact with permissive cells and allowing the cycle of replication to begin. The antiviral compound being tested is then applied and successfully replicated viruses counted as plaque-formed units (PFU) after revelation by staining cells with crystal violet. Percentages of viral inhibition and of cells free of infection can then be calculated.Virucidal assays identify compounds that kill viruses, by for example, inactivating recognition proteins. Viruses are exposed to the sample under study and then a known quantity of virus is used to inoculate cells in 6-well plates; in some protocols, agarose is use to stabilize neighboring cells to favor the transmission of viruses. Viral neutralization is quantified by counting PFU after viable cells are colored with crystal violet . This asAlgae and their extracts have numerous applications and have historically stimulated significant economic interest, mainly as a source of new drugs such as antivirals. therefore, we report crude extracts and compounds isolated from algae that showed antiviral activity against both enveloped and non-enveloped viruses. Some examples of these compounds and extracts from algae with antiviral activity are listed in Osmundaria obtusiloba has been reported to have higher antiviral and virucidal effects against the Chikungunya virus (CHIKV) than ribavirin, which is used as a drug to control the virus  and type 3 (DENV-3) (Red seaweed he virus . The λ- (DENV-3) .Spirulina platensis has antiviral effects against Adenovirus type 40, a non-enveloped virus  non-enveloped viruses. EMCV infection causes death among pigs in production units, primates in research centers, and animals in zoos ; this macroalgae and microalgae diet appears to have improved innate immunity and increased the resistance of shrimp to infection by WSSV . SeaweedA wide variety of compounds obtained of micro and macroalgae has already been explored and tested against viruses and their cell infection capabilities.Several studies of macroalgae compounds have shown promising antiviral effects against viruses that cause animal diseases causing serious economic losses. There are no effective treatments, either antivirals or vaccines, currently available against many of these diseases. A study in 2012 reported that the brown algae compound fucoid had an antiviral effect, albeit weak, against the Newcastle virus (NDV), which causes serious diseases in poultry and thereby substantial financial loss .The first seaweed compound with antiviral activity against Canine Distemper Virus (CDV), a morbillivirus related to the measles virus that infects dogs and other carnivores , was repGriffithsin sp., has activity against viruses such as the human immunodeficiency virus (HIV), hepatitis C virus (HCV), human papillomavirus, herpes simplex virus 2 (HSV-2) and the Japanese encephalitis virus (JEV), the most frequent cause of viral encephalitis in Asia (The Griffithsin protein (GRFT protein), produced by a red alga called  in Asia . GRFT al in Asia . Studies in Asia , 2010. T in Asia .Human noroviruses cause gastroenteritis and phlorotannins from macroalgae have been reported to be active against murine norovirus (MNV), a model for human noroviruses .The red seaweed compound carrageenan prevents the replication of Rhinoviruses , which are more common causes of infection than any other respiratory virus. Carrageenan has also been reported to help improve symptoms of common cold and reduce high viral loads . The merFucoidan and another polysaccharide from a brown seaweed have virucide activity against Influenza A (H5N1), Hantavirus and Respiratory syncytial virus (RSV), and also other non-respiratory viruses .Spirulina platensis and called calcium spirulana (Ca-SP), this isolate showed antiviral activity against replication of several enveloped viruses, including Herpes simplex virus type 1, human cytomegalovirus, measles virus, mumps virus, influenza A virus, and HIV-1 -mediated interferon-alfa (IFN-α) secretion (An extract from the brown algae ecretion .The antiviral effects of macroalgae extracts against the HMPV virus involve interaction with the viral particles outside the cells and thereby preventing infection. Meroditerpenoids of this species have both virucidal effects and the capacity to inhibit the penetration of viral particles into cells. The binding of HMPV to heparan sulfate involves charge-charge, heparan sulfate blocks the binding of HMPV to the receptor and this occlusion inhibits infection of cells .Many groups who have demonstrated that compounds and extracts from macroalgae have antiviral effects report the need for studies to elucidate the mechanisms of action of the bioactive compounds . Figure Algae are a natural source of compounds with antiviral properties, have proven efficiency against enveloped and non-enveloped viruses, this compounds and extracts from algae have inexpensive to obtain, especially those of marine origin . FurtherVarious compounds from algae have potent activities against viruses, and are strong candidates for the control and treatment of viruses that affect humans and animals. These bioactive compounds should be further explored for health applications, both in clinicals and the environmental. They are also promising for use as low toxicity sanitizers of high virucidal capacity. More studies are required both for prospecting algae for active molecules and for the development of products suitable for applications in viral control.JR, RC, AC, IT, DR-L, and GF: original draft preparation and manuscript reviewing and editing. GF: final manuscript supervision. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patients and families are entitled to an open disclosure and discussion of healthcare incidents affecting them. This reduces distress and contributes to learning for safety improvement. Complex barriers prevent effective disclosure and continue in the English NHS, despite a legal duty of candour. NHS maternity services are the focus of significant efforts to improve this. There is limited understanding of how, and to what effect, they are achieving this.A 27-month, three-phased realist evaluation identifying the critical factors contributing to improvements in the disclosure and discussion of incidents with affected families. The evaluation asks ‘what works, for whom, in what circumstances, in why respects and why?’.Phase 1: establish working hypotheses of key factors and outcomes of interventions improving disclosure and discussion, by realist literature review and in-depth realist interviews with key stakeholders  and documentary analysis) in up to 4 purposively sampled NHS trusts.Phase 3: consider hypotheses and design outputs during seven interpretive forums.Phase 1 study approval by King’s College London’s Ethics Panel (BDMRESC 22033) and National Research Ethical Approval for Phases 2–3 (IRASID:262197) (CAG:20/CAG/0121) (REC:20/LO/1152). Study sponsorship by King’s College London (HS&DR 17/99/85).Findings to be disseminated through tailored management briefings; clinician and family guidance (written and video); lay summaries, academic papers, and report with outputs tailored to maximise academic and societal impact. Views of women/family groups are represented throughout. The first investigation of interventions supporting disclosure in NHS maternity care.Methodology includes multidisciplinary co-design throughout the research cycle, with wider applicability for health service research.A realist approach examines various contexts, mechanisms and outcomes of intervention success.Research does not examine disengagement among some maternity providers.Besides patients’ entitlement to an open disclosure of clinical incidents affecting them6However, there is often disagreement or uncertainty over the principles, purpose and impact of disclosure practices. Their enactment often falls short of the expectations of harmed individuals,9In the English NHS, each clinician’s professional duty of honestyThe primary aim is to develop actionable evidence to inform maternity providers of those factors that, in particular situations, will improve the disclosure and discussion of adverse incidents in NHS maternity care with affected women/families. The secondary aim is the co-production of outputs  to benefit these groups during these events. The overarching research question is ‘what are the critical factors that can improve the incidence and quality of open disclosure in NHS maternity services?’. We will explore the actual or anticipated consequences of ongoing improvement programmes for different participants in particular contexts.The study is co-designed and co-produced with three national patient and public involvement and engagement (PPIE) partners, including charities and associations representing women/families who have experienced harm in maternity care. These partners are core members of our co-investigator group (CIG). The work is also informed by a wider project advisory group (PAG) that includes eight individual women and families with direct experience of harm in maternity care. The PAG advises on study progress, outputs and dissemination.The ongoing interventions in NHS maternity care comprise policy-led, complex interventions promoted in services in the expectation that incidence and/or quality of women/family involvement in the disclosure and discussion of adverse events will be improved. A realist, theory-driven evaluation approach informs study design. In health service evaluations, realism examines the interaction between a complex social intervention or ‘programme’, the contexts of strategic and everyday implementation work, and the un/intended outcomes for different participants.Realist evaluation follows a staged approach that moves from identifying initial working and interconnected hypotheses from secondary sources to the ‘testing’ (refinement or overturning) of these hypotheses using primary data to identify those contingencies that drive and direct improvement.18The 3-phased, 27-month, qualitative study will:Establish a series of working hypotheses by literature scoping and expert stakeholder consultation (Study Phase 1a).‘Test’ these working hypotheses by in-depth interviews with a range of national stakeholders (Study Phase 1b) and by ethnographic research (Study Phase 2).Agree with national stakeholders and different interest groups and experts, the critical factors required to trigger and sustain interventions to improve the disclosure and discussion of harm with women/families in NHS maternity care, and co-design outputs to support these generative factors (Study Phase 3).Follow the quality standards for realist evaluation.19The study runs from May 2019 to April 2022 with 9 months COVID-related research interruption.See 10.1136/bmjopen-2020-048285.supp1Supplementary dataThe PROSPERO registered realist review will identify and extract literature from electronic databases from social science, nursing, and medical and health service management. The purpose of the review is descriptive and will identify papers and documents of relevance to disclosure and discussion of harm in international maternity services. Initial scoping searches will identify keywords, synonyms and spelling variations. Searching will include free text and database-specific subject headings (such as MeSH terms), advanced Boolean truncation, ‘explode’ and other techniques. The database search will be supplemented by ‘snowball’ strategies, scanning reference lists from relevant papers and advice from subject experts. Inclusion criteria will be ‘maternity and perinatal services’ and ‘disclosure and discussion of harm’. Following realist methodology for data gathering,Following RAMESES guidanceOne-to-one, open-ended, audio-recorded telephone interviews conducted with approximately 20 national stakeholders in service improvement and patient/family engagement in NHS maternity care using a topic guide developed from Phase 1a findings and piloted with co-investigators. This interview study will (1) explore interviewees’ various experiences and views concerning the programme theories developed from the realist review,Interviewees will be sampled for maximum diversity across national stakeholder groups. Advice from the CIG and the PAG and snowball sampling with interviewees will guide the interviewee approach and selection.See 10.1136/bmjopen-2020-048285.supp2Supplementary dataUp to four NHS maternity services, identified as high performing or improving (in terms of supporting interventions for strengthening disclosure practices with women/families after harm in maternity care), will be selected as ethnographic case studies. An ethnographic methodology will enable in-depth interpretation of the context and practices of clinical or organisational relationships, including the situated and often taken-for-granted qualities of these practices, including their negotiation and legitimation.A case study comprises 10×3-day visits, completed over 10 months, with periods between visits for researchers to discuss and compare emergent findings. Initial hypotheses and their refinements or revisions (developed in Study Phase 1) will focus the comparative case studies. However, they will also document (1) how relevant policy and procedures are promoted, managed and monitored as well as interpreted and evaluated by recipients , (2) factors that influence the ‘when and how’ of procedural enactments in actual clinical settings by different participants, including women/families, clinicians, administrators and management and governance teams, (3) the interplay of formal and informal local workplace cultures and wider public and policy debates and (4) personal, team and service histories of disclosure experiences, including their potential to influence wider revisions in the ‘Being Open’ agenda, patient–clinician–manager relationships and their acceptance as routine.Our sampling follows social science principles. Due to expected challenges in engaging managers or clinicians in some maternity services, the sampling frame includes only cases of positive deviance to maximise engagement in the study. A positive deviance approach posits that behaviours (and situations) the produce poor practice or experience are variations on the same processes that produce successful practices. Therefore, focusing on success is a more effective tactic for understanding how improvements are achieved.Further information on the sampling framework is described in 10.1136/bmjopen-2020-048285.supp3Supplementary dataApproach and recruitment of selected organisations, site principal investigators (PIs) and key gatekeepers are tailored from a theory-based, business-model approach to recruitment to clinical studies. A description of the application of this business model to the study is described in 10.1136/bmjopen-2020-048285.supp4Supplementary dataEach ethnographic case study will triangulate findings collected by the following methods:Focused observations [estimated 25 hours] of formal and informal events and routines intended to secure improvement in disclosure of adverse incidents with women/families .Documentary data including redacted incident reports; meeting minutes, action plans; organisational and service bulletins; training reports; quality and safety improvement reports; and incident reports from families to construct a retrospective picture of open disclosure work within that case study.With participants’ informed consent, in-depth interviews will be audio-recorded on encrypted devices and transcribed verbatim. The observational data will be recorded as low inference notes and later word-processed by that researcher. All documentary data will be redacted before inclusion in the study.Following initial analysis of case-study data, seven forums of purposively selected individuals will validate findingsPotential participants will be identified during participation with Phase 1 or Phase 2 and sampled for maximum variation in their experiences of disclosure practice improvements. A maximum of 25 participants will be invited to any one of the 7 local forums. A final national forum, including local forum representatives and national policy-makers, will accommodate up to 60 participants and be externally facilitated. The national event will be hosted at the sponsoring university. Wider consultations of study findings and output development will be with established online forums for harmed patients/families and clinicians interested in maternity safety improvement.To ensure that the views and interests of women/families, and the wider public, remain the focus of the study, our PPIE strategy supports representation at all study phases . We have followed the new national standards,The involvement of women/families and their charity and association representatives in all stages of the research cycle .A multidisciplinary and multi-sector research team that includes public members.Ongoing collaboration with an extensive and varied PAG, including their involvement in the summative forum.Use of interpretive forums (described above).The study recognises the need for co-development of outputs so that different interests, values and subject positions can be accommodated. Standards for reporting qualitative researchData will be organised and analysed following a realist logic approach. Retroductive analysis (moving between inductive and deductive approaches) will identify and explore main context–mechanism–outcome (CMO) patterns, particularly the generative causal mechanisms shaping these configurations. This approach is to refine, develop or refute initial programme theories developed progressively from Study Phase 1  and Study Phase 2 (ethnographic case studies). Additional CMO configurations may be elucidated at Study Phase 2 and examined retroductively across this data set to inform, revise or add to the programme theories. Data analysis will be conducted at the close of each study phase to maintain an ongoing and iterative approach to programme theory refinement. Two researchers trained in realist evaluation will independently identify and explore main CMO configurations. Then with additional researchers and stakeholders, explore programme theory refinement in the light of these. Phase 2 interview, ethnographic and documentary data, will also be analysed in a triangulating fashion to develop concrete descriptions of the generative mechanisms underlying open disclosure interventions and the contextual factors that trigger effects at particular times. We will seek to identify convergent and contradictory evidence within and then across the interventions’ different organisational, interpersonal and individual contexts. Coding and data management will be organised and audited using qualitative data analysis software, Nvivo (V.12), and CMO data coding sheets will be developed for the analysis.Where possible, cross-tabulations and scattergrams will be used to plot the relationship between apparently anomalous aspects of improvement work in this area and other social variables .A stakeholder analysis using the RAPID AIIM matrixThe hypotheses generated will also be developed using conceptual frameworks drawn from the social sciences  and perspectives on team and organisational safety and resilience. RAMESES II reporting standards for realist evaluations will be followed for the presentation of data collection, findings and discussion.30Outputs will be robust and actionable evidence about the organisational strategies. These team, service and network practices can support and enhance the quality and extent of open disclosure within NHS maternity care and wider NHS care provision within particular circumstances and with respect to different interests groups. Our findings are intended to impact three organisational areas of healthcare: the micro-level of disclosure processes and relationships; meso-level of service management and organisation of these processes; and macro-level of policy. Therefore, our dissemination strategy, with outputs tailored to the audience,Co-designed briefing documents and guidance for maternity service managers and policy-makers.Co-designed information materials  and video animations for services, clinicians and women/families (and promotion of these by our Stage 3 study participants).Accessible public information and lay summaries of study findings disseminated through our dedicated Twitter account and website.Peer-reviewed academic journal articles .A summary of findings was sent to all study participants who have consented to receive this information.More widely, the dissemination plan is underpinned by all RCUK identified factors that help to generate academic and societal impact. The research will enhance the evidence base for improving the use and quality of open disclosure in NHS maternity care, influencing policy and practice; will produce theoretically informed knowledge of the critical factors for fostering, enhancing and sustaining open disclosure; and will support the growth of networks and knowledge exchange between NHS maternity providers, women/family interest groups and associations, policy-makers and non-maternity NHS providers.We have identified this study as a high risk, qualitative research study because we are:Conducting research on a highly sensitive and potentially emotive topic for all concerned.Interviewing and observing clinicians and managers whose care might have resulted in harm.Observing meetings with women/families and managers that may become adversarial.The primary ethical issues requiring mitigation are:Non-consent or withdrawal of consent to study participation : in these situations, we will always respect the withdrawal of study participation and state this in all participant information and consent forms. We also will seek to focus observations of collective routines on more public workplace activities .Disclosure of negligence : we will make it clear in all participant observations that we have a duty to disclose staff negligence. We will establish a system for researchers concerned about negligence to alert the PI within an established time frame and prompt notification of the relevant Freedom to Speak Up Guardian.Participant engagement : we know that obtaining initial and ongoing engagement with participants is possible if done sensitively and ethically. We will reassure all trusts and services that we will not be approaching, interviewing or observing women and families directly.Non-malfeasance regarding study participants: in research information and methods, we will follow current guidance on interviewing people about potentially sensitive topics or traumatic experienceNon-malfeasance regarding PPIE representatives : we have structured PPIE representation across the study, so that leadership and support roles are clearly defined. We have ensured that all PPIE co-applicants and PAG members are highly experienced in research and engaging with diverse interest groups. We have also ensured linkage between the PPIE PAG lead and the study PAG lead to ensure consistency of support and representation.Issues of anonymity, confidentiality and informed consent will be addressed in the recruitment of all participants, data collection processes and data storage. The principles of beneficence and non-malfeasance will be adhered to.Throughout the study, the MRC/HRA guidance ‘GDPR and Data Protection Act 2018: key facts for researchers’ has been followed.This is the first study to investigate the implementation of interventions for disclosure and discussion of harm in NHS maternity care.Project methodology includes multidisciplinary and user representative co-design of study questions, research focus, study outputs and dissemination strategy, with wider applicability in health service research.A realist approach identifies ‘key ingredients for potential success’ for maternity providers engaged in disclosure improvement.The study does not examine reasons for disinterest or disengagement among some maternity providers.


Nucleic acid analysis is used in many areas of life sciences such as medicine, food safety, and environmental monitoring. Accurate, reliable measurements of nucleic acids are crucial for maximum impact, yet users are often unaware of the global metrological infrastructure that exists to support these measurements. In this work, we describe international efforts to improve nucleic acid analysis, with a focus on the Nucleic Acid Analysis Working Group (NAWG) of the Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology (CCQM). The NAWG is an international group dedicated to improving the global comparability of nucleic acid measurements; its primary focus is to support the development and maintenance of measurement capabilities and the dissemination of measurement services from its members: the National Metrology Institutes (NMIs) and Designated Institutes (DIs). These NMIs and DIs provide DNA and RNA measurement services developed in response to the needs of their stakeholders. The NAWG members have conducted cutting edge work over the last 20 years, demonstrating the ability to support the reliability, comparability, and traceability of nucleic acid measurement results in a variety of sectors.The online version contains supplementary material available at 10.1007/s00216-021-03712-x. Nucleic acid (NA) analysis is fundamental for many areas of life sciences including biotechnology, cell biology, genetics, microbiology, and molecular biology. Applied nucleic acid analysis is increasingly required for applications in different fields such as medicine, pharmacy, veterinary medicine, food safety, and environmental monitoring. Nucleic acid analysis encompasses the detection, identification, and quantification of nucleic acids from different organisms, often from diverse matrices. Accurate and metrologically traceable measurements of nucleic acids enable reliable results to support decision makers like healthcare workers, sanitary inspectors, and competent authorities.In the last few decades, nucleic acid analysis has rapidly developed supported by an increasingly diverse array of technologies. After the understandable slow beginnings of RNA sequencing in the 1960s, DNA sequencing in the 1970s, and the invention of polymerase chain reaction (PCR) in the 1960s, all these analytical approaches faced extremely intensive developments. Currently, RNA sequencing is an indispensable tool for transcriptome-wide analysis and is contributing to a fuller understanding of RNA biology , 3; and Despite broad use of nucleic analysis, comparability of nucleic acid quantification results is unsatisfactory among laboratories in many areas. This is especially evident where quantitative analysis of nucleic acids is required. For example, in the food and feed safety area, national reference laboratories and official control laboratories in the European Union use common validated methods to determine the mass fraction of the genetically modified organisms (GMOs) in samples. Reports on laboratory performances in the proficiency tests provided by the European Union Reference Laboratory for Genetically Modified Food and Feed (EURL-GMFF)  usually It is unfortunate that metrology, the science of measurement, and metrological considerations (such as routes to traceability and sources of uncertainty) are sometimes overlooked in a number of applied areas, with those applying nucleic acid analysis typically assuming their systems are fit for purpose in this respect. Certainly, many breakthroughs in sequence discovery, genome evaluation, and routine monitoring have succeeded without the assistance of the measurement science community. Yet as these fields have pushed to offer ever more high-throughput (“omics”) and precise quantitative solutions, they have been met with challenges associated with standardization and traceability of measurement results. Many of those working in these spaces neither realize that measurement science is a field in its own right, nor that a global infrastructure exists to support them in this respect. Given the wide variety of applications in the nucleic acid analysis space, there are numerous examples where applying measurement science could support improving the routine application both in basic research and applied scenarios. This overview outlines the benefits of metrological support for nucleic acid analysis in the life science sectors that are more metrologically established, while also championing advancements in the other sectors.Many international organizations and societies are making efforts to improve the consistency of results among laboratories in general such as the International Organization for Standardization (ISO)  or the EOne of the international groups dedicated to improving the comparability of nucleic acid measurements independent of the field is the Working Group on Nucleic Acid Analysis (NAWG)  of the CActivities related to nucleic acid analysis within CCQM began in 1999, the year that the XXI General Conference for Weights and Measures (CGPM)  discusseAn Ad Hoc Biometrology Task Group was established, and in 2000, it presented a report on new measurement challenges. In 2001, this task group became the BioAnalysis Working Group (BAWG) of the CCQM . In 2014The focus of the NAWG is to support global comparability and metrological traceability of measurement results in the area of the analysis of nucleic acid polymer sequences, their modifications, and their abundance. Members of the NAWG are NMIs and DIs that provide nucleic acid measurement services developed in response to the needs of their national and international stakeholders. The ubiquity of the nucleic acid analysis methods, the molecules they target, and the associated challenges are agnostic to sectors in most cases. Consequently, as an international working group that focuses on nucleic acid analysis regardless of sector, the NAWG is uniquely placed to advance the measurements in one sector using knowledge from another . This coRegional metrology organizations (RMOs) also organize activities for metrology in nucleic acid analysis. In the Asia Pacific Metrology Programme (APMP) , the TecIn the Euro-Asian Cooperation of National Metrological Institutions (COOMET) , the bioWithin the Inter-American Metrology System (SIM) , the fieEURAMET is the European Association of National Metrology Institutes . NucleicThe primary focus of NAWG is to support the development and maintenance of measurement capabilities and dissemination of measurement services from NMIs/DIs. This is supported via interlaboratory studies to evaluate the competencies of NMIs and DIs and provide evidence of the validity and international equivalence of measurement services for customers and stakeholders worldwide. Based on their performance in the interlaboratory studies, NMIs and DIs can submit their calibration and measurement capabilities (CMCs) for review. Following the successful review by RMOs and designated CCQM members, CMCs are entered into the International Bureau of Weights and Measures (BIPM)  key compIn parallel with recognizing current and future needs in standardization and traceability, NAWG is also addressing some of the fundamental scientific challenges associated with nucleic acid analysis. Nucleic acids vary in their stability which can impact both reference materials and biobanks, as well as routine testing during sample handling, isolation, and purification. DNA is generally considered stable; however, low mass concentrations (less than 5 ng/μL) of both DNA and RNA may require the addition of stabilizing “carrier” molecules (such as yeast tRNA or other background heterologous RNA/DNA) to prevent decreases in concentration over time. RNA can be less stable than DNA, both due to inherent chemical reasons and because RNases, which can quickly degrade RNA, can be both ubiquitous and stable in the environment. Reduced stability of an analyte  may impact the quantity of a given sequence or the composition of its matrix, both of which may affect the measurement result. Furthermore, information on the wider target sequence composition may also be useful as factors like fragment size may also affect stability, resulting in potential discrepancies between methods , 55.Sequence, the order of nucleotide monomers in the polymeric nucleic acid single-strand or double-strand molecule, is a nominal property. Sequence value has no size or magnitude; it is established by what is called an examination procedure in metrology , 56. SeqScientific challenges associated with the measurement of a given nucleic acid vary depending on the complexity of the nucleic acid in question  as well as the complexity of the matrix in which it has been presented, as nucleic acids are almost exclusively measured in solution. Consequently, considerations associated with sources of uncertainty and routes to traceability frequently include volume measurements as an additional factor. Nucleic acid analyses typically require multistep processes with prior manipulation of the sample to isolate and purify the nucleic acids for further analysis . When conducting nucleic acid analysis, a key distinction is whether the analyte is a part of a larger molecule  or whether it is contained within the sequence being measured (such as when measuring actionable cancer genetic variants or genetic polymorphism). From an analytical point of view, these two categories can present distinct challenges when considering sources of uncertainty. Furthermore, the analytical sources of error can differ when the same nucleic acid sequence is measured in different matrices  Fig. a.Fig. 1T8 g/mol). Additionally, samples can consist of mixtures of different genomes, which further complicates measurement/examination. Further potential sources of error are added when additional steps are required to prepare nucleic acids for analysis, such as purification, nucleic acid digestion , adaptation , modification (bisulfite conversion), or reverse transcription (generation of complementary nucleic acids). Extraction (purification) is often required when performing nucleic acid analysis, because the matrix is typically unsuitable for the final molecular analysis steps. All these steps contribute to the uncertainty associated with the final analysis.When discussing a particular measurement/examination, and associated challenges, the type of sample (including the properties of the nucleic acid and its matrix) must also be considered Fig. a. At theWhen considering a given analyte, the type of nucleic acid analysis Fig. b can be The NAWG has conducted leading work in nucleic acid analysis, demonstrating its ability to support the reliability, comparability, and traceability of nucleic acid measurement results. NAWG had dedicated extensive efforts to understanding and evaluating the absolute quantification of nucleic acid with digital PCR (dPCR). For example, NAWG has investigated the influence of the partition volume on the absolute quantification of DNA in terms of copy numbers –65 and aMultiple NAWG members were involved in the development of guidelines on standardization for applying nucleic acid analysis. These guidelines give researchers advice on how to approach experimental design and how to report data to aid reproducibility –70; manyNucleic acid analysis for food authentication is most metrologically advanced (in terms of traceability and understanding sources of uncertainty), relative to other routinely applied nucleic acid measurements. Therefore, most of the NAWG-supported CMCs for NMIs exist in the food analysis sector. To date (as of September 2021), all completed NAWG Key Comparisons have been in the area of food analysis and related to the needs of NMIs and DIs to provide services for detection, identification, and quantification of genetically modified organisms (GMOs) and food adulterations (Table S1).The use of GMO crops has increased significantly since the 1990s. Commercial cultivation of GMOs contributes to global feed, fiber, food, and fuel production; however, the safety of GMOs and their products is a major concern in some countries. National legislation regulating GMOs and their products varies significantly across jurisdictions. A global reference measurement system, including reference materials and reference methods, needs to be established to facilitate international trade and provide consumers with information on the levels of GMO constituents. Nucleic acid analysis methods are commonly used to quantify GMO content in processed food and feed , 80 and NAWG is working to support members in developing nucleic acid reference materials and calibration services for relative GMO quantity and food adulteration. This process involves DNA extraction from a complex biological matrix, followed by measurement of specific genomic DNA fragments—the GMO-specific sequence and the endogenous (species-specific) gene-specific sequence. The measurements are performed either by qPCR using an independent reference material as a calibrant or by dPCR –83.Zea maize L.) seed powder in the CCQM-K86 study [Oryza sativa L.) seed powder in the CCQM-K86.b study [Brassica napus L.) seed powder [A series of four key comparisons enabled NMIs and DIs to demonstrate and document their capabilities in measurements of the number of copies of specified intact sequence fragments extracted from different matrices and to determine their relative quantity. In the first two studies, matrices were rich in polymeric carbohydrate (amylose and amylopectin) and poor in fat: maize  in 7 NMIs/DIs at present (Table S2).While molecular testing is used in clinical diagnostics, reference methods are not as prevalent in this sector as they are in clinical chemistry; however, due to the desire of stakeholders to apply increasingly advanced high-throughput and quantitative measurements, this is changing and NAWG activities in the health sector are increasing. Currently, molecular diagnostic tools are used to genotype patients, to quantify pathogenic burden, to quantify transcriptional surrogate biomarkers of disease, or to measure disease predictors using subtle changes at the epigenetic level. To support NMI measurement capacity in these areas, a series of pilot studies focused on the identification and quantification of nucleic acid sequences were conducted (Table S3). In accordance with the BIPM guidelines measurement comparisons in CIPM MRA (CIPM MRA-G-11) , pilot sTo date, health-related NAWG pilot studies have mainly focused on the relative or absolute quantification of specific targets in simple matrices (aqueous buffer or cell suspension). The studies used a variety of sample types including pure synthetic and natural RNA and DNA, as well as whole cells.The initial health studies aimed to investigate the capabilities to support measurements of mRNA biomarkers. Two studies were organized using exogenous synthetic targets from the External RNA Controls Consortium (ERCC)  as measuFollowing the progress in the field and to further explore the potential for using higher-accuracy SI-traceable methods for nucleic acid quantification, a study on absolute quantification of HIV-1 RNA copy number (CCQM-P199) was proposed followed by a similar study on SARS-CoV-2 copy number quantification (CCQM-P199.b) which was NAWG’s response to the COVID-19 pandemic. Both studies demonstrated that NAWG members are capable of high-accuracy measurement of RNA molecules in buffered solutions. The CCQM-P199.b study demonstrated SARS-CoV-2 quantification was possible with most laboratories submitting values with ± 40% of the mean . ReportsIn addition to studies organized by NAWG, NMIs and DIs are establishing their measurement capacities in support of different health areas within their regional metrology organizations. Within the aforementioned projects , reference measurement procedures for nucleic acid measurements were or are being developed. One of the aims of the BioSITrace project was to establish dPCR as a primary reference measurement procedure for DNA copy number quantification through comprehensive evaluation of sources of error and comparison with mass spectrometry measurements. A frequently occurring mutation in colorectal cancer (KRAS G12D) was used as a model, and the accuracy of dPCR for copy number quantification of point mutations was assessed by evaluating potential sources of uncertainty influencing measurements . This woMycobacterium tuberculosis, and HIV, and their resistance were investigated [Similarly in the frame of Infect-Met and AntiMicroResist projects, methods for reliable quantification of several infectious agents, human influenza A virus, human cytomegalovirus, stigated –97. One stigated . The SEPstigated .https://www-s.nist.gov/srmors/view_detail.cfm?srm=8375), and human DNA [Besides the development of accurate measurement procedures, NMIs and DIs are developing controls and reference materials to support both local and international health sectors. For example, the National Institute of Standards and Technology (NIST) offers a range of reference materials for biometrology, including materials for cancer measurements –102, viruman DNA , 105. Thuman DNA , BRAF V6uman DNA , 108. Thuman DNA .In response to the COVID-19 pandemic in 2020, a number of NMIs and DIs have developed SARS-CoV-2-related reference materials (RM), aiming to support nucleic acid testing . Most ofAs we progress into the next decade, NAWG activities will likely continue to support food-associated testing with key comparisons reflecting additional unmet needs, such as different matrices , species , and molecular challenges . It is anticipated that food-associated measurements will expand to the agriculture/biotechnology sector; studies to support the monitoring of crop disease are planned which will expand the capacities of NAWG in view of the One Health approach. In line with its strategy heading for 2030 as well as the CCQM strategy document 2021–2030 , NAWG wiDeveloped capacities will also be of value to the other sectors such as industrial biotechnology where novel methods, such as CRISPR CAS-9–based genetic modification, are being applied , 119. BiThe increasing need for genomic, transcriptomic, and epigenomic analyses means that the NAWG will need to explore the development of strategies to support advanced sequencing capabilities, including for purity analysis. The metrological support in this area is lacking , and chaLast but not least, DNA measurements have become a valuable tool for environmental biodiversity monitoring. Sequencing of environmental DNA  allows the identification of bacterial and eukaryotic species. Environmental DNA measurements, including quantitative DNA analysis, are used to study biodiversity and to monitor ecosystem changes. The NAWG strategy includes DNA  sequencing–based species identification and bacterial quantification; participating NMIs/DIs will establish calibration and measurement capabilities in these areas in the near future.Increase research accuracy and therefore our understanding of the biological systems we studyEnable the translation of findings to routine application through preempting considerations that will ensure test applications are both robust and reproducibleFacilitate routine application of nucleic acid analysis methods by enabling developers and users to demonstrate confidence in delivering the most accurate measurementsAs the use of nucleic acid analysis is increasingly applied across a wide range of sectors, measurement science will facilitate more a rapid and efficiency application. This will be needed to:Along with associated relevant organizations, the CCQM NAWG and associated NMIs/DIs will continue to develop routes to ensure measurement accuracy and traceability for nucleic acid analysis. This will support measurement accuracy as molecular methods become increasingly applied for routine measurements to a wide variety of sectors.Supplementary file1 (DOCX 37 KB)Supplementary file2 (PDF 441 KB)Below is the link to the electronic supplementary material.


This paper aims to develop a telehealth success model and discusses three critical components: (1) health information quality, (2) electronic health record system quality, and (3) telehealth service quality to ensure effective telehealth service delivery, reduce professional burnout, and enhance access to care. The paper applied a policy analysis method and discussed telehealth applications in rural health, mental health, and veterans health services. The results pointed out the fact that, although telehealth paired with semantic/organizational interoperability facilitates value-based and team-based care, challenges remain to enhance user (both patients and clinicians) experience and satisfaction. The conclusion indicates that approaches at systemic and physician levels are needed to reduce disparities in health technology adoption and improve access to telehealth care. A telehealth platform integrated with an interoperable electronic health record (EHR) system can contribute directly toward achieving the often-discussed “quadruple aim” —better hDespite the benefits of telehealth in rural health, mental health, and Veterans Administration health services, disparities continue to exist in access to care. Patients without internet service, appropriate devices, or digital literacy skills experience greater challenges in accessing care via telehealth. The COVID-19 pandemic has also caused substantial financial strain on hospitals, and it is uncertain if the current reimbursement and payment model for telehealth service/devices and regulation flexibility for virtual consulting will continue after the pandemic is over.To help integrate telehealth into clinical practice and improve patient care, health policy at the systemic level should accelerate the uptake of telehealth. On the industry level, hospitals should identify adoption strategies for different types of telehealth services and evaluate telehealth products for health care delivery. On the physician level, health providers should offer the same level of care and follow the same treatment guidelines for telehealth services as with in-person visits and ensure that their practices are compliant with applicable regulations.Telehealth has become a rapidly growing sector of health care delivery systems. Previous studies show evidence that telehealth tools and services increase the overall effectiveness of physicians in (1) counseling patients with chronic conditions, 2) psychotherapy support for behavioral interventions, and (3) remote monitoring of patients [ psychothThe shortage of health providers and increasing consumer demand (from the aging population and people diagnosed with chronic diseases) were key factors in expanding the scope and scale of telehealth services . The 201The COVID-19 pandemic accelerated the adoption of telehealth tools and services. Amid the pandemic, some hospitals are seeing 500 to 600 patients per day via video or telephone visits . To enabForward triage to screen patients with COVID-19 symptoms before arrival to a health care facility so as to reduce exposure to the virus Continue patient care and provide virtual consultation to nonvirus patients, especially those with chronic diseasesThis paper applies a conceptual model  based onDevice interoperability and data integration are key aspects of telehealth delivery. Hospital interoperability  covers tFor value-based care to achieve and protect patient safety, the EHR system needs to deliver accurate and clinically appropriate data across care settings to both physicians and patients. Studies suggest that hospital sharing of diagnostic data with providers within their system is associated with lower patient mortality, and the hospital interoperability level is associated with improved process quality related to conditions of acute myocardial infarction, heart failure, and pneumonia at acute care hospitals -15.However, establishing a telehealth platform in a short period of time amid pandemic conditions could put health information—patient names, address, dates, diagnoses, and more—at higher risks to safety and security . The intIntegrating telehealth programs into a hospital’s existing EHR system infrastructure helps maximize the benefits of telemedicine, as providers and staff already have experience working with the baseline system . Over 95In 2020, the US Office of the National Coordinator for Health Information Technology (ONC) established requirements for a secure standards-based application programming interface (API) to support each individual patient’s access and control of their electronic health information ,23. The Advanced interoperability—especially at semantic and organizational levels—can enable telehealth to expand access, exchange information, and provide user-centered services to both physicians and patients . CurrentApproximately 80% of rural areas in the United States are classified as medically underserved and in health professional shortage areas ,29. ThesFor rural residents, telehealth care increased access to experienced providers and high-quality care ,35, imprThere are two primary uses for tele–mental health: provider consultations with mental health specialists in primary care and emergency department settings, and the direct provision of mental health services including home-based services ,38.For people experiencing serious mental illness, telehealth has the potential to improve quality of life and general mental health, reduce depressive symptoms, build more confidence in managing depression, and increase satisfaction with mental health and coping skills compared to treatment offered in-person only ,39. For As one of the early adopters of telehealth, the Veterans Health Administration (VHA) is currently the largest telehealth provider in the United States . In 2018A telehealth program paired with the right EHR system can serve as a care collaboration platform and help optimize team-based care delivery ,46. It cTelehealth interventions, particularly remote monitoring and SMS text messaging, were associated improvements in obstetric outcomes, perinatal smoking cessation, breastfeeding, and schedule optimization for high-risk obstetrics . For at-An EHR system with organizational interoperability allows institutions to aggregate community-level data from disparate sources to track influenza/disease trends for population health ,52. For The COVID-19 pandemic in the United States is affecting different areas at different times and levels: cases spike in some states while others face the threats of both COVID-19 resurgence and seasonal flu . Many hoEarly in March 2020, CMS modified policies to lift originating site restrictions and expand the type of visits allowed virtually . HoweverWith hospitals and the health care system faced with uncertainties about the duration of this pandemic and the structure of future telehealth benefits, the development of clear regulatory requirements and timetables could help reduce administrative and technological constraints associated with virtual health care delivery and encourage further investment in health care information technology (IT) infrastructure ,61.The COVID-19 pandemic has created substantial financial difficulties for both hospitals and the health system ,63. As aAlthough most hospitals in the United States have adopted interoperable EHR systems, there is little evidence about whether small, rural, and safety net hospitals are keeping up . CompareSubstantial disparities in access to telehealth services also remain . EvidencTo ensure that EHRs cooperate effectively in an interoperable structure, substantial governmental regulation has been put into place. In the United States, CMS and the ONC regulate EHR privacy, security, and standards for hospitals or health providers and health IT developers ,76. In JIn the European Union, to facilitate cross-border EHR interoperability, the General Data Protection Regulation established explicit rules to process and protect patient health data . On the Studies suggest that telehealth programs paired with the right EHR system enhance care access, increase patient satisfaction, and reduce medical spending ,85, and To help integrate telehealth into clinical practice and improve patient care, on a systemic level, health policies should accelerate the uptake of telehealth, including tele–mental health, to improve care quality, cost-effectiveness, and value of care . FederalOn an industry/organization level, hospitals need to identify strategies to adopt and integrate different types of telehealth services, and evaluate telehealth products for health care delivery ,70. FutuOn the physician level, clinicians who provide telehealth should offer the same level of care and follow the same treatment guidelines they would follow for in-person visits . Moreove


The Living Alone with Cognitive Impairment (LACI) Project bridges research and policy to develop policy recommendations to address the needs of people living alone with cognitive impairment (PLACI) through new expansions of long-term services and supports. There are an estimated 4.3 million PLACI in the United States. Access to formal LTSS is critical to them because they lack cohabitants to assist with activities of daily living and navigating LTSS, especially during the COVID-19 pandemic. To bridge research with policy, seventeen Policy Advisory Group (PAG) members were recruited, including representatives from state and local government, and LTSS policy experts. Between November 2020-January 2021, a total of 17 individual meetings were conducted with PAG members and one webinar convening of the group. The PAG identified preliminary recommendations in three areas, including: 1) important areas of inquiry for qualitative and quantitative research, 2) best practices for addressing equity across diverse racial/ethnic minority groups, and 3) preliminary policy recommendations that leverage existing innovations. The LACI Project team is actively incorporating the PAG feedback by: a) modifying research questions for the quantitative and qualitative research, b) convening a diverse Community Advisory Group, and c) crafting preliminary policy recommendations based on PAG input. To conclude, engaging the expertise of the PAG to develop policy recommendations to increase LTSS for PLACI is a promising method of bridging research and policy. The engagement of policy experts ensures that fore-coming research is designed to address the most important policy gaps and all policy recommendations are actionable and timely.


Population and Health Outcomes; (2) Access for All Clients; (3) Costs and Cost Effectiveness; and (4) Experiences of Clients and Occupational Therapy Practitioners. This article describes the development and expert reviewer evaluation of the PACE Framework. In addition, the PACE Framework's domains, subdomains, and outcome measure examples are described along with future directions for implementation in occupational therapy research, practice, and program evaluation.The use of telehealth to deliver occupational therapy services rapidly expanded during the COVID-19 pandemic. There are frameworks to evaluate services delivered through telehealth; however, none are specific to occupational therapy. Therefore, occupational therapy would benefit from a framework to systematically evaluate components of telehealth service delivery and build evidence to demonstrate the distinct value of occupational therapy. The PACE Framework outlines four priority domains to address areas of need: (1)  The use of telehealth to deliver occupational therapy services rapidly expanded due to the COVID-19 pandemic as practitioners in community-based settings, early intervention, hospitals, nursing homes, outpatient clinics, and schools pivoted to using telehealth to serve clients. The American Occupational Therapy Association  defined profession specific but not necessarily different when approached through telehealth versus in-person service delivery.There are existing frameworks for the evaluation and measurement of healthcare services delivered through telehealth. Population and Health Outcomes; (2) Access for All Clients; (3) Costs and Cost Effectiveness; and (4) Experiences of Clients and Occupational Therapy Practitioners.The occupational therapy profession would benefit from a framework that serves as a resource to support evaluation of evidence-based telehealth practices. The purpose of this article is to describe the PACE Framework for measurement and evaluation of occupational therapy services delivered through telehealth. We draw from existing frameworks of telehealth measurement to propose four domains that are priorities for occupational therapy: (1) In October 2020, the American Occupational Therapy Foundation (AOTF) convened a Planning Grant Collective titled “Stimulating Research to Advance Evidence-Based Applications of Telehealth in Occupational Therapy.” This event led to the identification of several areas of telehealth research and practice. These areas were described in a publication with outcomes from that meeting . ExistinPrior to inviting stakeholder review of the PACE framework, the Institutional Review Board granted exempt status to the review process. We invited nine stakeholders with various backgrounds in occupational therapy practice and research and representation across practice settings , to review the PACE Framework and provide feedback. Specifically, we asked the stakeholders to use a sliding scale of 1–100 to rate the (1) clarity of the PACE Framework , (2) utility of the PACE Framework , (3) content of the PACE Framework , (4) distinctness of each construct , (5) alignment of outcomes within each construct , and (6) possibility of implementation of the PACE Framework (0=I would not recommend PACE Framework to a colleague to 100=I would highly recommend the PACE Framework to a colleague). We also asked stakeholders four open-ended questions focused on general feedback, inclusion of additional constructs, outcomes or measures, and the ways in which the PACE Framework may be implemented in their respective practice and/or research settings.We used descriptive statistics to examine quantitative stakeholder responses  and compiled qualitative responses for each question to refine the framework. We used content analysis  to examiAccess for All Clients s as it may be related to social determinants of health (see Results). We also emphasized that outcomes may include reported measures  and/or evidence from documentation or medical records. Third, we responded to reviewer suggestions about missing outcome measures by adding suggested assessments. We removed any condition specific outcome measures because researchers and/or practitioners are equipped with such knowledge of assessments specific to their contexts . Fourth, with regard to envisioned use, we emphasized that the PACE Framework may be used to support evidence-based occupational therapy services, and includes both outcome and process measures.Based on content analysis of qualitative responses, we discussed how to integrate stakeholder feedback within the PACE Framework. Qualitative comments that resulted in edits to the PACE Framework are shown in Population and Health Outcomes; (2) Access for All Clients; (3) Costs and Cost Effectiveness; and (4) Experiences of Clients and Occupational Therapy Practitioners. Within each domain, we included a number of possible outcomes and associated operational definitions that aligned with AOTA's Occupational Therapy Practice Framework – 4th Edition (2020d) and/or the The PACE Framework is comprised of four domains: (1) The PACE Framework was designed for outcome and process evaluation of evidence-based interventions delivered through telehealth. Although specific elements of the PACE Framework are applicable to in-person occupational therapy services, the entirety of the Framework was created with the intention of informing telehealth and hybrid service delivery. Therefore, the example outcome measures provided are easily administered through telehealth. Example outcome measures reflect observation, process evaluation, and self-, caregiver-, and practitioner-report, as well as evidence that may be gathered through chart and/or documentation review. There is a lack of evidence supporting administration of behavioral/performance-based assessments, and we chose not to include many of these in the PACE Framework . The PACDiversity, Equity and Inclusion in Occupational Therapy, Resources and the DEI Tool Kit  Equns Guide ; (3) Dis Toolkit  and (4) Services . While dPopulation and Health Outcomes domain include care coordination, occupational performance, participation, prevention, promotion of health and wellness, quality of life, role competence, self-determination/self-management, and caregiver and client well-being  of occupational therapy services provided through telehealth. Components of cost and cost effectiveness associated with telehealth may include a decrease in cancelled appointments and “no shows,” and indirect cost savings for clients such as less time off work and elimination of travel to therapy appointments. In addition, occupational therapy practitioners working in settings that require travel to clients’ homes or between facilities  also experience cost avoidance associated with decreased travel. Prevention of hospitalization/re-hospitalization, pressure ulcers, and other health-related complications are examples of cost-avoidance that may occur and factor into the value of occupational services provided through telehealth.Telehealth is a natural fit for occupational therapy interventions aimed at increasing participation in authentic contexts through the use of occupation. Telehealth creates opportunities for providing and measuring occupational therapy services in authentic contexts, and the inclusion of caregivers during telehealth sessions changes the overall experience for the client and the occupational therapy practitioner. Measuring client, caregiver/care partner, and provider satisfaction are all essential to understanding the overall experience of telehealth. Preferences for and acceptability of all components of telehealth, such as the videoconference platform and session frequency or intensity, should be considered. Assessing the client, caregiver, and practitioner experience early and at frequent intervals will facilitate adoption and long-term use.The goal of occupational therapy is to facilitate participation in authentic contexts through the use of occupation. With a focus on participation and performance in everyday life, the profession of occupational therapy is well-positioned to serve as a leader in demonstrating the benefits of services delivered through telehealth. The occupational therapy profession must leverage expertise in participation, occupational performance, and authentic contexts to show the value of services delivered through telehealth regardless of population or setting.menu of domains, outcomes, and associated outcome measures that are possible within the context of telehealth. The PACE Framework is not meant to serve as a checklist of requirements for telehealth-based interventions; instead, we offer areas for outcome measurement, subdomains, and measurement tools to consider during the design, implementation, adoption, and dissemination of occupational therapy services delivered through telehealth. The four domains of the framework function as a Venn or logic diagram in that each domain is definable, independent from the whole, but all domains are also related to the whole and overlap in numerous areas  will likely vary widely. Some may choose to focus their work on a single aspect of one component of one domain, while others may address all four domains in their design. Similarly, the PACE Framework is meant to be useful in both a prospective and retrospective manner. Prospectively, the PACE Framework is designed to help guide study or intervention design by facilitating discussion of all aspects of the occupational therapy telehealth implementation process. Retrospectively, the PACE Framework can be used to organize and analyze data from research and program evaluation. Using the PACE Framework, occupational therapy can continue to build evidence that can be shared with various stakeholders .The PACE Framework shares similarities with other professions’ and organizations’ telehealth measurement frameworks . Across Access for All Clients is considered a construct with multiple sub-domains; services must be purposefully designed and implemented to ensure access for all clients. The PACE Framework outlines sub-domains of access that must be considered, which include but are not limited to the consideration of authentic contexts, use of clients’ and families’ everyday items during telehealth sessions, and scheduling issues that have been shown to disproportionately impact clients from lower socio-economic status and minority backgrounds. Aligned with diversity, inclusion, and equity initiatives, the PACE Framework's Access for All Clients domain and associated sub-domains are meant to call attention to the explicit and implicit biases that create barriers to telehealth across individuals and groups. We invite researchers, practitioners, and policy makers to think broadly about access and ways to create opportunities for clients across settings and populations to use telehealth.Finally, st century healthcare, meet the demands of payors moving towards value-based payments for services, and demonstrate the distinct value of occupational therapy services delivered through telehealth.The COVID-19 pandemic necessitated a shift in service delivery to telehealth across practice settings and occupational therapy practitioners adapted in response. The PACE Framework provides a means for occupational therapy practitioners and researchers to continue to build the telehealth evidence base in occupational therapy. The changing practice, policy, and payment landscape necessitates researchers and occupational therapy practitioners support best practices and demonstrate the efficacy of occupational therapy services. The PACE Framework facilitates a systematic approach to evaluating components of occupational therapy service delivery through telehealth. It is vital that occupational therapy demonstrates a concerted effort in the measurement and evaluation of services delivered though telehealth to keep PACE with 21