Periosteum is a thin membrane covering bone surfaces and consists of two layers: outer fibrous layer and inner cambium layer. Simple appearance of periosteum has belied its own complexity as a composite structure for physical bone protection, mechano-sensor for sensing mechanical loading, reservoir of biochemical molecules for initiating cascade signaling, niche of osteogenic cells for bone formation and repair, and “umbilical cord” for nourishing bone tissue. Periosteum-derived cells (PDCs) have stem cell attributes: self-renewal (no signs of senescence until 80 population doublings) and multipotency . In this review, we summarized the currently available knowledge about periosteum and with special references to antler-lineage periostea, and demonstrated that although periosteum is a type of simple tissue in appearance, with multiple faces in functions; antler-lineage periostea add another dimension to the properties of somatic periostea: capable of initiation of ectopic organ formation upon transplantation and full mammalian organ regeneration when interacted with the covering skin. Very recently, we have translated this finding into other mammals, i.e. successfully induced partial regeneration of the amputated rat legs. We believe further refinement along this line would greatly benefit human health. The periosteum is a thin membrane covering all bone surfaces except for articular, tendon insertions and sesamoid bone surfaces . The perDue to differences in the nature of dynamic mechanical and biochemical environments, there is considerable variation among periosteal cells and matrix associated with the species, sex, age, embryonic origin and the site/location of the periosteum , 4.In this review, we summarize the current knowledge about the periosteum with special reference to the antler lineage periostea. This review clearly demonstrates that periosteum is a type of simple tissue in appearance, but with multiple functions; antler lineage periostea add another dimension to the properties of somatic periostea, as it is capable of initiation of bony organ formation and full regeneration via interaction with the covering skin.The periosteum comprises an outer fibrous layer and an inner cambium layer, which differ in terms of the proportions of cells, fibres and matrix. Collagen and other extracellular matrix fibers of the fibrous layer are responsible for much of the unique anisotropy and mechanical toughness of the periosteal tissue as a whole . The outThe inner cambium layer is highly cellular and consists mainly of osteogenic cells at various developmental stages  and osteoblasts within a much finer collagenous matrix than the fibrous layer. The more mature osteoblasts line the bone surface and less mature ones or progenitor cells are away from the bone surface on top of these osteoblasts; these less mature cells reside within rich vascular and neural networks . The camThe preferential orientation or alignment of the collagen in the periosteum is with the direction of tissue growth . The col+ mononuclear cells and Macrophage-lineage F4/80+ cells).Periosteal cells or periosteal derived cells (PDCs) are heterogeneous in nature but consist mainly of fibroblasts, osteoblasts, mesenchymal stem cells (MSCs), mast cells and pericytes . The majThese cells can, to a large extent, remain undifferentiated through many passages in vitro without losing their differentiation capacity . DespitePDCs in the cambium layer of humans retain the ability to differentiate into fibroblasts, osteoblasts, chondrocytes, adipocytes, and skeletal myocytes. They are clonogenic independent of donor age and exhibit steady marker expression and growth up to 30 population doublings . In contPDCs in the cambium also exhibit a stronger alkaline phosphatase expression response than bMSCs to BMP2 or dexamethasone (osteo-inductive agents). PDCs and bMSCs exhibit distinct structure–function relationships and differentiation capacities attributable to their distinct milieus. For example, PDCs can be directionally induced to differentiate into osteoblasts, chondrocytes , myocyteCompared to PDCs of the cambium layer, the cell morphology of the fibrous layer is more typical with elongated fibroblasts . AlthougMast cells reside in the fibrous layer and synthesize and secrete the mature form of NGF (ßNGF). As mast cells are located close to the sensory nerve fibers, ßNGF secretion may play a role in the maintenance of the sensory network.Pericytes form a distinct population in the periosteum . They ar+ cells are abundant on the periosteal bone surface. They can induce expression of periostin and the recruitment of PDCs to the periosteal surface for bone formation and regeneration, thus playing an essential role in regulation of periosteum homeostasis, repair and regeneration. Resident TRAP+ cells of the periosteum are distinct from osteoclasts, and there are likely to be different macrophage subtypes that play different roles in bone formation, repair and regeneration. For example, a deficit of TRAP+ cells in the mouse periosteum impairs recruitment of PDCs for cortical bone formation [+ cells during bone growth and secrete PDGF-BB, which transcriptionally induces expression of periostin to create an osteogenic microenvironment in the fibrous layer of periosteum.TRAPormation . Macroph+, F4/80+ cells and blood vessels and fewer TRAP+ cells in the periosteum than other age groups [Another discrete population of resident macrophages is also found to be distributed along the bone lining surface within the periosteum in murine and human bone, and these cells are termed OsteoMacs . OsteoMae groups .Chang et al.  reported+ cells and LepR+ cells reside primarily in the outer fibrous layer of periosteum and may be subsets of PDCs responsible for periosteal bone formation, as such subsets have the potential to differentiate to osteoblasts for periosteal bone formation. In mice, Nestin+ PDCs are found primarily during bone development, whereas LepR+ PDCs are essential for bone homeostasis in adults. Both Nestin+ PDGFR-α+ and LepR+ PDCs of the periosteum form more CFU-Fs than do bMSCs [Both Nestindo bMSCs .The periosteal circulation is an important component of bone vascularization. The blood supply of the periosteum is derived from four vascular systems, namely the intrinsic periosteal system, periosteocortical anastomoses, and the musculoperiosteal and the nutritive periosteal systems . The perBlood vessels in human tibia periosteum exhibited a ring pattern  whereas The nervous system has emerged as an important regulator of bone metabolism through central control of the osteogenic cell activities of the periosteum . OsteoblThe adrenergic sympathetic nervous system controls bone formation and resorption mostly through the ß2-adrenergic receptors (AdB2R) in the appendicular and axial skeletons . AdB2R a+ mast cells [Destruction of the sympathetic system induces mast cell activation and ßNGF release to the extracellular milieu, suggesting that factors synthesized by the sympathetic fibers stabilize mast cells. In the non-osteogenic compartment of the periosteum, treatment with vasoactive intestinal peptide (VIP) decreases the ratio of activated/total ßNGFst cells . VIP-immst cells , 49. Senst cells .Periosteum throughout the bone surface is not uniform in structure, cell population and the function, but appears to vary considerably in different age, location, sex, embryonic origin and species.+ mononuclear, F4/80+ and Nestin+ cells, all abundant on the periosteal bone surface in young mice, decreased markedly during late adulthood, whereas LepR+ cells were abundant in adult mice [The cambium layer of the periosteum is at its thickest in the fetus and becomes progressively thinner with age. In the adult, it is so thin that it cannot be readily distinguished from the outer fibrous layer . Blood vult mice .+ cells are found in the diaphyseal and metaphyseal periosteum in juvenile rats; in mature and aged rats, however, Stro-1+ cells are significantly less and the intensity of Stro-1 staining is weaker compared with the juvenile group, indicating the highly osteogenic/chondrogenic nature of periosteum in young animals [A higher percentage of Stro-1 animals . NumerouBoth the cambium and fibrous layers in the periosteum of juvenile rats are well vascularized, while in mature rats, blood vessels are predominantly in the fibrous layer. The higher degree of vascularization in the periosteum of juvenile rats suggests a role in nutrient and osteoprogenitor cell supply. Both the thickness and number of cells in the diaphyseal periosteum decreased with age . InteresOverall, periosteum in bone formation, repair and responsiveness to hormones and cytokines declines with age, although the potency of osteogenic differentiation of the PDCs may be maintained.Besides age, changes in periosteum are also site-dependent, with differences in periosteal anatomy or activity evident throughout the skeleton. The morphology of the periosteum is highly variable between bones within an individual and even within bones The specific site plays a key role in the properties of the periosteum. For example, the rate of periosteal bone formation differs more than three-fold through the skeleton in rats . The ostIn in vitro studies of chondrogenic potential of the periosteum, the ilium, scapula, and tibia gave rise to chondrogenic PDCs whereas PDCs from the skull exhibited no signs of chondrogenesis , 59. OstIn summary, there is evidence of considerable variability in the osteogenic and chondrogenic capacity of the periosteum depending on the location but regardless of the ossification pattern . The appropriate choice of periosteum for bone and cartilage tissue engineering and regeneration should be a function of the specific bone to be utilized .There are two populations of adult PDCs that can be distinguished based on their embryonic origins: mesoderm-derivative and neural crest-derivative . The facSexual dimorphism within species is common, and hence the sex of the donor from whom cells are obtained may be expected to affect the biology of PDCs; for example, PTH and estrogen have been shown to affect proliferation and apoptosis of PDCs from different sex-origin .Animal studies support a positive effect of androgens and a negative effect of estrogens on the rate of periosteal bone formation . At pubePDCs in different species are also different. For instance, rabbit-derived PDCs (rPDCs) are smaller than human PDCs (hPDCs) under the same culture conditions  with strAs known from orthopedic practice, destruction of the periosteum leads to delayed bone healing or nonunion . The perDuring natural bone growth in young people, the cambium layer of the periosteum expands with an increasing girth and length of bones . In longAlthough remodeling of trabecular bone occurs in the bone marrow microenvironment, and growth and modeling of cortical bone takes place in the periosteum, the periosteum provides a supportive microenvironment with vasculature, nerves, PDCs, and osteoprogenitors, which resembles a unique bone marrow for the growth and modeling of cortical bone.Skeletal repair is a dynamic and well-orchestrated process that involves complex and spatiotemporally coordinated function of different cellular compartments and integrated molecular pathways. Immediately following cortical bone injury, the periosteum undergoes a series of changes that initiate endochondral and intramembranous bone formation at the site of injury.PDCs near the cortical bone injury site differentiate into chondroprogenitors whereas PDCs at the periphery of the cortex furthest away from the site adopt an osteogenic cell fate. The periosteum is the major contributor to cartilage and bone repair within the callus, whereas cells within the local bone marrow and endosteum form bone within the bone marrow cavity and do not migrate out of the marrow to form the callus . The per+ (paired-related homeobox gene-1+) PDCs contribute to cartilage and bone within the callus, while bMSCs have less potential to form cartilage and do not participate in forming new bone at later stages. The majority of bMSCs stay at the periphery of the callus and PDCs integrate far into the callus and cartilage by day 10 [Periosteum-derived Prx1y day 10 . In conty day 10 , PDCs ary day 10 . Thus, Py day 10 , 82Histologically distinct layers of the periosteum are associated with distinct molecular expression domains. Multiple factors and transduction pathways are involved in the regulation of periosteum functions.Canonical Wnt signaling is heavily involved in regulation of the periosteum. Wnt signaling is an upstream regulator of BMP signaling in osteoblasts  and multSeveral factors related to the BMP pathway have been identified in the activated periosteum including BMP-2, -3, -4, -5, -8, noggin, BMPRIA, BMPRII, and pSmad 1/5/8 . DeletioTGF-β is synthesized at high levels in the periosteum during fracture healing, enhances the proliferation and differentiation of PDCs, increases production of extracellular matrix and is chemotactic to bone cells . TGF-β cIn the early stages of fracture healing, Hedgehog signaling is activated for efficient periosteum-mediated repair and regeneration and is enhanced in early periosteal callus formation. Activation of Hedgehog signaling promotes osteogenic and chondrogenic differentiation of PDCs in synergy with BMP-2. Postnatal deletion of Smo, a receptor that transduces all Hedgehog signaling, impairs osteogenic differentiation of PDCs in vitro, and results in a halving of periosteal bone callus formation in vivo . Hedgeho+ cells around hypertrophic chondrocytes in Smo-deleted periosteal callus, suggesting a role of IHH in driving the expansion of callus formation during the early stage of endochondral bone repair [IHH is expressed in the nascent cartilaginous tissues in the periosteal callus adjacent to the bone surface at the initiation stage of healing. The periosteal markers, β-tubulin, Type V collagen, RAI14, Decorin and YBX-1, are all expressed in the cambium layer of the periosteum , and YBXe repair .PTHrP is a small polypeptide , and actNGF is a trophic factor for nerve fibers and is also involved in differentiation and survival of the osteogenic cells . The twoSemaphorin 3a (Sema3a) is a molecule that promotes osteoblast differentiation, beside its repulsive role on sympathetic and sensory fiber networks . HoweverThe complexes of ligand and the receptor of insulin-like growth factor (IGF) family increase locally in the fracture callus of human patients, and their expression is markedly increased in the PDCs of multi-layered periosteum in the developing bony calluses , 114. ThHIF-1α plays dual roles in signaling during bone regeneration via periosteum: (1) HIF-1α is necessary for increased VEGF production to mediate the angiogenic response during bone repair; (2) HIF-1α-dependent adaptations in glycolysis and mitochondrial metabolism ensure cell survival during the early stages preceding the arrival of the blood vessels .Periostin is the only protein that is present in a higher amount in periosteum than in other bone locations . PeriostThe synthesis of periostin is increased four-fold during the first 3 days after the fracture; by day 14 periostin is expressed at the junction between hypertrophic cartilage and bone, and by osteoblasts and osteocytes in the new bone matrix; by day 28 periostin is detected in newly formed periosteum at the periphery of the ossified callus . Deletio+ cells reduced periostin expression in the periosteum [+ mononuclear cells, maintains the periosteal microenvironment and regulates differentiation of PDCs for periosteum homeostasis and osteogenesis [Conditional ablation of platelet derived growth factor (PDGF)-BB in macrophage-lineage TRAPriosteum . Mechaniriosteum . PDGF-BBogenesis .In addition to biochemical induction of lineage commitment, studies have shown PDCs exhibit exquisite mechano-sensitivity, including lineage commitment independent of biochemical factors. In this respect, mechano-induction is much easier to control both spatially and temporally than biochemical signals. Periosteum is a highly specialized, mechanosensitive tissue. The native environment of PDCs is mechanically regulated by a combination of tension and shear. Mechanical force applied in vivo induces the expression of a variety of genes in the periosteum  and a raThe periosteum may exhibit directionally-dependent permeability and permeability is highly dependent on the stress-state of the tissue . Gross mCervus elaphus), the casting is followed immediately by healing and regrowth.Deer antlers are the only mammalian organs that can fully regenerate once lost . Before It is known now that periosteum covering the frontal crests (presumptive pedicle growth regions) of a prepubertal male deer is the tissue that initiates formation of the pedicle and primary antler , 135, anThe AP is the tissue responsible for the histogenesis of pedicles and primary antlers; this has been demonstrated through surgical manipulation. Deletion of the AP abrogates pedicle and antler formation, whereas autologous transplantation of AP elsewhere on the deer body induces formation of ectopic pedicles and antlers , 141; FiA combination of deletion and transplantation experiments has demonstrated that the different sub-regions of the AP  are endowed with different morphogenetic memory, which have been described as morphogenetic fields . In thisFurther studies have shown that aPDCs express mesenchymal stem cell (MSC) markers  and some embryonic stem cell (ESC) markers  , 148. SuOnce pedicle formation is initiated from the frontal crest, the AP no longer exists but is transformed into the pedicle periosteum (PP), which sheathes the shaft of a grown pedicle. As with the other types of periosteum, the PP also comprises two distinct layers: the outer fibrous layer and the inner cambium layer. The thickness of PP falls midway between that of the AP and the FP. Antler regeneration relies fully on the PP . Total PIt has been claimed that antler regeneration is a stem cell-based epimorphic process and that the stem cells for antler regeneration reside in the PP , 151. CeThe AnP is histologically a continuation of the distal PP but is thinner than the PP and is enveloped by a special pelage (shiny with a sparse population of hair follicles), known as the velvet skin or velvet. The AnP resembles long bone periosteum and lays down bone peripherally via intramembranous ossification during antler growth. Thus, the antlers are normally thicker than the pedicles from which they are derived. In countries where the velvet antlers are considered as a precious traditional medicine, the antler is removed during the growth phase. To protect the antler growth centre for the next year, the antlers are cut at the level around 3 cm above the junction with the pedicle. Usually, the residual antler bases have the potential to partially regenerate antlers , as such their growth is strictly under the control of androgen hormones. Pedicle initiation in puberty deer is triggered by the increasing level of testosterone and first antler generation from a fully grown pedicle follows as the testosterone level is decreasing , 163. BoSurprisingly, the aPDCs do not respond to testosterone (the major form of androgen) or DHT  directly in terms of proliferation when cultured in vitro. This is despite the fact that development of the pedicle and the antler is under the control of androgen hormones and the AP is the tissue that gives rise to the pedicle and antler in vivo and the aPDCs contain androgen specific-binding sites . HoweverThe somatic periosteum requires a nerve supply, particularly sympathetic nerves, for normal homeostasis and growth . It is kInteractions of the AP and PP with their closely associated skin empower the AP to initiate generation and the PP to initiate regeneration of the antler. These are active induction processes where the AP/PP convert the skin from a scalp type to a velvet type; in turn feedback from the induced skin drives the processes of antler generation or regeneration.For both pedicle and primary antler formation, proliferation of aPDCs in the AP is activated by elevated circulating androgens at the initial stage, as the pedicle is gradually built up through appositional growth. In this process, the overlying skin is pushed up and becomes mechanically stretched (tension); the consequence of this stretching is the development of a close association between the AP-derived tissue and the overlying skin and the initiation of the first antler is activated . This suAntler regeneration requires the PP to interact with the enveloping skin. During tissue sampling, we have found that along the longitudinal axis of a pedicle shaft, the degree of association between the pedicle skin and the PP varies: it is seamlessly fused at the distal one-third, but only loosely-linked at the remaining proximal two-thirds . MembranOverall, antler-lineage periostea are unique in that they: (a) have the ability to respond to androgen hormones to initiate cartilage/bone tissue formation; (b) interact with the closely associated skin to launch development of a postnatal organ (pedicle and primary antler) and full regeneration of mammalian organs (subsequent antlers); and (c) react to potent growth factors to drive bony antler elongation at an unprecedented growth rate.There may be potential to translate these unique attributes of the antler-lineage periostea for medical use.Specifically, we can make some predictions based on the findings: (1) a unique model for studying the interactions between the grafted tissue and the host environment during initial formation and maintenance of xenogeneic organs. Thus far, we have successfully established a nude mouse model through transplantation of the AP tissue for this purpose. Recently, we carried out single cell sequencing for these nude mouse xenogeneic antlers, and found that besides endothelial and immune cells that all came from the hosts (nude mice), a small amount of cartilaginous and bone cells (1–2%) were also derived from the hosts and left the rest of them (98–99%) from the grafted AP tissue , suggesting that the grafted tissue is fully integrated with the host systems for growth and maintenance. Revealing the mechanism underlying this full integration may help to alleviate severe rejection of organ transplantation in clinics. (2) A unique model for studying limb regeneration including amputated human legs and arms. Studies from the model systems (antlers and newt limbs) demonstrated that successful epimorphic regeneration relies on the potent proliferation potential of the distal periosteal cells, and the efficient interactions between the wound epidermis and the mesenchymal tissue on the surface of a leg stump. Based on these assumptions, we have successfully induced partial regeneration of the amputated rat legs through removing the interposing muscle layer and empowering the distal periosteal cells more potent proliferation potential (via delivering relevant genes). In the antler model, although there is a dermal layer interposing the wound epidermis and the underlying mesenchymal tissues, we found that the interactions between wound epidermis and the mesenchymal tissue can be relayed by hair dermal papilla cells . We beli


The coronavirus pandemic has had a considerable impact on all parts of society. Unsurprisingly, healthcare has been particularly affected, including cancer care and trials of new drugs. This article will summarize the impact the pandemic has had on cancer healthcare taking into consideration how the pandemic affected potential cancer patients and stopped them seeking medical advice for new symptoms. The pandemic also affected the ability of people to access healthcare services and undergo the tests necessary to diagnose cancer. This article will also discuss the impact of the pandemic on existing treatments and the trials of new drugs. In light of the unprecedented speed of development of new treatments and vaccines for the virus itself, it will also review whether some of these adaptations could be used to accelerate the development of novel cancer therapies.The coronavirus disease 2019 (COVID-19) pandemic has caused considerable global disruption to clinical practice. This article will review the impact that the pandemic has had on oncology clinical trials. It will assess the effect of the COVID-19 situation on the initial presentation and investigation of patients with suspected cancer. It will also review the impact of the pandemic on the subsequent management of cancer patients, and how clinical trial approval, recruitment, and conduct were affected during the pandemic. An intriguing aspect of the pandemic is that clinical trials investigating treatments for COVID-19 and vaccinations against the causative virus, SARS-CoV-2, have been approved and conducted at an unprecedented speed. In light of this, this review will also discuss the potential that this enhanced regulatory environment could have on the running of oncology clinical trials in the future. The emergence of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global healthcare crisis that reshaped both standard cancer care practices and oncology research . The reaThe COVID-19 pandemic affected how patients were first suspected of having cancer in several different ways. Routine screening services were typically paused in the early stages of the pandemic over concerns over viral transmission and as staff were redirected toward COVID-19-directed care. Disruption to screening services decreases the potential for early cancer detection in many cases, particularly in routine screening of at-risk populations such as breast screening of women with high familial risk and colorectal cancer (CRC) screening for individuals with inflammatory bowel disease (IBD) or Familial Adenomatous Polyposis (FAP) ,8,9,10. A further impact is reflected in the behavior of the common populace themselves. A common feature of many governmental responses to the pandemic was to enforce a widespread “lockdown”, essentially confining people to their homes. In the UK, a National Health Service (NHS) survey conducted in April 2020 to gain insight into public attitudes towards seeking medical advice for suspected cancer found that over 50% of the public had concerns and were hesitant about seeking help due to the pandemic. While shopping for essentials and seeking medical care were typically allowed, the overall impact of lockdown measures combined with the degree and nature of media coverage effectively discouraged people from seeking medical advice. Symptoms that may have normally provoked a visit to a primary care physician were not acted on, as people sought to adhere to the regulations in an attempt to avoid the virus or out of fear of burdening an already overwhelmed healthcare service . In addiA further consideration is the impact of the pandemic on primary care services. Many general practitioners ceased face-to-face services altogether, which also included a significant reduction in basic frontline diagnostics such as blood tests and X-rays. Primary care services were also forced to adapt to prevent the spread of SARS-CoV-2, particularly to the elderly and vulnerable at greater risk of fatal COVID-19. Social contact was avoided wherever possible, resulting in a switch to the widespread usage of telemedicine platforms to replace in-person consultations . It can All of these factors would have contributed to early cancer symptoms being missed, which was reflected in the reduction in referrals to secondary care. It has been widely noted that there was a significant decrease in the number of urgent referrals after the first lockdown was imposed in March 2020. The largest declines were observed specifically during the peaks of each wave of the pandemic. In England, NHS statistics recorded the largest fall in April 2020 when a 60% decrease in urgent referrals was recorded compared with April 2019 . OverallIn addition to the impacts on primary care, the COVID-19 pandemic has also had a massive impact on secondary care. Hospitals and health centers reduced their functioning capacity to maintain social distancing measures in accordance with government guidelines, which consequently delayed cancer diagnosis. Furthermore, any staff who displayed symptoms/tested positive for COVID-19 (or were exposed to someone who has tested positive) were also required to self-isolate as part of government guidelines, which further disrupted staffing levels and limited functioning capacity . The UK It was observed early in the pandemic that patients with cancer were at higher risk of developing severe and fatal COVID-19 ,4. This In the UK, NHS operational standards for new primary cancers state that treatment should commence within 31 days for 98% of patients receiving chemotherapy or other anti-cancer drugs, and for 94% of patients for radiotherapy and surgery. The overall performance for anti-cancer drugs and radiotherapy in 2020/2021 was above operational standards, which shows that services were able to adapt and continue with these treatments. However, despite efforts to maintain service levels, surgery was more significantly impacted during the pandemic and failed to meet operational standards, with only 88% of patients receiving surgery within 31 days . DespiteA further evolving area is the use of COVID-19 vaccinations in patients with cancer. Given the higher mortality rates from SARS-CoV-2 infection seen in these patients, the establishment of a safe and effective vaccine is crucial. Recent reports have suggested that COVID-19 vaccination for cancer patients is safe, immunogenic, and effective in protecting against symptomatic disease. However, the rates of seroconversion and protection offered by vaccination are generally lower in patients with cancer compared with the general population. Patients with hematological malignancies appear to be at particular risk, especially those who have received B-cell-depleting agents in the past 12 months . TherefoThe effects of the pandemic on clinical trials were felt throughout administrative and clinical practices. Clinical trial initiation and recruitment were typically halted at the beginning of the pandemic as infection control measures were implemented . FurtherIn the UK, the Medicines and Healthcare Products Regulatory Agency (MHRA) released guidelines in accordance with government restrictions to guide clinical trial management . The shiTelemedicine was also widely embraced as the best mode of communication to deliver the essential information to patients in remote video consultations, reducing the need for an in-person visit ,46. NotaA further demonstration of clinical trial modification during the COVID-19 pandemic, albeit outside of cancer research, was the Randomised Evaluation of Covid-19 Therapy (RECOVERY) trial. The RECOVERY trial took on an unorthodox approach to set up a large-scale randomized clinical trial using a digital portal. DigiTrials is a data platform that consolidates patient data across the UK health system, which made the patient population in critical care units across the UK more accessible for recruitment into the trial. The DigiTrial system also provided a universal platform for data collection and processing, which allowed for quicker analysis and reporting of results . The RECThe RECOVERY trial and other trials have served as an example demonstrating how a flexible protocol, the use of a data platform, and integration with standard care can considerably improve trial efficiency and turnaround time. With a simplified consent form and a carefully thought-out “trial by design” approach, the RECOVERY trial astoundingly received regulatory approval within 9 days, which is drastic compared to the average 30–60-day time frame. Many health research authorities are still currently fast-tracking ethical approval for COVID-19 research and have managed to bring the normal 60-day cycle down to just 10 days. Another paradigm shifting example has been the development of SARS-CoV-2 vaccines. Prior to the pandemic, the timeline from basic science and target identification through the phases of clinical development and licensing typically took 10–20 years, a time not inconsistent with the time it takes to develop a new anti-cancer drug. However, effective vaccines for COVID-19 were developed, tested, and licensed within a year of the virus first being discovered ,58,59. UThe acceleration of drug development aside, there are many other examples of innovative practice that have emerged during the pandemic, that can be further adapted and taken forward. As discussed above, the intensity and frequency of monitoring assessments for patients on study was streamlined during the pandemic, with the aim of avoiding exposure to the virus . As it nMany healthcare systems are permanently under a degree of stress, which was experienced even before the COVID-19 pandemic, both financially and due to a shortage of appropriately trained staff. Efforts should be made to integrate trial design more closely with standard hospital workflow to lessen the burden on health services, promote an increase in clinical trial activity, and to develop resilience so that clinical trials can continue, should there be future waves of COVID-19 or another novel infectious agent . One advThere have been many examples for how the administrative and regulatory burden imposed on research sites can be improved. New policies were implemented by CROs, sponsors, and regulatory authorities during the pandemic that facilitated a magnitude of administrative duties surrounding recruitment, site selection, and study monitoring by leveraging technology and simplifying reporting processes. This included implementing virtual online meeting platforms  and protected e-DocuSign (via AdobeSign) to support remote work for many administrative employees for a reduced dependence on physical paperwork. Standard practice in clinical trials requires all protocol violations to be thoroughly documented within the details of the trial to allow for accurate analysis of the data. The deviation reporting process during the pandemic was scaled back to combat the surge of administrative work because of the several protocol violations put in place to adapt trials. Only major deviations were reported in stand-alone deviation reports and all minor protocol deviations were reported on a weekly basis collectively, opposed to raising a report per deviation, whether it be major or minor . FurtherThe impacts of the COVID-19 pandemic on oncology care and clinical trials have been immense, and there is no doubt that the pandemic will leave a permanent impression on healthcare services. As devastating as the disruption has been, the response to the pandemic has seen many innovations and adaptations that will continue to be of great value in the future  Figure . The panIn clinical trials, the COVID-19 pandemic caused a momentary pause that necessitated a step back to begin initiating change on very complicated and established practices. In a matter of months, the clinical trial industry has made a huge leap in leveraging technology that may have taken years to implement into normal practices without these drivers. The successful digitalization of many administrative processes has opened the door for the application of innovative technologies and methodologies to improve working efficiency. In the longer term, this offers the potential to reduce the burden of clinical documentation and increase the speed of data acquisition and interpretation, which should also result in a faster translation to the clinic. The experience from the pandemic should also inform the development of new measures to make healthcare systems and clinical trial networks more resilient to future healthcare crises, such as further waves of COVID-19, novel infectious agents, or other challenges.


This series of eight papers  is presented by international leaders covering various aspects of lung cancer management, starting with diagnostic imaging and analyzing the novel perspectives of therapy.18F]FDG PET/CT singularly or in association with immune metabolic scores in the context of non-small cell lung cancer (NSCLC) treatment with checkpoint inhibitors [18F]FDG PET/CT, classifying patients into risk groups  to predict patient outcomes [18F]FDG PET/CT has prompted also the report of Monaco and colleagues [The target of the Special Issue was to provide an overview of the validated imaging techniques and future biomarkers for predicting responses to treatment, with particular focus on immunomodulatory regimens. In this regard, three original articles were directly dedicated to the use of metabolic information with 8FFDG PEThibitors ,3. In thhibitors ,5 obtainhibitors . Thereinoutcomes . As expeThe exponential number of studies published in the last decade on immunotherapy response monitoring  demandedLung cancer is the most common cause of cancer-related death worldwide, and efforts to further improve the prognosis for advanced NSCLC are still ongoing. In this framework, the treatment algorithm for lung cancer has experienced a rapid evolution in the last few years and some of the newer therapeutic options are associated with increased survival. As a result of the availability of new therapeutic options, recent years have also witnessed great advances in the subfield that concerns the imaging of metastatic or advanced NSCLC. Emerging data are showing how we can improve the accuracy of disease relapse identification and broaden patients’ selection for new treatments, as well as helping us refine and standardize our response to therapy assessment, even in the case of combined therapies. Several of these topics are covered in the present Special Issue, showing the added value of multi-modal imaging  in different clinical settings. The next step will be the effective transfer of all these advances to clinical practice. For a final transfer of new imaging tools and analytic approaches to clinical practice, it will be necessary to incorporate imaging (and non-imaging) biomarkers in a single pipeline to guide advanced NSCLC patients risk stratifications before and after treatment.


Artificial Intelligence (AI) and Internet of Things (IoT) offer immense potential to transform conventional healthcare systems. The IoT and AI enabled smart systems can play a key role in driving the future of smart healthcare. Remote monitoring of critical and non-critical patients is one such field which can leverage the benefits of IoT and machine learning techniques. While some work has been done in developing paradigms to establish effective and reliable communications, there is still great potential to utilize optimized IoT network and machine learning technique to improve the overall performance of the communication systems, thus enabling fool-proof systems. This study develops a novel IoT framework to offer ultra-reliable low latency communications to monitor post-surgery patients. The work considers both critical and non-critical patients and is balanced between these to offer optimal performance for the desired outcomes. In addition, machine learning based regression analysis of patients’ sensory data is performed to obtain highly accurate predictions of the patients’ sensory data , which enables highly accurate virtual observers to predict the data in case of communication failures. The performance analysis of the proposed IoT based vital signs monitoring system for the post-surgery patients offers reduced delay and packet loss in comparison to IEEE low latency deterministic networks. The gradient boosting regression analysis also gives a highly accurate prediction for slow as well as rapidly varying sensors for vital sign monitoring. Over the past two years, the healthcare sector has been severely affected. The COVID-19 outbreak has impaired the healthcare infrastructure and introduced many unthinkable challenges to the present healthcare ecosystem. The high strain on the healthcare sector has resulted in general degradation of overall healthcare services with the non-critical departments being most influenced due to the focused utilization of limited resources and qualified healthcare staff. One such aspect which has been most affected during the COVID-19 outbreak is post-surgery care and therefore, needs drastic measures to restore the healthcare standards. This is specifically needed in the less critical healthcare sectors where the dire need of continuous monitoring is evident but cannot be ensured due to lack of healthcare staff.The aftercare in a post-surgery phase is an important aspect of any surgery. The recovery of the patient depends on the effective execution of aftercare in the post-surgery phase. Although the patients in some surgeries can leave hospital in 3 to 5 days, the return to normal activities may take much longer. For instance, in weight loss surgeries, the patients can leave hospital within 1 to 3 days, but it takes 4 to 6 weeks to return to routine life and even then, the patients are expected to follow a relatively strict routine of exercise and maintain suitable eating habits . The regWhile the healthcare services have suffered in the past few years due to COVID-19, suitable technological interventions have also surfaced to mitigate the impact of such a health crisis and limit its devastating effects on the healthcare infrastructure. New and innovative technology solutions are needed to cope with the overwhelming load on the healthcare sector. The use of machine learning techniques and Internet of Things (IoT) has enabled smart healthcare systems to offer potential solutions to address surgery related and aftercare problems.An IoT enabled URLLC framework is proposed which offers highly reliable near real-time communication of the critical patients’ vitals. It also allows simultaneous channel access for critical and non-critical patients and ensures prioritized access to critical patients.The paper also proposes to use a gradient boosting based regression algorithm capable of predicting both slow and rapidly changing patient’s vitals. The proposed algorithm serves as an additional layer of protection for critical patients, where in the event of wireless communications failure, the ML algorithm will still be able to predict the patient’s vitals, thus raising alarms even if the wireless channel faces intermittent interference or sudden variations resulting in communication failure.This paper presents an IoT enabled and machine learning driven solution to monitor the vitals of the critical patients while focusing on post-surgery patients. In post-surgery patients monitoring of the cardiovascular systems, fluid and electrolyte balance, prevalence and treatment of infection and excessive bleeding, functioning of main organs, deep vein thrombosis, and anastomotic leak need to be monitored with high reliability and relatively low latency. Therefore, the proposed framework focuses on IoT enabled ultra-reliable low latency communications (URLLC) and machine learning based change in vitals prediction. The main contributions of the work are as follows: The IoT enabled remote monitoring and smart healthcare systems offer great potential to cope with the challenges in healthcare services ,5,6. TheThe IoT serves as an excellent solution with great potential to accumulate data from different sensors. However, there are certain limitations which need undue attention to make the system reliable and infallible when dealing with patients. While there are several works which address some challenges in IoT to make them more suitable for healthcare applications ,10,11,12Considering the key challenges in monitoring surgery patients during short hospital-based aftercare and extended monitoring in home environments, an IoT framework is proposed which not only retains consideration of the reliability and latency aspects of wireless communications but also provides a decision support system to enable quick hassle-free decision making for the medical staff. The proposed work not only saves time and medical resources but also offers more reliable and actionable information to implement improved healthcare services for the speedy recovery of surgery patients.The rest of the paper is organized as follows: A system model is presented in Over the past few years, IoT has evolved to incorporate a plethora of technologies including ubiquitous sensing, fog computing, big data, machine intelligence, decision support systems, cyber physical systems, distributed systems, edge computing, diagnostic systems, process automation, etc. Thus, the present day IoT enabled smart systems serve as the convergence of key enabling technologies capable of handling diverse applications with the desired precision and accuracy. With the rapidly increasing number of connected devices, and the evolution of microelectromechanical systems, the availability of big data and the ability of machine intelligence have enabled the emergence of true AI. The IoT infrastructure necessary to sample the real-world with the communication of sensory data whether it is the healthcare sector, industry, buildings or vehicles, is essential for sustainable future developments. To meet the challenges of big data and collective intelligence, effective IoT solutions play a significant role.The proposed IoT framework aims to provide Ultra-Reliable Low Latency Communication (URLLC)  in healtIn the proposed work, the communications from the sensor motes are established in a cluster, where hierarchical architecture is assumed for reduced delays and scalability. In each cluster, a star topology is formed, where communications from cluster nodes to cluster-head (CH) are facilitated by time division multiple access (TDMA) based channel segmentation. The cluster formation is initiated by the designated CH in setup mode, where IoT devices/sensor nodes request affiliation to one of the available CHs based on its geographic location and link quality. The selection of TDMA over more conventional Carrier Sense Multiple Access, Collision Avoidance (CSMA/CA) is preferred to avoid congestion in the network and enable guaranteed channel access in a specific timeslot for the communicating node. Despite the use of TDMA as the multiple access technique, suitable changes have been introduced to improve the overall accessibility of IoT devices and prioritize critical information to maintain low latency communications within the network. The communications from sensing nodes to CH takes place in a TDMA based superframe of duration As presented in All the communication channels are distributed among HPC and MCC, where communication on each channel uses the TDMA based scheme to avoid collisions and channel reliability opposed to carrier sense multiple access (CSMA) schemes. In a single channel scenario for IEEE low latency deterministic networks (LLDN), the probability of at least one failed communication in a superframe is modelled using binomial distribution ,21 and ck, as expressed in Equation (2). All channel communications are synchronized, where a synchronization beacon is issued at the start of every superframe. In addition, a control channel is also introduced, which allows the IoT devices belonging to high priority/vulnerable patients/systems to either request communication resource or CH reschedules their retransmission as needed. However, a more frequent practice, where the CH automatically reschedules communications of high priority nodes, is considered for evaluation purposes.Taking into consideration the multi-channel scenario where each superframe communication at channel, The nodes communicating over HPC have higher priority compared to the nodes communicating over MCC. In addition, the sensory data accumulated through the HPC belong to critical/vulnerable patients which are time sensitive and need to be communicated to CHs in regular intervals. A failure/delay in such communications can put the critical patients at risk. Therefore, the deviation from regular delay intervals needs to be maintained within certain thresholds.Under normal circumstances the communications from TDMA based HPC and MCC continue uninterruptedly. In case of failure in communication from one of the sensor nodes in HPC, i.e., the high priority nodes, the CH reschedules a communication on MCC, where failed communication is reattempted within the same superframe. The communication failure of an HPC superframe can be expressed asIn the case of HPC less than or equal to MCC, i.e., As expressed in Equations (3) and (4), binomial distribution is primarily used to express the failures in the superframe communications. The communication rescheduling allows a timely access to the channel, thus minimizing the average delay along with improving system reliability.Traditional applications accept a relatively high average variation from specified delay intervals between two consecutive communications. However, in the case of critical healthcare applications, deviation from a defined interval can severely elevate the health risks in vulnerable patients and thus, limit the effectiveness of IoT enabled smart healthcare over conventional systems. Therefore, the delay in the proposed scheme is modelled as the average variation from the expected interval. In IEEE LLDN, the average deviation from the mean delay in HPC can be approximated asIn the proposed scheme the delay is minimized with rescheduling of the failed HPC data communication. The average deviation in HPC superframe communications from the specified delay time interval can be expressed asSurgery patients are expected to be monitored over the course of recovery, whether body sensors or other monitoring techniques are used. In this work, along with the effective communication network to relay the patient’s vitals using body sensors and IoT infrastructure, predictive analysis and modelling are also performed. In a particular scenario, where the communication fails for a short period of time or excessive interference develops which causes brief communication failure, the communication of vitals becomes impossible. Therefore, to avoid such scenarios where the instantaneous communication failure can obstruct the patients’ vitals to be delivered, a predictor is developed to counter the issue. The predictor uses the existing trail of sensory data received from the IoT devices to predict the future values of slow as well as rapidly varying sensors to generate the appropriate response. The prediction algorithm runs on the CH and offers predictive analysis of the sensory data of critical patients. Since the vital signatures  of a patient can vary quickly , it is iTo achieve the prediction, two different scenarios are considered, where the patients’ sensory data are varied both linearly and exponentially to emphasize the possibility of slow change and rapid change in the patient’s condition. Further details on each of the machine learning techniques used for the predictive analysis are presented in the subsequent sections.One of the significant issues in developing intelligent systems for clinical healthcare is the unavailability of the vital signs based sensory dataset and the clinical dataset recorded from the patients during in-hospital treatment. Such scenarios require a longitudinal study to follow up and monitor the pre-surgery and post-surgery vitals as in the quantitative dataset about the medical condition being treated, such as obesity in the case of bariatric surgery. Tracking and monitoring of such clinical and sensory measures are vital in predicting the recovery curve and rehabilitation progress. To run the pilot study, significant resources  and ethical approvals are required from the healthcare providers. However, the development and acquisition of healthcare data from such scenarios in a short period of time is infeasible. Therefore, we generated synthetic sensory data simulating the real-life sensory traces/signals and tested the performance of the machine learning algorithm as a proof of concept. The synthetic data generated in this study are also not related to the accuracy of the data generation. Rather the study focuses on the change in the vitals’ monitoring which can be slow or rapid depending on patients’ health conditions. The aim is to justify that the proposed work can predict rapidly changing data with high accuracy. Therefore, after this proof-of-concept study, the aim is to develop a complete IoT based paradigm which can record and monitor healthcare vitals in post-operative in-hospital scenarios.To detect the vital sensory based indicators of patients, regression-based machine learning is used. In particular, this work developed an eXtreme Gradient Based (XGB) ,24 regreA 70/30 train and test split were used, i.e., 70% of the dataset was used to train the XGB regressor model and the remaining 30% to test the model.The performance of the proposed IoT framework is evaluated for the average delay and the reliability of communications. Since the proposed scheme facilitates periodic communications, delay and reliability are appropriate performance metrics for evaluation of the scheme. The proposed work shows notable improvements in terms of delay where the average delay in the proposed work is significantly reduced compared to IEEE LLDN. The delay in the proposed scheme . In comparison to IEEE LLDN, the proposed IoT based solution reduced the overall delay up to 80%. In addition, the average delay was also kept within the desired limits for critical healthcare patients. The overall packet reception rate was also improved in the proposed work as compared to IEEE LLDN. The findings also suggest that the proposed XGB based regression is capable of effectively monitoring and predicting the patients’ sensory data  in a normal as well as a critical situation. The results show that the XGB based regression is capable of predicting high sensory data fluctuations  within a short time window (<25 ms). Collectively, the proposed work also offers the potential to address the challenge of intermittent interference causing communication failures in short time frames, thus making the proposed system highly reliable.The study comes with several limitations. The vital signs’ sensory dataset is generated synthetic, and it would be interesting to see how the proposed IoT based model fits the real-world monitoring of patients when collected in the clinical setting. The proposed machine learning based vital signs detection in post-surgery patient monitoring is not comparable with any previous studies as none of the existing works has developed the scenario presented in this study to monitor postoperative patients in clinical settings through vital sensory traces and clinical measures. Future work should focus on the real-world implementation of the proposed IoT framework and to explore vital physiological sensory measures such as the electrocardiogram, electroencephalogram, respiratory sensors, pulse oximetry, etc.As a future prospect, this work can further be extended by interlinking the machine learning based analysis of patients’ vitals to evaluate the criticality index, thus, providing an extensive support system for condition monitoring and health analysis of surgery patients.


Biomechanical properties of mammalian bones, such as strength, toughness, and plasticity, are essential for understanding how microscopic-scale mechanical features can link to macroscale bones’ strength and fracture resistance. We employ Brillouin light scattering (BLS) microspectroscopy for local assessment of elastic properties of bones under compression and the efficacy of the tissue engineering approach based on heparin-conjugated fibrin (HCF) hydrogels, bone morphogenic proteins, and osteogenic stem cells in the regeneration of the bone tissues. BLS is noninvasive and label-free modality for probing viscoelastic properties of tissues that can give information on structure-function properties of normal and pathological tissues. Results showed that MCS and BPMs are critically important for regeneration of elastic and viscous properties, respectively, HCF gels containing combination of all factors had the best effect with complete defect regeneration at week nine after the implantation of bone grafts and that the bones with fully consolidated fractures have higher values of elastic moduli compared with defective bones. From an individual’s perspective, a fracture negatively affects the physical and mental health, whereas complicated cases such as hip fractures increase can lead to the permanent disability and increased the risk of death. Direct and indirect costs of the fracture care can be high. According to the report on Osteoporosis in the European Union, in 2010 care expenditures of the healthcare systems for the fragility fractures were €37 billion.–,,Autografts, allografts, and other bone grafts are current standard strategies for the bone fracture repair.in vivo from the mechanical parameters at the macrolevel can be a difficult task. Here, we aim to assess mechanical parameters of the cortical bone at the microlevel using BLS spectroscopy. It has proven to be a powerful noncontact, noninvasive, and label-free optical technique capable of assessing biomechanical (viscoelastic) properties at the micron-millimeter scale for a variety of biomedical applications.–,To evaluate the efficacy of the bone grafts to regenerate the critical-sized defect, Brillouin light scattering (BLS) spectroscopy is utilized. Methods based on applying tension or compression loads to failure are commonly used for the biomechanical testing. These methods are useful for measuring bones from small animals. Noninvasive techniques, such as dual energy x-ray absorptiometry, peripheral quantitative computed tomography, and microcomputed tomography  every 3, 6, and 9 weeks.Bone density after the sacrifice was evaluated using 2.5,,Incident laser beam from a single longitudinal mode 532-nm solid-state laser (Coherent Verdi G2) was focused on bone samples using confocal microscope via to 15 mW . Tandem 3–,,,–,,First, we measured the Brillouin shift of the bovine, ovine, chicken tibia bones, and rabbit ulna under the increasing compression load. Obtained spectra from the bone samples are in a good agreement with those reported in the literature.Regeneration of critical-sized defects in the rabbit ulnas was evaluated every 3 weeks. Corresponding x-ray images are shown in Complete closure in the defect areas was already observed after 9 weeks for the experimental groups with bone grafts containing the combination of stem cells and all BMP, whereas in the group with only stems cells the formation of endosteal callus was observed and complete regeneration was observed later at week 12.Next, we measured Brillouin spectra for the experimental groups with the grafts consisting of the HCF gel with different combinations of the stem cells and BMPs. Additionally, for each group, separate control with only HCF was tested. Compression experiments were performed to test the bone strength and BLS measurements were done simultaneously as a load was applied. With an increase in the compression load, significant variations in the Brillouin frequency shift was observed compared with the control samples with HCF gels only , droppinand BMPs  and onlyand BMPs  exhibite,In native bones the observed Brillouin peak frequency shift increased with a compression load , whereasFurthermore, FWHM values of the Brillouin peaks of investigated bones were also determined . AdditioIn solid materials, viscosity is a measure of the viscous-like deformation; materials with lower degree of viscosity can withstand more viscous-like deformation under constant loading.,,Here, measured Brillouin spectra were used to determine hypersonic longitudinal sound wave velocities to compare elastic properties of regenerated bones. The acoustic sound velocities in the control bones were found to be in the range of nd BMP-7 . These v,,In line with the previous studies, where HCF gels with stem cells and various growth factors were successfully used for the bone regeneration purposes, we showed the effectiveness of the MSCs combined with both BMPs.The sensitivity of the wave velocities to the changes in macro- and microstructural components in the bone matrix demonstrates extremely promising avenues for further employment of the BLS technique for tissue engineering applications in clinical settings for studying the quality of the bone grafts implantations through the characterization of the collagen fibrils, mineral content, and mechanical stability of the bone grafts itself and how different external parameters affect the regeneration process . Introducing fiber optics can enable a real-time monitoring and incorporation of the BLS system into the other imaging setups.,,,Traditional Brillouin spectroscopy setups take point measurements and long-time measurements of a weak Brillouin scattering light are required (acquisition time about 100 ms).Our work also has a few limitations, performing series compressive creep-recovery experiments can help to understand more time-dependent viscoelastic behavior of the regenerated bone matrix. Elaborate preparation process of the samples suitable for the BLS studies and long-time measurements are the future challenges of the BLS systems and can hinder its application in clinical setting.4In this work, we evaluated viscoelastic properties of the mammalian bones and the regeneration efficiency of the critical-sized defects in rabbit ulna using BLS spectroscopy and radiography methods. The bovine tibia showed superior fracture resistance compared with the ovine and chicken bones. The reported study also revealed that HCF gels containing different combinations of the stem cells and BMPs were most effective in bone regeneration, whereas a combination of all factors had the best effect with complete defect regeneration after 9 weeks. Variations in the Brillouin shifts under the compression load were observed for the bones, where defects were not able to completely regenerate. Obtained results indicate that the bones with fully consolidated fractures have higher values of the acoustic wave velocities relating to higher elastic moduli compared with the bones with defects. The addition of MCS and BPMs is critically important for the regeneration of elastic and viscous properties, respectively. Micro-CT and radiography images are in good agreement with BLS characterization. BLS spectroscopy (for sensing of hypersonic velocity and sound attenuation) in tandem with radiography (for imaging and mass density determination) is also complimentary for full viscoelastic property assessment. These findings demonstrate extremely promising avenues for further employment of BLS technique in combination with radiography for assessment of strength and viscous properties of large variation of viscoelastic strength and for tissue engineering applications.


Nursing homes (NH) were among the first settings to receive COVID-19 vaccines in the United States, but staff vaccination coverage remains low at an average of 64%. Using an agent-based model, we examined the impact of community prevalence, the Delta variant, staff vaccination coverage, and boosters for residents on outbreak dynamics in nursing homes. We found that increased staff primary series coverage and high booster vaccine effectiveness (VE) in residents leads to fewer infections and that the cumulative incidence is highly dependent on community transmission. Despite high VE, high community transmission resulted in continued symptomatic infections in NHs. Nursing home (NH) residents and staff were among the first to receive COVID-19 vaccines, following recommendations from the Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Immunization Practices (ACIP), due to both the high risk of severe disease and the high risk of spread in this congregate setting . Recent On September 5, 2021, average vaccination coverage among NH residents was 84% in the United States; however, coverage among NH staff was approximately 64%, with wide variability across facilities [Here we examine the impact of high community prevalence and the more infectious Delta variant of SARS-CoV-2 on the expected distribution of infections among vaccinated and unvaccinated people in the NH. We then look at the effect of different vaccination strategies for NH residents and staff, evaluating a range of levels of staff coverage and different scenarios of booster effectiveness.We build upon a previously published model of a NH with 100 residents and 100 staff ,7. We inStaff have a daily probability of infection from the community, which we vary to reflect different levels of community prevalence. Mandatory non-outbreak screening testing of unvaccinated staff is conducted twice per week for nursing homes located in counties with substantial to high community transmission . When a We include three vaccine effects of a two-dose vaccine in the model, basing estimates of VE on data from mRNA vaccine studies . First, We compare two primary vaccination strategies: 1) varying staff vaccination coverage between 40% and 100%, and 2) giving a third dose as a booster to all vaccinated residents . The effect of boosters on VE against infection is unknown, so we consider a range from 60%−90%. At the beginning of each simulation, we assumed everyone who is vaccinated has already received two doses; in scenarios with a third-dose booster, the booster is given on the first day, and takes 14 days to take effect.We show results from 100 simulations after two months. Our primary outcomes of interest are the cumulative incidence of symptomatic infections and the cumulative incidence of all infections (symptomatic and asymptomatic) in residents. We also look at the cumulative incidence of symptomatic infections and all infections in the entire nursing home.We estimated the distribution of cumulative incidence among residents after a two-month simulation period, disaggregated by symptom status and vaccination status . We focuWe evaluated the impact of varying levels of staff coverage and of booster dose effectiveness on the two-month cumulative incidence among residents. In these simulations, we assumed booster doses are provided to all vaccinated residents, including both residents in the nursing home at the beginning of the simulations and incoming residents. We found that increased staff coverage (top of figures) led to fewer infections, and the cumulative incidence was highly dependent on community transmission (left vs. right panels). Providing boosters to residents led to fewer infections, with the magnitude of the impact of boosters increasing with higher VE (right of figures). The trends were similar when comparing the cumulative incidence of symptomatic infections  with cumWe observed similar trends when looking at symptomatic infections  and totaSeveral factors influence the risk of outbreaks of SARS-CoV-2 in nursing homes, and multifaceted approaches are required to protect this vulnerable population at high risk of severe outcomes. We find that maximizing vaccine coverage among nursing home staff remains a critical tool for preventing infections, supporting pending CMS mandates . While bCommunity transmission is one of the main drivers of SARS-CoV-2 infections in nursing homes. The epidemic curves in nursing homes and in the United States follow similar patterns, highlighting that control of community transmission and continued infection prevention and control measures are important for protecting the nursing home population. Our results demonstrate that an increase in nursing home infections does not necessarily indicate lower or waning VE if community transmission is rising.The largest reduction in transmission occurred in simulations with both high staff coverage and high booster efficacy, although each scenario on its own also led to reduced transmission. Direct comparison of the two strategies is challenging because the impact of boosters depends on booster efficacy. Additionally, the two strategies require different numbers of vaccines; increasing staff COVID-19 vaccination coverage will require fewer doses in most nursing homes than providing boosters to all vaccinated residents, particularly given the high rate of resident turnover.Our results are subject to several limitations. As described previously ,7, while1


Fetal heart failure is mainly caused by congenital heart defect and arrhythmia. It is difficult to appropriately diagnose the severity of fetal heart failure simply by ultrasonography because the development of a fetal heart in fetoplacental circulation and how well the fetal myocardium can adapt to postnatal cardiopulmonary circulation are challenging to assess. In adult cardiology, natriuretic peptides (NPs) are the most useful biomarker of heart failure; however, studies investigating NP levels in the fetuses and amniotic fluid are quite limited. Furthermore, little is known about their production and metabolism. This review summarized the most relevant findings on NP levels in the umbilical cord blood and amniotic fluid. The findings can then extend their use as a diagnostic biomarker of heart failure in fetuses with congenital heart defect and/or arrhythmia. The patin utero . Sustainin utero . Therefoin utero . An accurhythmia .The development of a fetal heart in fetoplacental circulation and how well the fetal myocardium can adapt to postnatal cardiopulmonary circulation are difficult to assess. Thus, fetal heart failure is still challenging to diagnose. Recent studies have shown that the cardiovascular profile score is a comprehensive echocardiographic marker of fetal heart failure . This meNatriuretic peptides (NPs) are established as biomarkers of heart failure in adult cardiology ; howeverOur previous study showed that plasma NP levels in the umbilical cord blood were correlated with the severity of heart failure in fetuses with CHD and/or arrhythmia ; Table 1in utero (Fetal tachyarrhythmia or bradyarrhythmia was strongly correlated with high NP levels . Abnormain utero . MeanwhiPreterm birth and fetal acidemia are associated with high NP levels in fetuses with CHD and/or arrhythmia . Earliervia protease digestion in the amniotic fluid, similar in the blood (In the amniotic fluid, NT-proBNP levels increase in a stepwise fashion with the severity of fetal heart failure in fetuses with CHD and/or arrhythmia . In conthe blood . Amniotihe blood . AmniotiThere are few data on the association between amniotic fluid NPs and fetal heart failure. Previous studies have reported a good correlation between amniotic fluid NT-proBNP levels and the severity of twin-twin transfusion syndrome in monochorionic diamniotic twin pregnancies . Both dovia amniocentesis should be planned to identify the proper timing of delivery and improve the prognosis of fetuses with CHD and/or arrhythmia. Amniotic fluid NT-proBNP measurements are expected to complement the inadequate points of echocardiography in fetuses with CHD and/or arrhythmia.Several studies have investigated NP levels in the umbilical cord blood and amniotic fluid upon delivery. The effects of maternal blood or vaginal secretion cannot be completely eliminated during amniotic fluid NP measurements, even though the mode of delivery and labor were not associated with NP concentrations . PercutaA recent study has found the differential metabolism of ANP and BNP in the fetoplacental circulation . After pBy contrast, plasma BNP levels did not almost decrease after passing through the placenta, regardless of the type or presence of fetal heart disease. In adult cardiology, the half-life of BNP in the plasma is 10-fold longer than that of ANP . Bindingvia accelerating proBNP processing and activating the BNP/cGMP cascade (Reverse-phase high-performance liquid chromatography revealed that in the fetoplacental circulation, ANP and BNP mainly comprised the mature and precursor forms, respectively ; Table 1 cascade . FurtherSeveral studies have shown that there is no or little exchange of ANP, BNP, and NT-proBNP across the placenta . Fetus aThe major source of NPs in the amniotic fluid has not yet been established . Fetal uPlasma NP levels in the umbilical cord blood reflect the severity of heart failure in fetuses with CHD and/or arrhythmia. Elevated NP levels are mainly attributed to an increase in central venous pressure secondary to arrhythmia or atrioventricular valve regurgitation caused by CHD. The plasma concentrations of ANP, BNP, and NT-proBNP in the umbilical cord blood had similar correlation profiles with the severity of fetal heart failure. Meanwhile, NT-proBNP levels in the amniotic fluid and umbilical cord blood are strongly correlated and amniotic fluid NT-proBNP levels increase according to the severity of fetal heart failure. In contrast, the ANP and BNP concentrations in the amniotic fluid are extremely low and, thus, are not good markers for assessing fetal heart failure.The fetus and mother produce and metabolize NPs independently of each other. Metabolism in the fetoplacental circulation is quite different between ANP and BNP. Fetal plasma ANP comprises the mature form, and the placenta and umbilical vessels may be the major sites of ANP metabolism. Fetal plasma BNP predominantly consists of the precursor form, which may reduce BNP metabolism in the fetoplacental circulation in addition to its lower affinity to NPR-C.The features of ANP, BNP, and their related peptides in the umbilical cord blood and amniotic fluid provided a strong basis for their use as biomarkers that can complement the inadequate points of ultrasonography.TM drafted the manuscript. HH and NM edited and revised the manuscript. 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.


The coronavirus-induced pandemic has put great pressure on health systems worldwide. Nonemergency health services, such as cancer screening, have been scaled down or withheld as a result of travel restrictions and resources being redirected to manage the pandemic. The present article discusses the challenges to cancer screening implementation in the pandemic environment, suggesting ways to optimize services for breast, cervical, and colorectal cancer screening.The manuscript was drafted by a team of public health specialists with expertise in implementation and monitoring of cancer screening. A scoping review of literature revealed the lack of comprehensive guidance on continuation of cancer screening in the midst of waxing and waning of infection. The recommendations in the present article were based on the advisories issued by different health agencies and professional bodies and the authors' understanding of the best practices to maintain quality-assured cancer screening.A well-coordinated approach is required to ensure that essential health services such as cancer management are maintained and elective services are not threatened, especially because of resource constraints. In the context of cancer screening, a few changes in invitation strategies, screening and management protocols and program governance need to be considered to fit into the new normal situation. Restoring public trust in providing efficient and safe services should be one of the key mandates for screening program reorganization. This may be a good opportunity to introduce innovations  and consider de-implementing non–evidence-based practices. It is necessary to consider increased spending on primary health care and incorporating screening services in basic health package.The article provides guidance on reorganization of screening policies, governance, implementation, and program monitoring. Key ObjectiveWhat are the challenges at health system level for reinitiating cancer screening in the postpandemic scenario, and how to optimize screening services by making them resilient to similar contextual threats?Knowledge GeneratedRestarting cancer screening activities in the post-COVID era will require a well-coordinated effort to reach out to the community more proactively, alleviate the concerns of the apparently healthy individuals to return to routine health care and reorganize clinical services to minimize backlogs in services. This should be considered as an opportunity to improve organization, quality, and reach of the cancer screening programs through pragmatic application of technology and innovations and de-implementation of existing non–evidence-based practices.RelevanceThe best practices in governance, organization, and implementation highlighted in the article will help the cancer screening programs to encounter disruptive consequences of the pandemic better and thus prevent the predicted surge in the number of deaths from cancers, especially in limited-resourced countries.1 Health system in every country is strained to the extreme as a result of the impact of the COVID-19 pandemic. Services deemed nonemergency such as cancer screening were scaled down or stopped as part of efforts to reduce risks of SARS-CoV-2 infection and also to reduce load on the health services. Measures to avoid nonurgent interactions with health facilities were endorsed by the WHO and the respective Ministry of Health during the acute phase of the transmission in the community.2 Different professional medical societies and voluntary organizations also advised to put cancer screening on hold.4 Most importantly, the screen-eligible individuals were hesitant to visit the health facilities because of the scare of getting the infection. As a consequence, a significant surge in the number of deaths from cancer and other diseases unrelated to COVID-19 is predicted in the near future, especially in the socioeconomically disadvantaged and other vulnerable populations.5The SARS-CoV-2 infection responsible for the first pandemic of the twenty-first century already claimed more than 2 million lives as of January 2021.2 Full or partial assignment of the dedicated health staff for NCD control to support COVID-19 in 94% of the responding countries is one such example. Several countries have already reported more than 90% drop in screening, diagnostic, and treatment activities following the declaration of a health emergency because of COVID-19.8 Scotland reported a 70% reduction in urgent referrals of patients with suspected cancer by primary care physicians during the surge of COVID-19 cases, and such drastic reduction in referrals will significantly delay cancer detection.10As the countries ease restrictions and reopen various essential health care facilities, putting cancer screening and management back on track will continue to face challenges. A survey conducted by the WHO in May 2020 in 155 countries not only reported major disruption of noncommunicable disease (NCD) control services (including cancer screening) in almost all countries but also highlighted the difficulties of reinitiating such activities.The public health policies and social measures adopted by the countries to respond to the pandemic are different, and there is no one size fits all solution to reorient health service components and maintain the nonemergency preventive services. Restarting cancer screening activities as the crisis situation continues or somewhat settles down will require a well-coordinated effort to reach out to the community more proactively, alleviate the concerns of the apparently healthy individuals to return to routine health care and reorganize clinical services to minimize backlogs in services.The objectives of this article are to enumerate the challenges at health system level for reinitiating cancer screening services in the post-COVID scenario and to suggest various approaches to optimize services for breast, cervical, and colorectal cancer (CRC) screening and improve their resilience to contextual threats.Characteristically, the unfolding of the COVID-19 epidemic occurs through a sequence of phases with different levels of infection transmission and burden of disease in the population  should be widely publicized through mass media. Screening programs with systematic invitation strategies should inform the eligible populations through letters, emails, telephone calls, or digital platforms about the measures taken by the program to minimize the risk of SARS-CoV-2 transmission. The opportunistic programs should ensure that the health staff entrusted to mobilize individuals for screening are appropriately trained to provide such information in an unambiguous manner. In some countries , community health workers make home visits to counsel and invite individuals to cancer screening. Creative use of mobile phones and innovative apps may help the health workers to contact eligible individuals more efficiently while minimizing person-to-person contact. Cancer awareness campaigns should aim to improve public health literacy on the consequences of delaying screening, diagnosis, and treatment and involve various stakeholders, including the NGOs and faith-based organizations. Informing populations of the early symptoms of common cancers and the consequences of ignoring them because of the outbreaks should be a key component of all campaigns.COVID-19 creates major disruptions in the systematic invitation procedure with screening appointments being delayed, deferred, or neglected during the acute phase of the pandemic. Strategies to deal with the backlog include increasing the number of screenings performed in a day (by extending the hours of service or by expanding the capacity), switching to more throughput testing technologies  for CRC screening and introducing human papillomavirus [HPV] test for cervical cancer screening), and task-shifting or -sharing. Health systems should prioritize inviting those who are at highest risk . Individuals with known comorbidities should be given appointment in a way to minimize wait time at the health facilities, and some of them with least risk  may be spared of any further screening. Information system should be adapted and calibrated to be able to manage the new program strategies in appointment and invitation management. Helplines or dedicated websites may be set up to address patient queries.15 Primary care providers need to be more proactive in counseling and motivating the eligible populations. Remote consultation through telemedicine is becoming popular in many countries with improved technology and adoption of regulatory and legal framework.16 These telehealth opportunities or virtual clinics could be used to invite eligible men and women to screening. As a result of rationing of personal protective equipments (PPEs) in the face of supply shortage, screening appointments may be given on selected days of the week to examine a large number of participants on a single day.Opportunistic screening is likely to decline significantly as the in-person visits by the asymptomatic patients to health facilities drop significantly during and after the acute situation.Restoration of screening or diagnostic services should continue to mitigate the risk of SARS-CoV-2 transmission and at the same time have contingency plans anticipating the likelihood of restrictive measures being reintroduced. Reorganization of screening services as the COVID-19 case load reduces should focus on capacity enhancement as well as adopting novel approaches to minimize person-to-person contact and maintain social distancing. Written standard operating procedures for infection control should be circulated among the providers and displayed prominently inside the clinics. Every clinic should have a designated staff in charge of monitoring compliance to the standard operating procedures. Irrespective of the nature of screening or diagnostic evaluation, the basic principles and safety protocols as listed in Table In the following sections, we have discussed the best practice measures that can be adopted to improve efficiency of screening for cervical, breast, and colorectal cancers.17 The kits for self-collection may be sent by post or distributed by the community health workers.The WHO's call to eliminate cervical cancer has motivated efforts across the globe to scale up screening services and implement HPV-based programs. The HPV-negative women won't need any clinic attendance for screening for at least 5 years. HPV-based screening offers a possibility of at-home sample collection by the women themselves, which avoids the use of public transport to clinics and unnecessary exposure within clinics, thereby reducing risk to both health care providers and patients. HPV testing obtained without a gynecologic examination, by women themselves either at home or clinic, provides a reliable result.Majority of the low- and middle-income countries cannot afford HPV tests and have to rely on visual inspection with acetic acid (VIA) test, which requires an examination by a health provider. In such settings, a screen-and-treat approach of immediate treatment of the VIA-positive women will reduce the number of clinic visits by the women and minimize client-provider interactions. We suggest that the current situation actually offers an incentive for the VIA programs to switch to HPV-based screening every 5 or 10 years. Many of the test platforms procured to detect SARS-CoV-2 virus can be used to detect HPV as well.18 Those with suspected high-grade lesions or cancer on cytology should be given priority appointment for colposcopy over those having low-grade abnormalities.19 Outreach VIA, colposcopy, and treatment services, which do not rely on electricity and combine all these interventions in a single visit, could provide a viable alternative to clinic visits in resource-constrained settings.20Depending on the prevailing travel restrictions and load on the services, a policy to triage patients for diagnostic evaluation may be considered. Appropriate triaging of the HPV-positive women can significantly reduce the number of women requiring colposcopy. Triaging HPV-positive women with HPV 16/18 genotyping and cytology (only for those HPV-positive women negative on HPV 16/18) reduced colposcopy referrals by nearly two-third in the screening program in Turkey.21Women living with HIV have substantially increased risk of cervical cancer. In the current health care landscape, it is important that screening services continue especially for this group of women. The WHO has recommended integrating cervical cancer screening services into antiretroviral therapy programs and screening should be planned at one of the scheduled visits to the antiretroviral therapy clinic.23 No formal study has yet documented the risk of an operator of getting infected with SARS-CoV-2 because of the aerosols generated during LLETZ procedure. A study on 35 patients infected with SARS-CoV-2 (eight patients were symptomatic) in China demonstrated that none of them had the virus detected in vaginal fluid or cervical specimen.24 The British Society of Colposcopy and Cervical Pathology advises to limit the use of diathermy to coagulate the bleeding points after LLETZ  and liberally use Monsel’s solution for hemostasis.25 Thermal ablation and cryotherapy treat the cervical precancerous lesions by tissue desiccation and freezing, respectively, and do not generate any smoke. Nevertheless, the use of PPE is recommended for the provider and assistants while performing colposcopy and treatment of an asymptomatic patient without known COVID status and it should comprise sterile fluid-repellent surgical gloves, eye protection, FFP2 mask, surgical cap, and gown.26To minimize number of visits, colposcopically suspected high-grade lesions should be treated immediately without waiting for histopathologic verification. Observational studies have documented the presence of HPV DNA  in the smoke generated during large loop excision of transformation zone (LLETZ) procedure and transmission of HPV DNA to the operator's nasal cavity.27Coordinated efforts are necessary to overcome the COVID-19 challenges and facilitate the resumption of CRC screening programs in a gradual and prioritized manner. Selecting candidates according to individual CRC risk with priority given to high-risk individuals may be considered in a program on the basis of invitation. This process can be coordinated with the screening registry staff or general practitioner who can stratify individuals by risk through phone calls or administration of online questionnaire. In addition, scientific societies should revisit some of their guidelines for patients with inflammatory bowel disease or postpolypectomy endoscopic surveillance to optimize the colonoscopy resources.28 conducted a study in Italy to verify the effectiveness and safety in performing selective diagnostic colonoscopies as part of the CRC screening program in a hospital declared as COVID-free hospital. They found that in spite of fewer cases done during lockdown in comparison with data from the same period in 2019, both invasive cancer detection rate  and high-risk adenoma detection rate  were higher because of the prioritization of more high-risk cases.Screening and diagnostic services should be reintroduced in COVID-free centers to mitigate risk of infection and encourage population to participate. D'Ovidio et al8 Quantitative FIT should replace qualitative FIT as it is throughput and reduces the colonoscopy referrals.30During the pandemic, flexibility in CRC screening methods should be considered. Switching to FIT in programs that use endoscopy-based screening is an example. Moreover, applying an FIT test would allow using the mail system to send and return test kits. Alternatively, the samples can be deposited in drop boxes kept at health facilities. By sending the FIT test kits to the eligible individuals by post, the National Bowel Cancer Screening Program in Australia could maintain reasonably high participation rate to CRC screening even during the worst period of the COVID-19 outbreak.31Differently from cervical and colon cancer screening, breast cancer screening has no alternative for a self-collected screening test. As the screening activities resume while the COVID-19 pandemic is still ongoing, breast imaging and further assessment must be performed using safe practices. On that note, we must balance the need to avoid delays of a breast cancer diagnosis while avoiding infection, which requires careful attention to PPE, physical distancing, and vigilance to maintain these practices; resuming activities should also involve prioritization and implementation of innovative interventions.35Recommendations from different medical associations and experts are proposing that the diagnostic procedures in symptomatic patients should be prioritized over screening procedures. All efforts should be made to avoid delayed diagnosis in situations as clinical suspicion of inflammatory or locally advanced breast cancer, imaging findings of BI-RADS 5 (high priority) or BI-RADS 4 (medium priority), symptomatic women with a new palpable lump or breast thickening that is clinically concerning, and suspicion of breast cancer in a pregnant woman.37Annual mammographic screening should be discouraged. One interesting strategy to reduce the number of clinic visits for the women may be a one-stop breast care. Health facilities would offer same-day diagnosis and integrated multidisciplinary care services, which include counseling, mammography, or clinical breast examination followed by appropriate diagnostic evaluation, which includes imprint cytology of breast core biopsy specimens. This model has been tested in both low- and high-resource settings, showing encouraging feasibility and outcomes.38 Cancer as a comorbidity certainly increases the risk of getting severe complications and dying from COVID.39 However, at least two studies have shown that cancer treatment does not increase the threat to life of a patient, even if they get infected during the course of treatment.41 Strategies that should be considered to ensure timely and adequate treatment of the patients with cancer during various phases of the pandemic are listed in Table The COVID pandemic has significantly disrupted treatment of patients with cancer with patients and the treating oncologists being hesitant to initiate or continue with treatment given the threat of the infection.42 Many clinical trials were put on hold as there were a lot of uncertainties around the balance of risks and benefits and how best to communicate the same to the prospective participants.43 Research evaluating the efficacy and/or implementation of new technologies and approaches in cancer early detection will face major challenges in the near future. IARC planned a multicentric trial to evaluate automated visual examination  as a cervical cancer screening tool in India and Thailand.44 The study initiation has been delayed by at least 10 months because of less frequent meetings of the ethics committees, suspension of courier services making procurement of consumables and equipment difficult, cessation or slowing down of cancer screening activities, the investigators being preoccupied with COVID-related duties, uncertainties around compliance of the trial participants, and safety concerns of the participants as well as staff because of the increased number of interactions. The biotechnology industries are quite cautious in investing in new innovations in the midst of the economic downturn. Some of the developers of new point-of-care HPV detection tests are investing their energy and resources in new technologies for the detection of SARS-CoV-2 and postponed the development of the HPV tests. The availability of fund for research will shrink significantly with major research-funding agencies already announcing major cuts in cancer research funding.10The COVID-19 pandemic has had a huge impact on clinical research other than those related to the infection and its prophylaxis or treatment.46 It will be necessary to modify some of the regulatory requirements. Remote consenting through online consultation followed by obtaining a digital signature (e-consent) and follow-up by telephone or video calls in situations not requiring sample collection or assessment by a health provider may become acceptable norms. Advantage should be taken of the enhanced digital literacy and acceptance of app-based COVID-19 symptom–reporting and alert tools to promote self-reporting of outcomes by trial participants using online platforms. The relationship between exposure to the trial-related interactions and subsequent infection with SARS-CoV-2 should be closely monitored, and appropriate actions should be taken if there are any concerns. Implementation research to identify the most pragmatic, acceptable, and cost-effective strategies to continue with cancer screening and treatment services during various phases of the epidemic should be prioritized.It is crucial to obtain clear directives and guidance from the national regulatory agencies for continuation of clinical research. To date, the US Food and Drug Administration and European Medicines Agency have published such guidelines.In conclusion, reintegration of individuals to the screening pathway depending on where they left at the time of suspension requires a coordinated approach and involvement of many stakeholders. It is an opportunity to learn from other countries as this has become a global problem and countries are at different stages of adapting cancer screening successfully to the changing health ecosystem. It is also an opportunity to improve the resilience of screenings to threats, which are likely to arise in a volatile and uncertain context. In these unprecedented times, reassessing a cancer screening program could be an opportunity of building back better services. Performing a situation analysis and planning accordingly, prioritizing and keeping focus on evidence-based practices, considering implementation of evidence-based innovations , and considering de-implementation of non–evidence-based practices  could be a good start point. The key is to remain flexible and vigilant and periodically assess severity of the outbreak in the population and adapting guidelines to the changing situation.


Alkali-activated materials (AAMs) present a promising potential alternative to ordinary Portland cement (OPC). The service life of reinforced concrete structures depends greatly on the corrosion resistance of the steel used for reinforcement. Due to the wide range and diverse properties of AAMs, the corrosion processes of steel in these materials is still relatively unknown. Three different alkali-activated mortar mixes, based on fly ash, slag, or metakaolin, were prepared for this research. An ordinary carbon-steel reinforcing bar was installed in each of the mortar mixes. In order to study the corrosion properties of steel in the selected mortars, the specimens were exposed to a saline solution in wet/dry cycles for 17 weeks, and periodic electrochemical impedance spectroscopy (EIS) measurements were performed. The propagation of corrosion damage on the embedded steel bars was followed using X-ray computed microtomography (μXCT). Periodic EIS measurements of the AAMs showed different impedance response in individual AAMs. Moreover, these impedance responses also changed over the time of exposure. Interpretation of the results was based on visual and numerical analysis of the corrosion damages obtained by μXCT, which confirmed corrosion damage of varying type and extent on steel bars embedded in the tested AAMs. These specifics need to be considered when interpreting the electrochemical measurements.It was shown that the corrosion rates in the different AAMs were not explicitly related to the compressive strength or porosity values of the mortars.In specific cases, the corrosion rates assessed from the EIS spectra evidently overestimated the actual corrosion rates. It is not clear whether this discrepancy was due to unsuitable modelling of the spectra or due to the presence of additional specific electrochemical processes not directly related to the corrosion of steel.It is evident that a number of open questions related to the corrosion of steel in AAMs still remain. In order to investigate these issues, our future research will consider the use of alternative monitoring techniques not based on electrochemical modelling that enable differentiation between the various types of corrosion, i.e., physical monitoring methods  and other techniques .