Hybrid joining (HJ) is the combination of two or more joining techniques to produce joints with enhanced properties in comparison to those obtained from their parent techniques. Their adoption is widespread  and is present in a vast range of applications including all industrial sectors, from automotive to aerospace, including naval, construction, mechanical and utilities. The objective of this literature review is to summarize the existing research on hybrid joining processes incorporating structural adhesives highlighting their field of application and to present the recent development in this field. To achieve this goal, the first part presents an introduction on the main class of adhesives, subdivided by their chemical nature  The second part describes the most commonly used Hybrid Joining (HJ) techniques  The third part of the review is about the application of adhesives in dependence of performance, advantage and disadvantage in the hybrid joining processes. Finally, conclusions and an outlook on critical challenges, future perspectives and research activities are summarized. It was concluded that the use of hybrid joining technology could be considered as a potential solution in various industries, in order to reduce the mass as well as the manufacturing cost. The development of efficient and flexible joining methods for structures is a critical step for cost-effective manufacturing, as well as for the repair and replacement of components in various types of structures in industry. The main joining technologies currently used in industry are: mechanical fastening, welding and adhesive bonding.Adhesive bonding provides several advantages for joining metals when compared to resistance spot welding or mechanical fasteners, such as rivets or screws . It is tThe decisions whether to use adhesives, mechanical fasteners, welding, or a combination of these methods depends on various factors. It must be remarked that all the different joining processes are not generally competitive between them and should rather be considered as being complementary. The appropriate joining technology for any application should be chosen between the best trade-off technological and/or economic value.In hybrid joining technologies, two or more joining processes are carried out, combining the best characteristics of each parent process. The main advantages of combining an adhesive with another joining method are: improved fatigue resistance (static and dynamic), more uniform stress distribution, peel and impact resistance (the point joint arrests crack growth in the adhesive bond), reduction in structural weight, better load sharing, sealing properties, production of continuous joints and increased safety.The most commonly used adhesives in hybrid joining processes are the structural ones which are selected with the aim of fastening together elements in order to produce high modulus, high strength and permanent bonds. They must be capable of transmitting structural stress without loss of structural integrity within design limits .Epoxies can be formulated to meet a wide variety of bonding requirements. Systems can be designed to perform satisfactorily at low  and high temperature . Epoxies yield good to excellent bonds to steel, aluminum, copper and most other metals and they have a wide field of applications. Epoxy-based adhesives offer the advantages of relatively low cure temperatures, relatively low cost and a variety of formulating and application possibilities. They also have the advantage that no volatiles are released during the curing process.Tg of polyurethanes is higher than that of silicones, but lower than that of highly cross-linked, structural epoxy resin adhesives [Polyurethanes (PU), whether one-part or two-part, are high-performance and very versatile and have a wide range of properties, including adhering to a varied range of substrates. Generally, the dhesives ,7. The odhesives .Acrylic adhesives polymerize by a free-radical addition process. They present excellent adhesion to unprepared or minimally surface prepared metals, composites and most thermoplastics.Cyanoacrylates cure through reaction with the alkalinity, in the form of moisture, held on the surfaces to be bonded. Cyanoacrylates are thermoplastic when cured and are limited in temperature capability and chemical resistance. Cyanoacrylates provide high bond strengths on plastics and rubber materials. Bond durability problems are encountered with silicones, polyolefins and some fluoroelastomers and with glass, where extensive surface preparation is required. In general, cyanoacrylates have an excellent lap-shear strength and good shelf life .Anaerobic adhesives are one-part acrylics that remain monomeric in the presence of air but polymerize in its absence. They are supplied in air-permeable containers. Since polymerization depends on the exclusion of air, anaerobic adhesives are best suited to the bonding of machined components. They have good resistance to solvents, and for these two reasons are used in automotive engine construction: for example, in sealing between castings and in the retention of gear trains on their shafts. In aircraft they are used for fixing roller bearings in instruments .−2 in the lap-shear test) up to the maximum allowable temperature. Such adhesives are expensive and not for general use [HTAs based on bismaleimides and polyimides are available for service temperatures up to 290 °C. They are cured under pressure at 175–200 °C and provide useful strength 15 MN meral use .The adhesive selection process is difficult as there is no universal adhesive that will fulfil every application and selection of the proper adhesive is often complicated by the wide variety of available options . In geneIntroduction of the main class of adhesives, subdivided by their chemical nature considering epoxy, polyurethane, acrylic and cyanoacrylate, anaerobic and high-temperature adhesives;Description of the most commonly used HJ techniques ;Recent advances on the application of structural adhesive joints in hybrid joining processes.There are many recent review articles regarding joining techniques of same and dissimilar materials combining mechanical fastening, welding and the use of adhesives. The focus of these reviews is to describe the process of joining and their mechanical and physical properties via simulation and laboratory experiments ,20,21,22Hybrid joining processes combine fundamental processes to achieve some unique characteristics or capabilities, often with synergistic results. These hybrid processes tend to be of more recent origin and have often been developed to overcome shortcomings of the basic processes for particularly challenging applications . As a result of the progress in the field of material engineering, development works are orientated to using thin sheets and small constructional elements. There is also a growing trend of combining traditional metals with polymeric composites. For instance, composites are more structurally efficient, in terms of strength-to-mass ratio, than metals and do not experience galvanic corrosion, while metals have better damage tolerance and failure predictability than composites and are unaffected by the solvents and temperatures which tend to degrade polymers. Therefore, in order to optimize the benefits provided by both types of materials, multi-material joints between metals and composite materials are increasingly being developed . To bondThe main objective behind the developments in advanced fastening and bonding processes is to successfully join new advanced materials with excellent joint properties. The principal techniques of advanced fastening and bonding methods are named hybrid bonded fastened joining and clinch bonding (clinch + adhesive). Hybrid-bonded fastened joints and clinch bonding are produced by simultaneous actions of adhesive bonding and a mechanical fastening technique.A hybrid approach of bonded fastened joints is developed in order to avoid individual limitations of fastening and adhesive joining for assembling of dissimilar materials, composites or composite materials and metallic materials. There are two types of hybrid-bonded fastened joints, such as the joints that use bolts/rivets known as hybrid-bonded–bolted (HBB) joints see c.A fastening system can help to sustain axial loads while the adhesive takes some of the load off the fasteners and redistributes the remaining load more uniformly. The fasteners, in turn, also take some load off the adhesive, particularly out of plane. Most important parameters such as type of joint configuration, type of fastener, adhesive material and its thickness (bond line), loading condition, type of adherend being used and its thickness, overlap length and fastener–hole clearance of hybrid bonded fastened joints are required to produce metallurgically sound joints ,25. TablClinching is known as a press-joining technique, aimed to join thin sheets using specially designed tools or without application of the tool, through interlock formed by plastic deformation of base materials. Clinching is an alternative joining method of riveting, screwing, adhesive joining and spot welding ,28,29,30Clinch with adhesives is called clinch bonding, where suitable adhesive is applied between workpiece sheets. Hybrid techniques of adhesive bonding and welding processes can be subdivided as weld bonding and other hybrid welding processes. The first is a hybrid of resistance spot welding and adhesive bonding (RSW-AB), while the second includes Friction Stir Welding (FSW-AB), Friction stir spot welding (FSSW-AB), Laser Weld Bonding (LBW) and Laser Spot Weld Bonding (LSWB). Typical features of RSW-AB and FSW-AB are briefly presented in the next subsections.Traditional techniques—and, particularly, welding—are not always easy to abandon, because of reliability, widespread knowledge and controllability of the process. This is the case of resistance spot welding (RSW), which is a well-known joining technique still widely employed today for assembly of body structural parts of vehicles. In the last few years, the process has gained importance in the aerospace, automotive and railway industries because it combines the advantages of spot welding, in terms of mechanical and thermal strength, with the stress concentration softening and tolerance to structural damage that are typical of adhesives . There iAs previously mentioned, Friction Stir Welding (FSW) is the one of the most promising processes in continuum joining, and although the FSW has several advantages over other welding techniques as regards joining aluminum alloys, it also has counter-difficulties. An example of the challenges that friction stir welding brings is, in the case of overlap configuration joints, the presence of a hook defect reduces the static and fatigue strength as this defect acts like a crack initiation point. Furthermore, the question of chemical corrosion of certain alloys is also a factor requiring prevention by the use of sealants ,39,40,41The process’ temperature range is between 300 and 470 °C ;The chemical nature of the polymeric adhesives used is relevant, in particular with reference to their thermal resistance (during the process) and chemical resistance (during the use in corrosion environment);The avoidance as much as possible of solvents, or nonenvironmentally friendly additives, in order to reduce the environmental impact of the process.The hybrid joining technology FSW-AB presents different challenges, such as:The FSW also finds its application in the field of welding of wood as in the works of Gfeller et al., Kanazawa et al. and Leban et al., where the combination of friction welding with the melting of wood lignin functioning as molten matrix of entangled fibers due to the friction welding action is studied ,43,44. FRecent advances on the application of structural adhesive joints in hybrid joining processes are presented.In the following sections the application of structural adhesives is described in dependence of the mechanical fastener used.The HBB joints with multiple fastener joints have been studied experimentally and numerically by numerous authors ,79,80,81The improvement of HBB joints’ performance compared to both individual joints is achievable when there is substantial load sharing between the adhesive and the bolts. The load sharing in the HBB joints depends on a combination of materials and geometric parameters and attaining an appropriate load distribution in the joint design is not a trivial task. For example, Lopez-Cruz et al.  demonstrMore recently, Liu et al.  conducteImanaka et al.  investigThe influences of different manufacturing processes, substrates and rivet materials on structural performance of riveted joints were studied in ,67,68,69The mechanical behavior of hybrid rivet-bonded joints was also studied by Pirondi and Moroni ,74. TheyMarannano et al. , in 2015Sadowski and Golewski ,77,78, uPresse et al.  investigRomanov et al.  performeSelahi  employedRelatively fewer investigations have been made on the clinch-bonding hybrid technique because its practical implementation is still very limited in manufacturing industry . The folA brief discussion on the applications of structural adhesives in the most common hybrids joining technology combining adhesive bonding and welding processes (RSW-AB and FSW-AB) is presented in this section.Contemporaneous presence of a spot weld and adhesive layer leads to competitive advantages over both simple adhesive bonding and RSW. As stated by Darwish et al.  in diffePeroni et al.  studied Sadowski et al. , conductHigher mechanical strength of the hybrid joints (polyurethane adhesive + spot-welded joints) compared with adhesive joints or resistance spot welded joints has been obtained in the work of Piwowarczyk et al. . SimilarThe failure process of weld-bonded joints is still not fully understood, and established failure criteria do not exist, mainly because of the coexistence of the weld nugget and the adhesive layer, which makes the stress and strain analyses more complex . CampilhFor the FSW-AB technique the use of suitable polymeric adhesives with high thermal resistance, good wetting and flow characteristics is mandatory in order to obtain a good-quality bond of the metal surfaces. The best candidates for this purpose appear to be epoxy-based adhesives (mono- or bi-component) and polyimide-based adhesives . By combA wide variety of adhesives are available from a range of adhesive manufacturers. The adhesive selection process is difficult as there is no universal adhesive that will fulfil every application. Properties of adhesive can vary greatly, and an appropriate selection is necessary depending on the hybrid process used. Epoxy adhesives use is still the most widespread, due to their peculiar characteristics . The polyurethane adhesives are mainly used in hybrid joints because of their superior flexibility at low temperatures, resistance to fatigue, impact resistance and durability. Polyimide-based adhesives find their niche in the case of the hybrid joining technology FSW-AB, due to the need to use suitable polymeric adhesives with high thermal resistance, good wetting and flow characteristics in order to obtain a good-quality bond of the metal surfaces;In a hybrid-bonded fastened joint the load sharing depends on a combination of materials and geometric parameters. Moreover, as confirmed by several authors, hybrid joints using rivets or bolts bear an increased maximum load and have higher initial stiffness, strength and energy absorption in comparison with nonhybrid joints. The improvement in hybrid fastened-bonded joints performance compared to both individual joints is achievable when there is substantial load sharing between the adhesive and the fastener. The load sharing in these joints depends on a combination of materials and geometric parameters and attaining appropriate load sharing in the hybrid joint design is a challenge. Most of the new advanced fastened hybrid joining processes  do not need an additional connecting part, which helps to reduce weight. They also do not require predrilled holes. Thus, they enable a sensible reduction of the overall joining time;Adhesive bonding combined with welding technologies provides joints with improved fatigue characteristics when compared to spot welding, due to reduction in stress concentrations at the weld-nugget periphery. They also exhibit improved mechanical and thermal properties. In particular, in weld-bonded joints the stress concentration decreases providing better mechanical properties as an increase in tensile shear and/or compressive buckling load. Finally, another key feature of the weld-bonding technology is the optimization of the quality of the sealing and the improvement of the overall resistance to corrosion. However, some technologies are not currently ready for practical application in industry  and further developments are necessary.Nowadays, joining is considered a fundamental part of innovative and sustainable manufacturing. The choice of the best joining solution for a given application needs to be based on several factors, such as the desired production volume, availability of equipment and required joint performance and not ultimately the financial resources. Emerging trends in manufacturing such as light weighting, increased use of multi-material structures and the need for joining of dissimilar materials motivate growing research efforts in the hybrid joining technologies. In this review, the vast range of current and emerging hybrid joining technologies are presented. The contribution of the adhesive for each hybrid joining techniques is highlighted and main conclusions are drawn:Due to their complexity and relatively recent development, there is a need for the development of robust design and process simulation tools for hybrid joining processes. The development of numerical models of the hybrid processes would allow a better understanding of all the phenomena involved. At the same time, they will represent a valuable tool for determining the influence of process parameters on the quality of the hybrid joints. This would greatly advance the understanding of these processes and promote further process development and optimization to expand their area of applications in industry;There is a need to investigate the effect of environmental factors  on the hybrid joints. These issues will need to be addressed before any potential implementation of hybrid joining technologies involving adhesives in industry;The development of new adhesives is continuously increasing. The adhesives need to have some specific characteristics depending on the hybrid process used. For example, for fastening adhesive hybrid joints the ideal adhesive to be used should have low stiffness, extreme elongation to failure and reversible deformation, while for weld-bonded joints the adhesives need to withstand high temperatures. There is a need to study a new class of adhesive  to be used in hybrid joining processes;In several industries , the use of hybrid joining technology could be considered as a potential solution in order to reduce the mass as well as the manufacturing cost. In addition, due to the increasing aspirations for more environmentally friendly technologies and lightweight materials, the joining of polymers, composites and multi-material hybrid structures for industrial applications is still a growing research and development area. Thus, there is a need for new developments on advanced hybrid joining technologies for new advanced materials.Some critical challenges and future research directions are summarized below:


The present paper provides an updated overview of the methodologies applied in photodegradation studies of non-steroidal anti-inflammatory drugs. Photostability tests, performed according to international standards, have clearly demonstrated the photolability of many drugs belonging to this class, observed during the preparation of commercial forms, administration or when dispersed in the environment. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques and in many studies the analytical data are processed by chemometric procedures. The application of multivariate analysis in the resolution of often-complex data sets makes it possible to estimate the pure spectra of the species involved in the degradation process and their concentration profiles. Given the wide use of these drugs, several pharmaceutical formulations have been investigated to improve their photostability in solution or gel, as well as the pharmacokinetic profile. The use of lipid nanocarriers as liposomes, niosomes or solid lipid nanoparticles has demonstrated to both minimize photodegradation and improve the controlled release of the entrapped drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a class of drugs usually applied in the treatment of acute or chronic conditions involved in pain and inflammation . These aNSAIDs can be classified according to their chemical structure or mechanism of action in: salicylates such as Acetylsalicylic acid; propionic acid derivatives such as Ibuprofen, Naproxen, Ketoprofen and Flurbiprofen; acetic acid derivatives such as Indomethacin, Diclofenac and Nabumetone; enolic acid (oxicam) derivatives such as Piroxicam; anthranilic acid derivatives (phenamates) such as Mefenamic acid; and selective COX-2 inhibitors (coxibs) such as Celecoxib .The light sensitivity of these drugs has been studied mainly in commercial formulations ,8 and inUnfortunately, despite most of the anti-inflammatory drugs for topical use showing simplicity of application and minimal systemic absorption, adverse cutaneous photosensitivity reactions have been reported . Such phThe sunlight-guided photocatalytic degradation of harmful drugs and chemicals can be exploited to eliminate them from the environment  or it caHowever, the incorporation of drugs into drug delivery systems (DDS) is now the most successful approach, and is able to reduce light degradation while simultaneously performing controlled release of drugs. Traditional DDSs have shown significant deficiencies, as they distribute agents non-specifically in the body, thus affecting both targets and healthy body cells. In contrast, nanoscale DDSs herald innovative nanotechnology in a wide range of potential therapies, including cancer . Among tLipid nanosystems offer several advantages, such as the possibility of improving the stability of the incorporated compounds and allowing their modulated release action. For example, for drugs, it is possible to improve their solubility in water, their thermal stability, and increase their oral bioavailability, as well as protecting them during the digestive process . These systems can also improve their organoleptic and functional properties ,24. ReceThis review provides an exhaustive collection of the most widely used approaches in the investigation of the photodegradation profile of NSAIDs and the lipid delivery devices proposed for their photoprotection.The quality of a drug and of the formulations containing it must be controlled and ensured during all phases of development. In this quality assurance system, the analytical methods adopted must be able to reliably measure, in addition to the active compounds, any degradation products present in the formulation.The provisions relating to the methods of determining and applying the stability studies are provided in the ICH  Guideline to guarantee the safety, efficacy and quality of the tested drugs. These rules describe the stability tests for the drugs over time in different environmental storage conditions  . Among t2. The cooling system keeps the temperature constant at 25 °C for radiant power values higher than 350 W/m2, while lower radiant power values do not induce an increase in the temperature inside the irradiation chamber. UV radiation can interact directly with the drug, causing molecular vibrations that could induce the breaking of bonds with the formation of free radicals or active species of oxygen, superoxide anions, hydroxyl radicals or single oxygen and consequently with the formation of photodegradation products naphthalene-1-one) have been formulated in microemulsion for topical use to achieve better photostability and pharmacokinetic profile. Stability tests on both the compounds have shown a significant increase of photostability in liquid microemulsion and microemulsion-in-gel, compared to ethanol solution and plain gel. In addition, permeation experiments on the microemulsion-in-gel formulations have shown a better performance compared to the plain gel for both the compounds, highlighting the potential of the microemulsions as delayed drug delivery systems [Other NSAIDs have been combined in micro- or nanoemulsions to increase light-stability. Nabumetone and a newly synthesized analog  have been prepared with different techniques, such as thin layer evaporation, freezing and thawing, extrusion through microporous membrane, and reverse phase evaporation method, obtaining, respectively, multi-lamellar vesicles, frozen and thawed multi-lamellar vesicles, small uni-lamellar vesicles and large uni-lamellar vesicles. The prepared complexes have been characterized by differential scanning calorimetry, demonstrating the influence of the cyclodextrin complex on the size of the liposomes and not on their lamellar structure.Liposomal matrices easily incorporate hydrophilic drugs into the aqueous core and then release them gently with minimal effect on the stability of the liposome. In contrast, the incorporation of lipophilic drugs into the lipid bilayer can interfere with the stability of liposomes . Therefo2, light stability increased significantly when the drug was entrapped in niosomal systems in presence of 5% ascorbic acid. Furthermore, the permeation capability of Diclofenac has been found to be about three times higher than that measured on the commercial gel [The new generation of vesicular nanocarriers is represented by niosomes, self-assembled vesicles composed of non-ionic surfactants with/without adequate amounts of cholesterol or other amphiphilic molecules. Niosomes have a mono- or multilamellar structure like liposomes, being able to incorporate both lipophilic and hydrophilic bioactive substances. However, they have lower production costs and greater stability during storage . Photostcial gel ,54.w/v) has been incorporated into the aqueous phase prior to preparation of the SLNs for their surface modification. The proposed formulations increased drug loading capability, entrapment, and delivery to anterior and posterior segment ocular tissues. Chemical stability has been investigated in storage conditions, demonstrating that the variation of the lipid component in the colloidal framework can improve drug release characteristics and chemical stability [Another alternative to liposomes is represented by SLN and NLC. The latter have shown greater solubility of the incorporated drugs than SLN. Photostability studies have demonstrated the efficiency of these vesicular systems in preserving drugs from light photodegradation ,62. For tability .Photodegradation of drugs represents a problem that has emerged in recent decades, and the definition of photoprotective systems is of fundamental importance in the modern pharmaceutical industry. Several strategies have been proposed to improve the tendency of some drugs to degrade when exposed to light. This review reports the main lipid nanocarrier matrices proposed for drug formulation and their application in ensuring a valid photoprotection of the incorporated drugs. Lipid nanocarriers are characterized by the trapping of the drug into a cavity of their structure, involving only weak binding interactions. They have several advantages as drug carriers, especially for topical administration, and have been shown to both improve the pharmacokinetic profile and significantly increase the light stability of the non-steroidal anti-inflammatory drugs.


Autophagy is an evolutionary conserved degradative process contributing to cytoplasm quality control, metabolic recycling and cell defense. Aging is a universal phenomenon characterized by the progressive accumulation of impaired molecular and reduced turnover of cellular components. Recent evidence suggests a unique role for autophagy in aging and age-related disease. Indeed, autophagic activity declines with age and enhanced autophagy may prevent the progression of many age-related diseases and prolong life span. All tissues experience changes during aging, while the role of autophagy in different tissues varies. This review summarizes the links between autophagy and aging in the whole organism and discusses the physiological and pathological roles of autophagy in the aging process in tissues such as skeletal muscle, eye, brain, and liver. Autophagy is a tightly orchestrated process that degrades and recycles cytoplasmic components in lysosomes to maintain cellular homeostasis. Although the phenomenon of autophagy was first reported by Thomas P. Ashford and Keith R. Porter in 1962 in the research of lysosomes in rat hepatic cells, the importance of this discovery was not realized . The conOver the last two decades, the molecular mechanisms and physiological functions of autophagy have been extensively studied. Analysis of the delivery route of autophagic cargo to lysosomes has shown that there are at least three types of autophagy: microautophagy, chaperone-mediated autophagy (CMA) and macroautophagy . In micrMycobacterium tuberculosis, group A Streptococcus, Shigella and so on)  . Recent d so on) . Since tAging is the decline of biological function both at the cellular and organismal level that occurs gradually and continuously. Lopez and colleagues have summarized nine hallmarks of aging: “genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrition-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication” . It’s noGenomic instability is a prominent feature of aging. It was reported that autophagy can support genomic stability by engulfing and digesting the hazardous cellular components and chromatin fragments and by reducing oxidative stress . TelomerC. elegans using fluorescently tagged LGG-1 (ortholog of Atg8/LC3), a marker of autophagosomes and autolysosomes and observed blocked late-stage autophagy in aged worms  and diabetic retinopathy (DR) in the retina, cataracts in the lens, glaucoma in the optic nerve and so on . Poor viAge-related macular degeneration is an irreversible sight-threatening disease featured by the intracellular lipofuscin accumulation of lipofuscin in RPE cells as well as extracellular drusen deposition between RPE and the Bruch’s membrane (BM). In early AMD, the autophagy activity is elevated to compensate for the exacerbate organelles damage caused by increased oxidative stress. Nevertheless, by late AMD, the autophagic system can’t handle the expanded requirements to clear damaged organelles and thus becomes overloaded and dysfunctional . CompromDiabetic retinopathy (DR), a common diabetic complication, is characterized by the apoptosis of neuron cells and dysfunction of glial cells . DR is oCataracts are a widespread eye disease in the elders, affecting approximately 20% of adults aged 65 years and older . With agGlaucoma is a common age-related chronic optic neuropathy with progressive degeneration of retinal ganglion cells (RGCs), resulting in damage to the optic nerve head and a concomitant vision loss . TrabecuAtg7-null mice  is the most prevalent type of dementia in the elderly and is pathologically characterized by the deposition of extracellular amyloid-beta (Aβ) and intracellular hyperphosphorylated tau proteins. TEM studies show that AD is generally accompanied by low or insufficient autophagic activity . In normParkinson’s disease (PD) is the second most common age-related neurodegenerative disease clinically featured by the progressive death of dopaminergic neurons in the substantia nigra. Another pathological hallmark of PD is the deposition of alpha-synuclein-positive protein aggregates termed Lewy bodies, indicating a deficiency in the protein elimination mechanism. Indeed, autophagy failure is recognized as an important pathophysiological mechanism contributing to the initiation and progression of PD. Autopsy of brain tissue from PD patients showed a build-up of autophagosomes, accompanied by the absence of lysosomal markers in dopaminergic neurons, suggesting the impaired autophagy flux . BelarbiThe liver is a vital metabolic organ and possesses high levels of metabolic-stress-induced autophagy. Hepatic autophagy supplies energy to starved cells by breaking down glucose, amino acids and free fatty acids, promoting the synthesis of new macromolecules, and controlling the quality and quantity of organelles like mitochondria. Therefore, autophagy is important for maintaining the balance of energy and nutrient in the liver. A study on perfused rat liver demonstrated that starvation elevated the autophagic proteins degradation rate from about 1.5% of total liver protein per hour  to 4.5% of total liver protein per hour . Liver-sRecent studies have shown that the autophagy capacity of older livers is significantly reduced compared to younger livers. Mohammad et al. revealed that the expression of LC3 and the number of autophagic structures declined with age in mice . The redUnlike other visceral organs, the liver has an amazing ability to regenerate. Liver regeneration is an energy-consuming process that requires an extensive supply of energy for hepatocytes division and growth. Autophagy, especially mitophagy, selectively removes the damaged mitochondria and promotes mitochondrial biogenesis, which decreases ROS production and increases ATP synthesis, providing the environment and energy required for liver regeneration. The regeneration ability of the liver is impaired with age and improving autophagy seems to be a promising way to promote regeneration in aged livers. The mTOR signaling pathway is the most well-known autophagy regulatory pathway. However, mTOR not only regulates autophagy but also plays important role in cell proliferation. Although inhibition of mTOR activity can induce autophagy, it impairs cell proliferation, which is critical for liver regeneration. Therefore, activation of autophagy through an mTOR-independent pathway is a better strategy . AmiodarIn summary, autophagy has convincingly been shown to be a prerequisite for longevity and healthspan, and altered autophagy contributes to aging and the transition of the healthy state of several tissues into a presenescent state . AlthougHY, YM, and CY prepared the figure. WL, PL, and HY wrote and approved the final text. All authors were involved in the manuscript writing, including discussion of content and writing, and editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Coarctation of the aorta represents a narrowing of the thoracic aorta. Hypertensive patients with blood pressure differences ≥20 millimetres of mercury have an indication for surgical or interventional treatment. Implantation of a covered stent became the preferred therapy for the management of this pathology in adolescents/adults. Case report: We report the case of a 14-year-old male sportsman, who presented in the emergency room with headache, dizziness, and tinnitus. The clinical exam revealed blood pressure differences between the upper and lower limbs of up to 50 mmHg. Based on the clinical and paraclinical data, we established the diagnosis of coarctation of the aorta and severe secondary arterial hypertension. The case was discussed by a multidisciplinary team and accepted for covered stent implantation. The 24 h blood pressure Holter monitoring after the procedure indicated the persistence of stage I arterial hypertension. Conclusions: Coarctation of the aorta is a congenital cardiovascular anomaly with high morbidity and mortality rates. Arterial hypertension, heart failure, and aortic dissection are complications of this pathology, some of them being sometimes direct consequences of secondary hypertension. Periodic cardiology follow up after the procedure is mandatory to assess the hemodynamic response, to identify potential complications, and to stratify the cardiovascular risk. Coarctation of the aorta (CoA) represents a narrowing of the thoracic aorta, frequently localized at the insertion of the ductus arteriosus just distal from the left subclavian artery ,2, with The care of patients with this pathology depends on a series of factors such as the severity of the stenosis, age of the patient, and clinical manifestations. Both in children and in adults, delay in diagnosis can occur due to normal development and lack of symptoms ,4,5. TheThe therapeutic approach in CoA is established by a multidisciplinary team. Options include surgery or percutaneous treatment . HyperteWe present the following case report in order to underline the systemic implications of aortic coarctation in the life of adolescents and the techniques used to repair it and in order to contribute to early diagnosis in childhood since it is not customary to measure the pulse and blood pressure in both upper and lower limbs during physical examination.We report the case of a 14-year-old male sportsman (contact sport), without significant personal pathological history, who presented in the emergency room with the following symptoms: headache, dizziness, and tinnitus, and a clinical exam revealed elevated BP values (180/115 mmHg). It is worth mentioning that approximately 5 months ago elevated BP values were recorded at school but without any measures taken at that time.The clinical exam at the time of admission revealed extreme anxiety, warm extremities, rhythmic heart sounds, grade III systolic murmur, with interscapulovertebral and bilateral carotid irradiation, the bilateral absence of femoral pulse, BP differences between the upper and lower limbs of up to 50 mmHg . We found no changes in the blood parameters, and the surface electrocardiogram pointed out left ventricular hypertrophy (LVH) . The 24 Transthoracic echocardiography revealed a continuous curve on the Doppler interrogation of the abdominal aorta, concentric LVH, preserved systolic function of both ventricles, narrowing of the aortic isthmus, with a maximum gradient of 85 mmHg and diastolic run-off, and a severely dilated left subclavian artery .We performed a CTA in order to accurately assess the descending aorta, and we identified a focal narrowing of 0.7 cm diameter, multiple periscapular collateral arteries, and bilateral dilated intercostal and subclavian arteries .Based on the clinical and paraclinical data, we established the diagnosis of isthmic CoA and severe secondary AHT.In terms of AHT, we decided to initiate antihypertensive drugs (beta-blockers) before the procedure, taking into account the result of the abdominal ultrasound, which were well tolerated hemodynamically.The case was discussed by a multidisciplinary team and accepted for interventional treatment—implantation of covered stent under general anesthesia, with the patient ventilated with positive pressure using a laryngo-tracheal mask. The first contrast injection in the aortic arch was performed in the antero-posterior and latero-lateral projection, based on which, we identified a narrowing of the isthmic area of 7 mm, with a peak-to-peak gradient at this level of 23 mmHg, as well as a dilated left subclavian artery and multiple aorto-aortic collaterals. During the procedure, a Cheatham-platinum (CP)-covered stent of 4.5 cm was implanted on a balloon in balloon (BIB) of 20 mm × 5 cm inflated up to the burst pressure of 4 atm, which allowed the gradient reduction to 2 mmHg. The last three injections were performed in the antero-posterior and latero-lateral projection in the aortic arch, visualizing the normal position of the stent, without impairing the left subclavian artery’s emergence and without suggestive images for dissection or periaortic hematoma. These findings were also confirmed by the control native chest CT .The postprocedural echocardiographic assessment visualized the stent placed at the isthmic level with a maximum residual gradient of 22 mmHg and a mild persistence of the gradient in diastole along with an improvement in the pulsed color Doppler aspect of the abdominal aorta. On the 1st day after the procedure, the patient presented hypertensive episodes accompanied by severe anxiety resulting in the decision to adjust the dosage of the betablocker therapy and to associate an angiotensin-converting enzyme inhibitor, with subsequently controlled BP values.The clinical exam pointed out bilaterally present femoral pulses, and no BP differences between the upper and lower limbs. The 24 h BP Holter monitoring indicated the persistence of stage I AHT, and therefore, we recommended the continuation of the antihypertensive therapy. The echocardiographic examination showed findings similar to those of the immediate postprocedural evaluation.CoA represents 4–6% of all congenital cardiac malformations . Taking The clinical diagnosis of CoA is based upon the characteristic findings of BP difference between the upper and lower limbs and diminished or delayed femoral pulses ,5. In ouSurgical repair has been the standard for this pathology, but in time the interventional treatment has replaced the surgical treatment in cases with appropriate anatomy. Regarding those cases presenting complex CoA anatomy, including those with transverse arch obstruction, tortuous segments of re-coarctation, distortion of adjacent arterial branches, or when repair of associated cardiac defects is needed, indication for surgical repair is suitable. Surgical repair of CoA can be performed by several techniques  ,17.The Coarctation of the Aorta Stent Trial (COAST) has been an influential prospective study examining the safety and effectiveness of interventional treatment in children and adults with CoA. Torok et al. suggested based-on literature data that the CP stent is a safe and effective treatment option for this pathology in older children and adults with native or recurrent CoA. Follow up for the COAST trial is planned for up to 60 months after stent positioning and will provide further insight regarding these issues . The stu2 [The implantation of a covered stent in CoA patients became the preferred therapy, proving its efficacity in 96–98% of the cases . It has 2 . As in o2 ,20,21. TStent implantation for CoA is considered a success when the pressure gradient measured during the procedure is <10 mmHg, detecting at the same time an improvement in the aortic lumen of >90% of the diameter of the normal adjacent aortic arch vessel ,20. In oIn terms of secondary and residual AHT, in the aforementioned study, the authors pointed out an improvement of BP values at three months after the procedure, without the normalization of the BP profile and with residual AHT being considered a frequent complication after CoA correction. According to this study, the patients remain exposed to an increased cardiovascular risk with premature morbidity and mortality . Other sCoA is a common congenital cardiovascular anomaly with high morbidity and mortality rates, which is frequently misdiagnosed. AHT, coronary disorders, sudden death, heart failure, stroke, endocarditis, and aortic dissection are complications that stem from the evolution of this pathology when left untreated, some of them being sometimes direct consequences of secondary hypertension. Covered stent implantation in patients with CoA has become the preferred therapy for teenagers and adults due to the reduced risk of aortic wall injuries and proved efficiency in more than 95% of the cases. Periodic cardiology follow up after the procedure is mandatory in order to assess the hemodynamic response, to identify the potential complications, and to stratify the cardiovascular risk.


Assuming a continuum between psychotic experiences and psychotic symptoms aligned between healthy individuals and patients with non-psychotic and psychotic disorders, recent research has focused on subclinical psychotic experiences. The wide variety of definitions, assessment tools, and concepts of psychotic-like experiences (PLEs) might contribute to the mixed findings concerning prevalence and persistence rates and clinical impact. In this narrative review, we address the panoply of terminology, definitions, and assessment tools of PLEs and associated concerns with this multitude. Moreover, the ambiguous results of previous studies regarding the clinical relevance of PLEs are described. In conclusion, we address clinical implications and highly suggest conceptual clarity and consensus concerning the terminology and definition of PLEs. The development of an agreed upon use of a “gold standard” assessment tool seems essential for more comparable findings in future research. In the last decades, contrary to the categorical approach of the “Kraepelinian dichotomy” , researcThe concept of psychosis as a transdiagnostic and extended phenotype  has resuRegarding the definition and terminology of PLEs, comparable confusion was reported as described for different concepts of ARMS/UHR , 25, 26:Associated phenomena are anomalous self-experiences (ASEs) defined as disturbances in the subjective experiences of the self , 33 and Overall, until now, there is no general consensus concerning the definition and conceptualizations of PLEs or associated phenomena, which may result or at least contribute to inconsistent findings and problems concerning the interpretation of results.and perceptions, some only assessed either thoughts or perceptions. Associated psychological factors including distress were assessed only in a few of the studied assessment tools  defined as deviations from experiences consistent with typical “reality models”  includinAlbeit generally assumed as non-clinical phenomena, PLEs have been identified as early indicators of psychosis , 68, 69 Since negative associations were reported between some specific PLE subtypes and psychopathological dimensions as depression  and physIn line with other researchers, we support the idea of conceptual clarity, consensus, and clear definitions regarding PLEs and associated concepts , 13, 25.As previously suggested, an empirically established and agreed upon consensus catalog of terms, definitions, criteria, and categorization of PLEs according to psychopathological significance can help to achieve more standardized research and comparable data . To deveWell-validated screening instruments might help to detect distressed people with PLEs seeking help in general medical practice or in non-specialized psychiatric services. These may then be further assessed, in a clinical interview, in order to differentiate between actual psychotic symptoms or a clinical high-risk syndrome or PLEs without reaching any of the above. Finally, as part of a future consensus, not only definitions and assessments should be agreed upon but also the semantics used: Psychotic experiences in individuals from the healthy general population without associated distress should not be termed as symptoms   but as eBH contributed to the concept of the review, the literature search, and draft of the manuscript. NM contributed to the concept of the review, supervision, and writing of 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.


Background: Cystic lesions of the jaw are commonly found in clinical practice. Large, expansive cysts raise challenges for the clinician from both diagnostic and surgical perspectives. The aim of our work is to present a combined, two-staged surgical approach in histologically confirmed non-aggressive cystic lesions of the jaw. Methods and Results: We report the case of an extensive mandibular cyst, associating a high risk of bone fracture, that is treated in the initial stage by cystic decompression through marsupialization with concomitant histological diagnostic confirmation, followed in the second stage by radical excision and mandibular reconstruction with titanium mesh, with the purpose of prevention for oro-cystic chronic fistula formation. Conclusions: Large odontogenic mandibular cysts imply a meticulously conducted assessment and treatment. Marsupialization should be taken into consideration for the treatment of large cystic lesions, followed by secondary enucleation, with minimal risks for the patient. The soft tissue healing process can be optimized with the use of titanium meshes, as an alternative for other reconstructive techniques, in the management of large cystic lesions. Odontogenic cysts are the most common cause of jaw radiolucent lesions and include a wide range of pathological entities. Radicular or residual cysts, keratocysts, and dentigerous cysts represent the vast majority of odontogenic lesions found in clinical practice ,2. RadicIt is very important to differentiate radicular or residual cysts from other bone lesions  that canThe present case report depicts the clinical characteristics and the therapeutic approach of a massive residual mandibular cyst, treated through a two-stage approach: initial cystic decompression with simultaneous diagnostic biopsy, followed by secondary radical excision. In order to reduce the risk of persistent oro-cystic fistula, bone reconstruction with titanium mesh was performed for the mandibular fenestration, thus providing solid support for the adjacent soft tissues. The particularities of this case are related to an atypical clinical behavior, with an aggressive growth pattern for an otherwise inoffensive clinical entity, and the therapeutic approach that allowed an accurate diagnosis and simultaneous treatment, through minimally invasive techniques, leading to optimal therapeutic results and no complications.In February 2019, a 53-year-old female patient was admitted to the Department of Oral and Maxillofacial Surgery, “Dr. Carol Davila” Central Military Hospital, Bucharest, with an important facial asymmetry on the left side, caused by the presence of a swelling affecting the middle and lower thirds of the face, that was noticed by the patient about three months before admission a. The leA detailed dental history from the patient revealed having multiple teeth extractions in the third quadrant a few years before with no other history of swelling and pain until now. Intraoral examination showed a bilateral terminal edentulous lower arch, severe attrition, and a bicortical swelling on the left side of the mandible. The oral mucosa lining was of normal appearance, except for a small central area of translucent color, corresponding to the previously mentioned renitent area b.The initial panoramic X-ray showed a very large radiolucent lesion, extended from the region of the first molar–the angle of the mandible–vertical ramus–coronoid process, leaving intact only the left condyle. The contour of the mandible was altered, and areas of peripheral sclerosis were present. The projection of the left mandibular canal was displaced downwards. There were no teeth, impacted or erupted, in relation to the lesion c.Native computed tomography (CT) revealed the presence of a large bony cavity extended in the left body and ramus of the mandible, measuring 80 mm × 35 mm in size. The cavity presented several areas of complete bone loss, with fenestration of the lingual and basilar cortical bone, deviation of the mandibular canal, and complete disruption of the superior wall of the canal d,e.Considering the major bone loss with a very high risk of mandibular fracture and the unknown diagnosis, we initiated a minimally invasive two-staged approach to treat this patient. In the first stage, the decompression of the cyst through marsupialization was performed. Under local anesthesia, we designed an ellipsoidal incision with the excision of an area of oral mucosa and adjacent cystic membrane, thus creating a fenestration of 1.5 per 1 cm between the cystic lesion and oral cavity. The cystic content, which had a greyish transparent aspect with small white inclusions, was evacuated and the edges of the oral mucosa were sutured to the cystic lining, using a technique of continuously running suture, thus preventing wound closure. The removed cystic tissue was sent for pathological assessment, which described the presence of inflamed non-keratinized squamous epithelium with cholesterol clefs and fibro-vascular tissues, suggestive for a residual cyst f.The patient was instructed on daily oral hygiene routine: tooth brushing and rinsing after every meal, as well as local chlorhexidine gluconate gel application for a period of three weeks, and was called every two weeks for follow-up visits. After 3 months, the patients’ appearance improved significantly, with almost complete restoration of facial symmetry a,b The iAt 6 months, the decompression effects were stable, and the patient underwent the second stage of the treatment. Under general anesthesia, radical cystic excision was performed. The bone defect corresponding to the marsupialization window was reconstructed with a titanium mesh, fixed with screws, in order to prevent the formation of a chronic oro-cystic fistula a. PostopThe surgical management of cystic lesions involving the jaws has become progressively less invasive and the choice for a certain technique is influenced by cystic characteristics, such as localization, dimension, or rate of recurrence ,16. In sThe Marsupialization technique implies the surgical creation of fenestration in one of the cystic walls and impediment of wound closure through specific sutures ; it reduThe main drawbacks of marsupialization are related to the incomplete removal of pathological tissue, which can be associated with higher rates of recurrence, as well as the prolonged time of healing . ConsideLarge odontogenic mandibular cysts imply a meticulously conducted clinicopathological assessment and treatment. Marsupialization should be taken into consideration in the treatment planning of large cystic lesions as an initial, less invasive, surgical step that leads to secondary radical enucleation, with minimal risks for the patient. Guided by the same principles of safety and simplicity, the healing process can be optimized through the use of titanium meshes, as an alternative for other reconstructive techniques, in the management of large cystic lesions.


The Society for Integrative Oncology (SIO) Online Task Force was created in response to the challenges facing continuity of integrative oncology care resulting from the COVID-19 pandemic. The Task Force set out to guide integrative oncology practitioners in providing effective and safe online consultations and treatments for quality-of-life-concerns and symptom management. Online treatments include manual, acupuncture, movement, mind-body, herbal, and expressive art therapies.The SIO Online Practice Recommendations employed a four-phase consensus process: (1) literature review and discussion among an international panel of SIO members, identifying key elements essential in an integrative oncology visit; (2) development, testing, and refinement of a questionnaire defining challenges and strategies; (3) refinement input from integrative oncology experts from 19 countries; and (4) SIO Executive Committee review identifying the most high-priority challenges and strategies.The SIO Online Practice Recommendations address ten challenges, providing practical suggestions for online treatment/consultation. These include overcoming unfamiliarity, addressing resistance among patients and healthcare practitioners to online consultation/treatment, exploring ethical and medical-legal aspects, solving technological issues, preparing the online treatment setting, starting the online treatment session, maintaining effective communication, promoting specific treatment effects, involving the caregiver, concluding the session, and ensuring continuity of care.The SIO Online Practice Recommendations are relevant for ensuring continuity of care beyond the present pandemic. They can be implemented for patients with limited accessibility to integrative oncology treatments due to geographic constraints, financial difficulties, physical disability, or an unsupportive caregiver. These recommendations require further study in practice settings.The online version contains supplementary material available at 10.1007/s00520-021-06205-w. For more than two decades, oncology patients in the USA and around the world who are interested in complementary medicine have been increasingly referred by conventional healthcare professionals for integrative oncology consultation and treatment services. Integrative care approaches may include dietary/lifestyle interventions, herbal medicine, acupuncture, mind-body, manual or movement therapies, and other traditional therapies, which are offered by a range of integrative and complementary healthcare practitioners. Integrative oncology care is provided in an evidence-based manner, often within conventional oncology settings. Unlike “alternative” or “complementary” medicine, which are practiced outside or in parallel with conventional care, integrative oncology is an integral part of the multi-disciplinary and interprofessional oncology model of care that operates in conjunction with the work of oncologists, oncology nurses, psychosocial oncology practitioners, palliative care services, and other healthcare professionals. The concept of integrative oncology has been defined by Witt and colleagues as a patient-centered, evidence-informed field that “aims to optimize health, quality of life, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and to become active participants before, during, and beyond cancer treatment” .In recent years, integrative oncology clinical practice has been supported by evidence arising from high-quality randomized controlled trials that indicate many integrative oncology modalities are both effective and safe for the management of issues that impinge on patients’ quality of life (QoL), such as cancer-related pain , chemothIntegrative oncology centers have become more commonplace around the globe, with most offering therapies following a patient-centered approach. This approach involves co-designing a program of care with patients by an integrative physician or healthcare professional who is dually trained in integrative oncology and supportive cancer care . The devThe COVID-19 pandemic has presented a significant challenge to integrative oncology practitioners worldwide, severely limiting their ability to ensure continuity of integrative care. Several recently published commentaries discussing the impact of the COVID-19 pandemic, and associated physical distancing regulations, on cancer care provision have recommended delays in cancer treatment and a reduction in the number of in-person treatments and consultations –12. PrioWhile online consultation/treatment recommendations have been previously developed for lifestyle interventions for individuals living with cancer, they have not accounted for the challenges posed by a global pandemic . More reIn order to address this challenge, the SIO has established the Online Task Force to share creative healthcare initiatives among integrative oncology practitioners, particularly those offering online consultations and treatment. This paper presents the SIO Online Practice Recommendations with the goal of supporting integrative oncology practitioners, including those trained in conventional and/or complementary medicine, in addressing their patients’ supportive care, QoL, and symptom management needs by providing effective and safe online integrative oncology consultations and treatments during this time of pandemic risk, which can be applied moving forward to expand the accessibility and reach of integrative oncology care worldwide even post-pandemic. For the purposes of this paper, the term “integrative oncology practitioners” refers to the variety of conventional and complementary healthcare practitioners that collaborate in the provision of integrative oncology care, including but not limited to, physicians, nurses, dietitians, psychologists, rehabilitation specialists, massage therapists, acupuncturists, and arts-based therapists.The SIO Online Task Force was established in March 2020 in response to the global COVID-19 pandemic that forced many integrative oncology programs to either close or significantly limit their clinical practice. In order to meet the challenges posed by the pandemic, a number of integrative oncology practices began to develop creative online solutions to enable them to continue treating their patients without compromising their safety. News of these local healthcare initiatives quickly spread via international videoconference meetings with SIO members from Israel, Italy, Germany, Switzerland, the USA, and Canada. In turn, they shared their strategies and offered practical suggestions for providing online integrative oncology consultations and practitioner-guided treatments to patients and their caregivers. These online initiatives were then presented to the SIO Executive Committee and Board of Trustees, who agreed to the creation of the SIO Online Task Force. The goal of this group was to develop recommendations to support integrative oncology practitioners in providing evidence-based integrative oncology care to patients, caregivers, and oncology staff through online programming and resources, in the comfort and safety of their homes. The SIO Online Task Force is comprised of seven researchers, clinicians , and administrators from four countries , representing a rich multi-disciplinary, interprofessional, and multi-cultural background.Oncology-related keywords .Complementary and integrative medicine-related keywords Keywords related to online consultation/treatment during the COVID-19 pandemic .Consensus methods that garner the perspectives and experiences of key stakeholders, including clinicians, administrators, and patients, have become commonplace and a standard process in the development of clinical guidelines . Given tFurther limits applied included articles published in English and limited to the following types of studies: clinical trials, comparative studies, meta-analyses, and systematic reviews. Practice guidelines were also included.Initially, 562 articles were identified; screening of titles and abstracts resulted in 524 articles being deemed ineligible see Fig. . Of the The findings of the scoping review, along with the clinical experience and insights of the integrative oncology teams in Israel and Europe, were presented to the SIO Online Task Force, which discussed and identified a number of core issues surrounding the provision of online integrative oncology care that required elucidation. Task Force members also identified several relevant clinical trials that assessed self-administered modalities, including self-acupressure , self-acDuring the second phase of the process, the Task Force developed a questionnaire to further delineate the core issues related to providing online integrative oncology consultation and treatment modalities. A draft questionnaire was prepared and reviewed by the SIO Executive Committee and a group of leading SIO members and clinicians  who were actively providing online integrative oncology consultations. The final version of the questionnaire addressed three domains: (1) general challenges to providing online integrative oncology treatments, with practical suggestions for ways to overcome these challenges (25 open-ended items identified as core issues); (2) integrative oncology modalities available in integrative oncology centers before the COVID-19 pandemic, and whether they were moved online during the pandemic ; and (3) specific challenges and practical suggestions associated with the provision of integrative oncology therapies via an online format . A final open-ended item was provided for respondents to share any additional insights regarding online integrative oncology consultation/treatment  , who grouped the responses into a preliminary list of 10 challenges that had been identified by respondents as being associated with online integrative oncology consultations and treatments. For each of these challenges, key principles of online care were identified and specific recommendations for practical implementation were developed. This list of challenges and recommendations were thoroughly discussed by members of the SIO Online Task Force and then reviewed by the SIO Executive Committee for final confirmation. The SIO Executive Committee is an interdisciplinary group of integrative oncology key stakeholders, including oncology health professionals , integrative oncology researchers, patient advocates, and clinical administrators. The final SIO Online Practice Recommendations presented in this article is, thus, the cumulation of a rigorous consensus process that engaged international leaders and clinicians in integrative oncology.skepticism about, or antagonism toward, the feasibility and effectiveness of an online integrative oncology treatment program. Acknowledge that resistance to online consultation/treatment may not be a concern only for the patient and/or caregiver, but also for the integrative oncology practitioner.Identify any ethical and medical-legal issues regarding the patient’s privacy and data security, selection bias by healthcare practitioners related to which patients are offered online consultations and the treatment modalities deemed appropriate for the online format, and the potential for specific online-associated risks .Be aware of technical challenges associated with the virtual environment before and during an online session.Assess and proactively respond to Prepare the online setting to ensure a quiet, safe, and private environment in which the therapeutic nature of the interaction can be maintained. This includes scheduling the session ahead of time; co-organizing the home setting with the patient and/or caregiver; and addressing the setting from which the integrative oncology practitioner will be conducting the online session, whether at the clinic or from home.Address potential care challenges at the beginning of the online session, including discussing the patient’s expectations and co-defining treatment goals, while continuously monitoring the patient’s attentiveness and fatigue, especially in light of the potential for distractions due to the online remote setting.communication during the online session, avoiding the use of technical and unidirectional instructions and establishing a space for patients to discuss their emotions, while emphasizing the clinical therapeutic goal, just as a practitioner would if the session were taking place in-person at a clinic.Ensure effective specific treatment effects, such as the relief of at least one of the patient’s leading concerns , while at the same time maximizing general and non-specific effects of the treatment .Strive to promote caregiver in the therapeutic process, based on the patient’s consent and ethical-therapeutic considerations. Clarify whether the caregiver is only there to assist the patient, or is also in need of support and treatment as well, especially in the context of therapies that are amenable to group participation, including mind-body and movement modalities .Consider including the conclude the online integrative oncology session while ensuring a sense of containment and encouragement by scheduling a follow-up session.Proactively plan how to continuity of care by discussing the need to schedule and coordinate the next consultation and treatment sessions, and to communicate with other integrative and conventional oncology practitioners involved in the patient’s treatment and care.Ensure Table The SIO Online Practice Recommendations for online treatment and care were created in response to the COVID-19 pandemic and are based on the insights and experience of an international group of experts dedicated to ensuring continuity of integrative oncology care despite the challenges posed by this global threat. Earlier guidance on the use of online consultation/treatment can be seen in the World Health Organization (WHO) 2019 Guideline recommendations on digital interventions for health system strengthening and the 2018 WHO Guideline on the integration of palliative care in response to humanitarian emergencies and crises , 34. TheAnother organization that has raised awareness regarding the use of online consultation/treatment during the COVID-19 pandemic is the European Society of Medical Oncology (ESMO). The ESMO recommendations for patients with lung cancer suggest that all non-priority out-patient appointments be converted to a telemedicine platform, acknowledging this option as a valuable tool while at the same time emphasizing that it should not completely replace standard practice . SuggestThe SIO Online Practice Recommendations for online consultations/treatment address challenges associated with telemedicine that may be different from those faced in the conventional medical setting. In the integrative oncology setting, the therapeutic relationship is reliant on verbal and non-verbal communication, and often involves hands-on treatments with the integrative oncology practitioner guiding the patient on the self-application of a therapy, such as self-acupuncture/acupressure, manual/movement modalities, and mind-body therapies. It is with these factors in mind that the SIO Online Practice Recommendations were established, with the goals of providing integrative oncology practitioners with the knowledge and skills to: (1) overcome the challenges faced in the online setting; (2) properly plan and schedule the current intervention and plan subsequent interactions; (3) monitor safety-related issues; (4) ensure ethical and open communication with patients and/or caregivers; and (5) document the online integrative oncology intervention and its outcomes.The SIO Online Practice Recommendations and the process through which they were created have been limited by a number of factors. As with other guidelines and recommendations published during the COVID-19 pandemic, the SIO Online Practice Recommendations were created in a short period of time and in response to an unexpected worldwide crisis faced by nearly all fields of healthcare, including oncology. However, the provision of integrative oncology presented additional challenges, especially when many integrative oncology services were either closed or operating with significantly restricted activity, including the cancellation of all group-based therapies due to physical distancing restrictions. The Online Practice Recommendations were also based on expert opinions of a select group of global leaders of integrative oncology services, and require confirmatory research. As such, the present SIO Online Practice Recommendations should be seen as a preliminary step, to be followed by mixed method research that explores the feasibility, effectiveness, and safety of the Recommendations across individual and group interventions, as well as among complementary healthcare practitioners and professional associations. A revised version of the Recommendations would then be developed and could be subsequently updated, as required, and subject to a formal critical appraisal process, such as the application of the AGREE II tool . The finFrom an equity, diversity and inclusion perspective, online integrative oncology care may improve access to some individuals who are unable to attend sessions in person due to a variety of economic and social reasons. However, the lack of recognition within the present SIO Online Practice Recommendations regarding the unique challenges posed by online care for those living with accessibility issues, such as hearing and visual impairment, is a limitation that requires attention. Future version of the Recommendations would benefit from the insights from other established telemedicine guidelines that have offered suggestions regarding appropriate accommodations and modifications for those living with accessibility needs –42.It is of utmost importance that the SIO Online Practice Recommendations not be seen only as a local and specific initiative in response to the COVID-19 pandemic. The use of online consultation/treatment is increasingly becoming a part of conventional medical practice, and those involved in the provision of integrative oncology care should not let themselves be left behind. The guidelines are, and will continue to be, relevant to other situations, including maintaining continuity of oncology care for patients with limited accessibility to the treatment center due to factors such as geographical distance or economic constraints; patients with reduced mobility, especially during active oncology treatment or with progression of disease; and patients whose caregivers are unable to facilitate and/or support their access to the integrative oncology care setting. At the same time, it is important to emphasize that online treatments should not become a substitute for face-to-face interactions. The integration of in-person and online interactions will provide patients with a richer repertoire of integrative oncology services access, and allow for tailoring treatments to patients’ needs, expectations, and health beliefs.ESM 1(DOCX 24 kb).


The bone marrow (BM) microenvironment is composed by distinct compartments with a specific cellular composition and tissue organization, where the different haematopoietic stem and progenitor cells reside, are maintained, and differentiate into multiple blood lineages .Several studies have demonstrated that these niches have a key role in the regulation of different steps of haematopoiesis. Indeed, the crosstalk with nearby cells  influences the behaviour of haematopoietic stem cells (HSCs) and contributes to their self-renewal, proliferation, lineage commitment, differentiation, and mobilization .Given the crucial role of the BM stromal cells in regulating haematopoiesis under physiological condition, it is not surprising that alterations within the BM niche have been shown to play an active role in the development and progression of haematological malignancies .Within this Research Topic, we have gathered several contributions that analyse the interactions between haematopoietic cells and the BM niche, with a main focus on how they are subverted by haematologic tumours, in order to promote the survival and expansion of malignant cells.Ferrera Pissarra et al. explore the role of ARHGAP21  in the marrow microenvironment. Comparing the BM of Arhgap21+/− and wild type mice, they detected an increase in the frequency of osteoblastic lineage cells, while there were no differences in the frequencies of endothelial cells and multipotent stromal cells. Consistently, the BM of Arhgap21+/− mice is characterized by higher levels of osteocalcin, and BM cells showed increased expression of Col1a1 and Ocn and decreased expression of Trap1 after osteogenic differentiation with increased capacity of generating CFU-OB (osteogenic colony-forming units) in vitro.Understanding the molecular mediators of normal haematopoiesis is crucial for the improvement of regenerative medicine and cancer therapies. Here, +/− mice transplanted with normal BM cells showed leukopenia during transplantation recovery, suggesting that ARHGAP21 could have a role in balancing the composition of the BM microenvironment and in determining its ability to support haematopoiesis.On the other hand, Arhgap21Recently, the development of single cell technologies has allowed to systematically identify distinct bone marrow cell types, giving us the first insights on the molecular and spatial composition of the BM niche, the relationships between the different cell types, and how they are altered by tumour development .Woods et al. provide us with an overview of the composition of the different niches within the BM and summarised recent single-cell studies that characterized both the murine and the human the BM-mesenchymal stromal cells (MSCs) biology, identifying several hierarchical subsets with specific transcriptional profiles and functions. They then focused specifically on osteo-adipogenic progenitors and on their role in the regulation of haematopoiesis both in homeostasis, aging or during the development of myeloid malignancies. Finally, due to the crucial role of MSCs in HSC maintenance and in leukaemia cell growth, they also examined the therapeutic potential of MSCs for rejuvenation of the niche and their potential anti-tumour ability.Herein, Chiu et al. summarize the role of certain amino acids in the complex interactions existing between MSC and the surrounding cells, with a particular emphasis on immune cells and malignant haematopoietic cells. Specifically, they focused on the possibility to target this crosstalk by interfering with amino acid metabolism or intercellular fluxes in different haematopoietic cancers, such as T-ALL, B-ALL, CLL and AML.MSCs contribution to the homeostasis of the BM depends also on their metabolism . Chiu etMiari et al. discussed the different mechanisms of BM-driven drug resistance in AML, focusing on the pathophysiological role of leukaemia-supporting macrophages. Indeed, single cells technologies have given us the opportunity to more accurately dissect the different subpopulations of macrophages, and to better understand which population should be targeted in order to tackle drug resistance in AML. Macrophages have been shown to promote the activation of anti-cell death pathways in AML cells, and different macrophage phenotypes can be associated with clinical outcomes in AML, conferring them a potential prognostic value.Acute Myeloid Leukaemia (AML) remains a high-risk haematologic malignancy, with a 5 years overall survival rate of around 20% despite the development of novel therapies . AcquisiMarconi Roversi et al. investigated the role of Haematopoietic Cell kinase (HCK) in mediating the activity of the CXCL12/CXCR4 pathway in AML, with the final goal to provide the rational for the development of anti-HCK therapies for this disease. The authors demonstrated that the inhibition of HCK can hamper CXCL12-driven migration of both leukemic cell lines and CD34 + cells isolated from AML patients’ bone marrow, through a decrease of the activation of the CXCL12/CXCR4/MAPK/ERK and CXCL12/CXCR4/PI3K/AKT signalling, and by causing a lower rate of actin polymerization, that reduced cytoskeleton dynamics.Given the poor clinical outcome of AML patients, finding therapeutic options is key. Jalali and Ansell focus on both cellular as well as non-cellular BM compartments and on how they are altered across a variety of aggressive and indolent lymphoid malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom Macroglobulinemia and follicular lymphoma, discussing strategies of intervention and their potential therapeutic impact in clinical settings.AML is not the only haematological disease in which alterations within the BM niche promote tumour cells growth, disease progression and overall patient outcome. In their review, Fröbel et al. review how inflammatory stimulus, acute stress and ageing are able to alter the composition of the BM, changing both the frequency of the different cell types and the secreted factors that are present in the niche. In their paper, they also described how these alterations may contribute to the development of chronic malignancies  and how these conditions are able to re-shape the BM niche. Furthermore, in order to study the cross-talk between niche cells and haematopoietic cells in vivo, xenograft models are key. In their review, Fröbel and others discuss which soluble factors, produced from the murine BM niche, can support human HSC engraftment and function in mice.One of the main players in the re-shaping the BM morphology is inflammation, that can change BM cellular composition and promote the development of haematological malignancies . Fröbel In conclusion, the present Research Topic has collected several contributions on the multifaceted role of the bone marrow microenvironment in the regulation of haematopoiesis and in the development and progression of blood cancers. The increasing knowledge in the field is paving the way towards novel therapeutic strategies that will be able to uncouple the pathological crosstalk between the different cells compartments and to finally improve the outcomes of these diseases.