Kaposi's sarcoma‐associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), the most common AIDS‐related malignancy. It also causes other rare, but certainly underreported, KSHV‐associated pathologies, namely primary effusion lymphoma, multicentric Castleman disease and KSHV inflammatory cytokine syndrome. Epidemiology and pathogenicity studies point to the potential for host genetic predisposition to KSHV infection and/or the subsequent development of KSHV‐associated pathologies partly explaining the peculiar geographic and population‐specific incidence of KSHV and associated pathologies and discrepancies in KSHV exposure and infection and KSHV infection and disease development. This review consolidates the current knowledge of host genetic factors involved in the KSHV‐driven pathogenesis. Studies reviewed here indicate a plausible connection between KSHV susceptibility and host genetic factors that affect either viral access to host cells via entry mechanisms or host innate immunity to viral infection. Subsequent to infection, KSHV‐associated pathogenesis, reviewed here primarily in the context of KS, is likely influenced by an orchestrated concert of innate immune system interactions, downstream inflammatory pathways and oncogenic mechanisms. The association studies reviewed here point to interesting candidate genes that may prove important in achieving a more nuanced understanding of the pathogenesis and therapeutic targeting of KSHV and associated diseases. Recent studies on host genetic factors suggest numerous candidate genes strongly associated with KSHV infection or subsequent disease development, particularly innate immune system mediators. Taken together, these contribute toward our understanding of the geographic prevalence and population susceptibility to KSHV and KSHV‐associated diseases. ARTantiretroviral therapyCCL2C‐C chemokine ligand 2CCND1cyclin D1CDKN1Acyclin dependent kinase inhibitor 1ACFLARCASP8 and FADD‐like apoptosis regulatorEPHA2Eph receptor A2FcγRFc gamma receptorsIL8RBIL8 receptor, betaKICSKSHV inflammatory cytokine syndromeKIRkiller cell immunoglobulin‐like receptorsKSKaposi's sarcomaKSHVKaposi's sarcoma‐associated herpesvirusMBLmannose‐binding lectinMCDmulticentric Castleman diseaseMDM2mouse double minute 2NFκBnuclear factor kappa BNFκBIANFκB1 inhibitor alphaNKnatural killerPELprimary effusion lymphomaPTENphosphatase and tensin homologueSNPsingle nucleotide polymorphismSSASub‐Saharan AfricaTLR4toll‐like receptor 4TP53tumour protein 53VEGFvascular endothelial growth factor1Kaposi's sarcoma‐associated herpesvirus  is a gammaherpesvirus with a particularly high seroprevalence in sub‐Saharan Africa  and the Mediterranean region (20%‐30%).KSHV seroprevalence exhibits peculiar geographical epidemiology and incidence of KS and other KSHV‐associated diseases outside the setting of HIV are population‐specific.2KSHV prevalence varies geographically and is particularly high in SSA (30%‐50%) and the Mediterranean region (20%‐30%).KSHV infection is necessary for the development of KS, MCD, PEL and KICS but insufficient for tumorigenesis. Precipitating factors such as HIV infection or immune suppression are required for KSHV‐associated oncogenesis. Even so, HIV/KSHV co‐infection does not always result in cancer development. The most common of the KSHV‐associated pathologies, KS, is distinguished into four epidemiological forms. Classic KS primarily occurs in men from the Mediterranean and Eastern European region due to immune suppression related to old age, while endemic KS is found in Central Africa mostly in younger males.These observations point to genetic susceptibility to KSHV infection following exposure and/or progression to KS or other KSHV‐associated pathologies.3IL6, IL8 and IL13,VEGF),NFκB),MBL)‐2,FcγR),HLA killer cell immunoglobulin‐like receptors (KIR)HLA ligands and linked genesCCND1), IL6, C‐C chemokine ligand 2 (CCL2) and FADD‐like apoptosis regulator (CFLAR).EPHA2) to be significantly associated with KSHV infection and KS development.TNF)‐α and ‐β,IFNγ,SDF1), cyclin dependent kinase inhibitor 1A (CDKN1A),CCR5)CASP8)Thus far, immune‐modulatory genes have been the focus of investigations of candidate susceptibility genes. In particular, published studies have reported significant associations of KSHV infection or its associated pathologies with genetic polymorphism in genes encoding interleukins 3.1PDCD6IP), ubiquitin‐specific protease (UBP), F‐box and leucine‐rich repeat protein (FBXL2), cyclic AMP‐regulated phosphoprotein 21 (ARPP‐21), leucine‐rich repeat flightless‐interacting protein 2 (LRRFIP2) and C‐C motif chemokine receptor 4 (CCR4).A foundational study conducted by Plancoulaine et alMBL2 haplotypes (based on combinations of two promoter region genotypes (−550 H/L and −221 Y/X) and a structural region genotype (exon 1 A/O)) associated with intermediate expression of MBL, an innate immune system protein, were found to be associated with lower CD4 count in HIV and KSHV co‐infected patients compared to patients with only HIV infection.NFκB1 promoter 28 362 491) and the 3′ UTR region of the NFκB1 inhibitor alpha  were found to be associated with the presence of antibodies to KSHV lytic antigens.KIR3DS1 (an activating haplotype of KIR) and HLA‐B Bw4‐80I (the Bw4 haplotype with an isoleucine at position 80) as well as HLA‐C group 1  homozygosity was indeed found to be protective against KSHV infection.Two triplet infants have been reported with familial hemophagocytic lymphohistiocytosis related to compound heterozygous perforin mutations and KSHV infection; in these cases, a defective perforin‐granzyme pathway is suggested to have led to reduced viral clearance ability and therefore to the onset of symptoms related to lytic KSHV infection.EPHA2, in relation to KSHV infection. Mutation analysis revealed a novel heterozygous transition (NM_004431.5:c.2572C>T) associated with KSHV infection in a cohort of HIV‐infected South African patients stratified by KSHV status.VEGF, shown to augment entry of KSHV into target cells,Key molecules involved in the initial stages of KSHV entry are interesting candidate genes for KSHV association studies. We investigated sequence variants in a major KSHV entry receptor in endothelial cells, As the necessary etiological agent for the development of KS, MCD, PEL and KICS, enhanced susceptibility to KSHV infection subsequently increases the risk for KSHV‐associated pathologies. However, KSHV‐associated tumorigenesis may be caused by additional underlying genetic factors as described below.3.2As the most prevalent of the KSHV‐associated pathologies, KS, also the most common AIDS‐related malignancy worldwide, has been the focus of most studies concerning genetic susceptibility to KSHV‐associated pathology. Other KSHV‐associated pathologies, namely MCD, PEL and KICS, are considered rare although are almost certainly underreported due to difficult diagnoses, particularly in resource‐limited regions where HIV burden is high. Consequently, there is a lack of research into the rarer KSHV‐associated pathologies and particularly on potential host genetic contributors; therefore, only few reports were identified for inclusion in this review.3.2.1STIM1) mutation resulting in T cell immunodeficiency.INFGR1 mutation  who developed and died from classic KS.CTLA4 haploinsufficiency, associated with defective NK cell function, has recently been shown to have facilitated classic KS development in the case of a 52‐year‐old HIV‐negative male of Italian ancestry.WAS deletion (NP_000368.1:p.Asp130_Glu131del) provides further evidence of a possible predisposition to classic KS.There is evidence from several case reports to suggest that genetic primary immunodeficiency predisposes to KS.IL6 promoter  which is associated with increased levels of IL6 was noted in a familial clustering of classic KS and was further associated with KS in HIV‐infected men and renal transplant recipients.IL13 promoter region  was associated with classic KS in patients latently infected with KSHV.IL8 promoter SNP , linked to below normal IL8 expression, was identified in a cohort of patients with classic KSIL8 SNP  was reported to decrease risk of classic KSvGPCR), IL8 receptor beta (IL8RB), were similarly found to be protective against the development of classic KS.Several notable associations have been identified in genes encoding proteins that are known to be pro‐inflammatory. A SNP in the FcγRIIIA, was associated with AIDS‐KS in a cohort of HIV‐positive men and was found to enhance IgG affinity in vitro and promote NK cell activation.KIR3DS1 (an activating haplotype of KIR) and HLA‐B Bw4‐80I (the Bw4 haplotype with an isoleucine at position 80) was protective against KSHV seroprevalence  homozygosity to be protective against KSHV infection  of the IgG binding receptor, HLA class I and II haplotypes have been thoroughly investigated. KS development post kidney transplant was associated with HLA‐CW4 in a small study.HLA‐A*24/B*18/Cw*12/DRB1*11/DQB1*03 haplotype was present in family members with KS and not in those without KS, with the DRB1*11 subtype present in most family members.HLA haplotypes were associated with an increased  or decreased  risk of classic KS.HLA‐C*07:01 has also been associated with classic KS, while HLA‐A*11:01 was found to decrease riskHLA‐B*2705 was similarly reported to be protective.HLA‐B14 has been reported to be underrepresented among AIDS‐KS cases,HLA‐B*14:01, was found to be a risk allele for AIDS‐related KS.HLA‐DRB1*1302 in linkage disequilibrium with DQB1*0604 was identified as a risk haplotype for AIDS‐related KSHLA‐DRB1 alleles with a phenylalanine residue at position 13.HLA‐DR5 has been noted to be present at an increased frequency among (presumed) AIDS‐related KS,Additionally, several HLA‐DMB gene region were found to increase AIDS‐KS risk. Most significantly, a SNP in the HLA‐DMB intronic region  was associated with a four‐times higher risk of AIDS‐KS in HIV‐KSHV co‐infected men.TRIM31, NM_007028.3:c.1261G>A, rs1116221) and lymphotoxin alpha  were observed to be protective whereas SNPs within HLA‐DMB linked genes, transporter associated with antigen processing 1 , TAPSAR1 microRNA , G‐patch domain and ankyrin repeats 1  and lymphocyte antigen 6 family member G6C , were associated with increased risk of AIDS‐KS.Several variants identified in a SNP screening of the CCND1, IL6, CCL2 and CFLAR  and viral CC chemokine ligand (vCCL), respectively). Various combinations of these SNPs  were associated with AIDS‐KS.Recently, human genes that are cellular homologues of KSHV‐expressed genes have been investigated hypothesising that virally expressed homologues, which promote immune‐silent proliferation, may be advantaged by genetic SNPs in their cellular counterparts.EPHA2 tyrosine kinase domain to be significantly associated with KS in a cohort of HIV‐infected South African patients stratified by KS status.EPHA2, in addition to being a key entry receptor for KSHV into endothelial cells, has been implicated in oncogenesis via alteration of its canonical signalling pathway and noncanonical signalling pathway mediated by phosphorylation of key tyrosine and serine residues.3.2.2In addition to KS, rare  KSHV‐associated pathologies MCD, PEL and KICS may develop in KSHV‐infected patients, particularly in the context of KSHV/HIV co‐infection.TLR4) SNP  which results in decreased surface expression of TLR4, an important pattern recognition receptor in activation of the innate immune system, was associated with increased incidence of MCD in KSHV+ HIV‐1+ patients compared to non‐KSHV cancer controls and patients with KSChildhood MCD, like classic KS, may be favoured by rare inborn errors of immunity against KSHV infection as suggested by Leroy et alKICS and PEL, under‐researched in themselves, are yet to be investigated in relation to genetic associations.4IL6 promoter polymorphism (XM_011515390.2:c.‐84‐153C>G) with increased risk of AIDS‐related KS and iatrogenic KS,HLA‐B*1401 allele with increased risk of AIDS‐KSHLA‐B*2702/5 haplotype with decreased risk of AIDS‐related KS.The major limitation of genetic association studies, including those reported in this review, is lack of consistent replication due to the small number of studies conducted and difficulties related to case‐control association studies. Indeed, few associations reported here have been satisfactorily replicated yet, with the exception of the reported association of an IL6 promoter GC genotype and the HLA‐DRB1*11 allele in a familial clustering of classic KS, are thought to bypass this limitation although these are limited in population applicability and statistical power and also require validation.Observed associations may well be ethnicity‐ and geography‐specific, especially with regards to HLA haplotypes, as allele frequencies vary and as such may not be able to be replicated in studies conducted in different populations. Even so, replicability is hindered by heterogeneous study populations, with proposed associated genetic polymorphisms potentially being artefacts of population stratification or other confounding factors between cases and controls.HLA haplotypes reported here are certainly indicative of an association with KS, particularly in class I and II HLA types. However, the heterogeneity of studied populations and different HLA genotyping techniques  of the p53‐modulator, MDM2, which has been suggested as a potential risk factor for development of visceral KS, PEL or MCD after the heterozygous form was found to be associated with cutaneous classic KS in Caucasians and the homozygous form identified in a number of PEL cell lines.While classic Improved understanding of specific genes involved in KSHV infection and KSHV‐related disease causation may have implications in the development of new therapeutic targets, and candidate gene association studies are therefore a relevant avenue of research. Although many different genetic variants predisposing individuals to either KSHV infection and/or KSHV‐associated diseases appear to exist which makes designing a therapy against all of them rather difficult, there are a few promising candidate genes: familiar KS has been linked to inborn defects in T cell immunity, in particular T cell effector functions and possibly interferon signalling,6KIR‐HLA), downstream inflammatory pathways  and oncogenic mechanisms (EPHA2 oncogenic pathways). Infectious diseases and related pathologies are likely to become an increasing global public health burden, particular in parallel with the HIV epidemic and in the era of HAART.The rationale for an underlying genetic risk of KSHV infection and subsequent KSHV‐associated disease development is well established in the literature through epidemiological observation. The numerous association studies reviewed here point to interesting candidate genes that may prove important in achieving a more nuanced understanding of the pathogenesis and therapeutic targeting of KSHV. Taken together Figure , the stuThe authors have no competing interest.Melissa J. Blumenthal and Georgia Schäfer conceptualised the review. Melissa J. Blumenthal performed the literature search and wrote the manuscript. Georgia Schäfer, Arieh A. Katz, Elena Maria Cornejo Castro and Denise Whitby contributed to the interpretation and critically revised the manuscript. All authors read and approved the final manuscript.


Wound healing treatment in diabetic patients worldwide represents around 2.1 trillion dollars to global health sectors. This is because of the complications presented in the wound healing process of skin ulcers, such as a lack of macrophage and fibroblast growth factors  that are both needed for extracellular matrix (ECM) synthesis. Therefore, there is a need for research on new and cost-effective materials to enable ECM synthesis. Such materials include co-electrospun nanofibers used as wound dressings, since they have a similar morphology to the ECM, and therefore, possess the advantage of using different materials to accelerate the wound healing process. Co-electrospun nanofibers have a unique structural configuration, formed by a core and a shell. This configuration allows the protection and gradual liberation of healing agent compounds, which could be included in the core. Some of the materials used in nanofibers are polymers, including natural compounds, such as chitosan  and gelatin . Synthetics such as polyvinyl-alcohol (PVA) (mainly as a co-spinning agent to chitosan) can also be used. Another bioactive compound that can be used to enhance the wound healing process is eugenol, a terpenoid present in different medicinal plant tissues that have scarring properties. Therefore, the present review analyses the potential use of co-electrospun nanofibers, with chitosan–PVA–eugenol in the core and gelatin in the shell as a wound dressing for diabetic skin ulcers. Wound healing treatment in diabetic patients worldwide represents around 2.1 trillion dollars to global health sectors. Moreover, the natural healing process is compromised in diabetic patients. In the second phase of the process (inflammation), platelet and macrophage growth factors (PDGF and TGF-β1 respectively), together with chemokines and cytokines, do not generally act on their cellular receptors. This lack of interaction translates into an absence of signalling cascades, jeopardising the cell proliferation, migration, and differentiation, which stops the wound healing process and could lead to amputation or even the death of the patient.2The International Diabetes foundation reported an increase in the global diabetes prevalence from 151 million in 2000 to 463 million in 2019. It is predicted that the prevalence will increase to 578 million by 2030. This global increase would translate to a global economic burden of up to 2.1 trillion dollars upon health sectors for the treatment of derived complications from the disease, above all, skin wounds.et al.3 proposed a chitosan hydrogel for skin ulcers on diabetic feet (skin ulcer in the foot), and applied the treatment once every two days for three months. At the end of the study, the patients showed considerable healing of the wounds. A downside of the hydrogel treatment was that application could be messy, and there may be alternative materials that can accelerate the healing process.To overcome the problems described, there is a need for research on new materials that can help the wound healing process for diabetic patients. Escárcega-Galaz 4Nanofibers obtained by electrospinning are a good alternative considering their versatile formulation (they can work with a large number of polymers) and the use of a cheap and simple processing technique. Another advantage of nanofibers is the increase in coverage area that can be obtained; this can be related to a higher healing power in comparison to fibres on a normal scale. Nevertheless, there are drawbacks to the electrospinning process and a high number of parameters can influence the final product, including the solution, process conditions, and environmental conditions. However, once the appropriate parameters are reached, the nanofiber production can progress smoothly.5One variant of the electrospinning process is co-electrospinning, which has the same principles and works under the same parameters. The only difference is that with co-electrospinning, the resulting nanofibers have a more functional core–shell structure. This conformation enhances the processed materials, with improved healing properties.6,7 PVA was selected for material reinforcement and because of its good interaction with chitosan.8 Eugenol is a natural terpenoid with immune-modulatory activity as evidenced by Vishteh et al.9 more than 30 years ago.The reviewed evidence indicates that the more promising materials are gelatine for the shell fraction, and chitosan–PVA, and eugenol for the core fraction. Gelatine and chitosan are highlighted because of their biopolymeric nature, as well as their therapeutic properties.In this context, the present review analyses the potential of co-electrospun nanofibres, with gelatine for the shell fraction and chitosan–PVA–eugenol in the core as a treatment for diabetic wounds.2.4 The resulting nanofibres have properties that give great application spectra in the biomedical field: high surface area to volume ratio and high porosity.10 There is evidence of their application as scaffolds for tissue regeneration,11 cartilage,12 bone,13 drug delivery,14 and wound dressings.15Among the techniques for nanofibre production, electrospinning is the one with the most advantages. It produces nanofibers at the laboratory or industrial level, with considerable reproducibility and efficiency. Moreover, it enables control of the nanofiber dimensions and great versatility in the use of polymeric materials.16Each application has been made with a variety of materials, specifically relating to the polymer–solvent mixture. The most important properties for choosing the adequate material is high molecular weight, as this allows entanglements that form the polymeric chains, and solubility.2.1.5,16 The syringe supplies the polymeric solution at a rate established in the pump.22 The collector could be a fixed aluminium foil, or a rotating mandrel.23 The selection of the collector depends on the desired fibre alignment, since a metallic sheet produces randomly aligned fibres, whereas a rotating mandrel produces aligned fibers.24 Finally, the voltage power source provides a charge to the polymeric solution so that it can start its trajectory towards the collector with the opposite charge.23The electrospinning apparatus  consists2.2.25 The process is as follows: a droplet of the polymeric solution forms on the needle tip of the syringe. As the electric field increases, electrostatic charges start to concentrate upon the droplet. This produces a charge repulsion, which acts against surface tension, changing the droplet form to an elongated conical shape, known as a Taylor cone.26 As the field strength increases, the repulsive electrostatic force overcomes the surface tension and a charged jet of the polymeric solution starts to flow from the Taylor cone's tip towards the collector.27 The jet is a summary of the instabilities produced by the electric charges.28 Then, when the viscosity of the solution is defeated by the attraction forces, it produces a thread as a result of the materials' motion and stretching. Finally, the solvent evaporates, and the fibres solidify on the collector,28 with nano- to micrometric diameters.27 The electrospinning is considered a simple technique; however, it is a complex procedure. The many parameters influencing this process are generally divided into three categories: solution, processing, and ambient conditions  using a high voltage supply previously described.nditions , which m2.3.2.3.1.Mw produces nanofibers with larger diameters, whereas a low Mw polymer does not form fibres, but beads instead. An important characteristic of this parameter is its relation to the viscosity and the polymer chain entanglements.23 This behaviour was recently tested by Tian et al.,30 where they used polycaprolactone (PCL) with an average Mw of 80 000 g mol−1 at a concentration of 15% w/v and diluted it with a mixture of chloroform and ethanol, where the chloroform ratio was constant. In contrast, ethanol was varied from 1.9 : 1, 1.4 : 1, 1 : 1, 0.5 : 1, 0.3 : 1, and 0.1 : 1. For the electrospinning process, they used a flow rate of 400 μL h−1, a positive voltage of 10 kV, a distance of 15 cm between the needle and collector, and a volume of 2 mL. These authors directed their assay towards the polymer crystallisation; they studied the entanglement behaviour of the material. By using differential scanning calorimetry (DCS), they concluded that Mw is strongly associated with recovery of entanglement.A polymeric solution with high 2.3.2.31 Low ST helps the process as long as a low electric field is used.32 It is important to clarify that ST is a function of the solvent used in the polymeric solution.23 Fortunately, there are different ways to change the ST of the materials used, by using additives, like ionic liquids or organic/inorganic salts, while varying the solvent or the surfactants.23High ST creates instability in the jet, which could disrupt the process and deliver droplets and beads instead of fibers.2.3.3.η is not directly or indirectly proportional to the nanofiber diameter. In this case, when the solution has a very high η, the jet cannot form. On the other hand, if η is very low, there is a jet ejection, but no fibre formation occurs. Hence the need to research the optimal η of the polymer solution. η basically determines the concentration range of the polymeric solution to obtain uniform and continuous nanofibres26 Tiwari and Venkatraman33 confirmed the effect of η on simple or core-shelled electrospun fibres, using a copolymer of polylactic acid (PLA) and polygalacturonic acid (PGA) in an 80 : 20 ratio, with chloroform and N,N-dimethylformamide (DMF) as the solvent. These authors measured the solution viscosities and plotted them against the solution concentration so that they could prove the η-concentration dependency. For a better understanding, this relationship will be discussed with the following parameter.Unlike the other parameters, 2.3.4.η. If we have a polymeric solution with low concentration, there is not just fibre formation, but the presence of beads as well. If we increase the concentration, the shape changes to uniform fibres followed by an increased diameter, and this is a reason for a higher η resistance. There are four concentration regimes for polymer solutions: 1. concentrated, 2. semidilute entangled, 3. semidilute untangled, and 4. dilute. According to the study of Tiwari and Venkatraman,33 they reported an especially important concept, an overlap in concentration (C*). Its importance lies in the polymeric chain behaviour since it is in this concentration, where the individual chains that were separated from the solvent at the dilution start overlapping with each other; however, they remain untangled. As the concentration increases, the solution starts developing entanglements. This is a result of the induced topological constraints formed because of the larger occupied fraction of the available hydrodynamic volume in the solution.As explained before, this parameter is intimately correlated with 2.3.5.23Concerning the nanofiber diameter, as the polymeric solution's electrical conductivity increases, the fibre diameter decreases. This indirect proportionality is because of the incapability of the electrical force to produce an insufficient elongation of the jet.2.4.2.4.1.et al.34 since they observed an increased diameter from 111 nm to 214 nm on TiO2 nanofibers when varying the FR from 0.6 mL h−1 to 1.2 mL h−1. Also, this parameter is important because it influences the material transfer rate and jet velocity.A low FR is desired during the process since it allows for complete solvent evaporation. On the other hand, high FR values do not allow for solvent evaporation, which causes the formation of beads. Therefore, FR is directly proportional to the fibre diameter. This was proven by Someswararo 2.4.2.V and diameter is inversely proportional. Yuan et al.35 analysed the morphology of electrospun fibres of polysulfone/DMAC/acetone. They observed that an increase in voltage caused a decrease in the fibre diameter. They concluded that the phenomenon was a consequence of an increase of the electrostatic repulsive forces of the charged jet that resulted from the voltage increase. This effect on the jet leads to smaller diameters.This parameter is probably the most important in the whole electrospinning process. As discussed before, for an electrospinning process to occur, an electrical force must be applied to the material. In this sense, the relationship between 2.4.3.et al.36 studied the morphology of electrospun nanofibers of gelatine and chitosan, starting at a distance range of 5 cm to 15 cm with the other parameter's constant. They found that 5 cm was too small to either maintain a stable jet or have enough solvent volatilisation. Nevertheless, they obtained good nanofibers at 10 cm and 15 cm, and at 15 cm, the fibre density collected was low. The authors concluded that the effect was a consequence of the formation of smaller fibre jets due to the bending instabilities, and these could not reach the collector.The objective of this parameter is to give the jet enough time for the solvent to evaporate and the nanofiber to solidify on the collector. Dhandayuthapani 2.4.4.23 It has an effect on the alignment instead of affecting the fibre morphology. This alignment depends on the collector and the rotation speed. In the case of a rotating collector, the resulting nanofibers should have a certain order grade. This is contrary to the fixed grounded collector, whereby the bending instability of the charged jet causes the random deposition of the nanofibers.31The collector in electrospinning is the conductive substrate to collect the nanofibers.2.5.2.5.1.η; therefore, its increment is inversely proportional to the nanofiber diameter. This behaviour was confirmed by Mit-uppatham et al.,37 who spun polyamide-6 nanofibers and observed that their diameter decreased with increasing temperatures.The first environmental parameter to consider in an electrospinning process is the temperature. With the more basic equipment, the process is normally non-adiabatic and it is difficult to control the heat transfer. This affects 2.5.2.et al.38 since they evaluated the RH effect on polystyrene nanofibers. They managed a range of 31–38%, 40–45%, 50–59%, 66–72%, and observed that the range of pore diameter increased proportionally with the RH values.RH is perhaps the most difficult parameter to control in the basic equipment. High humidity results from the presence of free volume on the nanofibers. This effect was reported by Casper 3.39 The needle conformation gives a unique nanofiber conformation known as the core–shell. This process can have the same applications of electrospinning; however, the nanofiber conformation provides extra protection to any compound included in the core. Another advantage of this technique is that the trapped compound is protected from environmental stress and its release can be controlled.40,41Also known as coaxial electrospinning, co-electrospinning is a modification of the traditional electrospinning technique . The samet al.42 These authors produced co-electrospun nanofibers' with chitosan as the shell material, gelatine as the core, and aqueous acetic acid solutions as the solvent. To enhance the nanofibers water resistance, oxidised dextran and sucrose were used as cross-linkers, and the resulting material was biologically evaluated with human osteoblast-like cells (MG-63 cells). The treated cells grew at a normal rate in the nanofiber mats. They concluded that this favourable result was closely related to the ability of core–shell nanofibers to enhance the biological activities of both chitosan and gelatine. The enhanced cell attachment and proliferation resulted from the presence of gelatine in the core and chitosan on the surface of the nanofibers.There are reports of core–shell nanofibers used for biomedical purposes, such as a study by Jalaja 4.43Biopolymers are one of the most frequently used materials for electrospun nanofibers with a biomedical application. By definition, a biopolymer involves large macromolecules formed by covalent bonded monomers, which can be broken into smaller chains by the action of biological factors. Generally, biopolymers are classified based on their origin, that is to say, natural or synthetic.44 In the case of nanofibers for wound healing, some of the most reported natural biopolymers assayed are gelatine and chitosan. However, their mechanical properties are limited, hence the need to complement them with other materials.45 Synthetic biopolymers on the other hand, are recognized by their robust mechanical properties, and have a reduced production cost in comparison to natural biopolymers.46 Among the most assayed synthetic biopolymers as nanofibers for wound healing are PLA, PCL, and PVA.Natural biopolymers possess various properties of interest for biomedical application. Apart from being biodegradable and biocompatible, natural biopolymers present biological recognition, impacting positively upon cell function and adhesion.4.1.6 From this composition, 25% is a combination of positive and negative charged residues , 11% are hydrophobic , and the remaining percentage consists of proline, hydroxyproline, and glycine.36As addressed before, gelatine is a promising material to be used in the shell phase of the co-electrospun nanofibers. This biopolymer is a protein  that reset al.47 made a comparison among nanoparticles of different gelatine types compounds. The authors used models for positive and negative charges using methylene blue and eosin respectively, and sericin as a biologically active compound. The difference between the responses of each gelatine type can be explained as follows. The differences among the crosslinking degree could be a consequence of the added glutaraldehyde. This agent binds the aldehyde groups with the amine groups of gelatine. Since type B gelatine has a higher amount of free amine groups, it caused a higher crosslinking degree. Sericin is an active compound with a negative charge, which in this study was entrapped upon a gelatine type B nanoparticle also negatively charged.Aramwit As a law, equal charges tend to repel, an effect not seen in this case. Therefore, the authors proposed that perhaps electrostatic interaction is not always the main mechanism, but forces such as van der Waals interactions and hydrogen bonding could also take place on the release behaviour of molecules from carriers.48 and hemostatic effect.49 This behaviour was reported by Dubsky et al.,50 where they assayed electrospun nanofibers of PCL, gelatine, and cotton as a control, observing that either on day five or 10, gelatine was the compound with the higher wound closing percentage. Thus, gelatine can be postulated as a reliable compound for its use in biomedicine, especially gelatine B. It shares characteristics with chitosan.The property of gelatine to release bioactive molecules highlights the biomedical importance of this polymer. For example, its uses in adhesive and scaffolds treatments have been previously reported, along with macrophage stimulation4.2.7 Chitin, with a degree of deacetylation higher than 60%, is considered as chitosan.49 Chitosan's structure is formed by two monomers, N-glucosamine and N-acetyl-d-glucosamine, linked by a β (1–4) bond51 with an amine group and two hydroxyls as its active groups7 , so its amino groups can be protonated.57 The second mechanism is the occurrence of electrostatic interactions; this mechanism applies to Gram-negative and Gram-positive bacteria despite their different membrane components. Upon contact with Gram-negative bacteria, the electrostatic interactions take place between the cationic chitosan and the anionic lipopolysaccharide present in the outer membrane.58The first mechanism is related to a chitosan characteristic previously mentioned, its capacity to interact and chelate negatively charged metal ions. The interaction produces a cell wall disruption, which damages the microorganism's integrity.59 This acid has three key functions in the cell membrane: control of enzymatic activity and cationic concentration, environmental stress protection, and serving as an anchor of the cell to surfaces.60 Therefore, an interaction between chitosan and the teichoic acids quite possibly results in multifactorial cell death.The third mechanism involves the electrostatic interactions between chitosan and one of the most important components of the peptidoglycan layer in the cell surface, teichoic acid.61Finally, the diffusion mechanism of chitosan within the bacterial cell depends on its molecular weight more than its charge properties. At a certain weight, chitosan can permeate the membrane of Gram-negative bacteria, possibly damaging the DNA/RNA synthesis, and their survival.4.2.2.Wound healing is a complex process in which a great number of different molecules are involved, such as the extracellular matrix (ECM). Therefore, it is imperative that we review the differences in the wound healing process between a healthy person and a diabetic patient.6 In a review article, Liu et al.58 explained the way chitosan (as a hydrogel) participates in the wound healing stages. In summary, the most important action of chitosan is to promote platelet activation.The wound healing process could be divided into four phases: haemostasis, inflammation, proliferation, and remodelling.62Platelets are essential components of the coagulation process since they release cytokines. In the inflammatory phase, the cytokines along with growth factors and chemokines, activate an intracellular signalling cascade, giving a place for cellular proliferation, migration, and differentiation, along with the recruiting of granulocytes and macrophages. This phase is when the difference between the wound healing process of a healthy person and a diabetic person starts to appear. In a healthy person, there is the presence of a platelet-derived growth factor (PDGF) and a transforming growth factor (TGF)-β1, both released from the platelets. However, a diabetic person has a deficient expression of these factors. This adds to the fact that the inflammatory phase is the foundation for the process. But, if it is present in excess, it could lead to tissue necrosis and systemic infection, which are known symptoms present upon the wounds of diabetic patients.et al.44 reported that chitosan was able to provide two very important features in the wound healing process for a diabetic person: it could induce the release of PDGF and (TGF)-β1, activating macrophage and fibroblast proliferation, thereby promoting cytokines and collagen synthesis, respectively. Chitosan also, provides a 3D matrix for tissue growth. If it is not enough, chitosan depolymerises to N-acetyl-glucosamine, one of the major components of dermal tissue essential for scar tissue repair.63 Moreover, this depolymerisation increases hyaluronic acid and collagen type III synthesis.64Okamoto 65 that, according to the electrospinning parameters previously addressed, results in the formation of droplets or beads instead of fibers.59 Therefore, chitosan needs an electrospinning agent to be able to form nanofibers with good characteristics. Some of these agents are PLA, PCL and PVA.23Despite having all the advantages presented above, chitosan shows some disadvantages. Its ionic nature, demonstrated by the protonated amines, makes the production of pure chitosan nanofibers rather difficult. This ionic nature of chitosan provides a high superficial tension4.3.η is directly proportional.8Polyvinyl alcohol (PVA) is a synthetic biopolymer that is highly soluble in water. Compared to other polymers with vinyl groups, PVA is obtained by hydrolysis of polyvinyl acetate (PVAc) in an alcohol solution, instead of a polymerisation process. Structurally, PVA is an atactic linear polymer, with hydroxyl groups randomly positioned along the chain . An esse66 Recently, Alavarse et al.29 assayed the possibility of using chitosan–PVA electrospun nanofibers as a delivery system for tetracycline hydrochloride. These authors reported that pure PVA nanofibers have good mechanical properties. However, its high hydrophilicity results in a high rate of biodegradation due to the hydroxyl groups. This behaviour is considered a disadvantage if the purpose of the material is for a wound dressing. Yet when combined with chitosan the degradation rate decreases, since inter and intramolecular hydrogen bonds between chitosan and PVA enhance the mechanical properties of the electrospun nanofibers. Therefore, the combination of these biopolymers would result in a win–win situation for obtaining electrospun nanofibers for wound dressings.Concerning the use of PVA in biomedicine, the type of material most reported for this end are hydrogels. PVA is used as a therapeutic agent based on its good biocompatibility.et al.67 However, in this case, a natural active compound (curcumin) was used.29 These authors reported that when the PVA concentration decreases, the repulsive forces of chitosan amino groups might interfere with an effective chain entanglement. Therefore, with this type of blend, a high PVA concentration is recommended to obtain beadless electrospun nanofibers. Additionally, reported in this study was the importance of the solvent in electrospun nanofiber processing. Because acetic acid has a higher vapour pressure compared to water, as the PVA concentration increased, the water to acetic acid ratio in chitosan–PVA–curcumin solution decreased gradually. Therefore, if the electrospinning parameters apply, this easy acetic acid evaporation resulted in a faster polymeric jet solidification and good nanofiber morphology.Another recent report of the use of chitosan/PVA blend electrospun nanofibers for therapeutic use is the study by Sedghi in vivo assays on mice that electrospun nanofibers possess the necessary biocompatibility, adhesion, and lack of cytotoxicity to carry on with this application. Also present in There are numerous assays which have proved the possible use of different biopolymers as a wound healing scaffold, specifically on diabetic patients. 4.4.77 This biopolymer  is a synthetic biopolymer from the family of polyesters.opolymer  is appro81 Ho et al.82 fabricated electrospun nanofibers coated with chitosan oligomers (COS) for wound healing application. Their results showed that their materials presented a high bacterial inhibitory activity and biocompatibility, so long as COS did not exceed a certain concentration. Also, COS concentration affects reepithelization and wound healing in mice, with the samples of 15% w/v PCL and 8% w/v COS presenting the best in vivo performance. These authors bestow this activity to the free radical scavenging activity of COS in the wound site.Drug delivery, bone regeneration and wound healing are among the different biomedical applications with PCL that have been examined, however, the major obstacle for this application is the high hydrophobicity present on PCL. Therefore, there is a need to complement the materials with other polymers to counteract the effect, such as chitosan.et al.68 assayed the antimicrobial and in vivo activity on diabetic mice of PCL and gum tragacanth (GT) loaded with curcumin (Cur). These authors reported that their materials presented an effect on increasing the collagen content upon diabetic wounds, promoting healing, particularly in the early stages. These nanofibers presented a synergy between the GT high biological properties, PCL high physical–mechanical properties and the sustained release of Cur (a reactive oxygen species reductor), resulting in stable scaffolds in front of blood and fibrin as well.Ranjbar-Mohammadi 4.5.Lactobacilli.6 Lactic acid is the product of the fermentation of dextrose, derived from plant starch. This means that PLA is a biopolymer that could reduce the dependence on fossil-based resources for plastic obtention.83 PLA has a glass transition temperature range from 40 to 70 °C and a melting temperature between 130 to 180 °C, with a tensile strength of 440 to 59 MPa. These characteristics make PLA a hydrophobic semicrystalline polymer.6Another polyester of importance in diabetes wound healing is polylactic acid (PLA). This biopolymer  has the 84 Fang et al.85 prepared core–shell nanofibers with PLA as the shell and γ-PGA as the core by electrospinning for wound healing application. These authors reported beneficial cell proliferation and good biocompatibility, reflected as restoration of epidermal and dermal tissue on mice after 14 days.PLA possesses outstanding biodegradability and biocompatibility, making it a great material for regenerative medicine, gene transfer, drug delivery and tissue engineering.et al.86 fabricated aligned electrospun nanofibers from PLA and asiatic acid (AA) for wound healing acceleration. Also, they reported that their materials, particularly the samples with 30% AA, presented excellent accelerating reepithelization, ECM formation and angiogenesis in vivo in diabetic mice. These authors confer this behaviour to the AA effect on anti-oxidative stress, anti-bacteria, and anti-inflammation in vitro. Also, PLA aligned nanofibers promoted wound healing acceleration by facilitating fibroblasts and keratinocytes migration from the periphery to the centre of the wound, therefore promoting collagen formation and reepithelization.There have also been reports of PLA electrospun nanofibers for wound healing on diabetes induced mice. Han The literature indicates that, although a natural bioactive compound is present on the nanofibers, it is possible to obtain electrospun nanofibers with good characteristics. As such, other natural bioactive compounds could be used as well.4.6.87 Eugenol can be extracted from different plants, such as clove (Eugenia caryophyllata) and basil (Ocimum basilicum L.),88 and one of the best solvents for its extraction is glacial acetic acid.89 Several properties have been attributed to eugenol, such as antioxidant, antispasmodic, pharmaceutical, anti-inflammatory, antimicrobial, anaesthetic, and antiseptic. Also, it is recognised as generally safe by the FDA.88 It is classified as a category 3 compound by the US Environmental Protection Agency. The oral LD50 is >1930 mg kg−1 in rodents.88 However, when used at an optimal dose, eugenol even enhances the immune system response against infectious agents and tumour cells.90Belonging to the phenylpropene family, eugenol is structurally composed of an aromatic phenyl group and a propane tail , produce90 studied the effect of the antioxidant and anti-inflammatory properties of eugenol in a metalloproteinase (MMP-9) metastasis matrix. These authors reported that eugenol presented a high inhibitory effect on hydrogen peroxide compared to other reactive oxygen species (ROS) and had the ability to block lipid peroxidation induced by hydroxyl radical and block DNA oxidation. Also, eugenol inhibits MMP-9 by inactivating ERK-1 via its antioxidant activity.Nam and Kim91–93 As for the antimicrobial activity of eugenol, there is a general idea about its action mechanism, which relates to the alteration of its permeability mechanism by damaging and altering lysosome, microsome, and cell walls. This damage causes bacterial death by the leakage of its essential cell constituents.90 Finally, the aesthetic and antiseptic properties of eugenol can be attributed to its molecular structure, since it contains para-allyl and ortho-methoxy groups.89Another proposed mechanism  through 5.Electrospinning and co-electrospinning are simple, yet powerful processes which can create morphologically homogeneous nanofibers and can help cell growth and cell tissue regeneration. To summarise, if the materials conforming the nanofibers are biopolymers , the resultant membrane would be a dressing with the necessary physicochemical properties to carry out their application. Furthermore, if the wound dressing is accompanied by a natural active compound, such as eugenol, the target of the wound dressing would be cantered to influence healing upon a specific type of wound, such as diabetic wounds.The authors declare that there are no conflicts to declare.


This article uses quantitative and qualitative approaches to review 75 years of international policy reports on antimicrobial resistance (AMR). Our review of 248 policy reports and expert consultation revealed waves of political attention and repeated reframings of AMR as a policy object. AMR emerged as an object of international policy-making during the 1990s. Until then, AMR was primarily defined as a challenge of human and agricultural domains within the Global North that could be overcome via ‘rational’ drug use and selective restrictions. While a growing number of reports jointly addressed human and agricultural AMR selection, international organisations (IOs) initially focused on whistleblowing and reviewing data. Since 2000, there has been a marked shift in the ecological and geographic focus of AMR risk scenarios. The Global South and One Health (OH) emerged as foci of AMR reports. Using the deterritorialised language of OH to frame AMR as a Southern risk made global stewardship meaningful to donors and legitimised pressure on low-income and middle-income countries to adopt Northern stewardship and surveillance frameworks. It also enabled IOs to move from whistleblowing to managing governance frameworks for antibiotic stewardship. Although the environmental OH domain remains neglected, realisation of the complexity of necessary interventions has increased the range of topics targeted by international action plans. Investment nonetheless continues to focus on biomedical innovation and tends to leave aside broader socioeconomic issues. Better knowledge of how AMR framings have evolved is key to broadening participation in international stewardship going forward. The last two decades have seen a marked rise of attention to antimicrobial resistance (AMR) at the international political level.There have been multiple framings of AMR as a target for political intervention since the 1950s.Our analysis of 248 historical international and regional AMR policy documents and expert consultation revealed waves of political attention and the emergence of AMR as a sustained target for intervention at the international level during the 1990s.Since around 2000, the rise of new concepts like stewardship, the ‘One Health, One World’ paradigm and the ‘Global South’ has been accompanied by a shift of international policy-making from whistleblowing to governance.Our analysis highlights persistent biases such as a Northern dominance of report authorship, a deterritorialisation of stewardship policies regarding the Global South, and a neglect of the environmental One Health domain.We argue that critical engagement with how AMR is framed is crucial to developing more effective international engagement and maintaining political momentum for reform amidst declining attention.Defining AMR as a threat to Northern biosecurity risks ignoring important Southern perspectives and prioritising regional over planetary solutions.The last decade has seen unprecedented international efforts to address the global threat of antimicrobial resistance (AMR). A highpoint of attention was reached with the announcement of the WHO’s 2015 Global Action Plan.We show that understandings of AMR, and which areas were included in policy-making, have evolved substantially. Between the 1950s and 1980s, AMR was primarily defined as a Northern challenge that could be overcome via ‘rational drug’ use or selective drug restrictions. It was only during the 1990s that AMR emerged as a consistent focus of international reporting and that a growing number of reports jointly addressed human and agricultural AMR selection. Starting in the new millennium and accelerating after 2010, the Global South and One Health (OH) emerged as key foci in international reporting. Framing of AMR as a Southern risk has led to a deterritorialisation of international policy discourse and growing pressure on low-income and middle-income countries (LMICs) to implement AMR-focused reforms. It has also boosted the status of international organisations (IOs) like the WHO, who have no longer limited themselves to whistleblowing but assumed active governance roles within global stewardship and surveillance frameworks. Calls for interventions are now couched in the language of ‘One World, One Health’—although the environmental domain remains neglected. Realisation of the complexity of necessary interventions has also led to an increase in the range of topics being targeted by international action plans. Despite acknowledging the structural complexities of AMR, the international community has focused investment on biomedical innovation  and tends to leave aside broader socioeconomic issues related to food and health systems and pharmaceutical markets. Finally, our analysis sheds light on international governance as such, in particular how new actors and power dynamics emerged over time.Box 1Global North primarily refers to regions and countries within Europe, North America and parts of Asia, Latin America and Oceania that have high levels of wealth, living standards, technology and international influence. By contrast Global South refers to primarily low-income and middle-income and politically marginalised regions in Latin America, Asia, Africa and Oceania. Originating in work by Antonio Gramsci on regional relations within Italy, the terms North and South emphasise geopolitical power relations rather than the historically dominant focus on development and cultural difference. Similar to the core-periphery terminology, the terms also reference histories of colonialism, extraction and ongoing socioeconomic inequalities.89Refers to the exercise of power in the management of economic, political and social resources through all processes of interaction including laws, norms, economic relations, language, etc. Governance can be exercised both by governmental and non-governmental organisations as well as through markets or networks.90Based on the World Bank’s ATLAS methods, high-income countries have a gross national income per capita of US $12 696 or more (2020), middle-income countries have income levels ranging from $1046 to $12 695, low-income countries have a gross national income per capita of US$1045 or less.91The category of IOs refers both to organisations that were established by an instrument of international law and involve at least three members as well as to non-treaty-based state coalitions like the G7.7One Health refers to collaborative efforts of multiple disciplines at different local, national and global levels to attain optimal health for humans, animals and the environment. The term rose to prominence in international discourse around 2000 but is rooted in older traditions of one medicine and tropical medicine.25 39content analysis of international and regional AMR policy documents published between 1945 and 2020; (b) a consultative process involving experts in the field of AMR, to identify policy documents perceived to have the greatest impact. We did not involve patients or members of the public in the design of the study.Our analysis was based on two complementary but distinct approaches to identifying patterns of attention and discovering how AMR was framed over time; (a) ad hoc, national or regional basis while others were only active for a brief time. Smaller NGOs—but also some of the largest international donors—do not have accessible archives, published reports are not systematically captured by online databases, and distinctions between publication formats  are not always clear.Global health politics are shaped by a multitude of governmental and non-governmental actors. Since the origins of the international health system around 1900, non-governmental organisations like the Rockefeller Foundation, the Wellcome Trust or the Bill and Melinda Gates Foundation have influenced health policies at the national and international levels.To maintain analytical cohesion and avoid biasing results towards a select group of NGOs whose archives are available online, we have focused on reports by IOs and transnational organisations like the European Union (EU) whose archives are fully accessible and span multiple decades. For the purposes of this paper, the category of IOs refers both to organisations that were established by an instrument of international law and involve at least three members as well as to non-treaty-based state coalitions like the G7.The organisations whose reports have been included in our analysis are: Asia-Pacific Economic Cooperation (APEC), European Centre for Disease Control (ECDC), European Commission (EC), European Food Safety Authority (EFSA), European Medicines Agency (EMA), European Parliament (EP), EU, The Food and Agriculture Organisation (FAO), G7, G20, Organisation for Economic Co-operation and Development (OECD), Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), United Nations (UN), UN International Children’s Emergency Fund (UNICEF), UN Interagency Coordination Group (IACG) on AMR, The World Bank, WHO and World Organisation for Animal Health (OIE).Building on an initial overview presented by author CK at a multidisciplinary AMR workshop in 2019,First, databases of key organisations dealing with AMR were systematically searched, including WHO, FAO, OIE, IACG, CODEX, UN, OECD, World Bank, G7, G20, APEC, EU organisations (see above) and TATFAR websites.Second, to account for NGOs’ and individual government reports’ influence on international policy, further documents were identified by scanning the reference lists of the identified documents and adding reports by NGOs that were highlighted as influential by our expert consultative process (see part B).Third, to compensate for the temporal bias of digital repositories, we identified older non-digitised policy documents through the literature on the history of AMRFourth, we applied inclusion/exclusion criteria to this data set: our policy documents include policy action plans and guidelines, meeting reports, legislative frameworks, surveillance reports and substantive stakeholder engagement ; they exclude original research , simple communication materials , national legislation and intermediary policy documents such as meeting minutes or consultation summaries . No additional reports were identified that fit our selection criteria and we noted that the vast majority of our identified reports were not listed in academic databases, which have informed previous research in this area.14–1610.1136/bmjgh-2021-006909.supp1Supplementary data10.1136/bmjgh-2021-006909.supp2Supplementary dataet al and Ogyu et alOur coding evaluation framework was informed by methodologies adopted by Wernli Resulting analytical categories included year, author, document type, target audience, orientation, geography, aim of policy and intervention called for . Each doThe framework analysis of all included documents was undertaken by one author (KO) for consistency. The full list of variables and associated values can be found in To identify additional key documents published by organisations that do not fall into the above categories (part A), we conducted a consultative process with relevant experts. Twenty-five experts were identified and contacted due to their work in critical areas: history of drug regulation and AMR; social sciences of AMR, antibiotic markets and legal frameworks; involvement in antibiotic-related policy-making at the national and international levels. Ten (40%) of the contacted experts participated in the subsequent three rounds of consultation.Round One: experts were asked to identify the international reports they felt have had the greatest input on AMR/stewardship since 1945  and additional expert consultation (part B) identified 248 international and regional AMR policy documents. The majority of policy documents were authored by IOs ; followed by governments/transnational organisations ; we included nine additional reports from NGOs  see . Most poThe first international report on AMR was published in 1955.Despite surges in AMR data from the early 1970s and mid-1990s onwards as well as individual 1990s national level action plans and an abortive WHO call to action in 2001,et al,ndm-1 (2008) that drive home global interconnectedness  alongside the OH message (see below).The Global North has and continues to dominate international AMR reporting. Although our results are biased towards Europe by including the EU as a transnational organisation but mostly excluding nation-level reports by individual governments, Northern countries are consistently over-represented both in terms of authorship and focus of AMR reports. Prior to the identified governance shift of international AMR policy (see above), most international reports focused on AMR as a problem of the Global North see . As highBetween 1945 and 2000, most international policy documents focused on agriculture and/or human antibiotic use and AMR selection see . Since tThe interventions called for by the international AMR policy documents have also changed over time see  and paraThe rhetoric of reports targeting international antibiotic use, stewardship and AMR has closely followed wider moral economies. Mirroring postwar consumer movements,Initial international reports predominately called for more information and research. Governance and behaviour change at the level of the individual emerged as key aspects of international reporting during the 1990s. From around 2000 onwards, this was complemented by a focus on health infrastructures . The emerging ‘infrastructural turn’ paralleled calls for increased Northern financing to tackle AMR first at the national/regional and then—with the Southward expansion of stewardship discourse (see above)—at the international level. The post-2010 emphasis on the Global South has strengthened international calls for systems-level interventions in the form of improved water, sanitation and hygiene, infection prevention control and mass vaccination. In line with the described OH pivot, arguments for systems-level interventions are often framed using biosecurity terminology rather than in terms of collective structural responsibility. Resulting action plans remain primarily vertical and technology oriented and do little to address the horizontal socioeconomic factors underlying antibiotic consumption and threatening global ‘antibiotic infrastructures’.Antibiotic innovation is an outlier in this regard. Concerns about the ‘empty antibiotic pipeline’ were raised by industry and Northern policy reports in the early 1990s and began to feature in analysed reports from the early 2000s. The ‘empty pipeline’ narrative presents an attractive, tractable solution for AMR, a problem which was beginning to appear insolvable/ungovernable.21Tackling Drug-resistant Infections Globally: Final Report and Recommendations,The consultative process (part B) complemented and added value to the broader analysis of AMR reporting, through incorporating both informal but established knowledge of impact and significance. Due to their importance in opening the door for new approaches to safe-guarding antibiotic efficacy and conceptualising antibiotics as a global public good, the expert consultation led to the inclusion of documents like the 1977 WHO report on Essential Drugs  had significant expertise of antibiotic use and regulation in the African region, two (20%) in the European region, two (20%) in the US region, three (30%) in the Asian region and four (40%) of regulation at the IO level—with some respondents having expertise across multiple areas. None of our experts were specialists of the South American region and only two (20%) were scholars from the Global South. This means that our expert consultation may have missed policy documents targeting South America or reflecting South-to-South policy-making. We nonetheless believe that our identified top 10 of international reports highlight the salience of our broader content analysis (part A), illustrating no reports originating from or solely focusing on the Global South, a partial focus on OH (50%), and a dominance of the Global North in report authorship and focus  in perceived impact and significance.Our analysis shows that international attempts to control AMR evolved in waves. Political attention waxed and waned as a result of competition from other policy areas and of different stewardship approaches running out of steam in the face of the biological, economic, social and political complexities of AMR. The framing of AMR risks also changed over time and was linked to varying degrees of optimism or pessimism about the ability of antibiotic development to ‘keep up’ with AMR as well as with broader changes in political discourse relating to consumerism and sustainability.2–4Staphylococcus aureus 80/81.Awareness of AMR as a clinical problem dates back to the interwar period and national policies for ‘rational’ antibiotic use in human and animal medicine emerged during the 1940s. At the international level, AMR first emerged as a policy challenge in reaction to concerns about expanding agricultural antibiotic use and the global spread of resistant AMR re-emerged as a target of international policy during the mid-1990s in response to Northern warnings about the biosecurity threats posed by emerging infectious diseases, outbreaks of MDR pathogens like vancomycin resistant enterococci and stalling antibiotic innovation. Antibiotic use in agriculture continued to be a strong focus of international reports.41 42prêt-à-porter policy instruments like travel restrictions in response to identified threats were at the heart of this interventionist mode of governance, which was consolidated by the passage of the reformed International Health Regulations (IHR) in 2005.47The re-emergence of AMR as an international concern between 2010 and 2015 occurred against the backdrop of a reordered landscape of global health politics. Since 2003, numerous pandemic crises  had given rise to a new system of international health governance focused on biosecurity. Concerns about (re-)emerging infections at the intersection of human and animal health strengthened UN IOs’ role as the only institutional actors capable of staging politically legitimate interventions in sovereign (Southern) territories. Enhanced sentinel surveillance and the rapid deployment of The described changes also affected AMR politics. Amidst a rapid increase in the number of antibiotic reports, IOs’ role transitioned from raising awareness and reviewing data to managing the emerging physical and legal frameworks underpinning global antibiotic governance. Regulatory tools such as action plans and surveillance systems as well as broader instruments like the new IHRThe transition towards AMR governance was accompanied by an increasing focus on OH and the Global South. The parallel rise of both terms in international reporting is highly significant and reflected a growing realisation of the complexities of AMR as a global problem that was not amenable to interventions targeting high-income countries (HICs) alone.New Delhi metallo-beta lactamase 1 (ndm-1) in Klebsiella pneumoniae is emblematic of this reframing of AMR as a Southern threat. The gene enabling enzyme production had first been identified in a carbapenem resistant strain isolated in Sweden.Lancet editor Richard Horton apologised for reprinting the geographic name tag and numerous other transferable carbapenemases had been detected across the world since the early 1990s,ndm-1 quickly became a poster child for the ‘Southern’ reconceptualisation of AMR threats. International policy reports, academic papers and media reports soon used it as a key reference point in arguing for increased Northern investment in global—and primarily LMIC—stewardship.ndm-1 alongside climate change, zoonotic viruses and coastal flooding to galvanise British action on AMR.60The 2008 detection of transferable The international reframing of AMR as a ‘Southern’ risk was paralleled by the adoption of OH rhetoric. Tracing its roots back to Calvin Schwabe’s 1960s One Medicine philosophy and colonial era tropical medicine, OH had emerged as a distinct discipline focusing on human, animal and environmental health around 2000. By 2008, the WHO, FAO and OIE had adopted OH approaches in response to zoonotic threats.mcr-1) gene in Chinese pigs seemingly confirmed concerns and prompted international pressure on major users like China and Brazil to outlaw polymyxin feed additives.mcr-1 was detectable in strain collections from more than 30 countries and was already circulating in China in the mid-1980s.8 68Quantifying economic and health threats was an important part of the described policy shift towards international AMR governance and new Global South and OH rhetoric. In 2014, British Prime Minister David Cameron commissioned an independent economic review of AMR by former Goldman Sachs economist Terence James O’Neill. Underlining the role of soft power interests within international AMR governance, the initiative was explicitly framed as a way for ‘Britain to lead the way, using its international leadership and world-class pharmaceutical sector (…) to battle against antimicrobial resistant infections and bring new drugs to the world market’.mcr-1 episode and O’Neill report coincided with a peak of international action. On 26 May 2015, a tripartite initiative by WHO, OIE and FAO led to the passage of a global action plan on AMR by the World Health Assembly.The How long this surge of international attention for AMR will last and what its impacts will be is uncertain. Arguably, AMR awareness is already past its prime. Even before the reorientation of political agendas towards COVID-19, the annual number of international reports dedicated to AMR had peaked in 2017. This was despite an ongoing rise of global antimicrobial usage and AMR, an international outbreak of extensively drug resistant typhoid, stuttering antibiotic innovation and an ongoing neglect of environmental health within OH frameworks.Meanwhile, there are also signs of a growing divergence of problem analysis and political action at the international level. Recent reports by the World Bank,8Despite AMR’s reappearance on the agendas of the 2021 G7 and a high-level UN interactive virtual meeting,Greater awareness of the ways in which AMR is framed as an object of global attention and subject of international intervention seems key to breaking the described cycle of optimism and lethargy. Although the post-2010 wave of attention has led to novel and more complex policy solutions as well as lasting stewardship alliances, it should not make us blind to the geopolitics, Northern biases and (post)colonial tropes that are couched in the deterritorialised OH rhetoric of recent reports and action plans. It is clear that AMR will not be tackled by national politics and—in the absence of other credible actors—IOs’ increased involvement is to be welcomed. However, by continuing to frame AMR according to the biosecurity preoccupations of Northern donors, IOs and academics alike risk ignoring Southern perspectives, perpetuating a history of distrust and jeopardising LMIC buy-in and prioritising regional over planetary solutions. In the long-term, effective collective action on planetary challenges will only result from international partners working together as equals.


Endometrial carcinomas (EC) have been traditionally classified based on histopathology (types I and II). Determining the risk of a patient to experience disease recurrence is important to decide which patients need adjuvant treatment. The current endometrial carcinoma risk assessment approaches fail to accurately classify patients into low-and high-risk groups. Several studies suggest that combining molecular characteristics with the current risk classification in EC may improve patients’ stratification and treatment decision-making. In this review, we describe how evolving molecular trends can be used as prognostic factors to identify high-risk EC subpopulations. We also look at how the most recent patient-derived models can help researchers find new possible targets and treatments for EC patients.Endometrial carcinomas (EC) are the sixth most common cancer in women worldwide and the most prevalent in the developed world. ECs have been historically sub-classified in two major groups, type I and type II, based primarily on histopathological characteristics. Notwithstanding the usefulness of such classification in the clinics, until now it failed to adequately stratify patients preoperatively into low- or high-risk groups. Pieces of evidence point to the fact that molecular features could also serve as a base for better patients’ risk stratification and treatment decision-making. The Cancer Genome Atlas (TCGA), back in 2013, redefined EC into four main molecular subgroups. Despite the high hopes that welcomed the possibility to incorporate molecular features into practice, currently they have not been systematically applied in the clinics. Here, we outline how the emerging molecular patterns can be used as prognostic factors together with tumor histopathology and grade, and how they can help to identify high-risk EC subpopulations for better risk stratification and treatment strategy improvement. Considering the importance of the use of preclinical models in translational research, we also discuss how the new patient-derived models can help in identifying novel potential targets and help in treatment decisions. EC is the most commonly diagnosed malignancy in post-menopausal women. The highest incidence is seen between 55 and 64 years ,2. It isEarly onset of signs and symptoms such as postmenopausal bleeding or spotting in 80% of patients leads to early diagnosis of endometrial cancer, where treatment efficacy is high. When compared to an advanced stage, these tumors are mostly diagnosed as FIGO  stage I or II, with a 5-year overall survival (OS) rate ranging from 74–97% ,10,11. AEC is traditionally divided into two main categories, type I and type II EC, which can be distinguished clinically, morphologically, histologically, and genetically. Type I ECs, commonly referred to as endometrioid EC (EECs), represent up to 80% of the newly diagnosed cases and account for 15–20% of recurrences. They are typically low-grade tumors associated with perimenopausal obese women. They are also hormone-dependent with a favorable prognosis (85% 5 years OS rate) .Non-endometrioid ECs make up the majority of Type II ECs. They are more common in elderly women and are usually hormone-independent. This is a less common group 10–20%), but it is associated with a higher risk of disease recurrence and a poor prognosis (25–60% 5 years OS rate) 0–20%, bu. The mosPhosphatase and tensin homolog (PTEN), Microsatellite instability (MSI), TP53 Tumor protein (TP53), Polymerase ɛ (POLE), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), Catenin beta 1 (CTNNB1), AT-rich interaction domain 1A (ARID1A), KRAS proto-oncogene, GTPase (KRAS), Fibroblast growth factor receptor 2 (FGFR2), F-box and WD repeat domain containing protein 7 (FBXW7), Protein Phosphatase 2 scaffold subunit A alpha (PPP2R1A), Lysine Methyltransferase-2B (KMT2B), CCCTC-binding factor (CTCF), Chromodomain helicase DNA-binding protein 4 (CHD4), Ribosomal protein L22 (RPL22), AT-rich interaction domain 5B (ARID5B), CUB and Sushi multiple domains 3 (CSMD3), Collagen Type I Alpha 1 Chain (COL1A1), Human epidermal growth factor receptor 2 (HER2), Estrogen receptor (ER), progesterone receptor (PgR), Epithelial cadherin (E-cadherin), and Epidermal growth factor receptor (EGFR).In EC patients who are classified as low- or low-intermediate risk, surgery  is usually recommended ,19,20. AIn this review, we will briefly discuss the four major EC molecular subtypes described by TCGA, their prognostic relevance, and future development. In addition, we will discuss the potential reclassification of high-risk ECs (HR-ECs) using molecular characterization for better patient stratification. Treatment benefit, clinical implication, and future trends in EC management based on molecular classification will also be summarized. We will also outline the importance of molecular characterization in pre-clinical models.The use of the traditional risk assessment alone lacks the power to adequately preoperatively stratify patients into low- or high-risk groups for surgical planning and adjuvant treatment. This may result in over- and under-treatment of patients, which may have an impact on the results of various clinical trials because treatment is typically given to patients based on their risk categories. ,34. Inte. However, their work had some limitations such as the use of: (1) expensive and impractical methods for routine clinical practice, and (2) fresh-frozen tumor samples, requiring special sample handling, making it difficult for every hospital to perform such analysis for every patient. To overcome these limitations, two research teams developed practical and cost-effective molecular classifiers to aid in better risk classification of EC. Firstly, the ProMisE  study used immunohistochemistry for mismatch repair proteins, TP53 Tumor protein (p53), and POLE as surrogates of molecular markers and risk-stratified a large cohort of young women (n = 319) of less than 50 years of age and defined prognosis in this cohort [The TCGA research network project used whole genome sequencing, exome sequencing, microsatellite instability (MSI), and copy number analysis in 373 EC cases . The TCGTable 2s cohort . SecondlThe TCGA molecular classification was performed on tumors from the two most frequent histological subtypes, endometrioid, and serous EC (307 endometrioid and 53 serous). To molecularly characterize other histotypes, other studies have proven that the four main molecular classifications in EC may be applied to, and may also be clinically relevant for, other rare histological subtypes such as undifferentiated/dedifferentiated, clear cell EC’s and carcinosarcomas ,46,47,48In assessing the prevalence of the TCGA molecular subgroups across tumor grades, a systematic review and meta-analysis by Travaglino et al. in EEC reported that G1–2 EECs are predominantly in the CNL subgroup (63.5%), followed by the MSI subgroup (24.7%), the POLE-mt subgroup (6.2%), and the CNH subgroup (4.7%). G3 EECs were mostly seen in the MSI subgroup (39.7%), followed by the CNL subgroup (28%), the CNH subgroup (21.3%), and the POLE-mt subgroup (12.1%) .In similar studies where both grade and histology across the four molecular subgroups were analyzed, it has been reported that most G1–2 associated with CNL (84.4%), followed by POLE-mt group (60.4%), the MSI group (52.6%) and lastly the CNH (10%). On the other hand, CNH constituted most of the G3 (90%), followed by MSI subgroup (47.4%), the POLE-mt group (39.6%), and then the CNL subgroup (15.6%) . In termp = 0.000001), respectively [In applying molecular features in G3 EEC, four prognostic subgroups were identified. The 5-year recurrence-free survival (RFS) rates reported were as follows: POLE-mt 96%, MSI 77%, CNL 64%, and CNH 47%  endometrioid (type I) FIGO stage IB grade 3 tumors (type I/G3ECs), (2) non-endometrioid tumors (type II), (3) advanced stages of any histological type, and (4) presence of lymphovascular space invasion (LVSI) ,9. In adp < 0.001) [p < 0.001). The same trend was seen with OS at 5 years: 98% for POLE-mt, 88.5% CNL, 81.3% for MSI and 54.0% for CNH (p < 0.001). Regarding treatment outcome, the 5 year RFS with chemoradiation vs. radiotherapy alone was 59% vs. 36% (p = 0.019) for patients classified as CNH. The POLE-mt group did well regardless of treatment group; 100% vs. 97% (p = 0.637). Similar survival was seen in both treatment groups for MSI tumors; 68% vs. 76% (p = 0.428), and 80% vs. 68% (p = 0.243) for CNL [Various predictive models have indicated the influence of molecular subtypes on prognostic relevance within HR-EC. ,56,57,58< 0.001) . Léon-Ca< 0.001) , identifp  =  0.0002). They reported that, although the markers  alone within the four molecular subgroups were not prognostic, δ-H2AX+ expression within CNL  and DNA-pk+/FANCD2 within the CNH group  significantly predicted poor disease free survival [Another group, using DNA damage response biomarkers to further reclassify the HR group, identified five prognostic subgroups within this population from best to worst prognosis: (1) group 1 “POLE mutated/Microsatellite unstable” > (2) group 2 “no specific molecular profile with no DNA damage” > (3) group 3 “TP53 mutated/Non-Homologous End-Joining negative” > (4) group 4 “no specific molecular profile with high DNA damage” > (5) group 5 “TP53 mutated/Non-Homologous End-Joining positive”; survival . These rDespite the disappointing outcomes of some clinical trials in HR-ECs ,62,63, tMSI tumors, like POLE-mt, are immunogenic, explaining the increased interest in immunotherapy in the MSI group ,70,71. FIn addition to approximately 90% mutation in the TP53 gene in CNH, overexpression of epidermal growth factor receptor 2 (HER2) has been observed in this subgroup . In addiThe CNL subgroup, which lacks a distinct molecular pattern, is distinguished by a low mutational burden and is associated with a poor prognosis. Mutation of CTNNB1 is one of the most common molecular changes in this subgroup . AlthougSome retrospective studies revealed a potential impact of the molecular-based classification of EC on EC patients in the clinics. ESGO and ESTRO have recommended a new molecular-based clinicopathological risk stratification system for adjuvant treatment , where PThe ongoing randomized PORTEC-4a trial  is the first and only clinical trial that is investigating the use of an integrated clinicopathological and molecular risk profile for adjuvant therapy selection in stages I–II high-intermediate risk EC patients. . Other pIn general, PORTEC trials lack data on prognosis based on tumor staging, either by lymphadenectomy or sentinel lymph node staging prior to EBRT administration. Nonetheless, the ongoing randomized PORTEC-4a clinical trial  on molecular risk stratification may help guide adjuvant treatment decisions for better treatment strategy and patient management.Apart from histology, EC heterogeneity is reflected in genetic expression/alteration and other altered genetic pathways. HR-EC is associated with mutations in NRAS, APC, SMAD4, and expression of PD-L1/2, in addition to some of the genetic alterations listed in Treatment response with the mTOR inhibitor temsirolimus in women with recurrent or metastatic EC, for example, has been tested in patients with mutated PTEN. In particular, 14% of 20 women who had not previously undergone chemotherapy showed a partial response and 69% had stable disease, whereas 4% of 25 women who had previously received chemotherapy showed a partial response and 48% had stable disease. When compared to single-agent chemotherapeutic or hormonal agent regimens, 17% of the patients experienced disease progression under temsirolimus .p = 0.006). In addition, multivariate analysis revealed that ARID1A alterations predicted longer PFS after the checkpoint blockade (HR (95% CI), 0.61 (0.39 to 0.94), p = 0.02) [In another study looking at the expression of ARID1A in various solid tumors, including EC, patients with ARID1A-mutated tumors had significantly longer median PFS after anti-PD-1/PD-L1 immunotherapy than patients with ARID1A wild-type tumors  . As a reA modest clinical efficacy in EC patients with PD-L1 positive tumors treated with pembrolizumab has also been reported. In a phase Ib trial, 24 patients with PD-L1 positive recurrent metastatic EC were included in the study, and, after pembrolizumab treatment, the ORR was 13%. . Figure The use of various preclinical models to enable potential drug target identification and also guide novel effective drug development is the pivot in EC research . PatientSeveral studies in PDX and organoid models have demonstrated how these models, both histologically and genetically, resemble the primary tumor ,95,96,97For example, Urick and Bell identified for the first time PADI2 (peptidyl arginine deiminase 2) as a novel therapeutic target for these tumors’ analysis of FBXW7 in serous EC cells . In anotDepreeuw et al. established and characterized a panel of 24 EC PDX models. In one model derived from a patient who had previously received multiple lines of chemotherapy with PTEN, PIK3CA, and KRAS mutations, combining NVP-BEZ235  and AZD6244 (MEK1/2 inhibitor) treatment, resulted in stable disease . FurtherA drug screening performed in EC patients-derived organoid cultures identified menin-MLL inhibitor (MI-136), as a potential therapeutic target for endometrial cancer due to its regulation of the HIF pathway . PaclitaThere is no doubt that patient-derived preclinical EC models have paved the way for drug screening and novel drug development in ECs, but these models could be further improved. The way forward could be to molecularly risk-stratify these models into various risk categories and then test a treatment regimen based on their molecular profile. These preclinical findings will then be used to determine which drugs may perform better clinically or could be tested on humans, facilitating the design of novel clinical trials.Treatment efficacy in EC, especially in the high-risk subgroup, has not yet shown satisfactory results, despite increased efforts in improving treatment strategy. Patient risk stratification is of utmost importance in assigning the most appropriate treatment regimen to avoid under- and or over-treatment of patients. The TCGA molecular classification of EC has added a risk assessment tool to the current risk stratification. In recent years, several retrospective studies after TCGA have indicated how incorporating molecular features or testing into traditional risk assessment may help in identifying the high-risk population, and further aid in reclassifying the HR-EC subgroup. Furthermore, the application of molecular or genetic risk profile in patient-derived EC preclinical models may facilitate the development and the evaluation of the efficacy of novel targeted drugs, as well as assist in identifying predictive/prognostic biomarkers to assess patient treatment response.


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Molecular medicine is emerged with the progression of life science, representing the third medicine revolution after clinical anatomy and experimental medicine in the last centuries. As a multidisciplinary field, molecular medicine integrates physics, chemistry, biology, and medical technology, which aims at deciphering the structural, molecular, and cellular mechanisms that drive pathogenic process and at developing molecular tools and interventions for the diagnosis, prevention, and treatment of human diseases. A milestone in molecular medicine is the launch of Human Genome Project (HGT) in 1990, promoting the advance of diverse subdisciplines including epigenetics, genomics, transcriptomics, proteomics, and metabolomics. As a result, many new pathogenic factors are uncovered in recent years, such as gene mutations in inherited disease, posttranslational modification in aging, and noncoding RNAs in cancer. 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