Since the discovery of conductive polyacetylene, conductive electroactive polymers are at the focal point of technology generation and biocommunication materials. The reasons why this research never stops growing, are twofold: first, the demands from the advanced technology towards more sophistication, precision, durability, processability and cost-effectiveness; and second, the shaping of conducting polymer research in accordance with the above demand. One of the major challenges in conducting polymer research is addressing the processability issue without sacrificing the electroactive properties. Therefore, new synthetic designs and use of post-modification techniques become crucial than ever. This quest is not only advancing the field but also giving birth of new hybrid materials integrating merits of multiple functional motifs. The present review article is an attempt to discuss the recent progress in conducting polymer grafting, which is not entirely new, but relatively lesser developed area for this class of polymers to fine-tune their physicochemical properties. Apart from conventional covalent grafting techniques, non-covalent approach, which is relatively new but has worth creation potential, will also be discussed. The aim is to bring together novel molecular designs and strategies to stimulate the existing conducting polymer synthesis methodologies in order to enrich its fascinating chemistry dedicated toward real-life applications. Conducting polymers are considered as the fourth generation of polymeric materials. The physicochemical properties inherited from typical polymeric materials combined with the fascinating electrical conductivity approaching metals in cases, brought this class of materials in the focal point of scientific research towards energy applications for decades ,3,4,5,6.−10 to 10−5 S cm−1, is converted into a polymer which is in the ‘metallic’ conducting regime (ca. 1 to 104 S cm−1).A key and unique property of a conducting polymer is the presence of conjugated double bonds along its backbone. However, conjugation alone is not enough to make a polymer conductive. The other prerequisite is that some charge carriers in the form of extra electrons or holes have to be injected into the material. Such doping not only induces carriers into the electronic structure but also leads carrier delocalization along the polymer chain and to charge carrier mobility, which is extended into three dimensions through interchain electron transfer . During The physicochemical properties of a conducting polymer crucially depend on several factors such as: the chemical identity of the monomer, molecular weight, presence of functional groups and side chains attached to the monomeric units, and even on the polymer conformation. On the other hand, the conduction property of the polymer is directly influenced by any factors affecting the electron delocalization along the main chain. Therefore, designing a conducting polymer is much more than only overcoming the synthetic complexity. Time to time functionalization of conducting polymers is perhaps more challenging compared to the synthesis of the parent molecules ,13. TherThe physicochemical property of a polymer can be engineered even more drastically by making a copolymer with another polymer or with the help of grafting. Conducting polymers as the components in block-copolymer systems have been reported for nanostructural control as alternative to lithography . HoweverThis review specifically aims to bring together the novel strategies built around conducting polymer grafting to stimulate the real-life applications of this class of materials. We will emphasize on key and recent report based on novelty in strategy, urgency in terms of application and variations in grafted materials. While covalent grafting is a more conventional approach noncovalent immobilization of polymeric counterpart with the parent polymer is no longer a fantasy either. Therefore, we will also discuss the importance and the essence of noncovalent grafting of conducting polymer with the help of limited examples. Ultimately, our goal will be to critically assess and demonstrate at the same time, how the power of grafting can revolutionize the fate of conducting polymer chemistry from academic interest to technology generation and biocommunication.The covalent approach for the synthesis of graft copolymers is the conventional method of grafting. It ensures a highest degree of property mixing among associated species and thus, offers the scope of material design as per the requirement. General methods to synthesize graft copolymers are of three types: (i) ‘grafting to’, (ii) ‘grafting from’ and (iii) ‘grafting through’  35]. In. In35]. graft–polyaniline via oxidative polymerization of aniline in acidic medium using ammonium persulfate (APS) catalyst (graft–poly(2-methoxyaniline) ethylmethacrylate (PTDU), which shows thermo-responsiveness in presence of halides and exhibits light induced conformational change. The thermoresponsive behavior was introduced to polythiophene backbone via ATRP of 2-(dimethylamino)-ethyl methacrylate (DMAEMA) from polythiophene macroinitiator (PTI) giving PTDU. Then, cationic PTDU was prepared by the quaternization of amine groups of DMAEMA with 6-chloromethyl uracil , reversible addition-fragmentation chain transfer polymerization (RAFT) is another popular and well accepted technique to develop a variety of conducting polymers-based brushes for wide range of applications. Grafting of side chains not only increases the solubility and processability of conducting polymers but also introduces modulation of properties by external stimuli such as temperature, pH, salt concentration, and electrical potential etc. Conducting polymer grafting can also be done by click reactions ,55. Usinl uracil . Attachmgraft–poly(ethylene oxide)(P3HT–g–PEO) copolymer. To synthesize this copolymer, random copolymer of 3-hexylthiophene (P3HT) and 3-(6-bromohexylthiophene) (P3HT-Br) were prepared via oxidative polymerization and treated with sodium azide (NaN3) to form azido-functionalized polythiophene. Finally, polythiophene–graft–poly(ethylene oxide) was synthesized from alkyne terminated PEO via alkyne-azide click reaction , followed by alkyne-azide click reaction between them. Using Kumada cross-coupling reaction thiophene-functionalized poly(vinyl chloride) (PVC) macromonomer (ThPVCM) was prepared by Massoumi et al. [2+/Cu+ catalyst system that allows polymerizations of both the backbone polythiophene and branched polymers in a single step , which after attachment with glucose oxidase (GOx) enzyme can act as a glucose sensor. For the synthesis, thiophene-functionalized polypeptide macromonomer by the N-carboxyanhydride (NCA) ROP was prepared first and then electropolymerization of the macromonomer was done. This biosensor was reported to possess better sensitivity and repeatability due to inhibition of leaching. Moreover, Guler et al. [g–polyphenylalanine (PTh–g–PPhe) and attached GOx to develop similar type of biosensor. Further, RGD was attached to the polyphenylalanine chains of this graft copolymer to promote better cell adhesion.Apart from the grafting of regular polymers people also use covalent grafting of polypeptide as an alternative approach to composite formation in order to prevent leaching of polypeptides from the scaffold materials. As for example, Akbulut et al.  preparedr et al.  synthesid,l-lactic acid) , poly(glycolic acid) (PGA) with conducting polymers has gained much attention as a novel approach. To summarize the developing research on the synthesis of conducting polymer-based biomaterials and improvement of their properties after grafting, very recently, Sliva et al. [In order to develop electroactive biomaterials for biomedical applications, grafting of biocompatible and biodegradable polymers such as poly(caprolactone) (PCL), poly macromonomer was synthesized using ROP of caprolactone. Then, PPy–g–PCL was achieved by oxidative polymerization of Py–g–PCL monomer. Recently, Sliva et al. [d,l-lactic acid) (PEDOT–co–PDLLA) as a scaffold materials for neuronal tissue engineering. The copolymers were synthesized via subsequent EDOT−PDLLA macromonomer production using ROP of lactide in presence of EDOT-OH, followed by chemical copolymerization of EDOT monomers.Apart from the oligomer approach macromonomer approach is also very effective for the development of degradable conducting graft copolymers. To exemplify, PCL grafted PPy was synthesized by Guo et al.  aiming ta et al.  reportedIn recent years, the development of all-conjugated donor-acceptor based polymer solar cell has gained high attention because the presence of both donor and acceptor segments in a single polymer chain can contribute easily to fabricate high performance solar cell. The general methods for the synthesis of all-conjugated donor-acceptor graft copolymers are beautifully summarized in a mini-review article by Wang et al. . The synThe above examples give a good idea about how the covalent grafting of conducting polymers are a steadily growing area. The key issue in this effort is to define the purpose of grafting. The nature of grafted materials entirely depends on that purpose. Therefore, the same conducting polymer backbones are being grafted with various polymeric or oligomeric materials. In the covalent grafting approach, the grafted materials have a high degree of contribution to the overall system. Therefore, complementarity in property and function makes this approach unique.The term grafting more commonly refers to a covalent attachment to the polymer backbone. However, in cases, covalent grafting might have its own demerit too. Complex synthetic design and modification techniques, undesired property modification, irreversible nature of attachments, are a few key issues which prompted chemists to think about a more adaptive approach. Such concerns give birth to an entirely unconventional grafting strategy where the associated components stay together via noncovalent bonding. Therefore, one might also term this as supramolecular grafting.To date, there are only a few reports on supramolecular grafting with nonconducting polymer, which for example, utilized quadruple hydrogen bond formation , and hosMw 550 was used as the hydrophilic chain of the dopant, the doped polymer was soluble in water, NMP and chloroform [g–poly(methacrylic acid) (PTMA) was prepared by ATRP of tert-butyl methacrylate upon a polythiophene backbone followed by hydrolysis of tert-butyl groups. The resultant grafted polythiophene acted as both a template and a dopant for the synthesis of PANI nanostructures by oxidative polymerization of aniline. A nanorod hybrid morphology was observed up to a 1:10 composition . On the other hand, for 1:20 composition a helical nanorod was produced along with some small size spheroids. The hybrids were semiconducting in nature and exhibited reproducible photoconductivity by alternate “On” and “Off” switching of white light. Polymerization of adsorbed aniline on the surface of the micellar polythiophene moiety has been postulated and considered responsible for helical PANI chain and variable morphology based on the relative ratios of involved conducting polymer components  by phosphonic acid containing hydrophilic tail. When poly(ethylene glycol) monomethyl ether (PEGME)with molecular weight loroform . Free-stloroform . The thiloroform . In thismponents .A similar approach involving supramolecular polar interaction could be adopted to form other conducting polymer hybrids. Electrostatic interaction between cationic conducting polymer and anionic biopolymer like DNA has been used successfully to align two polymeric materials. The key difference with conventional grafted system is that here the attachment is multipoint along the parent polymer backbone. A supramolecular hybrid formation between poly(o-methoxyaniline) (POMA) and DNA was utilized by this author as a tool for the formation of semiconducting DNA hybrid and POMA radical cation stabilization. An uncoiling of POMA chain on the DNA template facilitated by the attractive interaction between DNA anion and POMA radical cation and repulsive interaction among POMA radical cations was key event involved in this stable hybrid formation ,82,83. SUtilizing a similar electrostatic protocol, polyaniline-poly(styrene sulfonate) (PANI-PSS) hydrogels have been developed by Dai et al. . A hieraIn addition to polar interaction, solvophobic interaction can be a leading driving force for supramolecular association. Shinkai and co-workers pioneered in using β-1,3-Glucan polysaccharides as novel one-dimensional hosts for various species including conducting polymers . In one As mentioned earlier, the hypothesized effectiveness of supramolecular grafting lies in its minimal interference with the electronic and electrical properties of conducting polymer. Therefore, a host-guest interaction mediated grafting strategy could be promising technique because of two key reasons: first, nonpolar nature of attachment will ensure retention of electronic property along the conducting polymer backbone; and second, strong host-guest binding could reproduce the close association of covalent grafting for significant property mixing. To the best of our knowledge, the only work of supramolecular conducting polymer grafting in its true sense is reported by these authors, where PANI was grafted with PEG coupled with b-cyclodextrin (βCD-PEG) forming a pseudorotaxane with the aniline moiety . The supAuthors believe that in supramolecular grafting the synchronization of additive approach and adaptive behavior can revolutionize polymer modification techniques to address multiple issues associated with processability and device fabrication based on conducting polymers. Finally, the non-covalent mode of attachment of the monomer implies that a strategy applied to one conducting polymer can potentially be employed for a wide range of conducting polymers.Grafting is undoubtedly a fascinating expansion of the conducting polymer family bridging its chemical assets with the real-world demands. Unparallel electronic and electrical property together with environmental responsiveness can couple sensibly with flexibility, processability and biocompatibility of nonconducting traditional polymeric systems to generate many breakthroughs in technology generation and biocommunication strategy. Apart from conducting and non-conducting polymer pair, association or co-assembly of multiple conducting polymers in the same system could also be an excellent extension of the above chemistry.


The formation of the vertebrate vasculature involves the acquisition of endothelial cell identities, sprouting, migration, remodeling and maturation of functional vessel networks. To understand the cellular and molecular processes that drive vascular development, live-imaging of dynamic cellular events in the zebrafish embryo have proven highly informative. This review focusses on recent advances, new tools and new insights from imaging studies in vascular cell biology using zebrafish as a model system. Vascular development is an early and essential process in the formation of a viable vertebrate embryo. Blood and lymphatic vascular networks are composed of a complex mix of cell types: for example smooth muscle cells, fibroblasts, pericytes and immune cells are intimately associated and even integrated within mature vessel walls . The innin vivo. New cellular labels have been developed , T-cell acute lymphocytic leukemia 1  and fli1 proto-oncogene, ETS transcription factor a (fli1a). In addition to genetic analyses, recent studies have used dynamic imaging of cell behavior as angioblasts migrate to the midline to give rise to the dorsal aorta (DA) and the posterior cardinal vein (PCV).Vascular development is typically thought of as occurring in a stepwise manner progressing through vasculogenesis, angiogenesis, lymphangiogenesis, vessel remodeling, and maturation. Vasculogenesis involves the initial formation of the major vessels in the embryonic midline from angioblasts that originate in the LPM . In zebrci1Tg(etv2:EGFP) transgenic line, Kohli and colleagues observed that two distinct medial and lateral angioblast pools migrate to the midline separately and sequentially (ci6Tg(etv2:kaede), the angioblast populations could be labeled in a spatially and temporally controlled manner with Kaede um43Tg(tp1:creert2) transgenic line to label Notch-signaling active ECs, revealed that all Notch active early angioblasts contribute to the DA but not the PCV /Kdrl  signaling is essential for angioblast migration . In the  midline . Howeverebrafish . In an eebrafish  are requebrafish . Angiobligration .Studies of the dynamic process of angioblast migration from the LPM have significantly improved our understanding of vasculogenesis, yet much remains to be understood. Recently, lineage tracing somite cells using the Kaede protein and Cre/loxP technology revealed that a subset of somite cells termed endotome give rise to angioblasts that colonize the DA . How thiOnce the DA and the PCV are formed at around 22 h post-fertilization, ECs sprout from the DA and migrate to form the ISVs, a process termed primary angiogenesis . In thisdll4 in tip cells zf415Tg transgenic line, which expresses a Ca2+ indicator in ECs  transgenic line, ECs were fluorescently labeled as they progress through S/G2/M phase of the cell cycle (ncv6Tg(kdrl:nlsEos) transgenic and a GFP-tagged alpha tubulin construct revealed differences in daughter cell size post tip-cell mitosis that were due to asymmetric cytoplasm redistribution , which is only expressed in ISV ECs when they are sprouting. To ask whether Tm4sf18 is a novel amplifier of Vegfa/Kdr/Kdrl signaling, embryos were treated with a suboptimal dose of Vegfr inhibitor to force the ECs to rely on the proposed positive feedback mechanism. EC dynamics during ISV sprouting in tm4sf18 mutants were then analyzed. Consistent with Tm4sf18 being an amplifier of Vegfa/Kdr/Kdrl signaling, tm4sf18 mutants had delayed emergence of both tip and stalk cells from the DA. tm4sf18 mutants also showed delayed recovery of Vegfa/Kdr/Kdrl/Erk signaling after brief treatment of Vegfr inhibitor  transgenic line that expresses F-actin-binding peptide LIFEACT tagged with EGFP in ECs  and the microenvironment in angiogenesis, have received less attention than EC autonomous mechanisms, with imaging the ECM a particular challenge. Using forward genetic screening, transmembrane protein 2 (Tmem2) was found to be required for both primary angiogenesis and hyaluronic acid (HA) turnover in the ECM . When HAturnover . The useturnover . A produturnover . Importa mutants . Consist mutants . Thus, tOnce ISVs and the DLAV are formed, a second wave of angiogenesis, termed secondary angiogenesis, commences from the PCV from around 32 hpf . Secondabns9Tg(fli1:Has.B4GALT1-mCherry) transgenic, which labels endothelial Golgi, revealed that most ECs polarize against flow, resulting in most aISV ECs having a ventral polarity, while most vISV ECs have a dorsal polarity  is expressed preceding secondary sprouting in a subset of venous ECs, largely along the dorsal wall of the PCV  transgenic line revealed that a subset of PCV ECs expressing prox1a in the PCV display distinctive behaviors preceding sprouting  strain during ISV lumenization. They found that lumen expansion is driven by flow-induced hemodynamic forces that drive formation of highly dynamic apical membrane protrusions into the cell body, a mechanism they termed “inverse blebbing” ubs5Tg(fli1a:GAL4FF) line, which expresses the EGFP tagged junctional protein Zona Occludens 1 (ZO1), revealed that the initial contact site between filopodia form ZO1-positive junctional spots. These initial contacts dynamically elaborate into junctional rings as the mutual surface area between the tip cells increases  . The firncreases . A similncreases . Apart fncreases . The fornections . This real spots .Live imaging has thus revealed how junctional rings are formed and how key molecules regulate this process. Following the formation of junctional rings, junctional remodeling and lumenization commence, which involves either ECs migrating over each other to form elongated junctional rings and a multicellular lumen, or lumen extension through via membrane invagination to form a unicellular lumen . For a dAs discussed above, a key step in formation of a mature multicellular tube is elongation of initial junctional rings between ECs . High-reuq11bhTgBAC(cdh5:cdh5-TFP-TENS-Venous) transgenic vessels, which express a FRET-based Ve-cadherin tension sensor at the junctions, revealed that the Ve-cadherin tension in DA EC junctions decreases progressively during this vessel maturation process  transgenic line that expresses ciliary axoneme GTPase ADP ribosylation factor-like GTPase 13B (Arl13b) tagged with GFP revealed that endothelial primary cilia bend in response to flow and local mechanical forces ] (ci6Tg(etv2:EGFP) transgenic strain demonstrated that the VA-As migrate as a string of cells and do not connect to a lumenized vessel prior to connecting to the facial lymphatic sprout ] . Dynamicc sprout . Unlike c sprout .lyve1b, flt4, mrc1a, and prox1a  and fluorescent granular perithelial cells (FGPs)], which express lymphatic markers such as d prox1a . These ed prox1a . Therefod prox1a , perhapsin vivo cell biology.Overall, the above examples of venous derived tip cells contributing to arteries, novel vascular structures, unique contributions to developing vasculature and vessels giving rise to potentially non-vascular cells, all serve as examples of the plasticity and heterogeneity of the vasculature. Of particular note, these studies all relied upon the utility of the zebrafish model for live-cell imaging and dynamic in vivo systems is essential. With the unique attributes of the zebrafish for cellular imaging, continued advancements in microscopy and the expanding numbers of transgenic tools available, we can expect that future efforts will lead to unprecedented resolution of the cellular and molecular mechanisms controlling dynamic EC development and maturation. Live imaging of EC behaviors, analysis of cellular heterogeneity, organ-specific vessel formation and function is expected to continue to uncover novel mechanisms in the future. Moreover, the development of disease models for a range of vascular pathologies coupled with application of the approaches discussed in this review, offer exciting prospects to understand disease biology and generate new therapeutic avenues.In recent years, a combination of developmental genetics and live cell imaging using the zebrafish as a model system, have uncovered highly conserved molecular mechanisms in vascular development and led to a deeper understanding of the EC phenotype. Deciphering molecular mechanisms in blood and lymphatic vessels during development and pathogenesis has increasingly pushed the boundaries of genetic and genomic studies. This is partly motivated by new techniques and opportunities, such as single cell RNA-seq and CRISPR-based gene editing. While new genetic approaches will allow us to resolve the transcriptional changes associated with single cells and to manipulate any gene in the genome, it will become increasingly important to understand how genetic changes influence the cellular phenotype. Understanding phenotype in physiologically intact KO wrote the manuscript and designed the figures. BH reviewed and edited the text and figures. Both 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.


This study investigates a pressing topic, related to the connection betweenemployees’ perceptions that the COVID-19 pandemic represents a pertinent threatfor their organization on one hand, and their exhibited creativity, a criticalbehavior through which they can change and improve the organizational statusquo, on the other. This connection may depend on their work-related taskconflict, or the extent to which they reach out to colleagues to discussdifferent perspectives on work-related issues, as well as their collectivisticorientation. Data were gathered from employees working in the real estatesector. The results inform organizational practitioners that they shouldleverage productive task conflict to channel work-related hardships, such asthose created by the coronavirus pandemic, into creative work outcomes. Thisbeneficial process may be particularly effective for firms that employ peoplewho embrace collectivistic norms, so they prioritize the well-being ofothers. Experiencing adverse, resource-depleting work situations can frustrate employees. Itundermines the quality of their personal well-being, their professional functioning,and even their future career prospects . In manyTo answer these real-world challenges, this study investigates a specific behavioralresponse to perceived pandemic threats—defined as the extent to which employeesruminate on the negative organizational impact of the coronavirus—namely, engagingin productive idea clashes with organizational colleagues . Work-reWe also anticipate that the benefits of work-related task conflict are particularlyprominent among employees with strong collectivistic orientations . TheseeTo ground our somewhat unconventional, theoretical arguments about the beneficialrole of employees’ perception of pandemic threats in spurring creativity, wedraw on conservation of resources (COR) theory . This thFurthermore, COR theory posits that personal factors invigorate this process. Forexample, resource gains might result from the personal satisfaction thatemployees feel when they can formulate adequate behavioral responses to problems. We spechow employees’ beliefs about the coronavirus’simpact can stimulate their creativity. It occurs through their dedicated effortsto involve colleagues in productive discussions and clashes, in efforts toprotect the organization from external threats . Women tend toavoid conflict more than men, so they might shy away from exchangingpossibly controversial, conflicting viewpoints  and organizational tenure below its mean, at its mean, and one SD above its mean. In linewith the proposed theoretical framework, we ran the Process macro’s Model 7, toestimate the moderating effect of collectivistic orientation on the path betweenperceived pandemic threats and work-related task conflict but not betweenwork-related task conflict and creativity.1The Process macro approach  providesp < .001, Hypothesis 1), which spurscreativity . The effect sizeof .297 for the indirect relationship between perceived pandemic threats andcreativity through work-related task conflict and a CI that does not include 0 provide evidence of the presence of mediation (Hypothesis 3).p < .01,Hypothesis 4) in predicting work-related task conflict. In particular, the Processmacro findings reveal that the relationship between perceived pandemic threats andwork-related task conflict is stronger at higher levels of collectivisticorientation . We test for the presence ofmoderated mediation (Hypothesis 5) by comparing the strength of the conditionalindirect relationship between perceived pandemic threats and creativity (throughwork-related task conflict) at different levels of collectivistic orientation. SD below the mean, to .200 at the mean, to .246 at oneSD above the mean. With a formal test of moderated mediation,which assesses the index of moderated mediation and its corresponding CI (The findings in nding CI , we findThis research is motivated by an important and timely topic: How does the COVID-19crisis interfere with organizational life, and how do employees respond in thecourse of their work? We examine the link between perceived pandemic threats andcreativity levels, with specific attention to two factors that help explain thislink. Consistent with the logic of COR theory , we theoExtant research normally focuses on the harmful effects of life-threatening events. But as This mediating effect of work-related task conflict is reinforced by collectivisticorientations, because people with such world views gain additional resources, suchas joy and satisfaction, from engaging with colleagues in productive idea clashes. They anhow andwhen employees’ preoccupations with the COVID-19 pandemic andits impacts might enhance their work behaviors. First, employees’ activeparticipation in work-related disagreements is an important mechanism that linksbeliefs about the detrimental impacts of the pandemic for organizationalfunctioning, as a work hardship, with increased creativity levels. Second, concernsabout collective well-being, instead of personal interests, fuel this process.Taken together, these results offer valuable insights into This study has some limitations; they offer opportunities for continued research.First, some care is required with regard to the presence of reverse causality.For example, creative behaviors could increase employees’ awareness of thedifferent skills that their colleagues possess, which might influence theirperceptions about pandemic-evoked work challenges. Measuring these constructsover time could provide a formal test of their causality. Still, our conceptualframework reflects the widely used COR framework, in which employees react toresource-draining circumstances with activities to avoid additional resourcelosses . FurtherSecond, as must any parsimonious study, we ignored alternative possiblemechanisms. Our focus on task conflict acknowledges arguments that it cantransform resource-draining situations into positive outcomes .Other bcontextual factors couldcatalyze the relationship between perceived pandemic threats and work-relatedtask conflict, including perceived person–organization fit (Third, a collectivistic orientation is highly relevant for this study. It alignsclosely with the idea that collectivist employees feel motivated to react tocrises with resource-gaining work efforts to help the organizational collective.But continued research could consider other relevant personal resources, such asresilience  or passition fit  or psychtion fit .Researcstrength of the relationships might vary with pertinentcultural factors. Notably, Portugal scores high on both uncertainty avoidanceand collectivism (comparisons should explicitly examinethe potential effects of cultural features in the proposed conceptualframework.Fourth, our conceptual arguments are not country-specific, and we expect that thenature of the hypothesized relationships should apply broadly, even if theectivism . EmployeMost employees today sense some threat related to the COVID-19 pandemic,prompting significant preoccupation about their current and future workfunctioning, as well as negative implications for their professional well-being. We idenassignments to specific job tasks and projects, includingthose that involve increased exposure to the coronavirus. For example, outsidesales representatives must meet with clients, so they suffer more exposure tothese dangers than do back-office support staff who can work completely fromhome. Arguably, collectivistic employees in jobs that involve greater pandemicthreats may be particularly dedicated to combining knowledge throughout theorganization, to come up with creative solutions to minimize their own andothers’ risks. Such assignments ultimately might increase the chances that theorganization overall finds creative solutions to the work-related harmsinflicted by the pandemic.Some employees may be especially well positioned to engage with colleagues inthis productive work-related task conflict, whether during a pandemic or ingeneral. When employees genuinely seek collective instead of personal interests, they arThis study has sought to advance understanding of the interplay between the currentCOVID-19 crisis and an organization’s internal functioning, though the implicationscan speak to other types of crises and difficult work conditions too. Employees’worries about the negative organizational impact of the crisis can triggercreativity, to the extent that they seek to overcome the resource-draining situationby pursuing constructive conflict and integrating different viewpoints to craftpertinent solutions. This beneficial role of work-related disagreements appearscontingent on employees’ desire to help their organizational peers with theseefforts. Thus, this role is more powerful among collectivistic employees. As theCOVID-19 crisis persists, further studies should use our findings as a springboardand pursue additional insights into how employees’ dedicated work efforts mighttransform external threats to organizational well-being into beneficial outcomes, incombination with the influence of valuable individual features of employees.


Inflammatory myofibroblastic tumors (IMTs) are particularly rare tumors that have been described in various anatomic locations, of which the urinary bladder is the most common. These benign tumors are amendable to conservative therapy but are notoriously difficult to diagnose given their mimicry of malignant sarcomas and sarcomatoid carcinomas, making an accurate diagnosis paramount to spare a patient radical and unnecessary treatment. We hereby present the case of a 37-year-old female patient who was diagnosed with an IMT of the urinary bladder during workup for painless gross hematuria. Patient was successfully managed with a laparoscopic partial cystectomy and is free of recurrence 5 years after surgery. IMTs are rare benign tumors that share the same clinical presentation as malignant bladder tumors. Deep biopsy and experienced pathologist are crucial in establishing diagnosis and avoiding patient radical treatment. This case is a classical demonstration of a remarkably rare tumor that was adequately managed with conservative therapy, achieving excellent clinical outcomes. Inflammatory myofibroblastic tumors (IMTs) are particularly rare tumors that have been described in various anatomic locations such as the lungs, pancreas, bladder, and prostate –5. FirstA 37-year-old female, nonsmoker, presented to our institution for painless gross hematuria. She had no previous history of abdominopelvic surgery, urinary or gynecologic instrumentation, nor any history of recurrent or chronic urinary infections. Physical examination and serum biochemical investigations were unremarkable. Urine analysis and microscopy revealed numerous morphologically normal red blood cells with the presence of inflammatory cells. Significant wall thickening of the right lateral wall of the urinary bladder centered around a 2 × 2 cm exophytic mass was seen on computed tomography (CT) scan, as seen in Histologic analysis of the resection fragments revealed evidence of ulcerations in the urothelium with submucosal proliferation of fusiform spindle cells with mild cytonuclear atypia and minimal mitotic activity in a richly vascularized and edematous myxoid stroma. Certain foci of necrosis were noted. A dense inflammatory infiltrate composed of lymphocytes, polynuclear neutrophils, and polynuclear eosinophils was present in the tumoral tissue . ImmunohGiven the histologic features and the immunohistochemical profile, diagnosis of a pseudosarcomatous myofibroblastic tumor of the urinary bladder was made. The patient successfully underwent a laparoscopic partial cystectomy to resect the remaining tumor mass . HistoloNonepithelial tumors of the urinary bladder make up 2% to 5% of primary neoplasms of the bladder . InflammPathologically, IMTs are described as gray-white or tan-yellow firm well-circumscribed lesions with sizes ranging from 1 to 20 cm and a variable degree of focal necrosis, hemorrhage or cystic changes, or calcification . A crossThe immunohistochemical profile of IMTs often overlaps with other malignancies, which makes the diagnosis of an IMT more difficult. In general, IMTs stain positive for vimentin, desmin, smooth muscle actin, muscle-specific actin, and keratin . ALK posClinically, IMTs are slow-growing benign tumors that are amendable to conservative treatment , 3. GeneIn conclusion, inflammatory myofibroblastic tumors are remarkably rare nonepithelial benign neoplasms of unknown pathogenesis that presents similarly to malignant diseases. These tumors present a diagnostic challenge due to the overlap of histologic and immunohistochemical features seen in malignant neoplasms such as leiomyosarcoma, embryonal rhabdomyosarcoma, carcinoid sarcoma, and other malignant soft tissue neoplasms. Certain histologic and immunohistochemical findings are somewhat specific to IMTs which aids in differentiating them. A deep transurethral resection biopsy and an experienced pathologist are paramount in establishing the diagnosis and avoiding the patient radical treatments. The standard of care is surgical resection with negative margins with chemotherapy and radiotherapy reserved for unresectable or incompletely resected tumors. These tumors generally do not recur or metastasize; however, cases of recurrence or metastasis have been reported. Our case is a classical demonstration of an IMT discovered in a 37-year-old female managed with a laparoscopic partial cystectomy and remains recurrence free after 5 years.


Integration of genomic technologies with breeding efforts have been used in recent years for chickpea improvement. Modern breeding along with low cost genotyping platforms have potential to further accelerate chickpea improvement efforts.The implementation of novel breeding technologies is expected to contribute substantial improvements in crop productivity. While conventional breeding methods have led to development of more than 200 improved chickpea varieties in the past, still there is ample scope to increase productivity. It is predicted that integration of modern genomic resources with conventional breeding efforts will help in the delivery of climate-resilient chickpea varieties in comparatively less time. Recent advances in genomics tools and technologies have facilitated the generation of large-scale sequencing and genotyping data sets in chickpea. Combined analysis of high-resolution phenotypic and genetic data is paving the way for identifying genes and biological pathways associated with breeding-related traits. Genomics technologies have been used to develop diagnostic markers for use in marker-assisted backcrossing programmes, which have yielded several molecular breeding products in chickpea. We anticipate that a sequence-based holistic breeding approach, including the integration of functional omics, parental selection, forward breeding and genome-wide selection, will bring a paradigm shift in development of superior chickpea varieties. There is a need to integrate the knowledge generated by modern genomics technologies with molecular breeding efforts to bridge the genome-to-phenome gap. Here, we review recent advances that have led to new possibilities for developing and screening breeding populations, and provide strategies for enhancing the selection efficiency and accelerating the rate of genetic gain in chickpea. Cicer arietinum L.) is one of the most economically important food legume crops. It is grown on an estimated 14.56 Mio. hectares, producing 14.78 Mio. tons in more than 55 countries of the world  to the soil through N2 fixation  technology have considerably curtailed sequencing costs . NAM and MAGIC populations are expected to accelerate the efforts of identification, isolation and transfer of key candidate genes to facilitate chickpea improvement.NAM populations are developed to increase the precision of QTL mapping by combining the strengths of bi-parental mapping populations and association mapping to efficiently capture rare alleles and enhance the chances of identifying novel genomic loci contributing to the trait of interest  was developed to cater for this need using RNA-Seq data from different organs and plant developmental stages of drought-tolerant cultivar ICC 4958 , of which 97 were common for both the genotypes  and FLIP 97-196C  under salt stress identified proteins associated with photosynthesis, stress responsiveness, and protein synthesis and provided novel insights into the salt tolerance mechanism in chickpea  populations  under the ambit of Excellence in Breeding (EiB). This genotyping approach is expected to be extremely useful for remotely located breeding units or those devoid of DNA extraction facilities. The implementation of such small SNP panels for tasks such as early generation screening, seed purity confirmation and identification of true F1s in chickpea breeding programmes is expected to increase in the future.Genotyping using high-density genotyping arrays can be very costly when large breeding populations needed to be genotyped for MAS, backcross breeding, gene tagging and QC analysis. For such applications, few markers are required, and therefore, single-plex high-throughput platforms like KASP, TaqMan and 10-SNP panel are more suitable. For chickpea, cost-effective KASPar assays  have been nicely described by Hurgobin and Edwards . PangenoThe current genomics landscape of chickpea has provided an opportunity to perform high-resolution genetic mapping. In the post-genomics era, sequencing-based trait mapping is being performed by sequencing the whole population or by sequencing the pooled samples belonging to extreme bulks for the trait of interest  mainly rely on sequencing bulk samples of RILs displaying extreme phenotypes specific to the trait under study  approaches used for crop improvement, including MABC, marker-assisted recurrent selection (MARS) and GS, the MABC/MAS approach delivered improved chickpea varieties with higher yield and climate resilience in recent years. Details pertaining to the recently released chickpea varieties using molecular breeding approaches are provided below and summarised in Table QTL-hotspot’ from ICC 4958 in the popular Indian chickpea cultivar JG 11. The ‘QTL-hotspot’ region is a promising target region in molecular breeding for developing drought-tolerant chickpea varieties  × 3*JG 11] – 29], which was named after the eminent pulse scientist late Dr Geletu Bejiga from EIAR, Ethiopia. This variety was officially released for commercial cultivation in Ethiopia by the National Variety Release Committee (NRVC), Ethiopia, and was commended for wider adoption in the dryland tropics to moist agro-ecological zone ranges. Notably, the variety had the highest grain yield of 3822 kg/ha at Arsi Robe, which corresponded to a yield advantage of about 15% over the check variety ‘Teketay’. Geletu also produced 100-seed weight ranging from 28 to 39.9 g as compared to recurrent parent at different locations. In Ethiopia, Geletu showed resistance against Fusarium wilt and root rot disease with disease ratings of 3 and 2, respectively, on a scale of 1–9 . Ethiopia became the first country to release a climate-resilient chickpea variety developed using marker-assisted backcrossing efforts.The MABC approach was successfully implemented at ICRISAT by introgressing the ‘QTL-hotspot’ region from ICC 4958 using the MABC approach. Based on yield performance in multi-location trials across India in the ICAR–All India Coordinated Research Project (AICRP) on chickpea, an improved Pusa 372 was released under the name ‘Pusa chickpea 10216’ for commercial cultivation in India. ‘Pusa chickpea 10216’ variety had a 11% yield advantage over its recipient parent under moisture stress in the central zone of India and a substantial increase in 100-seed weight. Notably, ‘Pusa chickpea 10216’ is the first molecular breeding variety with enhanced drought tolerance released in India.Pusa 372, a popular chickpea variety developed by ICAR-Indian Agricultural Research Institute (IARI) in 1993, was grown in the central zone, north-east and north-west plains zones of India and used as a control variety in late-sown national chickpea trials. However, in recent years, the productivity of this variety declined under drought conditions. Therefore, ICAR-IARI, in collaboration with ICRISAT, initiated efforts to enhance drought tolerance of ‘Pusa 372′ by introgressing the ‘The MABC approach has also been used to improve Fusarium wilt (FW) resistance in two elite high-yielding desi cultivars, Annigeri 1 and JG 74, at the University of Agricultural Sciences, Raichur (UAS-Raichur) and Jawaharlal Nehru Krishi Vishwa Vidyalaya (JNKVV), Jabalpur, India, respectively, in collaboration with ICRISAT. In recent years, both cultivars showed high susceptibility to FW race 4 (foc4), an important factor reducing yield in Central and South India. Therefore, to improve their resistance, a genomic region conferring resistance against foc4 was introgressed using MABC, with WR 315 as the donor parent. Evaluation of backcross lines at various locations (wilt sick plots) throughout India demonstrated a yield advantage of about 8% and enhanced disease resistance over the recipient parent, Annigeri 1 and was released as ‘Super Annigeri 1’ for commercial cultivation in India  that are used for subsequent selections under GS (i)(r)/L) generally regarded as the ‘breeder’s equation’ can be enhanced by shortening the breeding cycles (L); this rapid generation advancement can be attained by modulating temperature, humidity, photoperiod and harvesting/germination of immature seeds  and Integrated Breeding platform (https://www.integratedbreeding.net/), will play a crucial role in addressing the challenges faced in chickpea breeding.Crop improvement depends mainly on the underlying genetic variations. Incremental genetic gains can be achieved by either enhancing the amount of genetic variation available for selection or increasing the speed, efficiency and accuracy of the selection to develop varieties rapidly having market-oriented traits. Genomics technologies have the potential to support both approaches. Optimum genomic resources are now available for chickpea, which can be used in breeding programmes. We hope that MAS/MABC approaches continue to improve elite/leading chickpea varieties for select traits via molecular breeding and that parent selection, screening early generation and GS are integrated, either in combination or individually, into chickpea breeding efforts to accelerate the rate of genetic gains. Although genotyping technologies will be more affordable in the coming years to facilitate sequencing of the entire chickpea population, high-quality phenotyping data for these lines will be needed to enable trait discovery. Several other resources including mathematical models, data analysis skills, field experiment design, barcode labelling and databases for storing genotyping and phenotyping data will be important for the successful execution of breeding efforts. To this end, multi-institutional collaborative initiatives, such as the EiB platform (Integrating a sequence-based holistic breeding approach for chickpea improvement has the potential to develop superior varieties and provide substantial productivity gains. Here, the use of functional genomics approaches and genome-wide selection will help to capture genes and superior alleles, respectively, for inclusion in molecular breeding programmes to bridge the gap between genotype and phenotype. In conclusion, we see enormous potential of genomics technologies to modernise breeding approaches to deliver next-generation chickpea varieties, which will have a substantial impact in farmers’ fields.


Current conventional endoscopes have restricted the accuracy of treatment delivery and monitoring. Over the past decade, there have been major developments in nanotechnology and light triggered therapy, potentially allowing a better detection of challenging lesions and targeted treatment of malignancies in the gastrointestinal tract. Theranostics is a developing form of personalized medicine because it combines diagnosis and targeted treatment delivered in one step using advances in nanotechnology. This review describes the light-triggered therapies , nanotechnological advances with nanopowder, nanostent, nanogels, and nanoparticles, enhancements brought to endoscopic ultrasound, in addition to experimental endoscopic techniques, combining both enhanced diagnoses and therapies, including a developed prototype of a “smart” multifunctional endoscope for localized colorectal cancer, near-infrared laser endoscope targeting the gastrointestinal stromal tumors, the concept of endocapsule for obscure gastrointestinal bleed, and a proof-of-concept therapeutic capsule using ultrasound-mediated targeted drug delivery. Hence, the following term has been proposed encompassing these technologies: “Theranostic gastrointestinal endoscopy.” Future efforts for integration of these technologies into clinical practice would be directed toward translational and clinical trials translating into a more personalized and interdisciplinary diagnosis and treatment, shorter procedural time, higher precision, higher cost-effectiveness, and less need for repetitive procedures. Conventional gastrointestinal (GI) endoscopy allows the visualization of diseased regions and treatment at a macroscale. Lesions in the GI tract can be missed if they are localized in the submucosa, if their morphology is flat or depressed, if they are surrounded by an inflamed mucosa, or if they have not reached a detectable size (∼0.5–1 cm). In addition, conventional endoscopes do not allow dynamic monitoring while delivering treatment and can leave microscopic residual disease. “Theranostics” is considered a developing form of personalized medicine because it combines diagnosis and targeted treatment in one step using advances in nanotechnology while taking into account the uniqueness of disease signature.en bloc resection” of localized cancers of the GI tract. Endoscopic ablative therapies using thermal, photochemical, or radiofrequency energies applied to atypical lesions are other possibilities. However, current endoscopes limitations in both rigorously diagnosing and delivering targeted treatment arise mainly from the limited tip surface area that is small and does not allow integrating useful sensing and therapeutic features at a micrometric scale  and up to 100 nm. NPs are attractive to the medical field given that biological and living systems are of the same order of magnitude at the cellular level. NPs have been studied as potential drug delivery vehicles owing to their advantageous size and surface chemistry tunability. NPs can be tailored to improve the drug delivery efficacy while simultaneously reducing unwanted accumulation in healthy cells. The inner shell of NPs can be loaded with therapeutic drugs while the outer shell can be functionalized with antibodies to target abnormal sites. Additional structural stability and reduced aggregation is possible by coating NPs' outer layer with polymers such as polyethylene glycol to modify their surface. Nanoparticles that have been studied for drug delivery include metals, semiconductors, both natural and synthetic polymer-based “soft NPs,” polymer superstructures called dendrimers, and lipids such as micelles and liposomes. Micelles and liposomes are 2 types of NPs with hydrophilic heads and hydrophobic tails, creating cores that may be loaded with a therapeutic agent or contrasting dyes. Both have controllable self-assembly and are useful for transporting hydrophobic drug agents in the cell's aqueous environment  are particles with at least one dimension that is measured in the nanometric scale  showed the best results. In vitro results are promising, but future studies are warranted  is a well-established procedure for drainage of fluid collections in pancreatic pseudocysts, intraabdominal abscesses, loculated ascites ,26, gallin situ hybridization analysis  quantifies the systemic circulation of different gastrointestinal organs. It uses inert gas in the microbubble in a phospholipid layer acting as a contrast agent . It is aMost studies of the EUS for antitumor-agent delivery are still in phase I, confirming its safety awaiting further clinical trials. Cytoimplants consists of allogeneic-mixed lymphocyte culture delivered by the EUS-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cytoimplant produces cytokines directly within the tumor inducing its regression  by activIodine 125 radioactive seeds were successfully implanted in the pancreatic tumors under EUS guidance, resulting in a moderate local tumor effect ,41. EUS A “multifunctional endoscope-based interventional system” or “smart” endoscope has been proposed as a “closed-loop theranostic solution for colon cancer.” Synergistic effects on enhancing the tumor detection accuracy and providing treatment were exhibited by the combination of transparent electronics that allows visualization throughout the camera (fluorescence mapping and/or phototherapies), tissue characterization (through impedance and pH sensing), and removal of colon cancer (radiofrequency ablation therapy), whereas custom-designed biocompatible nanoparticles were loaded with phototherapeutic and chemotherapeutic agents activated with light .Active targeting of NPs was achieved through conjugating cetuximab-specific antibody, targeting the epidermal growth factor receptors that are overexpressed in the HT-29 colon cancer cells on the surface of NPs. NPs had a photothermally active core-shell structure that was loaded with fluorescence dye (rhodamine B), photodynamic dyes PDT (chlorin e6), and chemodrugs . After IV injection of the NPs, laser light emitted through the endoscope accessed suspicious sites targeted by NPs and observed through the transparent bioelectronics on the endoscope camera. HT-29 cancer cells were distinguished from the normal cells through impedance and pH differences. The cancerous tissue observed was resected using the forceps followed by radiofrequency ablation. Continuous monitoring of temperature, contact, and cell/tissue viability were ensured by the transparent bioelectronics. The photoactivation of NPs was localized to laser-irradiated regions and controlled by modulating the laser wavelength. NPs were locally activated using a continuous-wave red laser to induce PDT (ROS) and by using near-infrared (NIR) lasers for PTT (heat) and chemodrug release (Dox).in vitro, ex-vivo, and in vivo in the BALB/c nude mouse model. The most accentuated decrease in the tumor volume was in the combined therapy group  and was mediated by apoptosis.This “smart” endoscope has been tested Fujimoto et al.  used theThe concept of a theranostic capsule loaded with nanoparticles designed to target the bleeding site in the GI tract through endothelin-1 then mark these sites with fluorescein dye and release the treating agent (fibrin) to ensure hemostasis at the bleeding site has been proposed. One of the hypothetically described methods relied on the autologous fibrin glue and autologous platelet-rich fibrin derived from the patient's own blood .A proof-of-concept therapeutic capsule using ultrasound-mediated targeted drug delivery (USmTDD) with fluorescence imaging guidance has been conceived . This prOther potential therapeutic uses of endoscopic capsules include mounting of the nitinol clip released by an external magnetic signal focused on the capsule equipped with 4 permanent magnets  and obtaThe past decade has been marked by significant endoscopic advances mainly in refining visualization and endoscopic dissection and ablative techniques. These endoscopic advances were coupled with developing and functionalizing new nanoparticles.Using endoscopy to combine diagnosis with the delivery of a targeted treatment can be termed “Theranostic gastrointestinal endoscopy,” another potential added tool to the therapeutic arsenal of delivering a personalized care targeting the molecular signature of diseases and their hosts. Challenges for clinical application of these technologies are mainly related to innovating new endoscopes that allow integrating more complex functions and to further studying the behavior of light-triggered nanoparticles in humans.Future efforts would be directed toward translational and clinical trials with multifunctional endoscopes and capsules, with the integration of the rising field of artificial intelligence. This multifunctionality could clinically translate into a more personalized and interdisciplinary treatment, shorter procedural time, higher precision, higher cost-effectiveness, and less need for repetitive procedures.Guarantor of the article: Najib Nassani, MD, MSc.Specific author contributions: N.N.: study idea and concept, literature review, drafting the manuscript, reviewing the manuscript, and finalizing the manuscript. M.A.: literature review, drafting the manuscript, and reviewing the manuscript. B.C.: literature review, drafting the manuscript, and reviewing the manuscript. D.N.: literature review, drafting the manuscript, and reviewing the manuscript. R.E.C.: literature review, drafting the manuscript, reviewing the manuscript, and finalizing the manuscript. All authors agreed on the submitted version of the manuscript.Financial support: None to report.Potential competing interests: None to report.


The diagnosis of nipple and areola complex (NAC) lesions can be challenging even for expert dermatologists, since several differential diagnoses, including neoplastic and inflammatory conditions, should be acknowledged. NAC melanoma is rare; dermoscopy may aid in its correct evaluation. We report here 2 new cases of in situ NAC melanoma.A 60-year-old Caucasian woman presented with a 4 mm pigmented lesion on the areola at the edge of the nipple . During A 48-year-old Caucasian man presented with a 7 mm irregularly shaped macule affecting his left areola . He was Both patients underwent wide excision with a 5-mm margin.NAC melanoma represents an uncommon diagnosis, and until now only a few cases have been reported in the literature. The first dermoscopic observation was reported by Shiga et al , who desThe dermoscopic features of our 2 cases are concordant with those previously described. The differential diagnosis includes: melanocytic nevi, melanosis, and pigmented mammary Paget disease (MPD).Melanocytic nevi in this site often represent a challenging diagnosis, partly because of the irregular surface of the NAC, with duct orifices modifying the distribution of the pigment, thus favoring false-positive diagnoses. In a multicentric study, 16 out of the 66 nevi evaluated on dermoscopy 24%) were classified as melanoma using the 7-point checklist [4% were cMelanosis of the NAC can share some clinical features with melanoma, representing a possible cause of diagnostic concern. Melanosis may reveal a network and a cobblestone pattern which may be difficult to differentiate from melanocytic lesions.Dermoscopic features of pigmented MPD include structureless brown and red areas, pinkish background, irregular vessels and irregular blue and brown dots.Only a few cases of NAC melanoma with dermoscopic findings were reported in the literature. The cases presented here represent a clinico-dermoscopic report of in situ NAC melanoma.


Teaching point: Splenosis must be considered in patients with history of splenectomy or splenic trauma, later presenting with multiple peritoneal nodules. A 44-year-old man came to the emergency room for two-week progressive dyspnea. His medical history included morbid obesity, active smoking and childhood severe trauma that required splenectomy.The computed tomography (CT) pulmonary angiography performed to rule out a pulmonary embolism revealed several peritoneal nodules in the upper abdomen Figure .The additional abdominal contrast-enhanced CT revealed multiple other nodules and homogeneous disseminated peritoneal masses Figure . SplenosSplenosis corresponds to an ectopic autotransplantation of splenic tissue. Unlike accessory spleens and polysplenia, this is an acquired anomaly; it occurs following a rupture of the splenic capsule (post-traumatic or iatrogenic) with direct seeding of splenic tissue or haematogenous propagation.Splenosis nodules are mostly found in the abdominal cavity but distant localizations have also been described. As a benign entity, splenosis is most often asymptomatic and discovered incidentally. Therapeutic abstention is the rule, except in rare symptomatic cases.On imaging, splenosis nodules appear well defined and homogeneous. Nevertheless, splenosis can mimic primary or metastatic tumor lesions  or endometriosis.On MRI, they have the same signal characteristics as normal spleen tissue; hypointense on T1-weighted images and hyperintense on T2-weighted images relative to the liver.On CT, these nodules are isodense compared to a native spleen.The ultrasound appearance is not very specific, the nodules are discretely hypoechoic compared to the liver and present a posterior acoustic enhancement.Whatever the imaging technique, the enhancement kinetics of splenosis nodules is similar to that of healthy splenic parenchyma: intense enhancement, heterogeneous in the arterial phase (“Zebra spleen”), homogenizing in the portal phase.Tc99m-DRBC is the best examination method to confirm the diagnosis of splenosis, as the ectopic splenic tissue absorbs most of the damaged red blood cells . It is mIn the event of the discovery of isolated or multiple nodules in a patient with a history of trauma or splenic surgery, splenosis must be part of the differential diagnosis in order to avoid any unnecessary additional invasive procedure.


A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was ‘Is totally endoscopic coronary artery bypass grafting compared with minimally invasive direct coronary artery bypass grafting associated with superior outcomes in patients with isolated left anterior descending disease?’ Altogether more than 118 papers were found using the reported search, of which 4 represented the best evidence to answer the clinical question, which included 2 prospective cohort studies and 2 retrospective observational studies. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. There is a significant variation within the MIDCAB and TECAB techniques amongst the studies-including the experience of the surgeon, use of cardiopulmonary bypass, patient selection, and target vessel grafting strategies-highlighting the complexity of comparing these two minimally invasive procedures. Operative times were comparable across all studies, with TECAB patients having higher transfusions rates and conversion rates to either a median sternotomy or MIDCAB procedure. Overall safety was comparable between the two cohort groups, with similar length of stay and 30-day mortality. However, the TECAB group were more likely to require re-operation for bleeding and reintervention for early revascularisation with greater total hospital costs than the MIDCAB patients. Based on the available evidence, we conclude that TECAB is associated with a higher rate of transfusions, conversion to median sternotomy or MIDCAB, early graft failure and reintervention compared to the MIDCAB approach. We advise caution in adopting a TECAB approach. •Coronary Artery Bypass Grafting remains the gold standard for complex multi-vessel disease.•Demand for minimally invasive and robotic procedures is increasing.•Controversy remains regarding the optimal method for robotically assisted coronary grafting.•Overall safety is comparable between TECAB and MIDCAB.•TECAB is associated with a higher rate of early graft failure and reintervention. This is fully described in a previous publication in the IJS .2A 53-year-old male requires coronary artery revascularisation for unstable angina with a 95% proximal left anterior descending (LAD) artery stenosis. He requests a minimally invasive robotic approach in order to hasten his return to work and post-operative recovery. You plan to offer your patient a MIDCAB procedure, however, your colleague has had excellent results with a TECAB approach. You resolve to review the literature to determine if one approach is superior.3In patients with isolated left anterior descending disease is totally endoscopic coronary artery bypass grafting (TECAB) superior to minimally invasive direct coronary artery bypass grafting (MIDCAB) in terms of peri-operative outcomes including requirement for reintervention/target vessel revascularisation, freedom from major adverse cardiac and cerebrovascular events, and survival?4A literature search was performed on the MEDLINE database (1964 to present) using the OVID interface with the terms ‘coronary artery bypass’ [all fields] OR ‘coronary’ [all fields] OR ‘MIDCAB’ [all fields] OR ‘TECAB’ [all fields] AND ‘robotics or robotic surgical procedure’ [all fields]. The reference lists of initially identified papers were searched for other relevant studies. The search was current as of June 23, 2020.5A total of 118 papers were found using the reported search. From these 5 were not in English, 69 were irrelevant, 12 were case reports or editorial commentary, 15 focused on hybrid robotic procedures utilising PCI, and 13 were not specific to either procedure or failed to compare the two groups of interest. The remaining 4 papers directly compared TECAB and MICAB procedures and were therefore chosen as the best evidence to answer the clinical question.6The results of the four papers  are summarised in 7CABG remains the gold standard treatment for complex multivessel coronary artery disease, resulting in superior long-term symptom relief, lower rates of reintervention, and improved survival when compared to medical therapy and PCI . With thKofler et. Al  in 2017 Similarly, Yang et. Al , performPasrija et. Al , completJegaden et. Al , compare8Studies comparing TECAB and MIDCAB directly are limited in both number and quality. Although two prospective studies have been performed, the median follow-up for all included studies is at best 3 years. All current studies are single centred, with different protocols for following up patients, different primary outcomes, and various levels of operating experience, suggesting significant heterogeneity. Moreover, there is also significant variation within the MIDCAB and TECAB techniques amongst the studies reported-including the experience of the surgeon, use of cardiopulmonary bypass, patient selection, and target vessel grafting strategies-highlighting the complexity of comparing these two minimally invasive procedures. Based on the available evidence, we conclude that TECAB is associated with a higher rate of transfusions, conversion to median sternotomy or MIDCAB, early graft failure and reintervention compared to the MIDCAB approach. We advise caution in adopting a TECAB approach.Nil ethics approval required.Nil funding for research.Lucy Manuel- Literature search, analysis and writing of manuscript.Laura Fong- Analysis and editing of manuscript.Hugh Wolfenden- Analysis and editing of manuscript.Levi Bassin- Analysis and editing of manuscript.Name of the registry: NA-nil human participantsUnique Identifying number or registration ID:Hyperlink to your specific registration (must be publicly accessible and will be checked):Levi Bassin.Nil conflict of interest to declare.


We report 3 cases of Puumala virus infection in a family in Switzerland in January 2019. Clinical manifestations of the infection ranged from mild influenza-like illness to fatal disease. This cluster illustrates the wide range of clinical manifestations of Old World hantavirus infections and the challenge of diagnosing travel-related hemorrhagic fevers. Orthohantavirus within the Hantaviridae family, is an enveloped single-strand negative-sense RNA virus , a species of the genus <60 hours after admission.Asthenia, fever, chills, diffuse myalgia, and lumbar pain developed in a man 45 years of age 4 days after he returned to Switzerland from Samara, his hometown in central Russia . Four daThe next day, fever, lymphopenia, moderate thrombocytopenia, and hepatitis developed in the index patient’s daughter, who was 12 years of age . She wasThe wife of the index patient had had influenza-like symptoms in Russia during the week before her husband’s illness. Her serum sample tested positive for IgM and IgG against hantaviruses. We used a pseudovirus-based neutralization assay to confirm serologic results  Figure 1We sequenced the viral genome from blood samples taken from the father (GenBank accession no. MT822196) and the daughter (GenBank accession no. MT822195) using high-throughput sequencing  Figure 2This familial cluster highlights the wide spectrum of clinical manifestations of PUUV, which can range from an influenza-like illness (mother) to the classical nephropathy (daughter) to a rapidly fatal hemorrhagic fever with shock and multiple organ failure (father). Such a large spectrum of disease might be caused by the viral inoculum or host factors. Uncontrolled immune response and subsequent cytokine storm have been identified as key factors in the development of critical disease (Although specific antimicrobial drugs have been tested against PUUV infections, treatment is limited to supportive care. A small trial in Russia showed no effect of ribavirin on PUUV viral load or risk for death .PUUV usually causes limited renal disease but has a broad spectrum of clinical manifestations. Human hantavirus infections are rare in Switzerland and mostly acquired outside of the country. Physicians should consider viral hemorrhagic fevers when a patient has worsening influenza-like illness, thrombocytopenia, renal and hepatic impairment, and a plausible epidemiologic link to a region to which these viruses are endemic.Additional information on Puumala virus infection in family, Switzerland.


Highlighted Research Paper:Neurons Derived from Human Induced Pluripotent Stem Cells Integrate into Rat Brain Circuits and Maintain Both Excitatory and Inhibitory Synaptic Activities. Xiling Yin, Jin-Chong Xu, Gun-sik Cho, Chulan Kwon, Ted M. Dawson and Valina L. Dawson. Cell-based therapies aim to replace lost/damaged cell populations or to replenish sources of growth factors . More thectively . To miti culture , induced culture . Human i culture , providimedicine . Many remedicine . An impomedicine .in vivo generation of GABAergic neurons and the sequential generation of deeper, then upper, layer excitatory neurons of the six-layered cerebral cortex common to rodents and humans. Neural rosettes are a symmetrically dividing population of undifferentiated neuroepithelial cells  can be easily manipulated due to their visually distinct morphology. eNeuro publication, in vivo fate of hiPSC-derived neurons after transplantation into the neonatal rat brain.In a prior study, Professor Valina Dawson’s laboratory  developed a culture system that generates a balanced network of excitatory and inhibitory neurons, reminiscent of the human cortex . It is eal cells . In vitrin vitro or dissociated before transplantation into the brain of rat pups at postnatal day 1. Each recipient  was injected with 200,000 cells in the right cortex; nude rats were used to avoid an immune challenge. Ten weeks after transplantation, the fate and function of hiPSC-derived neurons in vivo were compared with hiPSC-derived neurons maintained in vitro for the same duration.The authors’ original hiPSC cell line was modified to express a red fluorescent protein (RFP) to track the fate of transplanted cells. in vitro, RFP-positive (RFP+) hiPSC-derived neurons coexpressed markers representative of one or more cortical layers, including TBR1, CTIP2, BRN2, and SATB2. Electrophysiological recordings also showed that cultured RFP+ neurons displayed both spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs). These observations are consistent with the authors’ prior study  and tetraethylammonium (TEA), a potassium channel blocker (d(−)−2-amino-5-phosphonopentanoic acid (d-AP5) were also used for selective inhibition of receptor activity. Together, these observations show that hiPSC-derived neurons can functionally integrate into recipient rat cortex and display aspects of synaptic transmission characteristic of both excitatory and inhibitory neurons.Ten weeks after transplantation, immunofluorescence analysis of forebrain slices revealed that >90% of RFP+ neurons had survived ructures . Patch-c blocker . Excitatin vitro. This delay was demonstrated by whole-cell patch-clamp recordings of input resistance, cell capacitance, AP threshold, and AP width. It is, however, not surprising that integration into a host brain may impede maturation, as previously suggested (in vitro. In addition, transplantation provides the local host environment in which extrinsic factors may contribute to neuronal survival, synaptic transmission, and disease states.Transplanted hiPSC-derived neurons took longer to achieve functional maturation compared with neurons maintained uggested . Lags inin vitro studies as they provide tissue architecture that is lacking in 2-D culture systems (The heterochrony of corticogenesis in rodents versus primates is an important consideration for human/rodent chimeric models. Compared with mice, the human brain has a 1000-fold difference in cortical neuron number despite a disproportionate 10-fold difference in the timing of neuron generation . Compara systems .in vitro. This improvement would help mitigate cost and time impediments as the prolonged maturation of cortical neurons from hiPSCs is an obstacle for the extensive use of many culture systems (The RONA culture model will also permit aspects of human corticogenesis to be further explored as postmortem human tissue samples may not be suitable if they exhibit disease states. The timed administration of other exogenous factors may lead to accelerated maturation of hiPSC-derived neurons  systems . Becausein vitro differentiation protocol to neurological disorders such as stroke, Alzheimer’s disease, and Parkinson’s disease. The balanced network of excitatory and inhibitory neurons is particularly appropriate for brain regions with focal trauma, such as non-diffuse cases of stroke. Human/rodent chimeric models can determine the fate of healthy or diseased state human neurons when transplanted into rodents models of neurological disorders or wild-type rodents, respectively. Chimeric models are most suitable for monogenic disorders in which neuron-intrinsic versus extrinsic factors can be more easily distinguished than for polygenic disorders. Chimeric models using older rodents can also provide the local environment of the mature brain that is more relevant to some disorders. Age is an important consideration because to increase the translatability of results, hiPSC-derived neurons from individuals with Alzheimer’s disease and Parkinson’s disease may require aspects of aging to be mimicked in vitro (Current research in Professor Dawson’s laboratory focuses on further characterization of transplanted hiPSC-derived neurons, for example, specific neuronal subtype expression. The ultimate goal is to apply this in vitro . When hein vitro . Such obUndoubtedly, the principal advance by Professor Dawson’s laboratory is the development of the RONA culture method that generates a balanced network of neurons that is representative of the ratio of excitation and inhibition in the human brain. Future research may uncover novel information about human neurological disorders that are poorly replicated in mouse models. The high failure of clinical trials investigating potential treatment options for Alzheimer’s disease is one example. The significance of hiPSC lines continues to increase, as evidenced by the recent creation of hiPSC lines for other neurological disorders such as bipolar disorder and schizophrenia .


The use of peripherally inserted central catheters (PICC) has been integral to the advancement of medical care in both in-patient and out-patient arenas.6We report a case of a fall associated with extraluminal PICC migration and perforation causing mediastinitis and severe sepsis after total parenteral nutrition (TPN) infusion in a 54-year-old woman. Our patient required a right-sided PICC for long-term home TPN due to severe malnutrition following gastric bypass surgery. During a routine home care visit our patient was found tachypneic, hypoxic, and short of breath. Computed topography imaging in the emergency department (ED) identified the injury, likely related to the recent fall. The patient experienced a complicated hospital course after removal of the PICC. Although rare, PICC line migrations and perforations cause serious complications that should be considered by emergency physicians evaluating patients with chronic indwelling vascular access.Given the efficacy and widespread use of PICC lines, we present this case as a rarely reported but life-threatening complication that requires particular attention. Emergency physicians should be aware of such PICC line complications when encountering patients with chronic indwelling vascular access. Peripherally inserted central catheters (PICC) have played an integral role to the advancement of medical care in both the in-patient and out-patient arenas.Peripherally inserted central catheters are placed with ultrasound guidance by a dedicated intravascular team or under fluoroscopy by an interventional radiologist into the large vessels of the upper arm: the cephalic, basilic, or brachial veins. Optimal tip location is considered to be at the lower one-third of the superior vena cava or cavoatrial junction.Peripherally inserted central catheters lines are generally well tolerated, although complications requiring prompt treatment can arise. Commonly cited frequencies of complications include deep vein thrombosis 30.6%),0.6%,3 ca4Venous perforation secondary to tip migration is a rare phenomenon that harbors potentially lethal complications. The frequency of PICC line perforations as a result of migration is not known, as few cases have been reported in the literature.A 54-year-old woman with a right-sided PICC line placed in November 2015 presented to the emergency department (ED) two months later for evaluation of neck pain and hypoxia. She reported a history of Roux-en-Y gastric bypass in 2007 and revision in 2011 for recurrent marginal ulcers that required long-term TPN through a PICC secondary to severe caloric malnutrition. A visiting home health nurse found the patient short of breath, and hypoxic with oxygen saturations in the 70s percentile on room air. The patient’s daughter reported an unwitnessed, ground-level fall three days prior.Upon initial ED evaluation, patient vital signs were as follows: temperature of 36.4° Celsius, blood pressure of 79/54 millimeters of mercury, heart rate of 136 beats per minute, respiratory rate of 18 breaths per minute, and oxygen saturation of 89% on room air requiring two liters of supplemental oxygen via nasal cannula. Physical examination demonstrated a moderately sized, tender mass to the lower right anterolateral neck, just superior to the clavicle with mild overlying erythema and tenderness along the right trapezius muscle. Radiograph of her chest identified bilateral pleural effusions, with suboptimal location of the PICC line along the proximal right clavicle, several centimeters from the cavoatrial junction .Computed tomography (CT) of the thorax identified a significant amount of gas and fluid collections located in the soft tissues of the right side of the neck with extension into the mediastinum .Bilateral pleural effusions were re-demonstrated from chest radiograph, and the tip of the patient’s right PICC line was found to have perforated the right innominate vein, terminating extraluminal in the right upper mediastinum . A non-oWhat do we already know about this clinical entity?Out-patient use of peripherally inserted central catheters (PICC) is increasing due to convenience and safety profile but can harbor life-threatening complications.What makes this presentation of disease reportable?This is the first reported case of venous perforation due to traumatic migration of a PICC line in an out-patient setting causing severe morbidity.What is the major learning point?Emergency physicians should be familiar with both the common and rare highly morbid complications of PICC lines in patients with chronic indwelling vascular access.How might this improve emergency medicine practice?Differentials in patients with PICC lines should broaden to include mechanical and physiologic complications, with lower thresholds for advanced imaging and laboratory evaluation.9/liters (L)  and a lactic acidosis of 4.1 millimoles (mmol)/L (0.5–1 mmol/L) requiring aggressive volume resuscitation and broad-spectrum antibiotics with piperacillin/tazobactam. Blood cultures were drawn and pending upon admission eventually growing Staphylococcus Epidermidis and Staphylococcus Hominis. The patient did not require vasopressor medications during her ED course. She was transferred to the medical intensive care unit for further management of severe sepsis with bacteremia, mediastinitis, and pleural effusions.Laboratory work returned remarkable for evidence of severe sepsis with a leukopenia of 3.9 white blood cells × 10Following admission, cardiovascular-thoracic surgery consult deemed the patient a poor candidate for mediastinal debridement given her profound malnutrition and she was treated medically with an extended course of vancomycin. The PICC line was removed and initial left-sided pleurocentesis was described as a yellow, turbid pleural fluid without odor, similar in appearance to TPN or tube feeds. The mechanism by which TPN extravasation was greater on the left hemithorax than right remains unclear. Our patient required serial pleurocenteses during the course of a complicated 18-day hospitalization, and she was ultimately discharged to a skilled nursing facility with gastrostomy tube placement scheduled 12 days later. At the time of writing this report, the patient continued to experience extreme weight loss and complications from her prior gastric bypasses.Given the breadth of applications and safety profile, PICC lines are nearly ubiquitous in patients requiring long-term vascular access. Our knowledge of PICC line complications, however, remains incomplete, namely, the frequencies, risk factors, and mortality associated with tip migration and vessel perforation. A search of the literature showed this to be a rarely reported phenomenon,7Commonly reported PICC line complications include blood stream infections, occlusion, and thrombosis with tip migration being among the least reported.Proposed risk factors of PICC migration and perforation include the PICC line material, orientation, and insertion arm. Fernando et al note softer materials such as silicone or polyurethane likely allow for greater intravascular movement and possible migration but have lower rates of perforations.Some researchers suggest that initial site of insertion may have predilections to vessel-specific migrations. For example, left-sided PICC line placement is an important risk factor for azygous migration,Complications of PICC line migrations with perforations are not only mechanical but also physiologic in nature and carry the potential for high morbidity and mortality. A case reportAnother case describes a fatal cardiac arrest after potassium-enriched solution was infused into the pericardial space via a perforated right-sided PICC, creating a rapidly progressive cardiac tamponade.As illustrated by previous case reports, there are a myriad of proposed mechanisms for and consequences of PICC migration and perforations that harbor lethal potential. Most reported complications were noted to have occurred in-patient, and of iatrogenic causes. Our case report, however, details a unique clinical scenario of a ground-level fall causing a traumatic PICC line migration and perforation of the right innominate vein resulting in mediastinitis. We present this case as a life-threatening PICC line complication that requires particular attention given its high associated mortality, but more importantly the location where the injury occurred. In this case, the patient was reported to have fallen at home with her evaluation initiated in the ED. Thus, emergency physicians need to be aware for the potential of such traumatic PICC line complications to facilitate prompt recognition and treatment when encountering patients with chronic indwelling vascular access.


Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.Infection with  Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent worldwide, with 10 million new cases and 1.2 million deaths due to tuberculosis (TB) disease in 2018 alone according to the most recent World Health Organization (WHO) Global Tuberculosis Report , which further complicates antimicrobial treatment options. MDR strains of Mtb are resistant to the two first-line anti-TB drugs rifampicin and isoniazid and recent years have seen the development of extensively drug-resistant TB (XDR-TB) which is additionally refractory to fluoroquinolones and second-line injectable antimicrobial drugs . CurrentAn additional factor that complicates TB control is the co-occurrence of other infectious and non-infectious diseases. Diseases such as HIV/AIDS and type 2 diabetes mellitus (T2DM), which also have high incidence in endemic regions, augment individual susceptibility to Mtb infection and worsen clinical outcomes of those with TB . SpecifiThe nature of the TB granuloma microenvironment is of particular interest in the search for host-directed therapeutic targets. TB disease is characterized by granulomatous inflammation, which typically originates in the lungs as a consequence of aerosol exposure to Mtb, but which can disseminate and develop in other regions of the body . The earTo overcome the challenges to develop new, more effective antimicrobial drug treatments and to combat drug-resistant infections, host-directed therapeutic (HDT) strategies are being explored. HDT involves developing treatments or repurposing previously approved compounds to target the host rather than the pathogen. In this way, HDT can potentially modulate host responses to better combat Mtb infection when used alone or in combination with antimicrobial drugs. The applicability of HDT in the treatment of TB has been recently reviewed . HDTs foOne additional area of interest has been preserving immune cell metabolism under conditions of chronic antigenic stimulation as occurs in a wide variety of infectious diseases including TB . CellulaBrucella abortus, Legionella pneumophila, and Chlamydia trachomatis . HIF-1 is a transcription factor that globally regulates the cellular response to hypoxic stress . HIF-1 rradation . Howeverradation . HIF-1α radation . The actradation . The actradation .Mycobacterium marinum, HIF-1α stabilization enhances IL-1β expression, and helps clear infections via activating neutrophils , which catalyzes the conversion of pyruvate into lactate, has a binding site for HIF-1α . LDH isoMuch of what is known about the role of lactate comes from extensive reviews of the tumor microenvironment . Lactatevia oxidative phosphorylation  are responsible for shutting lactate across membranes. Multiple MCTs exist, and cellular expression of MCTs depends on the physiological role of the cell . Highly e by 50% . The inve by 50% . Importae by 50% . CD147 ee by 50% . In somee by 50% . Within  subsets . Evaluat subsets . Increasrophages . MCT4 isrophages . MCT4 harophages . DespiteCombining knowledge about LDHs and MCTs, the lactate shuttle hypothesis posits that a metabolic symbiosis between hypoxic and oxidative tumor cells exists, wherein hypoxic, glycolytic cells produce lactate at high levels, and this lactate is transported to oxidative tumor cells, which convert lactate back into pyruvate to fuel their metabolism, and conserve glucose for hypoxic cells  Figure. This hyIndeed, a lactate shuttle has been proposed between astrocytes and microglia within the context of tuberculous meningitis (TBM), based on proton magnetic resonance based metabolomics of cerebrospinal fluid (CSF) samples of TBM-confirmed children . It is hvia MCT4 stimulates IL-8 production, tumor angiogenesis, and tissue perfusion, supporting a model where tumor cell lactate can stimulate angiogenesis in endothelial cells  are resistant to the suppressive effects of lactate on effector T cells, making these populations better able to survive in high lactate environments and assist in cancer immune evasion . It has via cytotoxic release of perforin and granzyme as well as through activation of macrophages and enhancing phagolysosomal fusion via IL-22 and IFN-γ production (via lactate-mediated mechanisms could reduce the phagolysosomal fusion capacity of macrophages, aiding the ability of Mtb to set up its intracellular residence in phagosomes. Decreased functionality of NK cells may prevent appropriate immune responses necessary to activate macrophages and induce mycobacterial killing, providing Mtb an additional advantage. Additional research is needed to explore the role of lactate in augmenting NK cell immunity within the context of TB.NK cell production of granzyme B and perforin is also reduced in the presence of lactate, and NK cells treated with lactate express fewer activation receptors . Additiooduction . ImpaireTumor derived lactate also significantly inhibits monocyte TNF-α secretion, impairs monocyte glycolytic flux, stimulates macrophage VEGF and TGFβ, up regulates monocyte IL-23 production, and inhibits the differentiation of monocytes to dendritic cells . MigratiUltimately, both the tumor microenvironment and the TB granuloma are formed and sustained by complex interactions between T cells, macrophages, and other immune cells. Both disease processes rely on immunosuppressive macrophage populations to prevent immune system elimination and appropriate infiltration of T cells and antigen presenting cells to elicit antigen-specific immune responses, as has been previously reviewed . Thus, fThe differences and similarities between cancer and TB must be weighed accordingly when pursuing research questions regarding the role of lactate, and the potential for modulation of lactate metabolism as a therapeutic strategy, in either context Table 1.Gpr81 gene (Lactate is one of many metabolites which signals through G-protein coupled receptors . Lactater81 gene . PPARγ hr81 gene . Mtb alsr81 gene . Based or81 gene . These ar81 gene .via conditioned media (via GPR81 activation, regulates TLR activation via interactions with arrestin B2 downstream of GPR81, and protects against inflammatory injury in pancreatitis and hepatitis models through GPR81 signaling (GPR81 plays a role in signal transduction across multiple body systems. Inflammation in adipose tissue initiated by LPS, zymosan, or turpentine stimuli resulted in the decreased expression of GPR81 . GPR81 ied media . Furtherignaling . Mtb infignaling . GPR81 hignaling .via VEGF inactivation abolishes mycobacterial spread (Within the CNS, GPR81 is concentrated along the plasma membranes of vascular endothelial cells, acting as a volume transmitter and serving as a feedback mechanism to counteract damage and save energy under hypoxic conditions . GPR81 il spread . Thus, lGPR81 has been shown to play a critical role in cancer, where silencing GPR81 in tumor cells reduced tumor growth, metastasis, cell proliferation, and mitochondrial activity . GPR81 evia agonizing or antagonizing this receptor in vitro and in vivo, but GPR81 shows promise as a novel HDT target to modulate TB disease.GPR81 plays a critical role in many processes that are important to the pathogenesis of TB. The anti-inflammatory responses stimulated by lactate activation of GPR81 may contribute to immune evasion by Mtb but may also be critical for controlling chronic inflammatory processes and limiting disease severity. The evaluation of the role of this receptor during Mtb infection has yet to be conducted, either All and all, this body of literature paints a complex picture of the multitude of roles lactate plays as both a metabolite and signaling molecule during chronic, progressive disease. Importantly, it reveals a significant knowledge gap and lag within the field of Mtb research with respect to these mechanisms and pathways when compared to the field of cancer research. Mechanistic knowledge of the metabolic interactions occurring at the host-pathogen interface will aid in the development of host-directed therapeutic strategies that can augment cell metabolism, thereby shifting immune cell phenotypes to those that are better equipped to combat TB disease. In the context of Mtb, shifting macrophage metabolism and augmenting the granuloma microenvironment will better equip the host to resolve lesions and slow disease progression, potentially limiting the establishment of latent infections. Specifically, this review reveals promising new areas of investigation into the immunomodulatory roles of lactate within the granuloma microenvironment.via lactate through GPR81 may serve to reduce excessive inflammation and dampen disease progression. It is also important to note that host responses within tumor microenvironments and inflammatory environments, although similar in some respects, are not equivalent, and diversity in response exists between diseases of infectious and non-infectious inflammatory origin (Increased glycolysis and lactate production by macrophages within the granuloma may serve to promote an Mtb survival niche, as lactate contributes to immune evasion and immunosuppression in the tumor microenvironment. The potential presence of active lactate shuttles between hypoxic cells and more normoxic cells within the granuloma microenvironment may serve as a target pathway for therapeutic intervention, as inhibiting this shuttle could limit the metabolic capacity of macrophages harboring Mtb, thus making the cellular environment less suitable for Mtb. In contrast, it is possible that the increased lactate production is a protective response which occurs by the host in the granuloma microenvironment, promoting M2 macrophage polarization, tissue remodeling and lesion repair. Additionally, anti-inflammatory signaling occurring y origin . This fuvia GPR81, augmenting the immune response to Mtb infection (Based on our knowledge and experience within the TB field, we have overarching hypotheses with respect to the role lactate plays in Mtb infection. Stabilization of HIF-1α during Mtb infection leads to a shift toward macrophage glycolytic metabolism, which is followed by production of large quantities of lactate. This lactate can then be shuttled to more oxidative regions of the granuloma microenvironment to preserve glucose for hypoxic cells. Lactate within the granuloma microenvironment can then serve as both an autocrine and paracrine anti-inflammatory, immunomodulatory signal nfection Figure 3DK and RB conceptualized this work. DK wrote the primary manuscript and RB provided edits. DK and RB both approved the final submitted version. All authors contributed to the article and approved the submitted version.This work was supported by funding from the National Institutes of Health, grant numbers 1F30OD024647, 1U19AI111224-01, 1R21AI107254, and 1R01AI106733. Funding was also provided by the Catalyst for Innovative Partnerships funding for ‘The Center for Metabolism of Infectious Diseases Accelerator’ by the Office of the Vice President for Research, Colorado State University.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.