Skin adverse reactions to diabetes medical devices have been reported frequently over recent years. Adhesives attaching glucose sensors and continuous insulin infusion sets to the skin are proven to cause both allergic contact dermatitis and irritant contact dermatitis in patients with diabetes mellitus. Several allergens contained in adhesives and/or parts of medical devices are documented to cause allergic contact dermatitis, with acrylate chemicals being the most common culprit-especially isobornyl acrylate (IBOA), but also 2,2′-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate or cyanoacrylates. Epoxy resin, colophonium and nickel were also identified as causative allergens. However, repetitive occlusion, maceration of the skin and resulting disruption of the skin barrier seem to have an impact on the development of skin lesions as well. The purpose of this study is to highlight the burden of contact dermatitis triggered by diabetes medical devices and to show possible mechanisms responsible for the development of contact dermatitis in a group of diabetic patients. The management of diabetes mellitus (DM) has been vastly improved due to the broader access to technological devices such as glucose sensors (GS) and continuous subcutaneous insulin infusion (CSII) sets. The two main categories of GS are flash glucose monitoring (FGM) and continuous glucose monitoring (CGM). FGMs do not require calibration with self-measurements of glucose levels from finger prick tests, but users need to scan the sensor manually. On the other hand, CGMs provide real-time tracking of interstitial glucose levels, though some of them still require calibration . AvoidinA review of the literature concerning the problem of contact dermatitis in patients with diabetes who use medical devices was conducted using PubMed and Web of Science between March 2023 and June 2023. No restrictions were placed on article types, publication date, country, journal or publisher. The following terms were searched for: diabetes medical devices, diabetes devices, insulin infusion sets, insulin pumps, continuous glucose monitoring system, flash glucose monitoring system, glucose monitoring system, glucose sensors, acrylate, acrylates, isobornyl acrylate, IBOA and contact dermatitis, allergic contact dermatitis and irritant contact dermatitis. A backward search (scanning the references included in relevant articles), as well as forward search , was also conducted. Since the clinical problem of contact dermatitis elicited by diabetes medical devices is not that widely explored and covered in the literature yet and many studies are currently being performed, personal observations were also included (these are appropriately indicated in the text).Contact dermatitis (CD) is a very common inflammatory skin disease characterized by pruritic, eczematous-scaling lesions sometimes accompanied by vesicles or impetiginization. The two main types of contact dermatitis are ACD and ICD, whose clinical pictures in most cases are indistinguishable. ICD is more frequent and stands for approximately 80% of all contact dermatitis cases . StatistWhilst several report studies and case series have been published across the past few years, there is a paucity of reliable systematic reviews or meta-analysis presenting the actual incidence rate of ACD and ICD triggered by diabetes medical devices. Nonetheless, contact dermatitis elicited by the use of insulin pumps and/or glucose sensors can be either allergic or irritant . There are risk factors for the development of local skin reactions to diabetes medical devices. One of them is the use of diabetes devices in the past, which could contain allergens (such as IBOA), regardless of the presence of skin lesions. Svedman et al. pinpointed that patients sensitized through the use of one medical device are not free from future episodes of ACD when using another product . AnotherACD is an example of a type IV hypersensitivity reaction according to Coombs and Gell classification, in which dermal dendritic cells (DCs) and epidermal DCs (Langerhans cells) play a key role in sensitization and elicitation phases. During the sensitization process, an individual is first exposed to an allergen (hapten), which reacts with DCs and, as a hapten-peptide complex, migrates to regional lymph nodes of the skin and prime naïve Th-cells. DCs present the haptens on their major histocompatibility complex molecules (MHC) to antigen-specific T-cell receptors (TCRs) leading to the formation of hapten-specific memory and effector T-cells. Upon re-exposure, the hapten is recognized by already sensitized hapten-specific T-cells, which migrate to the skin. Following this, hapten-specific cytotoxic CD8+ T lymphocytes, via proinflammatory cytokine cascade, elicit skin lesions that are clinically seen as ACD ,17. DCs,What is currently being investigated is why not all individuals exposed to an allergen become sensitized towards it and, consequently, might develop ACD. Genetic tendencies and environmental factors seem to predispose certain groups and put them at higher risk of developing ACD . Family The gold standard in the diagnosis of ACD is patch testing. When suspecting ACD connected to diabetes medical devices, acrylate-series patch tests including IBOA should be performed. From our observations, acrylate allergens very often do not give positive results until the last reading taken after 7 days, so it is crucial to perform all three readings after 48 h, 72 h and 7 days. The difficulties of patch testing and diagnosis of cases with contact dermatitis from medical devices have been discussed by Ulriksdotter et al. as the role of an untested allergen in the development of dermatitis must be kept in mind. Frequently, the causative allergen is not identified . Cases wThe question arises whether diabetic patients should undergo patch testing prior to using the device. There is, however, no unequivocal answer. This difficult topic is not covered in any guidelines and should be treated in a patient-oriented way. The decision on performing patch tests (or not) is strongly dependent on the clinical picture and symptoms patients present. If a patient has a history of contact allergy to glues, sealants, adhesives, etc., it seems reasonable to extend diagnostics with patch tests as possible results towards epoxy resin, colophony or isobornyl acrylate can help with choosing the appropriate device free from these allergens, thus preventing possible elicitation of ACD. On the other hand, exposing patients to new allergens during patch tests and possible sensitization, even if they do not present clinical symptoms of contact allergy towards any allergens, remains highly questionable. The identification of the causative allergen(s) in patients with contact allergy towards medical devices is immensely challenging, sometimes resembling the ‘trial and error’ method. Finally, not every patient using insulin pumps and/or glucose sensors eventually elicits contact dermatitis. Unfortunately, we have not found any official data describing the percentage of patients with DM experiencing contact dermatitis from the medical devices they use. From our observations, this number fluctuates by a few percent, though the trend is upward in recent years .In the following paragraphs, we outline the contact allergens eliciting ACD and evaluate the factors contributing to ICD in the users of diabetic medical devices.Acrylates are created by polymerization of monomers derived from (meth)acrylic acid. Acrylic monomers are proven to cause the most documented cutaneous reactions. In contrast, acrylic polymers are relatively inert, though every polymerized acrylate very often contains trace amounts of residual monomers . It has Isobornyl acrylate , the 2020 American Contact Dermatitis Society Allergen of the Year, is a liquid and reactive acrylate monomer widely used in plastic material and ink manufacture. In everyday life, IBOA can be found in glues, adhesives, resins, inks and solvents, in which it offers good resilience, flexibility and hardness . Therefotert-butyl-4-methylphenol) monoacrylate , which so far had not been linked with the problem of skin reactions to diabetes medical devices [tert-butyl-4-methylphenol)  also in three concentrations  [Apart from IBOA, Svedman et al. identified a new allergen in the adhesive of the newer DexcomG6-2.2′-methylenebis(6- devices . Therefond 1.0%) . MBP is nd 1.0%) . PresumaDPGDA (CAS 57472-68-1) has been previously linked with occupational dermatitis in the painting industry, accounting for 18% of positive patch test results in a group of patients allergic to acrylic monomers . In 2022Cyanoacrylates , thanks to their ability to polymerize rapidly, can form very strong bonds with metals, plastics, rubbers and biological tissues, and are used mainly in the production of fast-acting glues . In 2016Along with the first detection of IBOA in a medical device in 1995, other acrylate chemicals proved to be culprits in contact allergy cases, namely PEEA and BCA . BCA was2) but was not detected in the adhesive sensor patch (<0.5 μg/cm2). Six out of seven patients were concomitantly sensitized towards IBOA, which is also present in FreeStyle Libre [DMAA is an easily polymerized monomer used as a precursor in the synthesis of hydrogels and polymer coatings and was highlighted to sensitize (0.1% DMAA in PET) and elicit ACD in seven patients using FreeStyle Libre. When analyzed with GC-MS, DMAA was found in the extract of the sensor . Both patients were positive for epoxy resin , which the manufacturer was using to bind tubes and needles .Colophonium (known as colophony or rosin) is a mixture of >100 compounds derived from pine trees . The exaNickel remains the most common allergen that gives positive results in patch tests and can be found in many items and workplaces . There a1-Benzoylcyclohexanol is a UV photoinitiator compound contained in UV-cured glue. There is one report of 1-Benzoylcyclohexanol causing ACD in a user of an insulin pump .Sensizitation to methacrylates may induce cross-reactivity to acrylates, but not vice versa . HoweverAs stated previously, in a group of seven patients with skin reactions to FreeStyle Libre, all were sensitized to DMAA and six of them additionally to IBOA. The presence of both compounds was confirmed by the manufacturer, clearly pointing to co-reactions between IBOA and DMAA in these cases.Recent studies have shown that 44% of patients with FreeStyle Libre-associated IBOA allergy have positive patch test results to sesquiterpene lactone mix (SLM) . InteresThe summary of allergens causing ACD in patients using diabetes medical devices is presented in ICD is caused by the direct toxic effect of an irritant compound which disrupts the skin barrier and triggers innate immune response with release of proinflammatory cytokines . The firReliable data concerning the prevalence of ICD in diabetic patients are not available. Herman et al. report that approximately 1/3 of patients experiencing adverse cutaneous effects from diabetes medical devices had no positive patch test results, suggesting ICD as a diagnosis of exclusion . This nuThe overview of factors contributing to the development of contact dermatitis in diabetic patients is presented in Another form of rarely observed contact dermatitis is systemic contact dermatitis (SCD)  in which a patient first becomes cutaneously sensitized towards an allergen and upon a systemic re-exposure develops a sequela of systemic symptoms such as malaise, fatigue, fevers, vomiting and musculoskeletal disorders . The patThe principal treatment of ACD is avoidance of culprit allergens, something that is not easy to implement in the case of GS or CSII users. In cases of ACD, relocation of the device to a different body region is not helpful. According to the most recent guidelines, children and young adults under 25 years old should use CGMs . In compSince avoidance of allergens is in many cases difficult to implement or even impossible, patients try different barrier methods with varying success. These include barrier sprays, hydrocolloid dressings, BB kinesiotherapy tapes and others. However, barrier methods have substantial drawbacks: (i) applying extra protective layers underneath the medical device can result in false readings of glucose levels and/or inappropriate insulin infusions, (ii) the surface of the skin might not be dry enough to secure the adhesive and hence the device may detach after its application, (iii) sometimes barrier methods can elicit ICD or ACD and may lead to an exacerbation of dermatitis. Finally, it is generally recognized that acrylates  can penetrate protective barriers such as latex, vinyl and nitrile gloves ,73,74. TPractice shows that some patients who have changed GS from IBOA-containing FreeStyle Libre to ‘allergen-free’ Dexcom G6 or FreeStyle Libre 2 still experience contact dermatitis. It is postulated that either previous sensitization can somehow trigger contact dermatitis when using IBOA-free devices or that there are still allergens that have not yet been identified . Manufacturers usually do not provide a list of exact chemicals contained in devices or generally state that ‘polyacrylates’ are present without specification; sometimes we fail to obtain any information about the composition. Unfortunately, the ‘trial-error’ scheme is in some cases the only solution for patients who give up on their devices due to itching, pain or sleep deprivation. In acute contact dermatitis, topical corticosteroids (TCS) are the first-line treatment. As the use of TCS cannot be a long-term solution due to the side effects, patients can be recommended to use topical calcineurin inhibitors  to control the subinflammatory process.The identification of IBOA as the major contact allergen in diabetes medical devices was the praeludium to further research of other allergens that might be present in glucose sensors and insulin infusion sets. The management of diabetes device contact allergy is challenging, as avoidance of allergens is not always achievable and the ‘allergen-free’ equivalents can still elicit contact dermatitis due to the presence of untested allergens or via irritant, toxic pathways. As long as the precise chemical compositions of the medical devices are not officially disclosed by the manufacturers, the burden of contact dermatitis amongst patients using diabetes sets will be considerable.


Current management guidelines for ascending thoracic aortic aneurysms (aTAA) recommend intervention once ascending or sinus diameter reaches 5–5.5 cm or shows a growth rate of >0.5 cm/year estimated from echo/CT/MRI. However, many aTAA dissections (aTAAD) occur in vessels with diameters below the surgical intervention threshold of <55 mm. Moreover, during aTAA repair surgeons observe and experience considerable variations in tissue strength, thickness, and stiffness that appear not fully explained by patient risk factors. To improve the understanding of aTAA pathophysiology, we established a multi-disciplinary research infrastructure: The Maastricht acquisition platform for studying mechanisms of tissue–cell crosstalk (MAPEX). The explicit scientific focus of the platform is on the dynamic interactions between vascular smooth muscle cells and extracellular matrix , which play an essential role in aortic wall mechanical homeostasis. Accordingly, we consider pathophysiological influences of wall shear stress, wall stress, and smooth muscle cell phenotypic diversity and modulation. Co-registrations of hemodynamics and deep phenotyping at the histological and cell biology level are key innovations of our platform and are critical for understanding aneurysm formation and dissection at a fundamental level. The MAPEX platform enables the interpretation of the data in a well-defined clinical context and therefore has real potential for narrowing existing knowledge gaps. A better understanding of aortic mechanical homeostasis and its derangement may ultimately improve diagnostic and prognostic possibilities to identify and treat symptomatic and asymptomatic patients with existing and developing aneurysms. Ascending thoracic aortic aneurysm (aTAA) represents a significant cause of morbidity and mortality worldwide. The prevalence of aTAA in the general population is 0.16% to 0.34%, with an incidence of 10 cases per 100,000 patient-years . ThoraciFor high-risk patients with a genetic predisposition or bicuspid valve morphology, lower thresholds (4.0–5.0 cm diameter or growth rates > 0.3 cm/year) are considered ,7. ArounHowever, up to 96% of aTAA dissections (aTAAD) occur in vessels with diameters below the surgical intervention threshold . The solBeyond diameter  and geneConsidering the above, there is a clear need for a platform of research approaches and infrastructures, to enable the integration of clinical, genetic, mechanical, and biological concepts and data, to further our understanding of ascending thoracic aortic disease.In the present paper, we introduce and describe the MAPEX platform as initiated at our institutes. Because the approach and implementation of MAPEX are dictated by existing and integrative concepts around mechanical homeostasis and mechanobiology, we will describe the scientific underpinning and main research question in the next section.Mechanical homeostasis describes the active processes of biological tissue to maintain form and mechanical properties, such as strength, resilience, and elasticity . It is iAccordingly, we approach aTAA(D) from a pathophysiological perspective, focusing on where and how homeostatic processes derange or get disrupted towards pathology.Much of the current understanding of aTAA pathophysiology comes from histopathological studies of disease requiring cardiac surgery, where aTAA has been shown to associate with elastin degradation, cystic medial necrosis, and vascular smooth muscle cell (VSMC) loss within the tunica media of the aortic wall ,21. AcquBecause the dynamic interactions between VSMCs and extracellular matrix without a doubt play a fundamental role in tissue mechanical homeostasis, our platform is explicitly rigged to study such dynamics.Blood vessels are responsive to mechanical stresses, facilitating long-term growth and remodelling by adaptation of geometry, structure, and material properties . The twoA core concept we propose is that any circumstance, chronic or transient, that may derange mechanical homeostasis, has the potential to elicit a vicious cycle into pathophysiology.Accordingly, the sensing and actuating roles of endothelial cells and VSMCs should be considered, whilst pathophysiological triggers at these levels are very likely to derange mechanical homeostasis. As such, this serves as a framework for the study of aTAA formation, further detailed below.wall shear stress. Informed by the endothelium as a sensor, the regulatory “rule” of the vessel is to keep wall shear stress constant in the face of changes in blood flow: when wall shear stress increases due to a long-term increase in flow, a structural dilation will bring wall shear stress back to a normal level; and vice versa if flow decreases . Al. Al42]. Concomitant expansion of stem cell research with the MAPEX platform will allow us to validate and expand on findings from biomechanical and clinical data. Direct comparison of transcriptomic, and proteomic profiles between iPSC-VSMCs and primary cells will enable further insight into the nature of the disease and be of benefit to stem cell research and translation . IntegraThe accumulated and growing data will be used to address a range of main and underpinning research questions around aTAA(D) pathophysiology at different levels: genetic—omic—cell—tissue—vessel—patient. With the targeted substantial number of subjects, we will be able to apply multivariate analysis and AI approaches for testing hypotheses.In addition, computational biomechanical and physiological models will be used to integrate appropriate data to help interpret cell–matrix biology findings. Using variability estimates as input, these models are also used to simulate virtual patient populations, allowing (re)classification of actual patients.Because of the integrative multidisciplinary approach beyond aortic morphology, MAPEX will also allow the exploration of new markers by hypothesis generation through machine learning algorithms.We have adopted and developed a multidisciplinary view on aTAA formation, resulting in the MAPEX research platform . Our corArterial wall remodelling traits such as dilatation, stiffening, and calcification are governed by multiple signalling pathways, wherein homeostatic crosstalk between VSMCs and ECM plays a key role. Early signs of ECM degradation, including elastin degradation and fibrillin fragmentation by MMPs, can be monitored by DES and ISDES in blood plasma or urine. Other  relevant plasma biomarkers are TLR-4 , MMPs 4, FBN1 4, SEF 5050, TGF-βAs stated above , the regMechanobiological cues about (loss of) mechanical homeostasis, we believe, come from measuring the local strain differences across the aTAA . The aorBy computational modelling imaging-based geometry and video strains, we aim to derive patient- and location-specific estimates of aortic wall elastic properties and mechanical stress , as expeFurther in line with our physiological framework, we will consider the associations of (differences in) wall shear stress with (corresponding differences in) observed histological and cell biology findings. Other studies have investigated the association of wall shear stress with histology with some clear outcomes, implicating elevated wall shear stress as a hemodynamic driver of tissue degradation . Our worUltimately, the MAPEX platform—through its direct patient context—is well-suited to identify novel screening or prognostic biomarkers as well as help develop cell-based regenerative therapies.The MAPEX platform approach will allow us to profile mechanistic features at the cell tissue level and correlate these with existing clinical measurements, such as aortic diameter, and global and regional tissue deformation, as well as flow-related parameters derived from 4D-flow MRI.As a multicentre registry and because of its bio- and data-banking nature the MAPEX platform will provide opportunities for implementing multivariate statistics and AI to assess complex multi-scale analyses of the pathophysiological mechanisms.The integration of iPSC-derived VSMCs with 3D and dynamic mechanobiological phenotyping methods may offer patient-specific mechanistic insight into disease variants. Such insight has great potential in personalised screening programs to support and improve patient risk management/prognosis and cell-based/regenerative treatment strategies.The MAPEX platform brings an innovative integration of scientific approaches and methodologies in the field of ascending thoracic aortic disease. The combination of deep phenotyping at histological and cell biology levels with imaging-based wall shear stress and wall strain measurements is a key innovative strength of our MAPEX platform.The integrative interpretation of such data in the direct patient context has real potential of narrowing existing translational gaps and may ultimately improve the clinical management of (a)symptomatic patients with existing and developing thoracic aortic disease.


Non-invasive brain stimulation protocols are effective treatments for depressive episodes. Although the cognitive adverse effects of electroconvulsive therapy (ECT) are well documented, evidence regarding the cognitive effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) is mixed.The aim of this study was to synthesize research on the cognitive effects of non-invasive brain stimulation protocols and to differentiate between studies of major depressive disorder (MDD), bipolar depression and mixed populations.Following a systematic literature search of multiple electronic databases, a series of meta-analyses were conducted to estimate standardized mean differences (SMD) between pre- and post-treatment cognitive functioning across nine cognitive domains. Where possible, SMDs were estimated separately for MDD, bipolar depression and mixed populations. In studies that included both patients with MDD and bipolar depression, the percentage of patients with a diagnosis of bipolar depression was tested as a potential moderator.More than 150 treatment arms were included in the analyses. For ECT, we observed a small decline in language functioning and a decrease in autobiographical memory scores. There was no evidence of pre-post differences across other cognitive domains. For rTMS and tDCS, small to moderate cognitive improvements were observed for several cognitive domains, for example for executive functioning. Across most analyses, between-study heterogeneity was high and could not be accounted for by differences between MDD, bipolar depression or mixed populations.There was limited evidence that differentiation between studies of MDD, bipolar depression and mixed populations accounted for between-study heterogeneity in analyses of pre-post differences in cognitive functioning. Given that most studies included both patients with MDD and bipolar depression, this finding should be treated as preliminary. Across all the treatment protocols examined, more data are needed to investigate the cognitive effects of non-invasive brain stimulation in patients with bipolar depression.None Declared


Escherichia coli and lactic acid bacteria. However, emerging efforts by which to develop synthetic biology toolsets for “nonmodel” resident gut microbes could provide an improved foundation for microbiome engineering. As genome engineering tools come online, so too have novel applications for engineered gut microbes. Engineered resident gut bacteria facilitate investigations of the roles of microbes and their metabolites on host health and allow for potential live microbial biotherapeutics. Due to the rapid pace of discovery in this burgeoning field, this minireview highlights advancements in the genetic engineering of all resident gut microbes.Techniques by which to genetically manipulate members of the microbiota enable both the evaluation of host-microbe interactions and an avenue by which to monitor and modulate human physiology. Genetic engineering applications have traditionally focused on model gut residents, such as  The human gastrointestinal (GI) tract is an important organ system at the nexus of host metabolism, immune system regulation, and host-microbe interactions. The gut is home to trillions of microorganisms that interact with each other and the host to shape this dynamic environment. Many of these microbes are implicated in human health and development, and the alteration of microbial populations is strongly correlated with numerous disease states  1–5). M–5. M1–5)–Escherichia coli and Lactococcous lactis. For example, E. coli has been used as a diagnostic to detect and treat inflammation in mice , secondary bile acids, and antimicrobial peptides, among other potentially beneficial metabolites , 18, 19.Despite these intrinsic advantages, key limitations currently the impede universal adoption of resident gut bacteria as chassis for microbiome engineering applications. Chiefly, most genetic engineering strategies rely on empirical knowledge to introduce, maintain, and manipulate recombinant DNA in a target organism. The challenges of culturing many members of the human microbiome have limited our understanding regarding the genetic composition and metabolic potential of individual species. As a result, the development of genetic tools and engineering strategies has been slow until recent years. New culture techniques, improved microbial ’omics strategies, and increased interest in the gut microbiome has spurred investigations into the physiology of gut microbes, revitalizing engineering attempts . This miE. coli or L. lactis, synthetic circuits can be designed to implement diagnostic biosensors or to create cell-based factories for therapeutic immunomodulatory compounds .–25.20–25–ompounds , 26, 27.ompounds , 28, 29.in situ. The efficient and reliable editing of resident gut microbes can allow for these necessary genotype-to-phenotype studies to mechanistically link microbiome functions to host responses.Traditional methods by which to analyze the taxonomic composition of a microbial community using culturing techniques have largely been replaced by ‘omics profiling, broadly referring to metagenomics, metabolomics, transcriptomics, and proteomics. With ‘omics advancements, researchers can now rapidly assess the composition of complex environmental samples without the need to culture individual species –32. Thes–E. coli, this strategy is infrequently used with other bacterial species and can be challenging to implement with resident gut bacteria, especially obligate anaerobic species   . Howeveria (LAB) . This stia (LAB) , 44. In ia (LAB) . ThroughPlasmid-based systems must also contain selective markers for maintenance within the host. Selection is typically achieved with antibiotic resistance genes or auxotrophic markers so only cells that contain the plasmid survive in growth media supplemented with or deficient in a specific compound, respectively. However, these methods can be challenging to implement in poorly studied resident gut species . PredictAlthough plasmids are an effective tool, their inherent instability, variable copy numbers, incompatible replication origins, and needs for continuous selection pressure are not ideal for some applications , 53. IntBacteroides genus  sites. This strategy has been used to introduce lox sites to model and resident gut hosts where the intron containing the lox site acts as a “landing-pad” for a cargo vector containing complementary lox sites. Integration of the genetic cargo can then be incorporated into the target genome by expressing the Cre recombinase  system, have similarly been developed  and lithocholic acid (LCA), two of the most abundant small molecules in the microbiome in Clostridium scindens, an intractable producer. Then, they optimized and transferred the pathway into Clostridium sporogenes, a genetically tractable producer  and identified the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) as a candidate molecule. Multiple Bacteroides species  were then engineered to produce isoDCA by transferring hydroxysteroid dehydrogenase genes from the Gram-positive anaerobe [Ruminococcus] gnavus. When the engineered strains were introduced to a synthetic consortium in mice, isoDCA concentrations in the gut increased and induced host Treg differentiation , an anti-inflammatory cytokine, to ameliorate colitis in mouse models , uses signal peptides to deliver IL-10 to mucosal surfaces in mouse models of colitis . As a result, when the microbe was deprived of thymidine and thymine, a significant drop in viability was shown  biosensors that can detect markers of inflammation and intestinal bleeding in animal models (Bacteroides species and has identified and characterized new promoter-based systems by using both computational and functional methods (Engineered resident gut microbes are well-suited for gut-related disease diagnostics. Bacteria are naturally adept at sensing their environments, and resident gut bacteria can safely colonize and persist in the gut, making them a viable solution to monitor patients with chronic gut disorders. Initial forays into developing microbial diagnostics led to the creation of l models , 10, 107 methods , 23, 108 methods .E. coli Nissle 1917 biotherapeutic developed to treat PKU only expresses the necessary enzymes to degrade phenylalanine under anaerobic conditions (E. coli Nissle 1917 was also engineered to detect thiosulfate and release immunomodulatory AvCystatin to treat inflammation in vivo (E. coli targeted to sense and kill various bacterial pathogens have been created to activate in response to specific quorum-sensing molecules or markers of inflammation (in vivo (By merging diagnostic sensor systems with therapeutic production pathways, microbial “sentinel cells” can be engineered to sense and respond to disease . Sentinenditions , 95. Recammation , 110. Ad(in vivo . ComplemWith the inherent advantages of resident gut bacteria and an increasing number of genetic manipulation techniques being developed, resident gut sentinels could also address issues beyond inflammation and specific metabolic disorders. Based on their natural interactions with the host immune system, resident gut sentinel bacteria could be applied to the domain of immunoengineering for applications such as the treatment of autoimmune and inflammatory diseases as well as cancer. Furthermore, the gut-brain axis is another exciting area of research that could benefit from detailed mechanistic studies and sentinel monitoring enabled by gut symbiont engineering .The burgeoning interest in microbiome research necessitates the creation of additional experimental tools for resident gut microbes. When new microbe-disease associations are uncovered, a roadmap should be in place to quickly develop genetic tools to domesticate the relevant resident gut organism and to understand its mechanistic interactions with the microbiota and the host , 113. ReThe advancements of genomic tools for manipulating gut microbes have spurred the investigation into the mechanistic relationship between the host and the microbiome and have inspired the exploration of live biotherapeutics as viable treatments to mitigate disease. The published examples and proof-of-concept studies outlined in this minireview demonstrate the efficacy and potential for resident gut bacteria as target organisms for microbiome engineering and synthetic biology. The discoveries of additional genetic tools and the novel applications of the use of resident gut bacteria as engineering targets are critical to maintaining the momentum of the field and ensuring that bacterial diagnostics, therapeutics, and sentinel systems achieve their full potential.


The past decade has seen major advances in our understanding of how genetic disorders alter blood-brain barrier (BBB), blood-retinal barrier (BRB) and blood-CSF barrier (BCSFB) function. This has involved studies on patients but also on in vitro models derived from patient samples. Thus, human-induced pluripotent stem cells (iPSCs) used to derive neurovascular unit (NVU) cell types, including brain microvascular endothelial cell (BMEC)-like cells, are an important tool for examining the effects of patient-specific mutations. In addition, gene deletion and overexpression studies in animals and cells are extremely important in dissecting protein- and cell-specific effects on normal BBB/BCSFB function and pathology. They help to provide evidence that BBB and BCSFB dysfunction contributes to neural dysfunction in many neurological conditions . Although most studies continue to focus on the impact of gene mutations or deletions, the field of epigenetics has burgeoned providing insights into another level of barrier regulation. While these studies have focused on the effects of genetics/epigenetics on barrier function, it should be noted that normal barrier function is a major impediment to the treatment of genetic disorders impacting the CNS. For example, while enzyme replacement therapies can alleviate the peripheral symptoms of some lysosomal storage disorders, current protein-based therapies do not sufficiently penetrate the BBB to improve CNS pathologies.Fluids and Barriers of the CNS launched a thematic series entitled, ‘Genetic Disorders and Genetic Manipulation at the Blood-Brain Barriers’. It provides original research and reviews on these topics as outlined below.To reflect these fields of interest, Haploinsufficiency of the BBB glucose transporter, GLUT1, has profound effects on brain development. However, the effects of other genetic mutations on the BBB, the NVU and the BCSFB may be more subtle making it difficult to determine their role in overall neurological dysfunction. Claudin-5 has an essential role in brain endothelial tight junctions and BBB function. Hashimoto et al.  review rFolate transport occurs via folate receptor-alpha, the reduced folate carrier and the proton-coupled folate transporter. Folate is essential for normal neurodevelopment and transporter mutations can cause cerebral folate deficiency. Blood-CSF barrier transport at the choroid plexus plays a central role in brain folate homeostasis but results from Sangha et al.  indicateBrain endothelial mitochondrial dysfunction occurs in multiple neurological conditions (including stroke and Alzheimer’s disease). Lee et al.  used TEKXu et al.  examinedWhile there is increasing evidence for a role of BBB, NVU and BCSFB dysfunction in many genetic disorders affecting the CNS, it seems likely that neonatal jaundice (hyperbilirubinemia) does not impact BBB and BCSFB function in rats. Blondel et al.  examinedGene deletion/overexpression studies have been used to examine the role of particular proteins at the BBB, NVU, BCSFB and the blood-retinal barriers. Goncalves & Antonetti  review cHe et al.  have useSuch animal studies have generally been with rodents and particularly mice. It should be noted that Schaffenrath et al.  found BBvitro using HIF-1 siRNA. That group then expanded their studies to in vivo using cell-specific inducible knockouts [Genetic manipulations can be performed both in vitro and in vivo. Baumann et al.  found thnockouts  and founnockouts  have exaWithin the NVU, the importance of the extracellular matrix, including proteins such as laminin, has been underappreciated. This is changing thanks largely to the results of gene deletion studies showing marked effects on BBB function. Halder et al.  review sWhile genetic disorders may directly impact the BBB/NVU, they may also make the BBB/NVU susceptible to other injuries. Thus, Clark et al.  found thCompared to the BBB/NVU, there has been a relative paucity of studies using genetic manipulations of the choroid plexus epithelium. Jang & Lehtinen  review cEpigenetics is a growing field of barrier research. Ihezie et al.  review tThe BBB remains an enormous obstacle to treating neurological diseases, including genetic disorders. While there has been great growth in the field of biologics to treat human diseases, those agents very seldom cross the BBB. For example, proteins normally have very low BBB permeabilities and much research has focused on enhancing uptake. Sahin et al.  discuss In conclusion, this thematic series shows the breadth of ongoing studies examining the effects of genetic disorders on the BBB/NVU, using genetic manipulations to understand BBB, BRB and BCSFB physiology and pathology, exploring epigenetic regulation, and devising ways to allow therapeutics to enter the brain to treat CNS genetic disorders. It is hoped that such investigations and our greater understanding will help develop treatments for CNS genetic disorders and other neurological conditions.


Pharyngeal pressure generated by approximation of the base of tongue to the posterior pharyngeal wall (BOT-PPW approximation) is critical for efficient pharyngeal bolus passage and is a frequent goal of dysphagia management. This scoping review evaluated behavioral interventions available to improve BOT-PPW approximation. We searched MEDLINE, CINAHL, Ovid Emcare, Web of Science, SCOPUS, and ProQuest for studies that met the following criteria: (i) behavioral interventions targeting BOT-PPW approximation, which (ii) were assessed using BOT-PPW-specific outcome measures, and (iiia) performed over a period of time (Review Part 1) or (iiib) studied immediate effects (Review Part 2). Study quality was rated using the GRADE framework. Data were extracted and synthesized into dominant themes. Of the 150 studies originally identified, three examined long-term effects . BOT-PPW approximation only increased in the two single case studies. Twenty-one studies evaluating immediate effects were categorized as follows: (1) effortful swallowing, (2) Mendelsohn maneuver, (3) tongue-hold maneuver, (4) super supraglottic swallowing maneuver, and (5) non-swallowing exercises. Across all studies, varying levels of success in increasing BOT-PPW approximation were reported. Four of 21 immediate effects studies evaluated patients with demonstrated swallowing impairment, whereas 17 studies evaluated healthy adults. Quality assessment revealed low strength of the existing evidence base. The evidence base for rehabilitative interventions targeting BOT-PPW approximation is severely limited and translation is hindered by small sample sizes and methodological limitations. Further clinical research is warranted. Impaired swallowing (dysphagia) is a common consequence of many health conditions, including stroke , neurodeA common biomechanical characteristic of dysphagia is impaired approximation of the base of tongue (BOT) and the posterior pharyngeal wall (PPW) in the upper pharynx . While iOf note, even though the sequence of muscle contraction in the pharyngeal phase of swallowing is governed by central pattern generators in the brainstem , BOT-PPWWhile some previous reviews have focused on the biomechanical or functional effects of a specific, single intervention (for example ), to datWe adopted a scoping review methodology to evaluate the existing evidence base for interventions targeting BOT-PPW approximation and mapped the key characteristics of these interventions .We designed the original search in Medline, tested the search with a few key articles, finalized the search, and performed it in Ovid Medline. The master search was then translated into five more databases, CINAHL, Ovid Encare, Web of Science, Scopus, and Proquest . The search was undertaken on 17th June 2021, with an updated search carried out on 02nd February 2022 to ensure inclusion of the most recent relevant publications. No limitations were imposed on publication date, and only studies reporting original data, published in English, were included.The search terms included swallowing disorders, behavioral interventions, rehabilitation exercises, and terms relating to base of tongue to posterior to pharyngeal wall contact Table . We exclReview Part 1 focused on publications that (i). reported on outcome measures specifically representing BOT-PPW approximation, (ii). reported on a behavioral intervention, and (iii). that behavioral intervention had been implemented over a period of time in a rehabilitative approach .All publications identified across the six databases were imported into the software platform Covidence for screening . In addiDue to the very small number of studies identified in this initial screening, we repeated the screening process with a re-focused scope, including studies that reported on the immediate effects of interventions that were performed in a one-off manner and had a ‘proof of concept’ focus:during performance of that intervention in a one-off session .Review Part 2 focused on inclusion of publications that (i). reported on outcome measures specifically representing BOT-PPW approximation, (ii). reported on a behavioral intervention, and (iii). the effects of that behavioral intervention were investigated by the patient  as opposed to interventions that are performed on the patient, . The potential role of surgical, medical, or neuro-stimulation approaches in rehabilitating swallowing function is acknowledged. However, the intent of this scoping review was to collate the evidence base for behavioral interventions that can be completed by patients themselves. Therefore, studies were excluded if they (i) described a surgical or other medical intervention, (ii) did not directly report on objective outcome measures biomechanically representing BOT-PPW approximation , (iii) involved brain, magnetic, or electric stimulation, or (iv) provided no experimental primary data .For the purpose of both Review Parts, we defined behavioral intervention as an exercise that was actively and repeatedly performed Title and abstract screening, as well as full-text screening for both Review Parts were undertaken independently by two researchers, who were blinded to the other reviewer’s recommendation. Any conflicts were resolved by consensus. Studies that met the inclusion criteria proceeded to data extraction for each Review Part.For both Review Parts, data from included studies were extracted and collated in an Excel document by at least two researchers, who resolved any conflicts by consensus. Data relating to study design, participant characteristics , intervention evaluated, and BOT-PPW approximation outcome measures reported on were extracted Tables  and 3. WIn order to answer the primary research question, we grouped the characteristics of the reported interventions into broader themes that best captured similarities and differences across interventions. This was undertaken in an iterative cycle of refinement through discussion by the research team.Two assessors independently assessed the risk of bias of each included study using the critical appraisal tools from the Joanna Briggs Institute (JBI) , with anAfter deduplication, 150 studies underwent title and abstract screening in the Covidence software, of which 17 studies proceeded to full-text screening for Review Part 1 and 33 studies for Review Part 2. Of these, three studies met the inclusion criteria for Review Part 1 and 21 studies for Review Part 2 .Table Due to the lack of a strong evidence for the long-term effects of behavioral interventions targeting BOT-PPW approximation, we expanded the scope of this review to include investigations that evaluated the immediate effects of any behavioral interventions on BOT-PPW approximation, providing preliminary proof of concept support for their potential clinical utility. Table As outlined in Fig. n = 299) using pressure-based outcome measures (pressure peak or pressure duration) (n = 11 studies) [n = 1 study) [As a well-established and widely researched swallowing strategy, the effortful swallow is designed to increase global effort during swallowing by means of increased muscle contraction during the pharyngeal phase of swallowing . Fifteenstudies) , 35, 37 1 study) . Three s1 study) , 33, 36.1 study)  using lo1 study)  or compaAs outlined in Table Overall, the evidence base for the effortful swallow included the largest number of studies in our Review Part 2 of immediate effects on BOT-PPW approximation. However, these should be considered in the context of the overall strength of the evidence base, noting that all 15 studies were rated as “low” or “very low” quality based on the GRADE framework. While robust in their design as within-subject evaluations, they only provide evidence for a compensatory use of effortful swallowing in modifying swallowing biomechanics and mostly in healthy individuals. It is, therefore, impossible to extrapolate these findings to clinical populations with impaired BOT-PPW approximation, for whom the effortful swallow is often recommended clinically as a rehabilitative strategy.n = 54), of which one reported increased BOT-PPW approximation [The Mendelsohn maneuver refers to the voluntary prolongation of maximal hyolaryngeal elevation during swallowing . Four stximation  based onximation . The thiximation . The fouximation .Overall, the evidence base for this maneuver in the context of BOT-PPW approximation is weak and proof of concept studies in healthy participants contradictory. Biomechanically, it stands to reason that prolonged hyolaryngeal elevation during maneuver swallows would require increased and prolonged effort and may, therefore, synergistically modulate other biomechanical aspects of the pharyngeal swallow, including pressure generation at the level of the BOT. However, in the studies included in this review, maneuver swallows did not appear to consistently translate to increased peak pressure and pressure duration at this level, at least in healthy volunteers and when measured during maneuver swallows. Therefore, at present, it is not possible to draw strong conclusions from these findings as to whether the Mendelsohn maneuver may improve impaired BOT-PPW approximation in patients with dysphagia, e.g., if performed repeatedly over a period of time. Future high-quality research is required to evaluate its efficacy in this context.n = 161) [Increased PPW contraction may be targeted to compensate for reduced BOT retraction . As suchn = 161) , 40–43. n = 161) , 42 and n = 161) . In thren = 161) ).It is perhaps not surprising that BOT-PPW contact pressures were decreased during tongue-hold swallows in healthy volunteers, as the anterior positioning of the BOT biomechanically limits BOT retraction during swallowing. For this reason, it has been suggested that the tongue-hold exercise should not be used during bolus swallows, as the reduced posterior retraction, and resulting reduced BOT-PPW contact pressure are likely to impede pharyngeal bolus flow , 41. Of The super supraglottic swallow maneuver was originally designed to improve laryngeal valving during swallowing, particularly for individuals who had undergone a supraglottic laryngectomy . IndividIt is worth noting that although this maneuver was originally designed as a compensatory maneuver, it has been postulated that it could also be used as an exercise to improve BOT retraction . To dateWhile 20 of the 21 studies included in Review Part 2 investigated the effects of swallowing-related interventions on BOT-PPW approximation, one study evaluated the effects of maneuvers that target BOT retraction outside of the context of swallowing . These mAlthough these maneuvers were performed outside of the context of swallowing, it is worth considering that increased BOT posterior movement during these maneuvers may, if performed repeatedly over time, have a cumulative effect on BOT-PPW approximation. This may translate into improved pharyngeal pressure generation during swallowing, with positive effects on bolus clearance. Of note, it is likely that such potential benefits would primarily be driven by increased contractile strength of the BOT and PPW musculature, and perhaps less so by task-specific neuroplastic reorganization in swallowing-related cortical motor networks. The latter is more likely to contribute to functional changes observed following exercises executed during swallowing tasks, because such exercises address the neuroplastic principle of specificity, which non-swallowing exercises do not . Future (i)Only three studies evaluated the effects of long-term, repeated intervention paradigms, of which two were single case studies of individuals with dysphagia and one was an RCT of 20 healthy controls (Review Part 1).(ii)n = 17) studied healthy participants . Only four studies involved participants with dysphagia .In Review Part 2, 21 studies were included, which evaluated the immediate effects of primarily effort-based maneuvers. The majority of these ((iii)Across both Review Parts, all but one study were within-subject evaluations, mostly of healthy individuals, which provide solid proof of concept evidence for the possibility of behavioral modification of BOT-PPW approximation. However, in terms of the clinical applicability and generalizability of the existing evidence base to long-term clinical improvement, the overall strength of this evidence base in alignment with the GRADE framework is considered weak.In summary, the following key observations were made in relation to the available evidence base, which may aide the reader in their clinical evaluation and decision making:This scoping review evaluated the literature for behavioral interventions that aim to improve BOT-PPW approximation, either via repeated performance of an exercise regimen over time (Review Part 1) or in terms of the immediate effects demonstrated during execution of the maneuver (Review Part 2). This information is important to inform clinical dysphagia management decisions and hence was collated through a systematic search of the evidence base. Overall, this review demonstrates that there is a large body of research suggesting that BOT-PPW approximation can, in principle, be modified using several, in particular effort-based, behavioral maneuvers. However, there is little to no evidence documenting the effects of long-term exercise regimens in patients with dysphagia. In addition to the summary and interpretation of findings outlined above for each intervention type, in the following, we raise several broader issues that sit across both Review Parts and all intervention types for consideration in clinical practice and future research.Only three studies were identified that evaluated the effects of long-term exercise regimens on BOT-PPW approximation, including two single case studies , 23 and We identified five types of interventions, which included (1) effortful swallowing, (2) Mendelsohn maneuver, (3) tongue-hold maneuver, (4) super supraglottic swallowing maneuver, and (5) non-swallowing exercises that demonstrated immediate effects during execution of maneuvers. Four of these intervention types are executed in the context of swallowing and aim to increase BOT-PPW approximation primarily via increased peak effort or longer effort duration, or manipulation of anatomical position of the tongue, which in turn stimulates a more effortful contraction of the PPW to compensate. The fifth intervention type is characterized by movements that occur outside the context of swallowing, but similarly aim at increasing muscle strength through posterior movement of the tongue.It stands to reason that volitionally increasing contractile strength and vigor during swallowing would modify BOT-PPW approximation through synergistic modulation of muscle contraction across the swallowing network that is governed by central pattern generators in the brainstem and modifiable by cortical sensorimotor networks . As suchThe proof of concept evidence collated in this review largely appears to support the notion that cortically driven modulation of the swallowing motor response may yield beneficial biomechanical effects downstream. It is likely that for many patients with dysphagia who present with instrumentally demonstrated reduction of BOT-PPW approximation, and related pharyngeal bolus residue, effort-based maneuvers may, in principle, increase BOT-PPW approximation and in turn reduce pharyngeal residue. However, as outlined in Review Part 1, there is virtually no empirical evidence to support this hypothesis, and therefore, we propose that this should be an urgent key focus of future clinical research.We also raise the following point for consideration: it is unlikely that reduced BOT-PPW approximation is always the result of pharyngeal tongue weakness in patients with this biomechanical impairment. It is possible that in some individuals, heightened muscle tone and/or spasticity lead to the reduced dynamic movement of these structures during swallowing. For these patients, interventions focusing on increased effort will likely exacerbate their swallowing impairment, and therefore, diagnostic precision is critical in developing tailored dysphagia management plans.Most studies included in this review utilized quantitative assessment methods, primarily manometric, to evaluate changes in BOT-PPW approximation, using peak pressure or pressure duration as proxy measures for the contact of these structures during swallowing. Using objective, quantitative outcome measures are critical, as secondary functional outcome measures, such as pharyngeal bolus flow, degree of penetration or aspiration, or amount and location of residue are more meaningful in the context of clearly characterized changes in the underlying biomechanical processes. In addition, it is critical that future research evaluates individuals who present with the specific biomechanical swallowing impairment that the exercise is designed to target and that this impairment  be instrumentally confirmed prior to inclusion in the research. While proof of concept studies in healthy controls can demonstrate immediate biomechanical changes, their use in determining longer term effects is limited as in an unimpaired system with optimized BOT-PPW approximation, there is little physiologic need, or scope, for change.In the majority of included studies, BOT-PPW approximation metrics were assessed using low- or high-resolution pharyngeal manometry, or VFSS Table . Across In addition, we propose that future clinical research exploring the effects of long-term treatment regimens may consider using assessment tools that can simultaneously evaluate changes in BOT-PPW approximation and corresponding effects on bolus flow. It is possible that the limitations of quantifying BOT-PPW approximation using videofluoroscopy alone may have contributed to the lack of evidence for this important biomechanical bolus driving force. HRM with impedance or videomanometry can both contribute this information to the evidence base. Intervention studies using HRM with impedance or videomanometry are critical in populations with instrumentally confirmed BOT-PPW approximation impairment, given that previous research has documented the critical role of upper pharyngeal pressure in generating the bolus driving forces that facilitate bolus passage across the UES . Due to Given the small number of clinical intervention studies identified in this review, it is at this stage not possible to form a clear recommendation for or against any of the identified exercises. As outlined in Tables The inability to make definitive clinical recommendations on the basis of this review highlights the importance of future clinical intervention research in this space. This is a key requirement to facilitate the translation of the proof of concept research evidence base in healthy participants, which demonstrates promising potential for several intervention approaches, into clinically useful application. The challenges of clinical research in this space are acknowledged and likely relate to the recruitment of participants with dysphagia due to homogenous medical conditions and the availability of instrumental assessments in clinical research contexts. Only two clinical studies which reported biomechanical outcome measures also reported clinical outcomes. We propose that future clinical studies should report both clinical outcome measures such as residue, penetration or aspiration, as well as objective measures that qualitatively characterize biomechanical changes as primary outcomes. Collaboration of multiple clinical sites will likely facilitate future research that uses clearly defined clinical research protocols in patients presenting with dysphagia characterized by impaired BOT-PPW approximation. Clinical trials in patient populations are particularly important as there is little need for physiologic change in unimpaired systems, and translation of any effects found in an unimpaired system to dysphagic populations is limited.We acknowledge that, although non-traditional, the focus of this review was intentionally twofold, focusing both on long-term and immediate effects of interventions claiming to target BOT-PPW approximation. We limited the inclusion of studies to those directly reporting on primary biomechanical outcome measures that represent BOT-PPW approximation. We excluded any studies that reported on related, secondary outcome measures, e.g., pharyngeal residue or degree of penetration/aspiration, if no primary outcome measures were reported. This may slightly underestimate the existing evidence base but was considered important in the context of answering the research question. Second, only studies published in English were included, possibly resulting in some relevant research published in other languages being overlooked.This review identified five broad intervention types addressing BOT-PPW approximation, most of which have been evaluated for their immediate, compensatory effects on pharyngeal swallowing biomechanics in healthy individuals. Overall, the evidence base for these interventions is weak, necessitating further high-quality research to address current limitations. Exploring longer term intervention protocols in populations with demonstrated BOT-PPW approximation impairment will facilitate transfer into clinical application.


Drosophila have led the way in advancing molecular understanding of axon degeneration and nerve injury pathways. Both neuron-intrinsic as well as glial responses to injury will be highlighted. Finally, we will offer perspective on what additional questions should be answered to advance these discoveries toward clinical interventions for patients with neuropathy.The degeneration of axons and their terminals occurs following traumatic, toxic, or genetically-induced insults. Common molecular mechanisms unite these disparate triggers to execute a conserved nerve degeneration cascade. In this review, we will discuss how models of peripheral nerve injury and neuropathy in  Peripheral nerve damage and subsequent degeneration of axons occurs in a diverse group of syndromes and, taken together, makes peripheral neuropathy one of the most frequent human neurodegenerative conditions . Periphein vitro and in vivo in many organisms (s) mouse phenotype and, later, the responsible genomic alteration  ] . These dNMNAT1)]  and led NMNAT1)] .Drosophila melanogaster has led the way in identifying the molecular pathways downstream of axon injury that result in axonal fragmentation and disassembly. Using fly models of genetic, traumatic, or toxic nerve injury, mutations in multiple fly genes including Drosophilasterile alpha and TIR motif containing protein (dSarm), highwire (hiw), and wallenda (wnd) genes were first identified as axo-protective  focus will be on peripheral nerve injuries and disease models in Drosophila, though axon degeneration certainly occurs in central nervous system disorders such as Alzheimer’s Disease and tauopathies , early candidate approaches and unbiased screens identified Wallerian degeneration factors such as dSarm1 and Wallenda . In a pa factors .dSarm) is widely appreciated to be the “central executioner” for axon degeneration  repeat domain and promotes Sarm1 activation. As the NMN/NAD+ ratio increases, Sarm1 activity also increases  Wallenda/DLK  in mammals] and Wallenda [dual leucine zipper kinase 1 (Dlk1) in mammals] also promote injury-induced degeneration and were first recognized for this role using injuries in the fly larval segmental nerves and the olfactory nerves, respectively . Work inenda/DLK . Downstred axons .Drosophila can also be initiated by treatment with drugs that induce nerve damage. For example, in humans, microtubule-disrupting components of conventional chemotherapy cocktails disrupt axon transport in long axons, leading to their demise. Using the drug paclitaxel (taxol) to trigger peripheral axon degeneration in Drosophila larvae, additional neuronal axon degeneration factors were identified including membrane occupation and recognition nexus 4 (MORN4) and transmembrane protein 184b (TMEM184B) (Axon degeneration in MEM184B) , 2016. HDrosophila subperineurial glia also have engulfment functions in both development and disease  and TGFβ signaling, respectively , barrier function , synaptic regulation (astrocyte-like glia) and neuronal cell body contacts (cortex glia) . Drosoph disease . In the ectively .Drosophila glial surface receptor Draper initiates the phagocytic pathway involved in severed axon clearance  syndrome have yielded important insights into the pathological mechanisms causing sensory and motor neuropathy. CMT is linked to mutations in over 100 genes (Drosophila models of CMT2-associated mutations in Mitofusin2 (MFN2), have revealed that both loss- and gain-of-function human variants of MFN2 cause CMT-associated neurodegeneration and have implicated excessive mitochondrial fusion and disrupted mitochondria-ER contacts in disease pathogenesis  protein; these models also exhibit motor neuron death. By taking advantage of the extremely well-described trajectory of motor neuron cell fate decisions during Drosophila embryonic development , which causes motor neuron loss, can be modeled in elopment , Grice aelopment , 2022 weDrosophila findings to mammalian systems should be considered. First, Drosophila do not myelinate their nerves. In some peripheral neuropathies such as CMT Type 1A, Schwann cell disruption by mutations in peripheral myelin protein 22 (PMP22) or myelin protein zero (MPZ) cause secondary axon degeneration , which can later progress to numbness. Inter-epidermal nerve fibers in the skin that subserve these sensations can show dystrophic terminals and withdrawal from the epidermis . Patientn humans . This phn humans . Thus th+ depletion  on the surface of injured dendrites to recruit phagocytic cells, and finally an ultra-low NAD+ level that causes dendrite breakdown independent of phagocytosis  to evaluate the pathways leading to motor neuron dysfunction and loss  as a cause of ALS, and this alteration has since been appreciated to be the most common genetic alteration in sporadic ALS cases . While ntoxicity . Drosophed cells . For exaed cells , 2018. Mhenotype .in vivo is substantial. In contrast, Drosophila is a simple and powerful system in which genetic manipulations are simple and time-efficient, and appropriate disease models (such as those described above) are easily identified. Because it is predicted that roughly 65% of human disease genes have orthologs in Drosophila , either alone or in the background of a disease model. The costs and time associated with doing these rigorous experiments in mice osophila , the flyosophila .Drosophila model in which the orthologs (Sord1 and Sord2) were disrupted, the authors showed not only that the role of SORD in axon maintenance is conserved but that a pharmacological reversal of the phenotype is possible  of the human genes, or directly modifying the analogous amino acids in the fly ortholog via CRISPR. To give a few examples: Sorbitol dehydrogenase (SORD) homozygous mutations were recently identified in a cohort of patients clinically diagnosed with CMT. By creating a possible . In anotpossible . To modecomotion . These rDrosophila has become appreciated as one of the best models for understanding both neuron-intrinsic and extrinsic contributions to peripheral nerve maintenance and pathological forms of peripheral nerve loss. The number of human genomics studies who complete their first in vivo validations in Drosophila is growing. Additionally, a network of laboratories has united to use model organisms as rare disease profiling platforms, with Drosophila as one of the leaders in this movement (in vivo screening for enhancers and suppressors of nerve degeneration and cell loss.Considering the advantages in accessibility, cost, and evolutionary conservation described above, movement . For morDrosophila is to unite our understanding of how glial cells contribute to axonal damage responses. This field is still in its infancy. However, because of the conservation of functions of glia in Drosophila and mammals, glial-neuronal communication can be addressed well in flies using advanced genetic tools and forward screening approaches (A goal for future work on nerve injury in proaches . AnotherDrosophila to identify and characterize factors contributing to axon, dendrite, and synapse disruption will continue to keep flies at the leading edge of discoveries that, in turn, will improve our ability to mitigate the suffering of patients suffering from peripheral neuropathy.As mentioned above, caveats do exist for this model involving lack of myelination or an adaptive immune system. However, the myriad advantages of using MB performed the research, wrote the manuscript, and approved the submitted version.


Adipokines are signaling proteins involved in metabolic, endocrinological, vascular and immunogenic processes. Associations of various adipokines with not only insulin resistance but also with increased insulin sensitivity, increased systolic blood pressure, and atherosclerosis highlight the significance of adipokines in several components of metabolic syndrome and metabolic diseases in general. As pregnancy presents a unique metabolic state, the role of adipokines in pregnancy, and even in various pregnancy complications, appears to be key to elucidating these metabolic processes. Many studies in recent years have attempted to clarify the role of adipokines in pregnancy and gestational pathologies. In this review, we aim to investigate the changes in maternal adipokine levels in physiological gestation, as well as the association of adipokines with pregnancy pathologies, such as gestational diabetes mellitus (GDM) and preeclampsia (PE). Furthermore, we will analyze the association of adipokines in both maternal serum and cord blood with parameters of intrauterine growth and various pregnancy outcomes. Pregnancy is a unique state accompanied by various alterations in physiological metabolic, endocrinological, vascular and immunogenic processes. These alterations create an optimal environment for the fetus and allow for appropriate fetal development. While higher insulin secretion and largely stable insulin sensitivity are physiologically associated with the first trimester of pregnancy, metabolic and endocrinological processes during the second and third trimesters are characterized by insulin resistance and, therefore, relatively insufficient insulin secretion. This phenomenon is physiologically countered through hypertrophy or hyperplasia of the pancreatic β-cells and subsequently elevated insulin secretion . When thAdequate intrauterine and placental perfusion are maintained by proper placentation, appropriate development of placental blood vessels and sufficient intrauterine blood supply. This is facilitated in part by a physiological decrease in maternal median blood pressure and an increase in maternal plasma volume. Defective placentation, which is thought to cause placental dysfunction, is associated with both fetal and maternal complications of pregnancy, as it can lead to insufficient fetal blood supply, as well as hypertensive disorders of pregnancy on the maternal side.Adverse intrauterine conditions can lead to insufficient oxygen and nutrient (among others) supply of the fetus and interfere with intrauterine growth, and therefore to possible intrauterine growth restriction (IUGR). It is, therefore, imperative to closely examine these adapted processes to better understand the pathophysiology behind common pregnancy diseases. In this regard, adipokines present an interesting cross-link between physiological pregnancy adaptations and pathological processes. Particularly of interest is the function of these secretory proteins in metabolic processes throughout pregnancy and the fetal period. While adipokines such as leptin and adiponectin have been intensively researched over the last twenty years, novel adipokines such as progranulin and neuregulin have only recently emerged as possible biomarkers in pregnancy and the perinatal period. In this review, we aim to investigate the changes in maternal adipokine levels in physiological gestation, as well as the association of adipokines with pregnancy pathologies such as gestational diabetes mellitus (GDM) and preeclampsia (PE). For this purpose, we will examine eleven novel adipokines that have been the subject of such studies since 2010. The adipokines considered in this review include resistin, chemerin, retinol-binding-protein 4 (RBP4), growth differentiation factor 15 (GDF15), irisin, adipocyte fatty-acid-binding protein (AFABP), omentin-1, lipocalin-2, visfatin, neuregulin 4 (NRG4) and progranulin. We will focus on their role in physiological pregnancy, pregnancy complications and pregnancy outcomes.Ever since J.M. Friedman’s laboratory discovered leptin in 1994, the role of adipokines in various metabolic, vascular and immunogenic processes has been recognized. Adipokines are a vast group of signaling proteins and mediators secreted primarily from adipose tissue . Pro-infGestational diabetes mellitus (GDM) is a metabolic disorder that affects approximately 2–10% of pregnancies in the USA and Europe, and is characterized by glucose intolerance and maternal hyperglycemia with initial onset during pregnancy . During Preeclampsia (PE) is a serious pregnancy condition associated with elevated blood pressure, which is first diagnosed during pregnancy, proteinuria, edema and other signs of organ dysfunction. While the exact pathophysiology of preeclampsia is still the subject of current research, it is generally accepted that the root of the problem starts with faulty placentation and defective placental blood vessel development. This is often accompanied by a general endothelial dysfunction, which can affect multiple organ systems, and can overall lead to an insufficient blood supply of the placenta and, in turn, the fetus. Preeclampsia and other hypertensive gestational disorders are also associated with higher mortality for both mother and infant. Since the only causal therapy is premature delivery of the baby, research regarding prevention and early diagnosis is key.“The fetal origin of adult disease” was first coined by David Barker in 1990 . His theA key common denominator of abnormal birthweight, PE and GDM is the heightened risk of prospective cardiovascular and metabolic diseases, including metabolic syndrome in offspring ,7,8. ConWe searched PubMed/MEDLINE databases for published studies considering the adipokines resistin, chemerin, RBP4, GDF15, irisin, AFABP, omentin-1, lipocalin-2, visfatin, NRG4 and progranulin in gestational diabetes from 2013 through February of 2023, and, due to their smaller number, studies considering the aforementioned adipokines and preeclampsia or intrauterine growth from 2010 through February of 2023. We excluded studies that either assessed women with all types of diabetes and not GDM specifically, studies based on mRNA expression, in vitro or cell culture studies, editorials and comments, animal model studies, studies that considered adipokine levels in materials other than blood, serum or plasma, and studies which failed to report the number of cases and/or controls. Of the 133 articles yielded with this search, 122 studies relating to adipokines and pregnancy met our criteria and were included in this review. We also included a summary of all the studies that we reference throughout this article in the form of a table see .Resistin is an insulin resistance-inducing adipokine. It has been found to play a role in the development of GDM , is exprThere are conflicting reports on the dynamic of resistin levels in physiological pregnancy. A multicenter prospective study on 232 Saudi women showed that resistin levels decreased significantly from the first to the second trimester in healthy pregnant women . The oveNumerous studies have analyzed resistin levels in GDM pregnancies. Five studies, including two case-control studies, two cohort studies and a prospective observational study with 133, 80, 236, 480 and 196 participants, respectively, as well as one meta-analysis including 11 studies, found no significant difference in resistin levels between GDM and non-GDM pregnant controls ,19,20,21The relationship between resistin concentrations and PE has also been tackled in recent years. Here, the results seem to be slightly more homogenous. Five studies with 91, 196, 40, 153 and 60 participants, respectively, reported increased resistin serum levels in PE pregnancies in comparison to healthy pregnant controls ,30,31. AIn regard to parameters of intrauterine growth, one case-control study with 153 participants found maternal serum resistin levels to correlate negatively with child weight at birth; however, no association was found between maternal resistin levels and maternal BMI . In addiThe analysis of resistin levels in cord blood at birth also yielded several interesting results. A case-control study with 73 participants found cord resistin levels to be significantly lower in the offspring of mothers who had GDM in comparison to healthy controls . Higher Resistin appears to play an important role in GDM and possibly the pathogenesis of impaired glucose tolerance, and increased maternal resistin levels could be associated with the presence of maternal PE. Further studies are required in order to establish the possibility of using resistin as a biomarker for various pregnancy outcomes.Chemerin is also known as retinoic acid receptor responder protein 2 (RARRES 2). It is mainly expressed in adipocytes, hepatocytes and pneumocytes. The pro-inflammatory properties of chemerin stem from its stimulation of the chemotaxis of macrophages and dendritic cells. Chemerin has also been found to have insulin resistance-inducing properties and to correlate positively with BMI and HOMA-IR .Three separate studies, including two cross-sectional cohort studies with 222 and 212 women, respectively, as well as one case-control study with a total of 17 subjects, reported elevated chemerin levels in the serum of healthy mothers during pregnancy ,36,37. INumerous studies have looked at chemerin levels in maternal serum in cases of GDM. The results are very heterogeneous; five studies, including two meta-analyses, did not find a significant difference in chemerin levels between GDM mothers and healthy pregnant controls ,38,39,40With regard to PE, reports were much more uniform. Two case-control studies, two cohort studies, one cross-sectional study, as well as one systemic review found chemerin levels in maternal serum to be significantly elevated in patients with PE ,50,51,52Elevated chemerin levels in maternal serum were not only associated with GDM and PE pregnancies, but were also positively associated with fetal weight . Cetin eIn an observational study by Van Poppel et al., chemerin concentrations in arterial cord blood were elevated in the offspring of GDM mothers, while concentrations in venous cord blood were elevated in the offspring of obese mothers . ThroughIn summary, chemerin appears to be significantly increased in PE, while changes in chemerin levels in patients with GDM vary between studies. The association of both maternal and cord chemerin with birthweight also remains unclear; further studies are necessary in order to pinpoint the role of chemerin in intrauterine growth.RBP4 is a known member of the lipocalin family and is expressed mainly by adipocytes and hepatocytes. While RBP4 appears to be independent of BMI, it has been associated with obesity and insulin resistance .While changes in RBP 4 levels during physiological pregnancy have not yet been investigated, several studies examining its levels in gestational pathologies such as GDM and PE have been published in recent years. Two cohort studies found increased levels of RBP4 in maternal serum in GDM pregnancies in comparison to normal healthy gestations ,55, and In studies concerning PE, results were varying. One case-control study found significantly lower maternal RBP4 levels in PE pregnancies compared to healthy gestations . A retroMaternal RBP4 levels might also be associated with various parameters of intrauterine growth. Fruscalzo et al., reported lower RBP4 levels in mothers who later developed fetal growth restriction (FGR) , and fouRBP4 levels in cord blood have also been investigated. A nested case-control study found RBP4 to be elevated in the female offspring of GDM mothers but not in male offspring , while aWhile findings concerning maternal RBP4 in GDM and PE seem to vary, it is suggested that RBP4 could possibly be involved in the pathophysiology of late-onset PE by stimulating insulin resistance in obese mothers. Furthermore, cord RBP4 appears to be increased in GDM offspring and decreased in PE offspring.GDF15 was first identified as macrophage-inhibiting cytokine 1 (MIC-1) and is a member of the transforming growth factor beta superfamily . GDF15 aIn a longitudinal study examining GDF15 levels in all three trimesters in healthy pregnancies, GDF15 was found to increase significantly with gestational age and reach its highest level in the third trimester . This trOnly one study concerning GDF15 levels in maternal serum and GDM has been published thus far. However, a case-control study with 40 pregnant patients with GDM and 40 healthy pregnant controls found significantly higher levels of GDF15 in the serum of GDM patients during the third trimester. Furthermore, it demonstrated through a logistic regression analysis an increasing risk of GDM diseases with increasing maternal GDF15 levels . NeverthIn contrast, quite a few reports on the association of GDF15 with PE have emerged in recent years, although they provide varying results. A case-control study found significantly reduced levels of GDF15 in maternal serum in the third trimester in PE patients when compared to healthy pregnant subjects . This reThe associations of GDF15 levels in cord blood with various parameters of intrauterine growth were elucidated in a cohort study. Here, significantly higher levels of GDF15 were described at birth in comparison to subsequent time points in both appropriate for gestational age (AGA) and SGA infants . While tIn summary, the findings support an increase in maternal GDF15 in GDM, while they remain varied in the case of PE. Further studies are needed to assess the role of GDF15 with parameters of intrauterine growth.First discovered in 2002, irisin results through the cleavage of its precursor, fibronectin type III domain-containing protein 5. Due to its production involving muscular contraction, it has also been classified as a myokine . In addiWhile there were no findings concerning irisin levels in normal pregnancy, a prospective cohort study reported higher serum levels of the irisin precursor fibronectin type III domain-containing protein 5 in pregnant women during the entire gestation when compared with non-pregnant healthy controls .Three studies also investigated irisin levels in GDM patients. One case-control study with 74 GDM mothers and 74 matched healthy controls found significantly higher irisin levels in GDM patients after delivery; however, irisin levels were similar between both groups during pregnancy . SimilarThe association of irisin with PE was examined in a prospective cohort study. Garcés et al., reported no changes in maternal serum irisin levels during pregnancy in women with PE, but noted that maternal irisin levels decreased significantly in PE women during the third trimester in comparison to healthy pregnant controls .In order to explore the association of maternal serum irisin levels with intrauterine growth, Ökdemir et al., conducted a cohort study including 84 mothers and neonates who were classified according to birthweight . They foInfant irisin levels correlated negatively with infant neck circumference, and there was a strong linear correlation between maternal and infant irisin levels . HernandIn summary, maternal irisin seems to be decreased in PE, while reports are conflicting in the case of GDM. No association was found between maternal irisin levels and higher birthweight. Additional studies are needed to evaluate the relationship between irisin levels and parameters of intrauterine growth.Since it was first described in 1972, twelve different isoforms of AFABP have been identified. AFABP is a member of the fatty acid-binding protein superfamily and is secreted mainly by adipocytes and macrophages. It has been associated with diabetes, hypertension and cardiovascular events, as well as obesity .The role of AFABP in physiological pregnancy was described in a systemic review, where AFABP was found to be expressed in the human placenta, and an increase in placental AFABP expression resulted from exposure to a hypoxic environment . It was In GDM, there were varying reports. Two studies found no significant differences in maternal AFABP levels between GDM and normoglycemic pregnancies ,26; howeOnly two studies were available concerning maternal AFABP levels in PE. In a systematic review, Daskalakis et al., reported an association between increased serum AFABP in the first and third trimester of PE patients . Serum AA cross-sectional study also reported that maternal AFABP collected between the 12th and 14th gestational week was positively correlated with birth weight, and that AFABP seemed to be a promising prognostic marker for detecting macrosomia in pregnancy .The associations of cord blood AFABP have also been investigated. Joung et al., found AFABP levels in cord blood to be higher in neonates than those found in adults, and that preterm infants showed higher levels of AFABP than full-term infants . They alMost findings support increased maternal AFABP levels in GDM and PE. Higher maternal AFABP levels are also associated with a higher birthweight, while further studies are needed to assess the role of cord AFABP with pregnancy outcomes and intrauterine growth.Omentin-1 is largely expressed in adipose tissue, as well as to a smaller degree in mesothelial and vascular cells. It has been found to have both anti-inflammatory and anti-apoptotic properties and appears to be involved in endothelial dysfunction . The rolA few studies have considered maternal serum omentin-1 in physiological pregnancy. A cohort study including 36 pregnant women and 37 healthy, non-pregnant women reported significantly decreased maternal serum omentin-1 levels in uncomplicated pregnant women when compared to the levels found in non-pregnant controls . In lineIn the prospective case-control study described above, a stronger decrease in maternal omentin-1 levels throughout pregnancy was observed in women with GDM when compared to healthy pregnant subjects . SimilarIn comparison, fewer studies were available when evaluating the relationship between serum omentin-1 and PE. A cross-sectional study reported significantly lower maternal serum omentin-1 levels in women with PE when compared to healthy controls, and reported that in PE patients, serum omentin-1 correlated with BMI as well as systolic blood pressure . The autA case-control study assessing maternal serum omentin-1 levels in 40 mothers with either IUGR neonates or AGA neonates did not find any significant differences in maternal omentin-1 levels in AGA or IUGR neonates . In addiIn the case-control study mentioned above, cord omentin-1 levels were similar between AGA and IUGR infants . FurtherIn summary, maternal omentin-1 levels appear to be decreased in both PE and GDM. However, findings concerning omentin-1 levels in maternal and cord blood and parameters of intrauterine growth, as well as pregnancy outcomes, were varied, and further studies are needed in this area.Lipocalin-2 is a recently discovered adipokine and a member of the lipocalin family. It has been speculated that lipocalin-2 is involved in insulin resistance in obesity . While nIn a cohort study by Mierzyński et al., maternal serum lipocalin-2 concentrations at 24–29 weeks gestation were significantly higher in the GDM group when compared to those found in healthy pregnant controls . They alStudies considering maternal lipocalin-2 levels and PE have also been published. A case-control study with 22 PE patients and 22 healthy age-matched controls observed lipocalin-2 levels in maternal serum to be significantly increased in PE patients in comparison to the control group . A positTo examine the relationship between maternal circulating lipocalin-2 and parameters of intrauterine growth, Papasthanasiou et al., performed a cross-sectional study on a population including 80 mothers and their offspring, who were divided into AGA, LGA and IUGR groups . They foIn the previously mentioned cross-sectional study, lipocalin-2 in cord blood at birth was also analyzed . LipocalRecent studies concerning lipocalin-2 suggest that lipocalin-2 is increased in maternal serum in both GDM and PE. Higher cord blood levels of lipocalin-2 are also associated with IUGR neonates.Visfatin is a novel adipokine with direct associations with insulin secretion and diabetes. By binding to the insulin receptor at a site different from the binding site of insulin, it can interfere with glucose metabolism and lead to hypoglycemia . AlthougChanges in maternal visfatin levels during physiological pregnancy have been examined in several studies. In a systematic review  considerSeveral studies considering visfatin levels in maternal serum during GDM were published in recent years. In a prospective cohort study, no differences in maternal visfatin levels were observed between GDM patients and healthy pregnant subjects . SimilarIn PE, findings were more homogenous. Two studies reported similar maternal serum visfatin concentrations between PE patients and healthy pregnant controls ,125. In A case-control study evaluating maternal visfatin levels at delivery found a negative correlation between serum visfatin in women with GDM and birthweight as well as length at birth . SimilarIn their case-control study, Mazaki-Tovi et al., reported lower visfatin concentrations in cord serum when compared to levels found in maternal serum . They alIn summary, although visfatin has been the subject of several studies in recent years, reports vary on the dynamic of maternal visfatin levels in GDM and PE. Higher maternal visfatin levels appear to be associated with SGA offspring and preterm birth. Further studies are needed in order to fully establish the role of visfatin in pregnancy pathologies.NRG4 has recently emerged as a novel adipokine and is a member of the neuregulin family. Although it is secreted by several organs, it is highly expressed in brown fat tissue, plays a central role in energy homeostasis, and is associated with an improvement of metabolic disorders such as insulin resistance .Only a few studies concerning circulating NRG4 in pregnancy have been published so far. In a case-control study, Kralisch et al., quantified NRG4 both during pregnancy and after delivery in 74 women with GDM and healthy pregnant controls, and compared postpartum levels in a follow-up study with 25 women who previously had GDM and 25 healthy control subjects. The median postpartum levels of NRG4 in maternal serum were similar to the levels found in prepartum . The autOne case-control study investigated the association of maternal circulating NRG4 with PE. They found no significant differences between NRG levels in PE patients and healthy pregnant subjects, regardless of the severity of PE .In summary, NRG4 is a newly emerging adipokine, and further studies are required to investigate its association with parameters of intrauterine growth and pregnancy outcomes. Conflicting reports exist concerning its role in pregnancy pathologies.Progranulin, a glycoprotein, is a recently identified adipokine and is known to induce insulin resistance. It has been associated with inflammation, as well as wound repair and neurodegeneration . Few stuIn a cross-sectional cohort study, Ebert et al., concluded that progranulin levels in maternal serum are elevated during pregnancy, and this dysregulation is associated with pregnancy status and not with the presence of GDM .The previous cross-sectional study did not find an association of maternal progranulin levels with the presence of GDM but rather an association with pregnancy status itself, suggesting that GDM does not lead to a change in progranulin levels in maternal serum . HoweverIn the previous cross-sectional study, the authors also reported a negative correlation between maternal progranulin levels and the gestational age of neonates at birth, as well as birth weight .Although few studies considering progranulin in pregnancy are available, they support an increase in maternal progranulin in PE and a negative correlation with birth weight. Further studies are required to investigate the association of cord progranulin with parameters of intrauterine growth and pregnancy outcome.Despite numerous publications on adipokines and their role in pregnancy in recent years, reports on their profiles during pregnancy and pregnancy pathologies, as well as their possible association with pregnancy outcomes, remain varied, as is demonstrated in Few studies have analyzed adipokine levels in physiological gestation, yet in summary, they suggest a change in serum levels of various adipokines during pregnancy compared to the non-pregnant state. Whether these changes stem from placental co-secretion, from an increase of maternal adipose tissue volume, or from alterations of maternal metabolic processes, in general, remains unclear. What is known, however, is that metabolic processes change dramatically during pregnancy, which can lead to complications such as gestational diabetes, and that these complications during pregnancy are associated with an increased risk of metabolic disease later in life. The reviewed studies support the assumption that adipokines play an important role in the adaption of metabolic processes, such as changes in insulin sensitivity/resistance during physiological pregnancy. Nevertheless, the exact mechanisms underlying the changes in metabolic processes during gestation are still unknown. Furthermore, the direct relationship between adipokines in physiological pregnancy and various pregnancy parameters, such as gestational week and gestational weight gain, has also yet to be explained. Therefore, it is important to further understand the role of adipokines in the adaption of metabolic processes during  pregnancy and possibly establish standard values of adipokines in maternal serum that correspond with healthy gestation.Reports on maternal serum levels of adipokines in GDM were generally scarce and yielded conflicting results for certain adipokines such as resistin, chemerin, RBP4, visfatin and NRG4 . ResultsCompared to GDM, study results for PE were more consistent, and various adipokines, including resistin, chemerin, AFABP, lipocalin-2, and visfatin, were described to be elevated in PE as compared to healthy pregnancies . This stOnly a few studies investigating maternal adipokine levels and their association with parameters of intrauterine growth exist, and sample sizes are small, which makes it difficult to interpret the results . In summStudies concerning cord blood adipokines and pregnancy outcomes were also limited, and therefore the validity of their findings on larger cohorts is again questionable . ImportaIn conclusion, findings suggest that adipokines may play an important role in the complex physiological changes that occur during pregnancy, and could have implications for the management of pregnancy-related health conditions. While the changes in adipokine levels in maternal serum could possibly be explained by placental co-secretion or as a result of the increase in maternal adipose tissue volume, further studies are needed to establish the role of adipokines in the metabolic changes present during physiological pregnancy. Although certain adipokines such as AFABP and lipocalin-2 seem to be increased in GDM, while omentin-1 is conversely decreased, the potential of using adipokines as biomarkers for GDM in pregnant women must also be intensively researched. Here arises the prospect of one day utilizing adipokines as a therapeutic approach to treat insulin resistance and its associated pathologies. Studies also suggested that adipokines such as chemerin and resistin were associated with PE and placental dysfunction. This leads to the question of whether adipokines in maternal serum could also serve as biomarkers for PE and help identify patients with a higher risk of cardiovascular and metabolic diseases in later life after PE. The reviewed literature also supported an association between adipokines both in maternal and cord blood with various parameters of intrauterine growth; however, further studies are required on larger cohorts in order to better understand this association. As knowledge in the field of adipokines and pregnancy increases, the focus is drawn to the possible role of adipokines as biomarkers of mother and child health. Ideally, this would allow for standard values of certain adipokines in maternal serum during gestation and in cord blood at birth to be established, paving the way for better prediction of pregnancy outcomes for both mother and child.