Klebsiella pneumoniae, carbapenem-resistantPseudomonas aeruginosa, and methicillin-resistantStaphylococcus aureus (MRSA). The patient had a bacteremiaby MRSA, and molecular typing methods confirmed the colonizing isolate was thesame strain that caused infection. The second case is of a patient colonized byextended-spectrum beta-lactamases (ESBL)-producing Escherichiacoli and carbapenem-resistant Pseudomonasaeruginosa. During the follow-up period, the patient presentedthree episodes of bacteremia, one of these caused by ESBL-producing E.coli. Molecular methods confirmed colonization by the same clone ofESBL-producing E. coli at two time points, but with a differentgenetic pattern to the strain isolated from the blood culture. Colonization bymultidrug-resistant bacteria allows not only the spread of these microorganisms,but also increases the subsequent risk of infections with limited treatmentsoptions. In addition to infection control measures, it is important to establishpolicies for the prudent use of antibiotics in dialysis units.The emergence of resistance mechanisms not only limits the therapeutic optionsfor common bacterial infections but also worsens the prognosis in patients whohave conditions that increase the risk of bacterial infections. Thus, theeffectiveness of important medical advances that seek to improve the quality oflife of patients with chronic diseases is threatened. We report the simultaneouscolonization and bacteremia by multidrug-resistant bacteria in two hemodialysispatients. The first patient was colonized by carbapenem- and colistin-resistant To refine the analysis, we usedmolecular typing methods to confirm if the patients were infected with the samemultidrug-resistant strain that had been previously identified colonizing them.The study protocol was approved by the Bioethics Committee for Human Research at theUniversity of Antioquia (CBEIH-SIU)  and written informedconsent was obtained from each subject.Klebsiella pneumoniae andPseudomonas aeruginosa, according to CLSI criteria. TheK. pneumoniae isolate was positive for KPC carbapenemase byPCR and presented simultaneous resistance to colistin. Although themcr plasmid gene that generates the transferable resistanceto colistin was not detected, the alteration of the mgrB genewas mediated by the insertion sequence ISKpn25.The first case is a 90-year-old man with a history of type II diabetes mellitus,arterial hypertension, and remission of colon adenocarcinoma. At the time ofadmission to the study, the patient had been on hemodialysis for four years andhad a tunneled jugular dialysis catheter due to the dysfunction of differentarteriovenous fistulas. As background, he reported hospitalization andantibiotic use (aztreonam) in the last six months. In addition, he complained ofitching and frequent scratching around the insertion site of the catheter. Thepatient was positive in two of the three screenings for intestinal colonizationby carbapenem-resistant In the third screening, the patient was positive for MRSA in the nostrils and onthe skin around the catheter insertion site. Two months later, he presented anepisode of bacteremia due to this same bacteria. He received treatment withvancomycin and required dialysis catheter replacement. When processing the MRSAisolates from colonization and infection by pulsed-field gel electrophoresis(PFGE), it was confirmed that they corresponded to the same bacterial clone,which led to the conclusion that the colonizing strain was the same that causedthe infection . LaboratE. coliand for carbapenem-resistant Pseudomonas aeruginosa. During thefollow-up period, the patient presented three episodes of bacteremia caused byEnterobacter cloacae, and ESBL-producing K.pneumoniae and E. coli. The use of EnterobacterialRepetitive Intergenic Consensus (ERIC) confirmed colonization by the same cloneof ESBL-producing E. coli in two of the three screenings, butwith a different genetic pattern to the strain isolated from the blood culture in the last six months, as well as ahistory of multiple infections by multiresistant bacteria. He also reporteditching and frequent scratching around the catheter insertion site. In all threescreenings, the patient was positive for ESBL-producing  culture. LaboratStaphylococcus aureus is the most frequentlycolonizing bacterium and MRSA colonization has been reported with a percentageranging from 1.4 to 27% of hemodialysis patients, of which around 17 to 35% maydevelop bacteremia due to this same microorganismThe emergence of different resistance mechanisms threatens the success of importantmedical advances that improve the quality of life of patients with chronic diseases,and hemodialysis patients are no exception--Unlike MRSA, few studies have evaluated colonization by multiresistant Gram-negativebacilli (MDR-GNB) in hemodialysis patients and their role in the development ofinfectionsmgrB gene can be present in plasmids that also carrycarbapenemases such as KPC, causing strains with simultaneous resistance tocarbapenems and colistin, such as was observed in the case presented in thisreportThe picture is complicated because many of the resistance mechanisms mentioned are inmobile genetic elements, which favors their rapid spread from one bacterium toanother,Because infections by multidrug-resistant bacteria are associated with a two tofive-fold increase in morbidity and mortality compared to infections caused bysusceptible isolates, the prevention of both colonization and infection by thesemicroorganisms in patients in hemodialysis is crucialThe vascular access type is also important to the development of bacteremia inhemodialysis patients. Of all access-related bloodstream infections, 70% occur inpatients with catheters, so that the fistula is considered the preferred access dueto lower infectious complications and lower costFinally, in addition to infection control measures, it is important to establishpolicies for the prudent use of antibiotics in dialysis units, because the use ofthese drugs is an important risk factor for the spread of drug-resistant bacteria.Given the few antibiotic treatment options, this is an urgent strategy that must beimplemented.


This editorial to the Special Issue on Qualitative Inquiry in Mental Health Research with Young People provides an overview of the importance of qualitative inquiry to the field of child and youth mental health. The issue highlights research using qualitative methods to depict the lived experiences and contribution of young people in areas that reflect important mental health concerns, ranging from anxiety, non-suicidal self-injury, positive resilience in young people in times of crisis, and drug and alcohol treatment. Qualitative inquiry provides an opportunity for research participants to offer authentic experiential evidence to help shape policy and mental health service provision from an evidence-based perspective. Qualitative methods provide richly textured, thick description to supplement the breadth of understanding afforded by quantitative methods, elicit the perspectives and lived experience of research participants, explore issues that have not been well studied, develop conceptual theories or test hypotheses, or examine a phenomenon or intervention.This Special Issue aims to discuss new knowledge and cutting-edge developments in qualitative mental health research with young people through selected works, each making an important contribution to the extant knowledge base. It represents a forum for disseminating pertinent research findings and innovative ideas and methods from the field.Young people are rarely meaningfully involved in contributing to the development, implementation, and evaluation of interventions designed to address their mental health challenges . HoweverThis Special Issue highlights research using qualitative methods to depict the lived experiences and contribution of young people in areas that reflect important mental health concerns, ranging from non-suicidal self-injury, positive resilience in young people in times of crisis, and drug and alcohol treatment.The contributors to this Special Issue drew from a range of methodological perspectives and employed a variety of qualitative data collection methods, including arts-based methods, such as body mapping, photovoice and ecomaps, secondary documents, in-depth interviews, participant observation and journaling. The contributors also drew upon diverse forms of analysis including hermeneutic phenomenology, reflexive thematic analysis, case study, and narrative analysis. The studies described were conducted in Canada, Europe , and Australia.Cus et al.  use reflCOVID-19 has been associated with loneliness, distress, and anxiety in young people. In Dadich and colleagues’ [Francis and her colleagues  investigThe methodological article by Macken and her colleagues  exploresThe service experiences of young people and their parents/carers who completed Dialectical Behaviour Therapy (DBT) treatment in the UK were explored by Ratnaweera and co-authors . Young pSamir and colleagues  acknowleWoodgate and her colleagues  sought tThis Special Issue provides a broad overview of established and emerging qualitative methodological approaches and methods used to involve young people in mental health research. It represents the richness and strength of the field currently, which will no doubt continue to contribute mental health outcomes for young people moving forward.


Angiogenesis is one of the main processes that coordinate the biological events leading to a successful pregnancy, and its imbalance characterizes several pregnancy-related diseases, including preeclampsia. Intracellular interactions via extracellular vesicles (EVs) contribute to pregnancy’s physiology and pathophysiology, and to the fetal–maternal interaction. The present review outlines the implications of EV-mediated crosstalk in the angiogenic process in healthy pregnancy and its dysregulation in preeclampsia. In particular, the effect of EVs derived from gestational tissues in pro and anti-angiogenic processes in the physiological and pathological setting is described. Moreover, the application of EVs from placental stem cells in the clinical setting is reported. Extracellular vesicles (EVs) have been established as a means of cellular communication and are involved in physiological and pathophysiological processes through the transfer of bioactive molecules such as proteins, RNAs and lipids . EVs areAngiogenesis, the process by which blood vessels form for the delivery of nutrients to the body, is necessary both prior to and during pregnancy. A balance between pro and anti-angiogenic factors during pregnancy is key to a successful pregnancy. Imbalance of angiogenic factors, and subsequently, widespread endothelial dysfunction is considered the hallmark of pregnancy-related diseases such as preeclampsia (PE) . The cliDespite great scientific advances, PE is still defined as a “disease of theories”. Insufficient placenta development including abnormal spiral artery remodeling, placental hypoxia, oxidative stress, impaired angiogenesis and insufficient placental perfusion contribute to the development of preeclampsia ,18,19. OIn pregnancy, EVs can stimulate or impede angiogenesis according to their content and molecular expression, which in turn, is dependent on the cell of origin and on its pathophysiological state. For instance, hypoxic conditions observed in the first trimester of the pregnancy, modulate the release of EVs from cytotrophoblast and placental cells, both in number and as cargo . As the The influence of EVs on the angiogenic process has been reported in various in vitro and in vivo studies . EVs areIn pregnancy, a large number of studies focus on the activity of EVs released by maternal and fetal cells, including endothelial cells, immune cells, trophoblast and stem cells with the latter being present in the umbilical cord, placenta, amniotic fluid and amniotic membranes . These EThe concentration and profile of placental EVs in normal pregnancies has been extensively studied. Salomon et al., demonstrated that the concentration of EVs in maternal plasma increased more than two-fold towards the end of gestation . The EVsUC-MSCs are a well-known source of EVs with pro-angiogenic activity. They are involved in stimulating endothelial cell migration, proliferation, and angiogenesis in vitro and activating the Wnt/β-catenin pathway . Xiong eEVs derived from placental tissue have been singled out for their tissue repair properties via angiogenesis regulation. The interest in placental derived-EVs offers us additional information on the possible pathway those EVs can regulate during pregnancy. Salomon et al. extracted EVs from placental MSCs and subjected them to in vitro and in vivo functional assays . The resAmniotic fluid stem cells (AFSC) have recently been of interest in regenerative medicine. AFSCs express high levels of stem cell receptor factor, c-kit (CD117) and display the characteristics of multipotent cells, and they can differentiate into all the germ cell layers because of their fetal but non-embryonic origin . The parThe placenta is a complex organ responsible for most of the maternal and fetal health, and as such is composed of both maternal and fetal tissue. The membrane of this fetal tissue (amnion membrane) is comprised of cuboidal epithelial cells that stick to the basement membrane, and of an extracellular matrix with fibroblast-like cells. The 1 amnion epithelial cells released by the amnion membrane are represented by epithelial characteristics and membrane antigens. Administration of EVs released from these amnion epithelial cells have been used as a therapy in different diseases such as idiopathic pulmonary fibrosis . HoweverAs discussed above, placental-derived EVs play an important physiological role in mother and fetus communication through the delivery of a range of proteins, lipids, and nucleic acids . On the The anti-angiogenic effect of circulating EVs in PE appears to be, at least in part, mediated by the presence of Flt-1 or Eng in the form of membrane receptors on the EV surface, as these can act as decoy receptors by sequestering angiogenic soluble factors, similarly to the presence of the soluble forms. Tannetta et al.  showed tThe shedding of EVs into the maternal blood in PE has also been shown to correlate with systolic blood pressure . NeprilyNot surprisingly, the majority of studies that have investigated EV in the development of PE have focused on the effect of placental EVs on the endothelium. Vascular smooth muscle cells residing in vessels are also an important part of the processes that lead to placentation and vascular remodeling. EVs from extravillous trophoblasts were reported to promote vascular smooth muscle cell migration, thus suggesting their role in the remodeling of spiral arteries . HoweverBeside membrane-bound proteins, EVs derived from gestational tissues during complicated pregnancies contain multiple miRNAs, which may play an anti-angiogenic role under these conditions, particularly in PE . CronqviAltogether, the studies described above suggest that EVs derived from preeclamptic placentas play a direct role in endothelial dysfunction and contribute to PE development through their membrane-bound proteins and the release of internal molecules such as anti-angiogenic proteins and miRNAs. However, recent studies have challenged these theories. It has been shown that EVs isolated using the common methods may cause contamination of soluble bioactive factors that may affect their resultant bioactivities . O’Brien11 particles. However, the characterization of the amniotic fluid vesicles was not provided [Stem cell from gestational tissues such as the umbilical cord, the placenta, fetal membranes (amnion) and amniotic fluid appear to be a rich source of EVs with promising therapeutic activity. The advantage of therapeutic use of EVs relies on the lack of replication and immunogenicity in respect to the parental cells. The administration process is more straightforward than the one for cells, as they can be stored and generated with a higher economic benefit. Furthermore, unlike stem cells, no cases of tumor-related downfalls have been reported so far . Placentprovided . Unfortuprovided . The proBased on their origin and content, EVs can also be applied for diagnostic purposes. The characteristics of EVs would make them the perfect candidate to act as a marker of genetic disorders or early signs of pregnancy-related complications. For instance, the levels of Syncytin-2, a protein specific to the placenta, has been shown to be significantly reduced in serum-derived EVs from preeclamptic patients and could represent a potential biomarker to predict the development and severity of preeclampsia . MirandaEVs are important cell-derived bio-factors involved in cell-to-cell communication, and they are highly implicated in the physiological development of normal pregnancy and in the maintenance of endothelial homeostasis. Multiple sources of angiogenesis-related EVs are released from fetal tissues and are present in the maternal circulation. A better characterization of their differential cargoes during pregnancy appears to be an interesting field of research. Nevertheless, the pro-angiogenic and pro-regenerative EVs from placental tissues can be further exploited in different clinical settings. In particular, placental stem cell-derived EVs or amniotic fluid EVs are subject to increased interest for organ regeneration and repair. Finally, knowledge of EV function and cargo might be instrumental for the diagnosis and therapy of pregnancy-related disorders. Indeed, a large number of studies indicate that placenta-released EVs show altered phenotype and function. Placenta-derived EVs increase in maternal circulation in PE and when transferred in murine experiments, can highly affect endothelium in synergy with soluble factors to cause endothelial dysfunction.However, knowledge of the involvement of EVs in placental angiogenic processes is still limited, and more studies are still needed, especially on the early processes occurring in the first trimester.


Two eco-friendly healing bioproducts generated from microbial mixed cultures (MMC) for the production of polyhydroxyalkanoates (PHA) were used as surface treatments, with two residual materials used as the substrates, namely crude glycerol and pinewood bio-oil. Their ability to improve the durability of concrete samples containing recycled aggregates was assessed. To determine this protective capacity, 180 samples were analyzed using different tests, such as water penetration under pressure, capillary absorption, freeze–thaw and water droplet absorption test. Three types of conditions were used: outdoor–indoor exposure, re-application of biopolymers and application in vertical exposure conditions. The results showed reductions of up to 50% in the water penetration test and a delay in the water droplet absorption test of up to 150 times relative to the reference. The surface application of these bioproducts significantly reduced the degree of water penetration in recycled concrete, increasing its useful lifespan and proving to be a promising treatment for protecting concrete surfaces. The global population growth over the past 100 years has resulted in rapid industrial and urban development. Considering the properties of concrete, namely its versatility, resistance and low cost, a large increase in the demand for this material has been occurring, making it the second most extensively used material worldwide, only behind water  ,67 29,67Some researchers ,96,97,982O) in all tests, although the improvements were particularly noticeable in the pressurized water penetration and water drop absorption tests;The treatments with the bioproducts showed significant improvements relative to the reference concrete  and pinewood bio-oil (SP) as the carbon sources, were applied on the surfaces of concrete samples produced with partially recycled aggregate. The protective effects of the bioproducts were evaluated experimentally through six different tests. The conclusions obtained were as follows:The incorporation of two waste materials such as crude glycerol and pinewood bio-oil to produce the bioproducts used to improve the capacity and durability of recycled concrete has a positive environmental impact. This strategy involves two routes leading to a more circular economy, both by reducing waste and improving waste management, thereby reducing the consumption of energy and natural resources.In summary, this research shows the effectiveness of both bioproducts in protecting the surfaces of recycled aggregate concrete samples against water penetration and the consequent risk of deterioration and decrease in their useful lifespan; that is, the useful lifespan and performance of recycled concrete are increased, encouraging the use of construction wastes as aggregates, thereby reducing the volume of such waste.


Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer’s disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer’s Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed. Alzheimer’s disease (AD) is the leading cause of dementia . It is aTo mitigate the impact of AD on both the individual and society, novel disease-modifying therapies are urgently needed to treat the disease or delay its onset. The development of new therapies must also be accompanied by careful analysis of the populations most affected by AD and the potential impact of new treatment options on clinical practice. To this end, a variety of longitudinal observational studies are being conducted around the world to assess cognition, biomarkers, and the health of the aging population. These range from population-based community studies monitoring participants with and without dementia at enrollment, to studies of older adults from memory clinics with complaints of cognitive decline. International collaborations that leverage diverse clinical data and scientific expertise could improve our understanding of disease etiology and the natural history of AD, generate insights to inform the design of preventive and therapeutic trials, and inform health-service planning for optimal early detection of cognitive decline and patient access to new disease-modifying therapies as they become available.Cross-cohort analyses and networks of registries in AD have previously been established, each with its own objectives, e.g., to facilitate clinical trial recruitment , monitorIn August 2016, a group of investigators from around the world, representing observational prospective cohorts of individuals across the AD continuum, convened to form a scientific working group; its aim, to establish a research collaboration network as a resource to address important research questions related to the natural history and burden of AD. A group of investigators from established longitudinal cohort studies in AD were invited to participate, representing a diverse range of studies from around the globe. The resultant CONCORD-AD network brought together expertise and data insights from seven cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics and population-based cohorts, bringing together observations from individuals across the AD spectrum—from cognitively unimpaired (CU) people with or without subjective cognitive decline (SCD), to those with mild cognitive impairment (MCI), through to those with AD, as well as other types of dementia. Although each cohort was established with different objectives, this network provides the opportunity to address novel research questions across the cohorts and to leverage disease area expertise among the investigators.In this article, we introduce the CONCORD-AD network, provide an overview of the cohorts involved, report the common assessments used in the cohorts, and describe the key characteristics of the cohort populations. We show examples of knowledge gaps already being addressed by each cohort and highlight the diversity, similarities, and complementarity among these different data sources. We also provide recommendations on how such collaborations may evolve in the future, and the challenges and opportunities they can present.The seven cohorts participating in the CONCORD-AD network represent data from more than 20,000 individuals across the disease spectrum, with a maximum follow-up period of 27 years. The key characteristics of the different cohorts are summarized in n = 1,190; MCI, n = 295; AD, n = 322; June 1, 2018 analysis) through treating physicians at memory clinics and community appeals  imaging for current report), COGICARE sub-study of 3C, and Baylor cohorts. Dysphoria/depression, anxiety, apathy/indifference, and irritability/lability were the most common NPS overall  65]. Ps. Ps65]. 42, pTau, and tTau in subsets of participants; CSF biomarker data were collected for over 90% of participants in BioFINDER-1. In contrast, biomarker data were not systematically collected in the Baylor study and French cohorts. Amyloid PET, but no other biomarkers, was assessed in a subset of participants in the 3C Bordeaux  and AMI studies (61 non-demented participants) at 14 years and 7 years, respectively. Tau PET was only assessed in the BioFINDER-1 and MCSA cohorts.The availability of neuroimaging and fluid biomarker data varied substantially across the cohorts . The AIBAlthough established AD cohorts offer a rich potential for increased understanding of AD risk factors, clinical heterogeneity, and disease progression, the challenges of cross-cohort studies must be examined.It is important to acknowledge that existing cohorts have not been established according to a uniform set of aims and using the same methods, and that individual cohort studies have unique hurdles to overcome. The design and conduct of cross-cohort studies must be conducted in accordance with regional and national guidelines, which vary not only with geography but also over time. Moreover, as longitudinal studies can be conducted for decades, there will be multiple protocol changes and adjustments needed to align with evolving guidelines. Cohort studies require sufficient infrastructure and funding to conduct testing over long intervals, meaning that expensive biomarker and/or imaging analyses may not be feasible, especially for large or geographically dispersed cohorts, or where biomarker characterization is not the primary purpose of the study. Study design can also be informed by previous studies and the evolving knowledge of AD, then tailored to meet new aims. For example, the Swedish BioFINDER-2 study launched in 2017 was designed to complement the pre-existing BioFINDER-1 study and address emerging issues regarding the role of tau pathology in different dementias and in their preclinical stages . While BThe CONCORD-AD collaboration model involves the sharing of independently conducted analyses to address key questions about disease progression, and patient-related outcomes in diverse patient populations, including both population- and community-based cohorts. This model facilitates evaluation of the impact of population and disease heterogeneity  on critical scientific questions. The included studies had a variety of aims, affecting study design and choice of assessments. This heterogeneity of assessments, while expected, limited the direct cross-comparison of cohorts and capacity for integration of patient-level data.Dementia diagnosis methodologies and thresholds for impairment also differed between studies and, notably, have evolved and improved since the start of some of the older studies such as PAQUID, which was established more than 10 years before some of the other cohorts included. Participants with dementia may now be diagnosed at earlier and milder stages compared with 30 years ago .The guidelines for diagnosis of MCI have also evolved over time and definitions differ between cohorts. In the CONCORD-AD network, prospective MCI groups were not assessed in the three French cohort studies, and either the Winblad  or PeterInternational collaborations have the potential to leverage diverse clinical data in a variety of patient populations which ultimately could inform health-service planning for optimal early detection of cognitive decline. However, there are several challenges associated with early detection. Currently, in practice, AD is diagnosed with a variety of questionnaires that aim to measure memory function and neuroimaging tools, among other assessments . The assPopulations derived from specialist memory clinics differ from community cohorts as a result of differences in the demographics of individual participants, self-referral and healthcare professional-referral patterns, and differential access to healthcare services . For exaThe variability observed among cohorts highlights the impact of differing recruitment procedures and inclusion criteria. In clinical trials, with even more tailored inclusion and exclusion criteria, the trial population can greatly diverge from the original source population. By necessity, clinical trials often exclude those with comorbidities. This results in the recruitment of participants that may be healthier than the typical aging population, which could impact disease progression as captured by measures of cognitive and functional decline. Variations identified during cross-cohort comparisons could help further inform clinical trial design and recruitment in global clinical trials in order to include appropriate participants. These variations can also be mined for hypotheses related to the quantitative impact of methodologic or demographic difference on biomarkers or outcome measures.Cross-cohort comparisons also face challenges relating to the practical logistics of data sharing and data governance. While we can be mindful of differences in the study populations and timelines when looking at cross-cohort comparisons, it is not always easy or straightforward to combine data from different sources. The methodological challenges of analyzing and interpreting combined datasets can be lessened by describing the data for each cohort in detail, including the sources of the data, taking into account any specific underlying reasons for differences among cohorts, and clear communication from cohort investigators on potential caveats or limitations in the analysis and therefore subsequent interpretation of findings. The CONCORD-AD collaborative network eased difficulties in logistics surrounding data protection by sharing data summaries compiling population-level data for analysis rather than patient-level data, as shared in the GAAIN network.The primary advantage of the CONCORD-AD network is that it is a resource with a sufficiently large sample size to confirm or replicate findings of other studies and explore potential causes of heterogeneity in measures of interest, such as cognitive outcomes or rate of disease progression. Such a large cohort that includes patients across the wide spectrum of the AD disease course lends itself to be used for verification and replication of findings seen in smaller clinical trials. While data combined across the cohorts is not currently available, a potential future application of the CONCORD-AD network is harmonization of data to transparently integrate multiple pseudonymized data sources into a single federated database for use by researchers both within and outside the network. This could allow users to remotely access geographically dispersed data while ensuring data security and privacy.Secondly, there are also research applications that could be addressed within collaboration projects in the future. This could include data collaboration comparing the CONCORD-AD network with the natural history of AD, from preclinical through clinical stages of disease. This continues to be a major research area of interest with key goals to increase understanding of: 1) cognitive and functional decline in slower and faster progressors along the AD continuum in globally representative cohorts; 2) the natural history of biomarker levels within the disease continuum; and 3) cognitive decline in the presence/absence of key biomarkers, vascular lesions, and comorbidities, and how these relate to major events within the AD continuum . All of these would improve our understanding of the multiple pathological processes leading to cognitive decline in AD and other non-AD-related dementias and processes underlying resilience to age-related disease processes . ThirdlyThis report raises awareness of the need to align cohort study designs in order to facilitate cross-cohort comparison, but further advances can also be made in analysis and interpretation of current data. Current biomarker data can be applied to analyses of core AD biomarkers, such as phosphorylated tau, to monitor disease progression . AdditioCONCORD-AD was created as an approach to mitigate the impact of AD on society, by bringing together global resources and expertise with the purpose of generating insights that can improve understanding of the natural history of the disease, inform design of clinical trials at all stages of the disease, and inform health-service planning for optimal patient access to new disease-modifying therapies once they become available. Expansion of these types of networks could be done to include other well-characterized and diverse cohorts representing a wide range of socioeconomic, ethnic, and geographic groups across the AD continuum, as well as closer alignment in data collection in future studies. This would further strengthen the research community’s potential to better understand, and eventually conquer, AD.Click here for additional data file.


Macrodactyly is a rare congenital disorder of overgrowth affecting the digits of the upper or lower extremity. Mostly, patients are surgically treated during childhood to reduce the digit or to stop growth. There are no standardized guidelines for the treatment and follow-up of macrodactyly. Consequently, follow-up may not be regularly scheduled into adulthood.A retrospective, descriptive analysis of patients with the long-term progression of macrodactyly who presented at our tertiary referral hospital between July 2018 and March 2020 was performed. All patients from our local macrodactyly database were screened for progression of macrodactyly since adulthood; this resulted in four patients. The aim of these case series is to highlight the clinical features and disease course at long-term follow-up.All patients were surgically treated during childhood and showed progression of tissue overgrowth during adult life. All patients developed severe secondary degenerative bone changes in macrodactyly affected digits, such as ankyloses of joints, new bone formation, and bony spurs. Subsequently, tissue overgrowth and degenerative bone changes led to functional problems.Patients with macrodactyly may experience growth during adult life, which may progress to deforming changes. Consequently, patients should be informed about the possible growth, and the progressive growth should be monitored. Macrodactyly is a rare congenital disorder of overgrowth affecting the digits of the upper or lower extremity.Patients may encounter functional problems and difficulty in walking due to enlargement of the foot in length and width.,Recently, somatic gain-of-function mutations in the PIK3CA gene were detected in the affected tissue in patients with macrodactyly.Current medical management of macrodactyly is mainly ablative and not based on molecular targets. Treatment consists of debulking a part of the enlarged digit, epiphysiodesis to stop longitudinal skeletal growth, and amputation when the enlarged parts are no longer functional.Patients with the long-term progression of macrodactyly who presented at our tertiary referral hospital between July 2018 and March 2020 were included. All patients from our local macrodactyly database were screened for progression of macrodactyly since adulthood; this resulted in four patients. Data were extracted from the electronic patient files, which included: patient age, gender, anatomical location of macrodactyly, presence of symptoms, comorbidities, previous treatments, imaging results, histopathology results, and genetic test results. Our institutional review board approved a waiver of consent for this study and written informed consent was obtained from all patients. The guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement were followed.All patients are listed in A 59-year-old male with macrodactyly of the first, second, and third toe of the left foot presented at our hospital. At the age of 1, the first and second toe were amputated through the metatarsophalangeal (MTP) joint. At the age of 3, 4, 12, and 17 years, he underwent additional soft tissue debulking surgery. These procedures took place at another hospital; thus, comprehensive information is lacking.At the age of 54, he noted severe enlargement of the left forefoot. He experienced a total loss of sensory function of the forefoot and therefore did not feel any pain. He encountered functional problems and was unable to walk far distances. Additionally, he suffered from recurrent erysipelas of the foot, once complicated with osteomyelitis. On clinical examination, a deformed left forefoot was seen with a massive swelling at the plantar side and substantial hyperkeratosis. Also, he developed psoriatic lesions on the medial and lateral side of the foot .Figure 1Conventional radiograph and computed tomography (CT) scan of the left foot showed substantial hypertrophy of fat tissue, muscles, and bone tissue in comparison with the right foot. In particular, metatarsal II showed bone overgrowth with bony spurs toward the plantar side and synostosis with metatarsal I. Ankyloses of the Lisfranc joint were visible between the medial, intermediate, and lateral cuneiform bones and metatarsals I, II, and III. Additionally, ankyloses of the Chopart joint were visible, with partial fixation between the talus and navicular bone and partial fixation between the calcaneus and cuboid bone  & 3.FiguBecause of the substantial growth of his left foot and mobility disabilities, he needs additional surgical treatment. Currently, a Chopart amputation is planned because of the best functional advantages.A 33-year-old female with macrodactyly of the first and second digit of the left foot. At the age of 7, the second toe was amputated through the MTP joint, and the soft tissue of the first toe was debulked.Since age 30, the first digit grew progressively. She felt slight discomfort lateral of the second digit without experiencing any real pain. On clinical examination, the first digit was enlarged with a substantial swelling of the plantar side . The MTPBecause of the rapid growth of the first digit and the additional functional problems, she will undergo another surgery.A 44-year-old female with macrodactyly of the second and third toe of the left foot and concomitant syndactyly between these toes. Previously, at the age of 4 years, the third toe was amputated through the MTP joint and simultaneously the syndactyly was resolved.Several years before she visited our clinic, she experienced increasing pain in her forefoot and was unable to wear her orthopedic shoes because of the fast growth of the foot. The pain occurred dorsal and lateral of the second toe and radiated to the fourth and fifth toe. On clinical examination, her second toe was enlarged with a plantar swelling , and herConsidering the progressive growth of the second toe and accompanying complaints, she underwent further surgery on her left foot. The second toe was amputated distally from the MTP joint and osteoarthritic deformed bone was removed. The second toe was sent in for genetic analysis, which showed a somatic mosaic mutation in PIK3CA. The pathogenic variant c.3140A>T p.(His1047Leu) was detected with a variant allele frequency (VAF) of 25%. The surgical intervention led to pain reduction and increased functioning of her left foot.A 47-year-old female, known with macrodactyly of the thumb and index finger of the right hand. At the age of 18 years, the first surgery took place with soft tissue debulking of the thumb. However, post-operatively she experienced more functional problems. At the age of 38, she underwent further surgery of the thumb including soft tissue debulking, shortening of the proximal phalanx, and arthrodesis of the IP joint and metacarpophalangeal (MCP) joint. In the same year, a carpal tunnel release and a correction osteotomy of the thumb were performed, which led to an improved position of the IP joint arthrodesis. Nevertheless, she noticed an increase in swelling and tingling of the thumb and index finger.At age 47, she presented at our hospital because of the progression of swelling and worsened functioning of the thumb and index finger. For a few months, her thumb, index finger, and wrist were painful. On examination, a swelling was seen of the volar, radial side of the hand. Solid nodules were present at the MCP joint and proximal interphalangeal joint (PIP) of the index finger. Her wrist showed a position of 20 degrees ulnar deviation, and flexion and extension were limited.Conventional radiographs of her right hand showed complete consolidation of the IP and MCP joint arthrodesis of the thumb. Remarkable juxta-articular new bone formation was present in the thumb and index finger of the carpometacarpal (CMC) joint, MCP joint, and PIP joint (index finger). Also, new bone formation was visible of the scaphoid, trapezium, and trapezoid .Figure 8Given her functional problems, she was referred to a rehabilitation specialist. Subsequently, a splint was made for her right hand to improve her abilities. Additionally, she was referred to a clinical geneticist. However, she was lost in follow-up and genetic analysis of the affected tissue did not take place.Four macrodactyly cases with the severe long-term progression of overgrowth were described. All patients experienced rapid growth of the affected digit long after treatment. The results of this study show that tissue overgrowth can progress excessively during adult life. The long-term follow-up of these cases of macrodactyly provides useful insights into the condition.A remarkable finding was the degenerative and deforming bone changes. The phalanges and metacarpals in our patients were expanded and deformed at their distal ends. This may be explained by the periosteum being studded with nodules consisting of chondroblasts and osteoblasts, which are more numerous toward the end of the phalanges and account for the distal osseous enlargement.,In particular, patient 1 developed exceptional bony changes; however, other factors may have contributed to the deformation of the foot. Chronic osteomyelitis may lead to reactive new bone formation, bone deformation, and ankylosis.Not all patients with macrodactyly develop secondary degenerative joint changes. Ishida et al. investigated long-term term results of surgical treatment for macrodactyly of the hand.Unilateral involvement in macrodactyly is the most common, which was also noted in our patients. Hands and feet are affected with almost equal frequency. In both hands and feet, third digit involvement is the most prevalent, followed by second digit enlargement.For a long time, the etiopathogenesis of macrodactyly was poorly understood. However, now it is clear that postzygotic somatic mutations in the PIK3CA/AKT/mTOR pathway may be a cause of macrodactyly.However, between patients, growth trajectories vary greatly for unknown reasons. While some patients exhibit excess growth limited to childhood, others have progressive tissue growth during adult life. As the somatic mutation in PIK3CA remains present in the affected tissue, this may promote tissue growth continuously. Eventually, continuous tissue growth may result in the advanced stages of overgrowth. These cases are an example of continuous growth during adult life and illustrate the deforming changes the overgrowth can entail.After the discovery of somatic mutations in isolated macrodactylyPIK3CA somatic mutations have been found in various overgrowth disorders, such as megalencephaly-capillary malformation syndrome, muscular hemihypertrophy, Klippel-Trenaunay syndrome, and CLOVES syndrome.There exist several limitations in these case reports. These cases are not representative of all longstanding macrodactyly cases. However, this is inherent to the study design, since primarily patients who experience complaints or growth of macrodactyly would revisit the outpatient clinic. Secondly, the natural course of the disease could not be assessed, as the patients visited the outpatient clinic a couple of years after they experienced growth. Yet, this is unavoidable since patients are not monitored regularly during adult life. Unfortunately, we did not have genetic information on all patients. Two patients will undergo surgery soon, where the tissue will be taken for genetic analysis.In conclusion, our study shows that tissue overgrowth can continue and progress excessively in patients with macrodactyly without monitoring during adult life. Somatic mutations in PIK3CA were identified in patients with macrodactyly and may be responsible for this continuous growth. Clinicians should be aware of the possibility of continuous tissue growth and the deforming changes the progressive overgrowth can entail. Monitoring during adulthood may lead to earlier intervention, which may prevent excessive overgrowth and may preserve function. Therefore, clinicians should inform patients that growth may occur in a later stadium, and patients should receive instructions to revisit the outpatient clinic if worsening of function or growth occurs. Currently, no follow-up guidelines exist. Monitoring patients with macrodactyly regularly every three years is recommended. Follow-up should consist of an evaluation of the function, size, and degenerative changes of the affected digits by physical examination and conventional radiography.


During the infection and treatment of the SARS-CoV-2 viral infection, age and comorbidities play a major role in the successful management of COVID-19. The nutritional status changes which occur in the body vary with the age and underlying conditions and has a vital role in the functioning of the immune system and cellular membrane integrity, thus minimizing the vulnerability to the infection. Considering the data already published by eminent researchers, a few micronutrients have shown outstanding results as supportive therapies in the treatment of viral infections. Micronutrient like zinc improves the membrane barrier integrity, has anti-inflammatory activity, and is involved in antibody production. Vitamin A supports the phagocytic activity of macrophages, while vitamin C reduces the worsening of respiratory tract infections by restoring the dysfunctional epithelial barrier of the lungs. Vitamin D, vitamin E, selenium, and omega-3 fatty acid metabolites play a major role in immunomodulation and in the inhibition of proinflammatory cytokine production. Magnesium is involved in the synthesis of antibodies, while copper, vitamin B12, and folate have significant effects on immune cells. A few researchers suggest that iron supplementation has reduced the risk of acquiring respiratory tract infections in children. As the age of the patient increases, the need for micronutrients increases, thus leading to an imbalanced nutritional status which in turn increases the risk and fatality of the infections. The use of micronutrients in modulating the inflammatory, immune responses, and the epithelial barrier integrity is explored during the treatment of viral infections for faster recovery. The coronavirus, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has appeared in Wuhan, China, for the first time in late 2019, and the people who are infected with the SARS-CoV-2 virus suffer from severe respiratory illness.Indeed, the elderly and people with comorbidities are the most vulnerable to COVID-19 . The vitMicronutrients, along with their role in the maintenance and development of physical barriers, assist in enhancing immune function by being involved in the production of antimicrobial proteins and mediation of inflammatory processes . VitaminZinc supplementation has improved barrier integrity along with specific changes in tight junction complexes. Thus, zinc supplementation can also alleviate the proinflammatory effect of cytokines, thus preventing the impairment of barrier integrity. –17. Zinc2+ and zinc-ionophores (such as pyrithione) can increase intracellular zinc ion concentration, which aids in SARS-coronavirus inhibition [Zinc has both pro- and anti-inflammatory effects. An optimum intake of it helps in limiting the overproduction of inflammatory cytokines. Zinc supplementation is found to have a direct antiviral effect on respiratory syncytial viruses, dengue viruses, and coronaviruses . Chloroqhibition . As a rehibition .The innate immune response and cell-mediated immunity are regulated by Vitamin A. It is also involved in cytokine signaling and in humoral antibody immunity . CompromAs an antioxidant, vitamin C improves the activity and function of immune cells, the migration of white blood cells, and the function of leucocytes . Thus, vVitamin D helps in the production of antimicrobial peptides and thus takes part in innate immune responses . The lowThe protection of cell membrane integrity from detrimental effects of free radicals is observed upon vitamin E supplementation . SupplemSelenium acts as a cellular antioxidant and is involved in the immune response by acting on selenoproteins. It also has a major role in modulating cytokine production and inflammatory responses. Selenium supplementation increases the immune system response towards viruses , and thiAn indirect relationship is drawn by a research group between immune function and risk of infection by considering a study that includes selenium deficit mice. In which the Coxsackie B3 virus mutates into a more virulent strain that results in severe cardiomyopathy . They alResolvins, the metabolites of omega-3 fatty acids, are effective in inhibiting the migration of neutrophils, thus reducing the entry of neutrophils into the inflammation site . SpecialCopper can destroy a wide range of microorganisms by exhibiting intrinsic antimicrobial properties . ComplemMagnesium acts as a cofactor in the synthesis of antibodies . MeanwhiVitamin B12 is needed for cell division and replication. As a result, its role in the rapid proliferation of B cells is explained.Folic acid levels must be adequate to generate an appropriate antibody response to antigen .Thus, muIron supplementation in children reduces the risk of respiratory tract infections . BecauseConsidering the fact that elderly people and people with comorbidities are more prone to SARS-CoV-2 infection, the role of micronutrients is explored in alleviating the symptoms and improving the immune system of the body. The nutritional status of the body changes as age progresses, which in turn disrupts the immune responses, thus paving the way for the need for micronutrient supplementation. Micronutrients play a significant role in maintaining the cellular membrane integrity and permeability, especially in the alveolar epithelial barrier of the lungs. During any viral infection, disruption of tight junctions of the epithelial barrier is observed. Hence, micronutrients are considered important as they help in building the integrity of the epithelial barrier. They are helpful in the production of antimicrobial proteins and are also involved in inflammatory processes. Micronutrients neutralize the damaging effects of oxidative agents on cells. Every stage of the immune response relies on the availability of certain micronutrients. Certain micronutrients like vitamins A, C, D, E, and zinc are required to ensure the structural and functional integrity of the skin and mucus membranes as they form the first line of defense as physicochemical barriers against invading pathogenic microorganisms. Cell-mediated innate immunity, complement activation, and the release of proinflammatory cytokines are all heavily reliant on adequate levels of vitamins A, B12, C, D, E, folic acid, and minerals such as iron, zinc, selenium, magnesium, and copper. According to some research, low selenium levels increase susceptibility to viral infection. Parallelly, certain micronutrients like vitamin E, C, zinc, magnesium, iron, selenium, and copper are involved in the self-protection of immune cells by certain antioxidant mechanisms. Copper has intrinsic antimicrobial properties. While magnesium acts as a cofactor in antibody synthesis, Optimum levels of vitamin B12 and folate are required for proper antibody responses toward antigens. The metabolites of omega-3 fatty acids, resolvins, show an anti-inflammatory response and are involved in the stimulation of natural killer cells. Hence, a balanced immune system which is well maintained by certain specific micronutrients helps in reducing the risk of acquiring infections related to respiratory tract and viral infections and also helps in recovery at the molecular level when given as supplements along with antiviral medication. Thus, the deficiency of these micronutrients imparted a greater risk during the outbreak of SARS-CoV-2. The challenges faced during COVID-19 treatment can be overcome by micronutrient supplementation, keeping in consideration their increased demands of need with respect to age and various ill health conditions. By considering the data from observational and in vitro experimental studies conducted by renowned researchers, the role of micronutrient supplementation as supportive therapy along with antiviral or antimicrobial medication can be strongly established for safe and faster recovery.


Recent advances in the development of biomaterials have given rise to new options for surgery. New-generation medical devices can control chemical breakdown and resorption, prevent post-operative adhesion, and stimulate tissue regeneration. For the fabrication of medical devices, numerous biomaterials can be employed, including non-degradable biomaterials  or biodegradable polymers, including implants and three-dimensional scaffolds for tissue engineering, which require particular physicochemical and biological properties. Based on the combination of new generation technologies and cell-based therapies, the biocompatible and bioactive properties of some of these medical products can lead to progress in the repair of injured or harmed tissue and in tissue regeneration. An important aspect in the use of these prosthetic devices is the associated infection risk, due to the medical complications and socio-economic impact. This paper provides the latest achievements in the field of antimicrobial surgical meshes for hernia repair and discusses the perspectives in the development of these innovative biomaterials. Based on the combination of new generation technologies and cell-based therapies, the biocompatible and bioactive properties of medical products can lead to progress in repairing injured or harmed tissues and in tissue regeneration. One of the most common abdominal wall defects with an indication for surgery is represented by hernias, a protrusion of an organ outside its cavity through an area of low resistance . It is cThe biomaterials used for hernia meshes include a wide range of natural and synthetic polymers, with different structures  and characteristics . First-generation surgical meshes—based mainly on polypropylene (PP), have as their main advantage the high tensile strength , but also disadvantages related to recurrence, adhesion, and infections at the hernia site. The second generation of these medical devices proposes composite systems, combining various materials, and offers minimal adhesion formation. Biological materials represent the third generation of these prosthetic devices, being designed as a matrix for native cells to generate connective tissue that should replace the tissue in the defect of the wall. The main advantage of these devices is their superior biocompatibility, respectively the lack of inflammatory response from the body, while the main disadvantage is their higher cost compared to other types available ,8.Nowadays, there is a broad spectrum of synthetic prosthetic biomaterials  or biological meshes  that hernia treatment may benefit from, which have been the subject of some reviews in recent years ,13,14,15An important risk associated with the use of these prostheses is represented by the associated infections, due to the post-operative complications that affect the patients’ quality of life and have a high socio-economic impact ,17. In tIn this review, the latest achievements in the field of antimicrobial surgical meshes are presented and discussed. The burden of mesh-related infections is highlighted and different types of meshes with antimicrobial agents are presented, together with their advantages and disadvantages. The meshes presented in this work are divided into three categories: meshes with antimicrobial metals, meshes with antiseptics, and meshes with antibiotics .During the past few decades, the use of non-absorbable prostheses has been well established in the surgical treatment of hernias. Non-absorbable biomaterials commonly used include polypropylene PP, poly (PET) and expanded poly-tetrafluoroethylene (ePTFE) . PolyproAbsorbable meshes were created in order to reduce the foreign body response, more commonly seen in permanent prostheses . AbsorbaBiologically derived meshes were developed for the purpose of covering abdominal wall defects when there is contamination or highly probable contamination . In esseAs xenogenic prostheses, the most commonly used are small intestine submucosa meshes and acellular porcine derma tissue meshes. Thus, falling into the first group, a commercially available mesh consists of four layers of mostly acellular extracellular matrix. It enhances neovascularization and tissue formation, being also useful in contaminated areas by decreasing the risk of infection ,32. AnotStaphylococcus aureus and Staphylococcus epidermidis, but infections with Pseudomonas aeruginosa, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, or Candida albicans have also been reported.Mesh-related infections could occur weeks or years after surgical intervention and differ from incisional surgical site infections, occurring superficially, within 30 days of the intervention . The datProsthetic devices are generally made out of materials that do not possess intrinsic antimicrobial activity, thus justifying the infection risk associated with the use of these medical devices. The results concerning the influence of mesh type on the incidence of mesh-related infection showed that absorbable synthetic materials are generally more susceptible to bacterial colonization than non-absorbable materials ,41. The Staphylococcus aureus and Staphylococcus epidermidis, the results showed that ePTFE had significantly higher rates of bacterial adherence compared to the other tested polymers. The results highlighted that multifilament meshes had significantly greater bacterial adherence with both pathogens compared to all of the monofilament meshes. The larger filament diameter and smaller pores increased the bacterial adherence. The comparison between coated and uncoated meshes showed that there was no significant difference between titanium-coated PP and uncoated PP, while silver-chlorhexidine coating significantly reduced the bacterial adherence, highlighting the role of the antiseptic agent  C. The poS. aureus, S. epidermidis, and E. coli and the results showed that HApN inhibited both Gram-positive and Gram-negative bacteria growth, with the potential to prevent mesh-related infection [Recent studies proposed a new complex combination of four antimicrobial agents—rifampicin, gentamicin, vancomycin, and chlorhexidine. In order to obtain new materials, a polymer solution—hyaluronic acid-poly(N-isopropylacrylamide) (HApN)—was proposed. The hydrogel formed is being used as a coating for meshes when reaching body temperature. The in vitro studies evaluated the performance of this combination for meshes infected with nfection .Surgical meshes are medical devices that can be employed for the consolidation of the abdominal wall in the treatment of hernias. Polypropylene-based surgical meshes are the golden standard option; however, with the rapid development in the biomaterials field, numerous other non-degradable and biodegradable materials are emerging as promising candidates for the development of new surgical meshes. One of the many challenges related to the use of these medical devices is represented by post-operative infection. The presence of infection is correlated with decreased quality of life, increased healthcare costs, and a high socio-economic burden.In order to prevent surgical site infections, numerous strategies for the development of antimicrobial surgical meshes have been employed. Some commercially available antimicrobial surgical meshes are already used in the clinical setting, while others are only in the experimental stages of development.Some strategies for the fabrication of antimicrobial surgical meshes include the incorporation of antimicrobial metals, antiseptic substances, or antibiotics into different types of commercially available meshes. The preliminary results obtained with these devices are promising; however, more research needs to be carried out in the field until they can be clinically employed. More specifically, while some surgical meshes have been tested in vivo, most experiments were carried out on animals, with few examples of clinical trials. Extensive clinical trials need to be performed in order to fully assess the biocompatibility and the long-term safety profiles of these surgical meshes in humans, in order to offer more information on the biological behavior of these meshes .As the field of biomaterials continues to progress, it is expected that surgical meshes with improved characteristics, such as high flexibility, tissue biocompatibility, and resistance to shrinkage and adhesion, will be developed in the future.The methods used for the development of surgical meshes are magnetron sputtering techniques or physical vapor deposition in the case of metallic-coated meshes, impregnation of the commercially available meshes in antiseptic solutions, or the incorporation of antibiotics into polymers or cyclodextrines to obtain antibiotic-based surgical meshes.In the future, other fabrication techniques such as 3D printing could be employed to develop surgical meshes that are individually tailored to each patient’s needs and that would present improved antibacterial drug release properties ,88,89.Another future perspective for the development of antimicrobial surgical meshes consists of the development of antibiotic-based smart meshes . These dIn conclusion, given the important impact of infection on the public health system, numerous strategies have been applied for the development of different types of antimicrobial surgical meshes in this review, these meshes were classified into metallic-coated, antiseptic, and antibiotic-based surgical meshes and their properties were presented and discussed. Silver nanoparticles and other silver compounds were the most commonly employed metallic-based antibacterial agents for the development of metallic-coated surgical meshes, while chlorhexidine was extensively used as an antiseptic. Among antibiotics, vancomycin, beta-lactam antibiotics, and rifampicin were commonly employed for the development of antimicrobial meshes. Despite the need for further tests, especially for clinical trials, these novel medical devices present promising characteristics for the field of surgery. It is expected that 3D printing and the development of smart surgical meshes with incorporated sensors will play an important role in the mitigation of surgical mesh-related infections, thus improving patient quality of life.


SERS enhancement factors—defined as the intensity ratio between SERS and conventional Raman scattering signal for a given analyte normalized by the number of molecules probed—can typically achieve 8–10 orders of magnitude for the plasmonic substrates with inter-/intra-particle nanogap, while these values can exceed 10c optics . HoweverRecent years have been extremely advantageous to SERS spectroscopy, which, thanks to the development of nanotechnology and progress towards a higher level of the theory—in tandem with an improved detection sensitivity of Raman instruments and advances in computing power capacities—has grown to a role that goes beyond purely academic applications.All of these, together with an enormous enhancement of the intrinsically weak Raman scattering signal, supported by high selectivity and specificity of the SERS method, offer simple detection and identification of the analyte of interest and use for designed applications.Nowadays, a smart combination of computational approaches and vibrational spectroscopy aids the interpretation of SERS experimental results . On the All these novel materials and analytical approaches allow SERS technique to reach beyond the laboratory and develop devices operating in real-life conditions, supporting industry and the development of (nano)technology, as well as being useful in biology, medicine and diagnostics.This Research Topic contains seven articles: four research papers, two mini reviews, and one review, which cover a broad range of issues revolving around SERS-based sensing and its application in real-life problems.Kasztelan et al. explore a novel substrate consisting of graphene oxide and silver nanoparticles (Ag NPs). By meticulous screening of the synthesis conditions, control on the composite parameters, such as the shape of Ag NPs and the material load with Ag NPs, can be achieved. Combination of the here-utilized SERS-supporting components leads to increased intensity of the signal and sheds some light on the mechanism and general properties of such hybrid materials.Two of the original research papers included here focus on the development of new, high-performance substrates for SERS. Both studies represent the strong ongoing trend of steering away from single-component metallic plasmonic materials. Żygieło et al. approach the well-known issue of uncontrollable aggregation of hybrid magnetic-plasmonic nanoparticles, using Fe3O4/AgNPs as a proof of concept. There, improved stability is achieved by encapsulation of the material in nanosilica, whose generation is facilitated by 2-mercaptoethanesulfonate ions acting as both a SiO2 primer and a Raman tag. Improved stability and longevity of such nanotags increase the feasibility of real-world applications . Thorough optimization of the fabrication process and comprehensive characterization of the final product will help other researchers translate the results into their own studies.On the other hand, Dusa et al. constitutes a valuable input into substrate engineering from the theoretical side using finite-difference time-domain (FDTD) simulations. Various combinations of nanoparticles’ systems are considered  in the context of SEHRS (surface-enhanced hyper Raman scattering), in a broad range of excitation . Determined enhancement conditions are essential to properly select the right system for use in this method—complementary to SERS spectroscopy and valuable in the studies of biological systems.The work of Tay et al. covers the study on a novel paper-based sensor of narcotic drugs. Right functionalization strategy, in this case with iodide ions, improves the sensor’s performance by obtaining stronger signals and quicker detection. The ease of fabrication, using inkjet printing, is a strong advantage in the commercialization process of such devices. Moreover, such prepared nanosensors can be straightforwardly used in field applications.The final original research by Szaniawska and Kudelski survey the current studies on the determination of biochemically and medically relevant species. They highlight, among others, glucose detection and intracellular SERS as hot topics and point out towards combination with other techniques, like polymerase chain reaction (PCR) or paper-based sensors, the latter being perfectly illustrated by the research of Tay et al. mentioned above.Significance of developing efficient and reliable SERS-based sensors is emphasized in the mini-reviews from this Research Topic. Quarin and Strobbia. They present recent advances towards the SERS-based point-of-care diagnosis. Such a form of disease recognition promotes fast treatment and prevents disease spread, which is especially important in today’s world. They take into consideration various SERS-sensing mechanisms and their advantages in the point-of-care approach. The fact that most of the reviewed methods are based on the detection of various species of microRNA, which are markers for numerous diseases, is deemed extremely helpful.Urgency of application of SERS spectroscopy in medical diagnosis is carefully explained in the mini review by Xi and Liang provide an overview of the ongoing efforts to bring SERS closer to the patients, as they review clinical trials which employ Raman or SERS spectroscopy. It turns out that such studies have been recorded in Official Registries in many countries around the globe, including Japan, Germany, China, India and Australia. Various methods listed there  indicate the rising appreciation outside of the community for the increasing availability of Raman-based techniques. A long list of diseases, including diabetes, pulmonary diseases and various cancer types, is a promising sign in the context of future applications.Finally, We are sure that the reader of this Research Topic will be provided with the most current insight into the development of SERS sensing investigations and the mixed bunch of papers herein will introduce them to its current application studies, as well as inspire them to implement their own ideas in the field.


With the warming global climate, drought stress is considered to be the most important abiotic factor limiting plant growth and yield in the world. Drought stress has serious impacts on crop production. Many researchers have studied the influences of drought stress on crop production and plant physiology; however, few researchers have combined root exudates with root-associated microbiomes for their mutual effects under drought conditions. In this review, we systematically illustrate the impact of drought stress on root exudates and root-associated microbiomes, and then we discuss the mutual regulation of root-associated microbiomes and the host plant in helping the plant adapt to drought. Finally, we construct a framework for the mutual connections between the plant, root exudates, and the microbiome. We hope this review can provide some significant guidelines to promote the study of drought resistance in plants in association with the rhizosphere microbiota. Water is the most important resource for plants, and plant organs need to maintain 60–90% water content for sustainable activity. However, global climate change, caused by greenhouse gas emissions, has become more serious worldwide, leading to drought throughout the world . DroughtCurrently, the frequent changes in climate have increased the severity of drought events for plants . The plaFurthermore, plant roots can help maintain the inherited microbial communities that may influence crop growth, nutrition, and health . A previAlthough the composition of the root-associated microbiome has been determined in many crop species, the influence of abiotic stresses, especially drought stress, on the root-associated microbiota has been less studied . In thisRoot exudates are plant metabolites and are secreted in the rhizosphere, including various compounds secreted or released from different parts of the root system into the rhizosphere environment during the growth of plants . Root exRoot exudates, responding to the changing environment, can serve as positive or negative factors in plant growth ,9. A preRoot exudates serve as important carrier materials for material exchange and information transmission between plants and soil ,13,14,15With the rapid development of modern instrumental analysis methods and the wide application of root exudates in the fields of plant nutrition, agroecological and environment studies, etc., the research on root exudates has entered a new upsurge. Especially in the last decade, with the construction and improvement of rhizosphere microecology, root exudates have been considered an important part of plant nutrition and rhizosphere microecology research.Unlike animals, plants cannot escape various adverse environmental stresses and can only grow and develop in their germinating place where they finally complete their life cycle. Root secretion activity helps plants adapt to and gradually change the soil environment contacted by the roots, which is an adaptive response mechanism for plants to cope with environmental stress ,13,14. TIn general, the content of root exudates of plants under drought stress will be higher than that under normal conditions. Many studies showed that the total content of root exudates  of the plants increased with the level of drought stress intensity ,19. The Quercus ilex under gradient drought stress and subsequent recovery and found that the increased drought stress strongly affected the secondary metabolites , with the increased synthesis of alkaloids and terpenoids .,36.35,36The dialogue between a plant and fungus comes from plant photosynthesis and root exudation, molecular cues (SLs), secreted into the rhizosphere . It was Soil microbes can respond accurately and quickly to changes in soil environment, and small changes in soil environment can lead to changes in soil microbes, which can sensitively warn of small changes in terrestrial ecosystems. The soil water content is closely related to soil microbes, and drought will affect the rhizosphere microbial communities. First, drought will cause osmotic stress on soil microbes, which will directly affect them, resulting in their death and cell lysis. Second, drought will change the quality and quantity of carbon sources available to rhizosphere microbes by affecting plant photosynthesis and then indirectly affect the roots. Fuchslueger et al. (2014) demonstrated that water deficit caused a change in the microbial community composition; an increase of Gram-positive bacteria was driven by the drought stress, and drought decreased the C allocation below ground but did not influence the transfer of recently plant-assimilated C to fungi . ComparaFurthermore, the enrichment of Streptomyces (belonging to the Actinobacteria) under drought was shown to play a subsequent role in improving plant drought tolerance in the study . ThroughDrought stress leads to specific recombination of the rice root-related microbial community . It was In the soil environment, Gram-positive bacteria are more tolerant to drought than Gram-negative bacteria because their cell walls are thicker and some Gram-positive bacteria have the ability to form spores . HoweverVerticillium virens, and Sclerotinia) and specific amino sugars and sugar alcohols, indicated that the Gram-positive bacteria are related to a group of different compounds, including polysaccharides and glycoside hydrolases. Carbohydrates and amino acids produced by plants are powerful candidates among compounds that can promote the growth of a single germ layer . It is wBacillus subtilis  when plants are under drought stress [Bacillus sp. ESA 402, one of the plant growth promoting bacteria, in the rhizosphere of sorghum (Sorghum bicolor), which benefited the growth of the sorghum under drought stress [In addition, the metabolomics of roots under drought stress showed that the yields of many carbohydrates (including xylose and glucose) and amino acids  increased significantly . Malic at stress . Santanat stress . HoweverZingiber officinale), sorghum (S. bicolor), corn (Zea maize), wheat (Triticum monococcum), and others decreased with an increased level of drought stress intensity, while the number of bacteria and Actinobacteria in rhizosphere soil of cherry increased with the initial stress intensity and the decreased with a high level of drought stress [As for rhizosphere microbiotas, some scholars have used the dilution plate counting method to study the number of bacteria . They fot stress . Glycine soja) and cultivated (Glycine max) soybean [Santos-Medellín et al. (2021) also showed that Streptomyces were the most enriched Actinobacteria in the rice root microbiome after drought stress . Zhang e soybean . However soybean ,47. Ther soybean ,47. DrouThe ratio of fungi to bacteria is an important index for measuring the microbial community structure, which also reflects the nutrient status of the substrate ,49. The Studies showed that not only did drought influence root-associated microbiomes but, conversely, root-associated microbiomes regulated plants in resisting drought stress. Plant growth-promoting rhizobacteria (PGPR) can not only help promote plant growth but also help plants resist biotic and abiotic stress . It was In order to effectively absorb water and reduce water evaporation under drought conditions, the plant will decrease the leaf size and extend the root system into deeper soil ,52. PlanAlthough these strategies are promoted by plants, the contribution of bacteria also affects this protection. For example, although proline serves as the most vital osmotic agent in the plant cytoplasm, under environmental stress, proline accumulation occurs not only in higher plants but also in bacteria, which may also help the bacteria for drought tolerance and then in association with plant in resisting drought ,55. Rolli et al. (2016) showed that improved plant resistance to drought is promoted by the root-associated microbiome as a water stress-dependent trait . The stuThe mechanisms of the plant in responding to drought stress by the rhizobacteria have been shown to include the production of abscisic acid, cytokinin, indoleacetic acid, trehalose, 1-aminocyclopropane-1-carboxylate (ACC) deaminase, volatile organic compounds, and exopolysaccharides ,60. The They can also promote the plant absorption of nitrogen, phosphorus, and other elements in the soil, while plants can provide AMF with carbon sources generated by photosynthesis ,66,67. RIt is also shown that the extraradical hyphae of AMF colonized in roots extend into the soil. The extended and dense hyphae in the soil can contact and extract water from the soil pores, which is not accessible to plant roots and the root-hair zone . As a stTrehalose, as an important non-reducing sugar, can not only be used in plant energy storage but can also be of great significance in assisting plants to cope with drought and low temperature . FurtherBased on the review and illustration of the studied and current understanding of the relationship among the plant, root exudates, and microbiome, we constructed a framework for mutual connections among them under wild and moderate drought conditions . DroughtThe root cell extracts will contain more mineral material to keep the osmotic pressure by exchanging cell metabolism outside. Then the root exudates will change the root-associated microbial community structure, such as by increasing the abundance of Streptomyces. Then, the enriched PGPB or PGPF can stimulate the mineral extraction, which will help to regulate drought resistance in plants. However, there are also questions about the beneficial exchange of the root exudates for mineral between the plant root and soil microbes as well as the balance of the framework under the drought condition. Thus, in future studies, several aspects in connecting the rhizosphere microbiomes and root exudates of crop plants under drought conditions should be focused on: (1) the drought condition influence on root exudates, including primary and secondary metabolites; (2) the plant hormones secreted from the roots that regulate root-associated microbiota directly or indirectly; and (3) the crop plant exchange through the root exudates with the soil for mineral elements with the help of PGPB and PGPF.In summary, drought stress has been shown to seriously influence root exudates and root-associated microbiomes in previous studies. Drought stress influences root exudates, including sugars, amino acids, flavonoids, hormones, etc. This stress not only influences soil microbiomes but also seriously affects rhizosphere communities, which may help plants resist drought stress. However, the crosstalk of the root-associated microbiomes with the root exudates has not been clearly illustrated. Thus, further studies should be focused on this topic in the future as this will have theoretical and practical significance for crop production.


Background: Psychopathological models of adolescent borderline personality disorder (BPD) suggest that non-suicidal self-injuring (NSSI)—a particularly frequent symptom in girls—may constitute a way of coping with distress resulting from interpersonal concerns they typically experience as a developmental psychopathological feature.Objectives: Our objective was to investigate the relationship in BPD female adolescents between NSSI and the Sidney Blatt two-polarities model of personality development, which focuses on the psychological processes of interpersonal relatedness and self-definition.Methods: The study was conducted within the European Research Network on Borderline Personality Disorder in Adolescence, using the Depressive Experience Questionnaire (DEQ).Results: BPD patients  scored significantly higher than healthy controls on the two DEQ sub-factors assessing the more immature forms of Interpersonal Relatedness (Neediness) and Self-definition (Self-criticism) and significantly lower on the more mature form of Self-definition (Efficacy). BPD adolescents with NSSI showed significantly higher scores on both mature and immature forms of Interpersonal Relatedness (Neediness and Connectedness) compared to BPD adolescents without NSSI. A logistic regression analysis showed that the subfactor Neediness of the DEQ was the only significant predictor of the presence of NSSI among BPD adolescents.Conclusions: The preliminary results of this study suggests that NSSI in adolescents with BPD is developmentally linked to high developmental concerns in the domain of interpersonal relatedness, which may be taken into consideration in clinical practice. More studies are necessary to better understand the relationships between NSSI and developmental psychopathology in borderline adolescents. Nonsuicidal Self-Injury (NSSI), the repeated infliction of injuries to the surface of the body without suicidal intent , is partBPD is indeed the most frequent mental disorder among inpatient adolescents with NSSI , 6, as iCurrent research in psychopathology supports the notion that NSSI has two main psychological functions , 14: (i)One way to address the psychopathological functions of NSSI in patients with borderline personality disorder can be offered by the theoretical perspective proposed by Sidney Blatt of the two central dimensions of personality development: interpersonal relatedness and self-definition , 22. ThiDepressive Experience Questionnaire (DEQ) to assess these two dimensions which emerge as independent factors in analytic studies. However, subsequent theoretical developments have suggested that different levels could be identified among these dimensions, each following a developmental trajectory from immature to more mature forms of interpersonal relatedness and self-definition. Investigations using the DEQ have thus identified two levels within the Dependency factor : a first sub-factor, labeled Neediness, assesses feelings of loneliness, and insecurity as well as a marked vulnerability to nonspecific experiences of loss, rejection, and abandonment. The second sub-factor, labeled Connectedness, appears to assess a more mature level of interpersonal relatedness, including valuing intimate relationships and being concerned about disruptions of particularly meaningful, specific, and interpersonal relationships  . The overall model was significant  and explained 37% of the variance  = 1.11, BPD adolescents with NSSI behaviors may represent a specific subgroup of BPD adolescents with a more severe clinical profile and negative outcome. In our sample of BPD adolescents of our study, NSSI behaviors were associated with a poorer global functioning. This is in line with the results of previous works, which have shown that NSSI in BPD adolescents is linked with clinical severity , 35. ExpNeediness and Connectedness dimensions, but not on Self-criticism and Efficacy ones, of Blatt's model of personality development  polarity of Blatt's two-polarities model of personality development  the precise nature of emotional concerns around the psychological processing of loss; (ii) the extent of concerned social relationships; and (iii) the repercussions on subjective efficacy. Indeed, while Neediness corresponds to intense fear, regarding loss of any relation, with consequent feelings of rejection, helplessness and despair, Connectedness involves sadness regarding loss of specific and valued relationships, leading to rather sufferable loneliness. While high Neediness is considered a clearly maladaptive pattern involving early developmental issues, high Connectedness is considered more developmentally mature, and even somewhat adaptive  with positive strong correlations between these two sub-factors within BPD group and subgroups, which reflect the commonalties of these dimensions centered on relational issues at different level of maturity. Since Neediness is thought to reflect an early maladaptive pattern, we could suggest that it may be the modal variable of the whole IR pattern found in BPD adolescents with NSSI, as suggested by the results of the regression analysis showing that Neediness was the only significant predictor of the presence of NSSI among BPD adolescents. BPD Adolescents with NSSI would thus globally be characterized by higher anaclitic dependency, as it has been suggested in adult patients with BPD . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.FG participated in data analysis and interpretation and in writing the manuscript. MS, MC, and AP-S initiated and designed the protocol, collected data, participated in data analysis, and interpretation and in revising the manuscript. SS, LG, MR, and VD participated in data analysis and interpretation and in revising the manuscript. All authors read and approved the final manuscript and contributed sufficiently to the project to be included as authors.This research was supported by a grant from the Wyeth Foundation for Child and Adolescent Health and by a grant from the Lilly Foundation. Both had no role in conception and design of the article, in the writing of the manuscript, and in the decision to submit the paper for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The enzyme glutamine synthetase (GS), also referred to as glutamate ammonia ligase, is abundant in astrocytes and catalyzes the conversion of ammonia and glutamate to glutamine. Deficiency or dysfunction of astrocytic GS in discrete brain regions have been associated with several types of epilepsy, including medically-intractable mesial temporal lobe epilepsy (MTLE), neocortical epilepsies, and glioblastoma-associated epilepsy. Moreover, experimental inhibition or deletion of GS in the entorhinal-hippocampal territory of laboratory animals causes an MTLE-like syndrome characterized by spontaneous, recurrent hippocampal-onset seizures, loss of hippocampal neurons, and in some cases comorbid depressive-like features. The goal of this review is to summarize and discuss the possible roles of astroglial GS in the pathogenesis of epilepsy. Astrocytes have historically been thought to serve a primarily structural role by supporting surrounding neurons . Over thFollowing an acute central nervous system (CNS) injury, astrocytes undergo several morphological and functional changes. These “reactive astrocytes” are present in several pathological conditions While reactive astrocytes were originally thought to reflect scar tissue in response to neuronal injury and loss, recent studies have suggested that reactive astrocytes may in fact play important roles in the causation of many disorders, including epilepsy –20.Glutamine synthetase , an enzyme that is highly abundant in astrocytes, is of particular interest due to its roles in health and disease . SystemiGS serves important roles in nitrogen metabolism, acid-base homeostasis, and cell signaling in many species of prokaryotes and eukaryotes –38. GS iAfter its release from the presynaptic neuron, neurotransmitter glutamate interacts with receptors in the postsynaptic membrane, followed by its removal from the synapse into astrocytes. After uptake into astrocytes, glutamate may be converted to glutamine via glutamine synthetase . GlutamiThe human body contains large amounts of ammonia, produced mainly by the action of bacterial enzymes on colonic content and from the hydrolysis of glutamine in the small and large intestinal cells. While the gut-derived ammonia is mostly metabolized by the liver, via the urea cycle and the GS reaction, a small amount of ammonia (10–30 μmol/L) remains in the plasma under normal conditions. Much higher plasma ammonia concentrations are detected in pathological conditions such as liver disease and urea cycle disorders. Because ammonia is neurotoxic and easily crosses the blood-brain-barrier, an efficient mechanism for clearing brain ammonia is essential . Astroglin vivo brain microdialysis  in human patients with MTLE, as ascertained by simultaneous depth electrode EEG and dialysis –59. In adialysis . Furtherdialysis , 61, 62.dialysis , 61, 62.13) studies suggest that a slowing of the glutamate-glutamine cycle metabolism in the epileptogenic hippocampus is responsible for the accumulation and reduced clearance of glutamate in MTLE . MSO impedes the ability of GS to catalyze the conversion of glutamate and ammonia to glutamine by irreversibly binding to the catalytic sites of GS . In one Another study analyzed whether the neuroanatomical site of GS inhibition is an important determinant for the epileptogenic process and for the epileptic phenotype. MSO was infused unilaterally into different limbic regions of adult rats, including the angular bundle, the deep entorhinal cortex, area CA1, the molecular layer of the subiculum, the hilus of the dentate gyrus, the lateral ventricle, and the central nucleus of the amygdala , 72. RecThe prevalent idea that the neuroanatomical and electrophysiological substrates of focal epilepsies occur only in a circumscribed brain region, the seizure focus, has been questioned more recently –77. ManyAlbright et al. analyzed changes in neuronal networks during epileptogenesis in the intrahippocampal MSO-infusion model of MLTE . IntracrIn another study, whole brain diffusion tensor imaging (DTI) was used to assess any structural changes during early and late epileptogenesis in the hippocampal MSO-infusion model of MTLE . There wAn increasing number of studies in humans and animal models have linked astroglial GS dysfunction to the pathogenesis of focal epilepsies, particularly MTLE. Even very small and circumscribed deficiencies in GS affecting a subfield of the hippocampal formation or a nucleus of the amygdala can lead to epileptic seizures and comorbid, depressive-like features in laboratory animals. Moreover, such small deficiencies result in widespread and progressive changes in neuronal network activation and in the structure of the brain. While the mechanism by which GS dysfunction causes epilepsy remains unclear, several scenarios are possible such as reduced clearance of extracellular brain glutamate and ammonia, glutamine deficiency, and perturbed glutamatergic and GABAergic neurotransmission. Further studies are needed to determine the causes of astroglial GS deficiency so that more effective treatments can be developed to prevent such deficiencies and combat the development and progression of GS-associated epilepsies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.