Adolescents living in low- and middle-income countries (LMICs) are struggling with accessing sexual and reproductive health (SRH) services, and COVID-19 has escalated the problem. The purpose of this review was to identify and assess the existing literature on the impact of the pandemic on SRH needs and access to services by adolescents in LMICs. A scoping review was conducted to collate findings on the topic. Searches were performed on eight databases. Data were extracted and categorized into various themes. After removing duplicates and performing a full-text reading of all articles, nine articles were included in our review. Our findings generated several themes related to adolescents’ sexual and reproductive health during the COVID-19 pandemic. These include (1) limited access to sexual and reproductive health services, (2) school closure and increased rate of early marriages, (3) sexual or intimate partner violence during COVID-19, (4) disruption in maternity care, (5) adolescents’ involvement in risky or exploitative work, (6) intervention to improve sexual and reproductive health services during COVID-19, and (7) policy development related to adolescent sexual and reproductive health. Several recommendations were made on policies—for instance, the use of telemedicine and community-based programs as a way to deliver SRH services to adolescents during and after a pandemic. As the fastest-moving global public health crisis during this century, the COVID-19 pandemic is causing significant mortality and morbidity and creating daunting health and socioeconomic challenges. The restrictive measures that have been put in place by many countries to contain the spread of the virus may negatively affect access to essential sexual and reproductive health (SRH) services, particularly by adolescents living in low- and middle-income countries (LMICs) and fragile settings .Globally, approximately 1.8 billion people are between the age of 10 and 19 years, and 90% of them live in low- and middle-income countries (LMICs). Low- and middle-income-earning countries are countries that are considered either as low-income-earning countries or both low and high middle-income-earning countries. According to the World Bank, low-income economies are countries with a Gross National Income (GNI) per capita of USD 1025 or less, and middle-income economies (low and high middle-income countries) are those with a GNI per capita between USD 1026 and USD 12,375, using the World Bank Atlas method . LockdowWhat is known from the literature about the impact of COVID-19 on SRH of adolescents in LMICs?What interventions have been designed and implemented to promote SRH and access to SRH services for adolescents in LMICs during the COVID-19 pandemic?How can future studies overcome research gaps and inform programs and policies that meet the SRH care needs of adolescents in the context of the pandemic?The pandemic has caused further strain on health systems, specifically in LMICs, and has likely impacted adolescents’ SRH and access to SRH services. However, there is no comprehensive and integrated literature on the impact of the pandemic on SRH access and use among adolescents in LMICs. Our review has addressed this gap through an exploration of the SRH priorities and access to SRH services by adolescents in LMICs during the pandemic. The purpose of this scoping review was to identify and summarize the already existing research and literature regarding the impact of the pandemic on SRH needs and access to services by adolescents in LMICs. Specifically, this study aimed to identify research gaps in the existing literature, as well as to summarize and disseminate research findings for clinicians, service providers, and policymakers. The research questions that guided the study were:To explore the impact of the COVID-19 pandemic on the SRH of adolescents residing in LMICs and the types of interventions designed to improve access to SRH services, we used a scoping review methodology as guided by Arksey and O’Malley  and LevaA systematic literature search was conducted by an experienced health sciences librarian (MK) to identify all relevant published studies. Searches were performed in the following databases: Medline, EMBASE, PsycINFO, HealthSTAR, Sociological Abstracts via ProQuest, Cumulative Index for Nursing and Allied Health Literature (CINAHL) via EBSCOhost, Scopus via Elsevier, and the Cochrane Library via Wiley. These databases were searched using a combination of natural language vocabulary and controlled terms (subject headings) wherever they were available. Natural language terms were derived from three main concepts: (1) sexual reproductive health issues including, sex, sexuality, pregnancy/family planning, sexually transmitted infections, and others; (2) LMICs as defined by the World Bank; (3) adolescents. A few of the keywords used for the search in the electronic databases included adolescents, young adults, sexual health, reproductive health, reproductive rights, LMICs, COVID-19, pandemic, access to health services, teenage pregnancy, contraceptive, sexuality education, gender-based violation, unintended pregnancies, and female genital mutilation. In order to increase the search sensitivity, publication date, language, and study type restrictions were not applied. Other search methods were employed in order to retrieve additional evidence. These methods included hand searches of the reference lists and forward citation searches, using Scopus, of papers to be synthesized in the scoping review. Finally, the team reviewed the grey literature on this topic. All searches were performed in February 2021 . We included studies that involved broader age groups provided that they had subgroup data for 10- to 19-year-olds. Articles published in English from March 2020 to date were included. All primary research studies irrespective of study design were considered. Using Covidence, a web-based tool that helps to identify studies and involves data extraction processes , two revWe extracted relevant data from each study, including the year, study design, setting, the target population, and the outcomes that the researchers measured see . One revThe initial search retrieved a total of 261 articles. After removing duplicates and articles in other languages and reviewing abstracts with respect to the inclusion criteria, a total of 25 studies were considered relevant. Following a full-text review and consultation among the reviewers, nine articles were included in the final review and analysis using the PRISMA diagram  23]. Fi. Fi23]. A systematic analysis of the findings was conducted to identify relevant themes. Adolescents faced various SRH vulnerabilities during COVID-19, which can be categorized into several themes, including limited access to sexual and reproductive health services, school closure and increased rate of early marriages, sexual or intimate partner violence during COVID-19, disruption in maternity care, and adolescents’ involvement in risky or exploitative work. The review also generated other themes, such as interventions to improve sexual and reproductive health services, and policy development related to adolescent sexual and reproductive health during COVID-19. Findings of these issues and interventions are discussed in the following section in detail.Limited access to youth-friendly healthcare services was reported in various countries during the COVID-19 pandemic. In Kenya, some adolescents (17%) complained of not being able to go to their regular clinic for medical care, and others (3%) reported not being able to get their medication refills. More specifically, 2% of adolescents aged 15 to 19 years were not able to access medication refills, whereas 8% of adolescents reported missing antiretroviral therapy (ARVs) for 2 or more days in a row in the last 30 days [In addition, many older girls reported ignoring and not being able to access the needed SRH services during the pandemic, such as modern contraceptive and family planning services . AdolescA study conducted in Syria reported that teenage mothers expressed financial distress due to the pandemic, which affected their ability to buy sanitary pads. Alternatively, young girls resorted to using whatever material or cloth was available at home as they had no money to buy sanitary pads . SimilarIn contrast, despite the lockdown situation in a country such as South Africa, it was found that adolescents’ visits for perinatal care and family planning remained reasonably constant or modestly increased during the pandemic lockdown . An estiA study conducted in three different countries, including Ethiopia, Cote d’Ivoire, and Lebanon, reported mixed findings on the risks of child marriage amid the COVID-19 pandemic . In LebaThe frequency of intimate partner violence rose amid this pandemic. Adolescents reported being at high risk of experiencing intra-household violence and, in the case of Lebanon and, to some extent, Côte d’Ivoire, girls reported being at a heightened risk for community-level violence . In addiIn Afar, a town in Ethiopia, married girls were concerned about infection transmission and remained fearful of seeking antenatal care, due to which they opted for home-based births, resulting in several maternal deaths . One othThe pandemic caused great financial challenges to families and communities during the lockdown. As a result, youth were compelled to engage in or consider risky or exploitative work . In EthiInterventions to make SRH service available and accessible to adolescents were proposed during the COVID-19 pandemic lockdown. The UNFPA  was one Another intervention was the involvement of healthcare professionals to ensure that adolescents had access to age-specific, accurate, and up-to-date information on SRH verbally through the media and pamphlets. This information included access to information on contraceptives, comprehensive care, antenatal, intrapartum, and postnatal care, testing and care for HIV and other STIs, and menstrual health available to adolescents during the lockdown . FurtherAdditionally, telemedicine was encouraged as an intervention to provide services for safe and easy access to medical abortions, counselling, and screening to adolescents . MoreoveDourado et al.  assessedAs restrictions were imposed due to COVID-19 in most parts of the world, some countries and international organizations outlined the development of policies on adolescent SRH. Two of the articles ,20 and oAs reported by Herran and Palacios , communiThis scoping review synthesized the literature on the impact of the COVID-19 pandemic on the SRH of adolescents living in LMICs. Despite the growing conversation around SRH and the rights of adolescents amid COVID-19 among national and international stages, a dearth of literature remains on this topic specific to adolescents’ needs in LMICs. To the best of our knowledge, this scoping review is the first of its kind that systematically synthesizes the literature on the impact of the pandemic on SRH and the rights of adolescents in LMICs. The findings from our scoping review add to the discussion on the impact of the pandemic on SRH and access to services by establishing the diverse and multi-faceted SRH service needs specific to adolescents in LMICs. Moreover, our findings demonstrate that adolescents would benefit from programs and policies that address the impact of the pandemic on SRH and access to services in LMICs.The socioeconomic status of the adolescents contributed to their SRH during the lockdown. The current review suggests an increase in early marriages and unwanted pregnancies during the lockdown, because of the closure of schools. Both adolescent girls and boys were forced into early marriages during the lockdown. With adolescents staying at home long-term during this period, the parents of girls with a low socioeconomic background gave them out for marriage. In most of these communities, a dowry is usually paid to the parents of the bride, and the cost varies amongst communities. Some studies included in this review mentioned the closure of schools as a contributing factor to the increase in early marriages. However, the financial stress experienced in most countries due to COVID-19 ,25,26 coThe review also suggests an increase in unprotected sexual activities, and girls entering into an intimate relationship with the opposite sex during the lockdown, leading to more unwanted pregnancies amongst adolescent girls. In some countries, adolescents are sometimes required to obtain permission or endorsement from their parents, or spouses if married, before using a contraceptive ,28. ThisWe suggest that access to menstrual products was also halted during the pandemic due to various factors. Mobility restrictions and girls’ confinement to home limited their ability to buy their desired menstrual products and they were forced to use home-based material to manage menstruation. Affordability was another factor that contributed to the poor access to menstrual hygiene products. Our findings coincide with studies conducted in various regions across the globe that also found that girls suffered from poor menstrual hygiene management during COVID-19 due to limited access, disrupted supply to menstrual hygiene products, particularly disposable menstrual hygiene materials that require monthly replenishment with increased demands and rise in the product prices, a less hygienic environment for sanitary hygiene product disposal, reduced availability of clean water, and access to information about menstrual hygiene ,30.Adolescents also suffered from domestic violence (DV) and intimate partner violence (IPV), which significantly increased amid the pandemic. Our study highlighted several factors that perpetuated the situation, such as stress due to loss of income, economic instability or poverty, and men staying at home and not going to work due to lockdown orders. Similar findings were reported in other studies, where the households that suffered from unemployment and low income were the ones highly affected by intimate partner violence ,32 TheseSimilar to LMICs, cases of DV and IPV were also reported in Argentina, the USA, Pakistan, and several other countries due to pandemic-induced financial worries and the poor mental health of either of the partners ,32,33. MThe review found that there was limited access to sexual and reproductive health services. Some adolescents were unable to access medical refills for antiretroviral therapies (ARTs) during the lockdown, hence missing doses of their medication for several days. Moreover, adolescents reported not having access to contraceptives and menstrual hygiene products. This was also reported in other studies and was due to the social distancing or lockdown in most countries during the peak of COVID-19 ,36. HoweThe findings of our study suggest that schools have been playing a major role in delaying early marriages and adolescent pregnancies, and the closure of schools during the pandemic has had a dramatic impact on adolescents’ health. Child marriages can result in serious health consequences, including early and high-risk pregnancy, which may increase the risk of maternal and infant morbidity and mortality ,41. It cHowever, numerous studies suggest that keeping children in schools is the best way to prevent early marriages . School The review found that the COVID-19 pandemic created inconveniences and difficulties for adolescents in accessing SRH services. It was a struggle for most countries to be able to provide the needed SRH services for adolescents because of their unpreparedness for such global disasters. As mentioned by , countriDespite the preparedness to make SRH services available, accessible, and affordable to all in case of future pandemics, stakeholders and policymakers must consider the availability of resources and the culture of the people when adopting proposed strategies or programs. The review found that adolescents had access to SRH education and knowledge in schools and through their interactions with their teachers. In some countries or communities, introducing SRH services for adolescents in their homes could be a challenge. Discussion of topics pertaining to SRH has been mentioned to be restricted in some homes and communities ,48 becauThere are limitations to this review that need to be highlighted. The findings of this scoping review may not be generalized to countries other than low- and middle-income countries. The findings cannot also be generalized to all LMICs because of the cultural and socioeconomic diversity amongst these countries. This scoping review also only included studies published in English; therefore, studies pertaining to this topic published in any other languages were excluded. Most qualitative studies included in this review were descriptive in nature; therefore, they did not provide an in-depth understanding of the findings. There were also limited numbers of published studies on this topic available.The findings of the literature review on healthcare provide knowledge on the needed areas that require further research to improve the delivery of services. The gaps identified in the review show the need for further research, which will produce a wider understanding of the impact of a pandemic on the delivery of SRHS to adolescents and youth in low- and middle-income countries. One of the gaps identified in this review was that most of the studies focused on female adolescents. Therefore, further studies that target male adolescents are highly recommended. In addition, studies that would explore the multiple ways to ensure culturally accepted, reliable, available, and affordable SRH services for adolescents living in rural areas, adolescents with HIV, transgender adolescents, and refugees during future pandemics are highly encouraged. Moreover, the review found gaps in the use of other alternatives to provide SRH services during the lockdown. Hence, studies to improve the knowledge and ability of SRH service providers to use available technologies and other resources for the delivery of quality services when needed are also highly recommended.The findings of this scoping review identified various aspects of adolescents’ sexual and reproductive health that were highly impacted due to the COVID-19 pandemic. These include limited access to sexual and reproductive health services, including access to contraceptives, menstrual products, and medications for HIV treatment; increased rates of early marriage due to school closures and a lack of support from school management; a rise in intimate partner and sexual violence; disruptions in maternity care; and increased involvement of adolescents in risky or exploitative work. Findings from the studies and policy papers used in this review revealed several interventions designed and suggested to address SRH and access to SRH services for adolescents in LMICs during and after the COVID-19 pandemic. These interventions include: using schools, mass media campaigns, and radio programs for comprehensive sex education, prevention of unwanted pregnancies, and generating awareness regarding hormonal therapies; involving healthcare professionals to ensure access to age-specific, accurate, and up-to-date information on SRH through the media and pamphlets; providing contraceptives for longer periods; improving access to contraceptives through alternative delivery modalities such as pharmacies and community-based delivery; utilizing telemedicine for providing easy access to services such as medical abortions, counselling, and screening to adolescents; using adolescent-friendly phone lines for advice; provision of HIV Self-Testing kits (HIVST) and home-based testing of other STIs; distribution of condoms, menstrual supplies, HIV pre-exposure prophylaxis medications (PrEP), lubricants, and douches; and utilizing digital platforms for improving the socialization of adolescents and providing psychosocial services. Efforts are required for developing socially and culturally appropriate policies by employing community-based models to support adolescents and lessen the impact of COVID-19 on them, hence reducing SRH issues among adolescents. Enhancing job opportunities and the provision of career counselling during such a pandemic would aid in eliminating social isolation and overcoming its negative effects on adolescents’ SRH. Lastly, only a few studies have been conducted in this area; hence, there is a dire need for further research to add to the current knowledge on the topic.


The exposure to sun radiation is indispensable to our health; however, a long-term and high exposure could lead to cell damage, erythema, premature skin aging, and promotion of skin tumors. An underlying pathomechanism is the formation of free radicals which may induce oxidative stress at elevated concentrations. Different skin models, such as porcine-, murine-, human- ex vivo skin, reconstructed human skin (RHS) and human skin in vivo, were investigated during and after irradiation using X- and L-band EPR spectroscopy within different spectral regions (UVC to NIR). The amount of radical formation was quantified with the spin probe PCA and the radical types were measured ex vivo with the spin trap DMPO. The radiation dose influences the types of radicals formed in the skin. While reactive oxygen species (ROS) are always pronounced at low doses, there is an increase in lipid oxygen species (LOS) at high doses. Furthermore, the radical types arise independent from the irradiation wavelength, whereas the general amount of radical formation differs with the irradiation wavelength. Heat pre-stressed porcine skin already starts with higher LOS values. Thus, the radical type ratio might be an indicator of stress and the reversal of ROS/LOS constitutes the point where positive stress turns into negative stress.Compared to light skin types, darker types produce less radicals in the ultraviolet, similar amounts in the visible and higher ones in the infrared spectral region, rendering skin type-specific sun protection a necessity. The skin is the primary interface between the body and the environment and is permanently exposed to physical, chemical, and biological environmental influences, such as solar radiation or pollution. Solar radiation is essential for human life as it is important for the stimulation of vitamin D synthesis and well-being. However, a too high dose of solar radiation also leads to the excessive formation of free radicals  spectroscopy enables the non-invasive quantification and characterization of free radicals in tissue  and cell cultures. The following main events can be recorded by this method: (a) development of oxidative stress, (b) investigation of the antioxidative status, (c) penetration of active ingredients into the skin, and (d) structural analysis of molecules.This review focuses on the effects of oxidative stress induced especially by irradiation with light of different wavelengths in different skin models and types as well as further applications, whereby the EPR technology is the main examination method. In all investigations, the quantification and/or characterization of radicals are the central topics.Most radicals are highly reactive and short-lived  . These detection methods are primarily based on the detection of fluorogenic compounds by means of fluorescence spectroscopy or fluorescence microscopy  can be used to differentiate between reactive oxygen species (ROS) and lipid oxygen species (LOS) in the skin , visible (VIS), and near infrared, NIR) play a major role concerning the amount of radical induction in skin. For Caucasian skin the highest radical formation is observed in the UVA spectral region , it could be shown that in vitro skin equivalents  show the highest radical production after simulated solar irradiation  with a sun simulator. Since the RHS are supplied with nutrients up to the measurement vs. excised skin, they are metabolically more active, so that their radical production correlates better with the in vivo results than with those of the excised skin models Fig. ; furtherThe different skin models contain different amounts of antioxidants  and pyrimidine-(6–4)-pyrimidone photoproducts (6-4PPs)  in ex vivo porcine skin. A reversal point after irradiation with the highest irradiance (~ 244 mW/cm2) could be detected in the range of 0.5 MED  in addition to chemical and physical filters, as well as supplementation with AOs can also minimize the formation of radicals, and thus the development of associated skin diseases in deeper skin layers. In general, AOs are chemical compounds, which remove, detoxify, and/or slow down undesirable oxidation processes of cellular components, minimizing and/or impeding pro-oxidative effects  is a method for the treatment of tumors and skin diseases, in which a photosensitizer (PS) is irradiated with light of a certain wavelength, which causes generation of oxygen free radicals (photodynamic effect). These radicals promote, i.a., the selective destruction of cancer cells , but 40% of the produced radicals are induced by VIS and NIR. Depending on the skin model , different radical production regarding kinetics and quantity can be expected; reconstructed skin models represent the best model to in vivo skin due to the continuous supply of nutrients. Irrespective of the skin model, the irradiation dose per se influences the radical types formed in the skin. While ROS are always pronounced at low doses, an increase in LOS at high doses is given.EPR spectroscopy enables the risk assessment of exogenous factors, such as the skin exposure to radiation of different spectral regions with regard to the induction of radicals. Topically applied cream formulations or the effect of supplementing antioxidants on skin health during UV, VIS, and NIR irradiation can be evaluated.


Background: Auditory temporal processing tests are key clinical measures in order to diagnose central auditory processing disorder (CAPD). Although these tests have been used for decades, there is no up-to-date evidence to determine the effectiveness of detecting the abnormalities in central auditory processing in adults while the available national CAPD guidelines predominantly address CAPD in the pediatric population.Purpose: To determine the efficacy of the auditory temporal ordering tests [duration pattern test (DPT) and frequency pattern test (FPT)], and a temporal resolution test [gaps-in-noise (GIN) test] for detecting the central auditory processing abnormalities in adults with documented brain pathology.Research Design: Systematic reviews and meta-analyses.Study samples: Four databases, including PubMed, Web of Science, Embase, and Scopus, were systematically searched. The publications in the English language that recruited adults (above 16 years old) with pathologic brain conditions and described the diagnostic tests for auditory temporal processing were selected for review.Data Collections and Analysis: All data were systematically evaluated, extracted, categorized, and summarized in tables. The meta-analysis was done in order to determine the effectiveness of the DPT, FPT, and GIN tests.Results: The results showed significantly poorer performance of DPT and FPT, compared between participants with confirmed brain disease and normal controls, at the mean differences of percent correct −21.93  and −31.37 , respectively. Subjects with brain pathology also performed poorer in GIN test at the mean difference of 3.19 milliseconds .Conclusion: The results from the meta-analysis provide evidence that DPT, FPT, and GIN clinical measures are effective in the diagnosis of CAPD in adults with neurological disorders. Poor performance on these tests is significantly related to the confirmed brain pathology. However, different units in results presentation and variety of testing strategies are limitations for this meta-analysis. The standard pattern of result reporting and international protocols test strategies should be developed in order to conduct better meta-analyses with a larger collection of suitable studies and less heterogeneity. Central auditory processing disorder (CAPD) is a clinical diagnosis that is characterized by normal  hearing thresholds and a variety of hearing symptoms, including difficulties understanding speech in noisy environments, discriminating speech, localizing sounds, auditory inattention, or memory difficulties, that arise due to abnormal auditory processing within the brain. Individuals with CAPD require multisensory cues to support their listening and may experience cognitive or language difficulties . These aThere is a variety of tests that assess the different auditory processing domains, including auditory discrimination, temporal processing, dichotic listening, low-redundancy speech recognition , and binaural interaction . BaselinThe central auditory nervous system (CANS) starts at the cochlear nucleus in the brainstem and extends up to the primary auditory cortex and association cortices . The perAlthough there are various types of tests for CANS assessment, this review focuses on the studies that evaluate the ability of auditory temporal processing tests that are commonly used in clinical applications for central auditory processing evaluation , 4.Auditory temporal processing is important for the detection and discrimination of syllable, phoneme, and stress patterns and phonological awareness. Temporal processing of rhythm, meter, and tempo also supports musical perception . There avia the corpus callosum, and association to cognitive and perceptual processes  and a temporal resolution test (GIN test) and provide scientific evidence of their value in detecting central auditory processing abnormalities in individuals with documented adult-onset brain disorders who have well-established and/or documented brain pathology.The protocols of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline  and the *.” After the duplicates were removed, in order to avoid bias, the eligibility of papers was independently reviewed by at least two authors at each key step, including abstract screening, full-text reading, and data extraction. The results of assessments were then compared and determined for agreement in order to include the suitable studies for the systematic review and meta-analysis. If the consensus could not be reached by the two researchers, the studies were further evaluated and judged by a third reviewer. The risk of bias of the selected studies was evaluated following the QUADAS-2    and the studies) . The PICP: Adult participants without cognitive problems who underwent auditory temporal processing testsI: Auditory temporal ordering tests or auditory temporal resolution testsC: Comparison of results from each test between the normal participants and participants with underlying neurological brain conditionsO: Auditory temporal processing function.The studies that met the eligibility criteria were included in this review. All studies were categorized by the subtypes of the auditory temporal processing tests and subsequently classified by underlying conditions of participants. Participants with neurologic adult-onset brain conditions were diagnosed on the basis of neuroimaging and/or electroencephalography (EEG) investigations: computerized tomography (CT) scan, magnetic resonance imaging (MRI), other neuroimaging, or EEG, and/or a formal diagnosis of neurological brain disorder made by a medical specialist according to accepted diagnostic criteria. All data were systematically evaluated, extracted, categorized, and summarized in tables. To assess the effectiveness of the tests, only studies that recruited participants with confirmed brain disorders with control comparison were considered for further meta-analysis by using the evidence of documented brain lesions as a gold standard.I2 statistic.To perform the meta-analysis, the studies that reported participants with documented structural or functional brain lesions were considered for eligibility, depending on the presence of comparison between the disease and control groups and the similarity of the unit reported in the result of each study. The Review Manager (RevMan) program version 5.4.1, suggested by the Cochrane Collaboration , was appThe schemes of database searching and the results according to the PRISMA guideline are shown in After duplicates and ineligible study exclusion and the full-text assessment, 15 studies were recruited in this review. The risk of bias evaluation results, using QUADAS-2 and NOS, were shown in I2 value of 89%. Afterward, all papers were reevaluated, and the cause of heterogeneity was suspected to arise from the study by Troche et al.  .Several studies used the GIN test to assess temporal resolution processing in participants with documented structural/functional brain disease. The data extraction is shown in 2 = 86%) . Due to 2 = 86%) , which rsubgroup . HoweverThis study aimed to determine the efficacy of auditory temporal processing tests for detecting central auditory processing abnormalities in adults who have well-established and/or documented brain pathology. Confirmed pathology in the brain was used as the gold reference standard to determine the efficacy of the temporal processing tests in detecting auditory processing deficits. The results from three meta-analyses from DPT, FPT, and GIN tests all showed poorer central auditory processing abilities in individuals with documented brain pathology compared to normal controls. Overall, the meta-analysis provided essential evidence that DPT, FPT, and GIN are valid and sensitive clinical measures for central auditory assessment in adults. However, the meta-analysis could not be done in all included studies due to the limitation of different patterns of result presentation and groups of participants in studies. The discussion below shows more detail by topic.The meta-analysis results in six studies  showed sInterestingly, Troche et al.  performeAccording to the meta-analysis and sensitivity analysis , 6, the Using participants with confirmed brainstem or cerebral lesion as a gold standard, Musiek et al.  reportedThe results of the meta-analysis showed high sensitivity of DPT, FPT, and GIN test in detecting abnormalities in auditory processing in participants with brain pathology. Of interest, a recent study  identifiThe various underlying brain conditions are another possible cause for high heterogeneity. This meta-analysis included studies with a variety of brain pathologies, including stroke, MS, Parkinson's disease, and TLE. Although the results demonstrated that brain pathology caused lower performance in temporal processing, there was high heterogeneity of recruited studies for meta-analysis in DPT, FPT, and GIN. This could indicate that different brain conditions may differentially affect performance in temporal processing tests. Also, there was lack of information about the medications and treatments for individuals in several studies. Stroke and mass lesions may lead to focal CANS lesions that directly affect auditory temporal processing. MS is a progressive disease causing demyelination and axonal scarring  that couCategorizing the underlying brain diseases for subgroup analysis may reduce heterogeneity and clarify the effect of particular brain conditions on the temporal processing. Furthermore, the side of brain lesions may affect the temporal processing differently. However, most studies reported the overall results of temporal processing without considering the laterality of lesions. Even though the studies by Jafari et al. , LavasanAccording to our search results, there were only a few studies that directly compared the temporal processing performance between disease groups and controls. Several studies aimed to assess the efficacy of different testing strategies (such as efficacy of using different types of stimuli) rather than evaluate the central auditory function and these studies were excluded from this present study. Other papers were excluded, as they were judged to be of poor quality and/or subject to bias due to limitations in study design. Overall, there is a need for additional high-quality evidence  to demonstrate the effectiveness of CAPD diagnostic tests. Such evidence is pivotal to guide service delivery models for evidence-based clinical practice.According to our meta-analysis results, the DPT, FPT, and GIN are sensitive detectors of auditory processing deficits in individuals with brain pathology. Different types of brain pathology and different sites of lesion may differentially affect these test results, as this review also provided strong evidence that FPT is sensitive to the function of the auditory cortex, rather than other cerebral regions. By extrapolation, these three sensitive clinical measures may have the potential to detect temporal resolution and temporal ordering deficits, indicating CANS abnormalities, in adult individuals without obvious brain lesions documented on imaging, and this should be further investigated.Clinicians should be cautioned to interpret these test results in the context of other patient characteristics  and be aware that not all brain pathologies will lead to deficits in auditory processing function, depending on its location characteristics and natural history of the neurological disorder.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SC conceptualized and designed the study, searched the databases, collected and organized the data, assessed the quality of studies, performed the statistical analysis and systematic review, drafted the initial manuscript, and revised the manuscript. D-EB coordinated and supervised data collection, critically reviewed, and revised the manuscript. NK conceptualized and designed the study, searched the databases, organized the data, assessed the quality of studies, and critically revised the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The structure of the liver and hepatic extracellular matrix, decellularization, recellularization, and recent developments are discussed in this review. Additionally, the criteria for assessment and major obstacles in using a decellularized scaffold are covered in detail.Liver transplantation is currently the only effective treatment for patients with end-stage liver disease; however, donor liver scarcity is a notable concern. As a result, extensive endeavors have been made to diversify the source of donor livers. For example, the use of a decellularized scaffold in liver engineering has gained considerable attention in recent years. The decellularized scaffold preserves the original orchestral structure and bioactive chemicals of the liver, and has the potential to create a  Globally, end-stage liver disease is a primary cause of morbidity and mortality, accounting for more than one million deaths per year . End-staSince Thomas Starzl conducted the first liver transplantation in 1963, liver transplantation has evolved significantly over the last 50 years. Along with the renewal of immunosuppressive drugs, liver transplantation technology has increasingly advanced, resulting in the survival of numerous patients with end-stage liver disease . UnfortuIn recent years, the use of decellularized scaffolds in liver engineering has garnered considerable attention . DecelluTherefore, the recellularization of decellularized scaffolds holds great therapeutic potential for creating transplantable grafts for treating end-stage liver disease. This review provides an overview of the liver, hepatic ECM, decellularization, recellularization, and recent advances in liver engineering. Additionally, the review presents the detailed evaluation criteria and main obstacles for utilizing decellularized scaffolds.The liver is the largest internal organ in the body and is composed of various cell types, including hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells, stellate cells, and cholangiocytes . These cvia the common bile duct  and portal vein (PV), and transports the bile that is synthesized by hepatocytes to the gallbladder and duodenum ile duct . The livile duct  is the aThe hepatic sinusoid is a capillary-like channel lined with LSECs and flanked by hepatocyte plates and drains blood from the terminal branches of HA and PV into the central vein  McQuitt. KupfferThe hepatic ECM is a well-organized non-cellular tridimensional scaffold composed of collagens, proteoglycan, fibronectin, laminin and several other glycoproteins, all secreted by resident cells in liver, and provides a microenvironment for adhesion, growth, replication, migration, differentiation, and other vital activities of the surrounding cells . The hepThe composition of the hepatic ECM fluctuates with age. For example, older livers tend to have greater amounts of total collagen, sulfated glycosaminoglycans (GAGs), and lower levels of growth factors. Therefore, donor age should be considered as a critical component in determining the quality of the neo-liver during liver engineering .Liver engineering is presently considered a promising alternative strategy for organ scarcity. Additionally, the use of synthetic and decellularized scaffolds in liver engineering has emerged as a research hotspot in liver engineering. The decellularized scaffold is more advantageous than the synthetic scaffold because it preserves the natural microscopic structures and microenvironment, retains bioactive molecules, and allows for implantation of the liver through directly anastomosing the native vessels of the scaffold and the vessels of the recipient . DecelluSonication uses an ultrasonic bath or probe to transfer acoustic power into a solvent containing tissues or organs to disrupt cell membranes; an ultrasonic bath is preferred for decellularization. The collapse of microscopic vacuum bubbles generated during sonication releases violent shockwaves that shear the cell; the resulting cellular debris is removed by perfusion. The energy generated from the collision of the sound waves generates heat in the solution. Therefore, monitoring the temperature during sonication and cooling in a chiller are necessary to avoid heating and denaturation of the proteins and molecules. Sonication is mainly used with detergents to decellularize dense tissues, such as tendons, ligaments, and cartilage, as well as thin tissues, such as skin and blood vessels, where sonication allows the detergents to penetrate the tissues more effectively . SonicatRapid thermal changes in the freeze-thaw effectively lyse cells and aid in their subsequent removal . Hence, Immersing tissues or organs in a reagent is the most straightforward method of decellularization, and when paired with agitation, the outcomes of decellularization are improved. The reaction efficiency depends on the reagent type, duration of immersion, and intensity of agitation. A reagent for the removal of the cellular components is required, and the total duration should be minimized to avoid damaging the ECM scaffold . HoweverIonic, non-ionic, and zwitterionic detergents are commonly used for decellularization. The most extensively used ionic detergents are sodium dodecyl sulfate (SDS) and sodium deoxycholate (SDC), which solubilize cellular membranes and denature proteins . Triton Although diverse detergents are frequently combined for optimal decellularization, the efficiency of detergents nonetheless varies linearly with the exposure time and concentration, and varies inversely with the tissue thickness and density. Prolonged exposure times and high detergent concentrations can maximize the extent to which the ECM of the scaffold approaches the cell-free state. However, the ECM can also be disrupted and residual detergents may be present, particularly if SDS is used, which can penetrate deeply into the tissue and slowly dissipate. The disruption of the ECM and residual detergents may result in the formation of thrombi and cytotoxicity after recellularization and implantation, particularly in the liver because of its abundant blood flow and metabolic importance.Hypertonic and hypotonic solutions promote cell shrinkage and swelling due to osmosis and ultimately induce lysis, while having a negligible effect on the ECM . AlthougAlthough acids remove DNA by dissolving cytoplasm and breaking nucleic acids during decellularization, they are more currently and popularly used as disinfectants because they are strong oxidants . In a hiBecause of the polar hydroxyl groups, alcohols can diffuse into cells and resultantly dehydrate and lyse cells . BecauseChelates (such as ethylenediaminetetraacetic acid (EDTA) and ethylene glycol tetraacetic acid (EGTA)) bind metallic ions that are essential for protein interaction, resulting in the disconnection of intercellular integral proteins and disruption of cellular adhesion in the ECM. However, chelates alone are unable to completely remove cells and should be combined with detergents or enzymes . AdditioNucleases, trypsin, dispase, lipase, and collagenase are commonly used in decellularization, whereas nucleases and trypsin are most frequently used in liver decellularization. Enzymes can precisely remove cellular components, prevent unfavorable immune responses, and improve the efficacy of detergent-based decellularization.Nucleases are enzymes that cleave the phosphodiester bonds between nucleotides in nucleic acids. They typically expedite the removal of nucleotides and minimize the risk of immune responses during decellularization. Endonucleases, such as DNase and RNase, are frequently used to remove nucleic acids during liver decellularization . TrypsinEach of the aforementioned methods –3.3 has via the HA and PV is the preferred method for whole liver decellularization. To lyse and remove cells in the liver, detergents, enzymes, and other reagents are perfused into the vasculature of the liver; this approach ensures that the maximal integrity of the ECM is maintained. For example, decellularized liver contained less residual DNA, with a more homogeneous ECM, under oscillatory pressure and pressure-controlled perfusion; this approach also required a relatively short time, and more collagen and GAGs were retained in the decellularized liver  DNA content <50 ng/mg dry ECM weight; 2) DNA fragment length <200 base pairs; and 3) lack of visible nuclear content with DAPI and HE staining. Narciso et al. lately described a novel method that combines phase-contrast images of decellularized tissues and fluorescent images of DNA staining of cell nuclei, allowing faster and easier quantification of DNA content . HoweverAlthough the abovementioned criteria have been widely adopted, they all lead to destructive end-points in analyses of the scaffold, and the degree of decellularization cannot be determined in real-time. Consequently, it is difficult to tailor decellularization to the distinctive attributes of each liver. Therefore, it is essential to develop a new non-invasive method to monitor and adjust decellularization in real-time to achieve individualization .Akhyari et al. employed rheological evaluation and biomass compositional analysis of the perfusate for the real-time and non-invasive monitoring of heart decellularization. They discovered that the total protein, DNA, and biomass content in the perfusate was proportional to its viscosity. Based on this finding, the decellularization protocol could be adapted for a single organ. Furthermore, this finding demonstrated that the adverse effects of reagents on the ECM could be minimized if the pump profile, perfusion pressure, and revolution speed in the feedback control system were controlled . Geerts As the mold for liver engineering, the quality of the decellularized scaffold is crucial for successful liver recellularization and transplantation. However, there is currently no unified criteria for assessing the quality of the scaffold. The majority of qualitative and semi-quantitative studies have used morphological and molecular characteristics to assess the decellularized scaffold. The morphological assessment uses the appearance, HE staining, and SEM of the scaffold to evaluate its remaining microscopic anatomy and three-dimensional structure. The molecular assessment includes quantitative assessment of the residual DNA, cytokines, and ECM proteins. In addition, many studies have compared the mechanical strength, tension resistance, and other physical properties of the decellularized liver with those of the native liver .Philipp et al. recently used macroscopic, microscopic, and morphological assessments to develop a morphological workflow for analyzing the microstructure of decellularized mouse liver scaffolds with mild histological damage   expression in repopulated HepG2 cells and hepatocytes . Thus, ein vitro survival of hepatocytes remains challenging. In addition, loss of the typical morphology and liver-specific functions provide evidence that the prolonged culturing of hepatocytes results in de-differentiation. Nonetheless, different stem cells and endothelial cells that have been applied in recellularization show great potential.The decellularized scaffold must be repopulated with functional cells to execute various physiological functions. The most vital cells are hepatic parenchymal cells, hepatocytes; however, the long-term in vitro. Therefore, obtaining sufficient viable hepatocytes is the biggest impediment to using primary hepatocytes for recellularization. The primary hepatocytes in a decellularized liver scaffold, cultured in a dynamic perfusion system, have higher viability, function, and can most crucially, proliferate, when compared to those cultured under static conditions  are pluripotent cells that are derived from the blastocyst stage of early mammalian embryos and can differentiate into various cell types and are capable of self-renewal . Under cin vitro fertilization with the consent of the donor  are multipotent stem cells with high proliferative capacity for self-renewal and can differentiate into the cell lines of the resident tissues . MSCs weThe daedal vasculature system of the liver is indispensable in metabolite transport and homeostasis. Therefore, endothelialization of the decellularized scaffold is crucial for successfully reconstructing a bioengineered liver. Currently, human umbilical vein endothelial cells (HUVECs) and LSECs are the most frequently used endothelial cells. To create an ideal whole liver scaffold, Verstegen et al. decellularized human discarded liver and demonstrated that implanting HUVECs into the scaffold effectively rebuilt the endothelial system . SimilarThe vasculature in the liver has a hierarchy, which involves the hepatic sinusoids to the larger vessels. However, most studies on revascularization have focused on larger vessels, instead of the microvasculature in the hepatic sinusoids. The absence of basement membrane resulted in severe damage to the microstructure of the hepatic sinusoids during decellularization. As previously mentioned , the hepSeveral cells collaboratively accomplish hepatic functions; therefore, the liver cannot be recellularized with only 1 cell type to perform complicated hepatic functions. To generate a competent liver, the decellularized scaffold must be methodically infused with various cells, and these cells grow in the right site. A combination of the HA, PV, vena cava, and common bile ducts can be used for recellularlization. The common bile duct guides the hepatocytes to their anatomical sites, and re-endothelialization of the HA or PV can prevent thrombosis and guarantee sufficient blood perfusion to the rebuilt liver.via the common bile duct and PV, respectively, can rebuild bile duct-like structures, while hepatocytes can settle in the liver parenchyma  that hamper cell adhesion to the ECM and induce anoikis  ineluctable damage and denaturation of ECM proteins during decellularization, which hinders adhesion and proliferation of implanted cells; 2) imperfect revascularization, which lowers the hemocompatibility of the scaffold and increases the risk of thrombosis; and 3) elusory immune response, which causes inflammatory and rejection responses, resulting in loss of the graft. Future research that concentrates on these limitations will be valuable. Additionally, a better understanding of decellularization and recellularization of the liver is fundamental for producing transplantable liver grafts and ensuring the long-term survival of these grafts, especially if these insights are coupled with a deeper understanding of the mechanisms of the immune response.


Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases. The extracellular matrix (ECM) is an important component of the vascular wall, allowing it to withstand a wide range of tensile stresses, while preserving its shape and integrity. This is explained by its complex composition, where elastic fibers provide distensibility, while collagens, hyaluronic acid and proteoglycans provide strength and a supporting structure. This network is aided by fibronectin and laminins that, by connecting vascular cells to the ECM, provide the interface for the detection of changes in ECM physical properties . ChangesThe importance of these mechanisms is illustrated by the impact of aging on vascular ECM. After a lifetime of continuous cycles of stretching and recoiling, elastic fibers degenerate, reducing vascular distensibility, and excess collagen deposition accentuates vascular stiffness. These changes are accompanied by increased pulse pressure and myogenic tone, arterial rarefaction, compromised perfusion and damage to organs such as the brain, the kidneys and the retina ,4,5. ThuHere, we discuss the impact of aging on vascular ECM and how the depletion of homeostatic mechanisms that govern ECM composition can influence the mechanical properties and function of large arteries. As the media layer is responsible for the load-bearing capacity of the arteries, we discuss the reciprocal relationship between aging ECM and smooth muscle cells (SMCs) that leads to a range of phenotypes that further exaggerate age-induced vascular changes. Uncovering the essential elements for this crosstalk may give rise to new approaches to prevent or delay age-related vascular pathologies.From the inner to the outer surface, the arteries are divided into three basic compartments: intima, media and adventitia. In the intima layer, endothelial cells (ECs) display in its surface heparan sulfate glycosaminoglycans (such as syndecan) and hyaluronic acid, forming a type of surrounding ECM called glycocalyx . This stAging imposes dramatic changes in the structure and function of arteries with progressive thickening associated with intimal hyperplasia due to the migration of SMCs ,24 Figu. These SECs are mechanosensors of the cardiovascular system. They line the luminal arterial surface and, thus, are exposed to hemodynamic forces in the form of a frictional dragging force termed shear stress (SS) ,27. LamiA whole set of sensors  enables the ECs to detect and transduce flow changes to modulate the cellular response. These sensors are represented by a diverse range of molecules, including ion channels and G-protein-coupled receptors (GPCRs), along with the proteins present at cell structures including the cilia, membrane domains (caveolae and lipid rafts), cell–cell junctions and cell-ECM adhesion complexes . These cIn addition to their role in vascular tone, ECs act as guardians of the vascular wall, exhibiting selective permeability to circulating factors (such as cytokines and growth factors) and preventing the infiltration of inflammatory cells. The upregulation of angiotensin II signaling through its cognate receptor (AT1), together with the reduction in NO availability and the consequent increase in reactive oxygen species (ROS) , promoteIn addition to changes in the function of ECs and intimal hyperplasia, the media layer also contributes to impairment of the function of the great arteries with aging. The progressive fragmentation of the distensible elastic fibers promotes the stiffening of aging arteries, which is further accentuated by the deposition of stiff collagens ,51 Figu. The damFragmentation of medial elastic fibers exposes the entire artery to increased mechanical stress. In the adventitial layer, this is illustrated by the change in the appearance of collagen fibers from wavy ,55,56 toSMCs are responsible for the maintenance and the remodeling of medial ECM, and thus, they are constantly sensing ECM properties, including its composition, density and stiffness. This process (termed mechanosensing) is primarily mediated by cell surface receptors or integrins. Integrins are α-β heterodimers connecting the different ECM molecules to the actin cytoskeleton at focal adhesions . In thes1-integrin ), arachidonic metabolites, vasoactive polyamines, cytokines, chemokines and ECM-degrading enzymes . These mAs aging and arterial stiffness are at the interface between physiological adaptation and the onset of cardiovascular disease, understanding the signaling mechanisms underlying aging SMC phenotypes would shed light on new approaches to prevent or delay arterial stiffness and improve cardiovascular health. It was recently showed that Senolytics (desatinib plus quercetin) decrease senescent cells in humans, declining plasma levels of key SASP factors, including IL-1α, -2, -6 and -9 and MMP-2, -9 and -12 . In addiVascular calcification accompanies aging and atherosclerosis, but hitherto, it has not been a direct therapeutic target . In thisIn this review, we highlight the active role of environmental sensing by SMCs and its relation with the ECM to affect arterial aging. In this scenario, elastic fiber degradation and undamped exposure to hemodynamic factors trigger signaling pathways in the promotion of a broad spectrum of SMC phenotypes that ultimately cause intimal hyperplasia, collagen deposition and the establishment of a constant low-level state of inflammation contributing to the aging on the vascular wall . The celWe postulate that the gradual elastic fiber fragmentation and increased exposure to hemodynamic forces gradually increase the stiffness of SMCs over time, leading to collagen secretion. As collagen is known to promote cell proliferation , this isIn summary, we highlight the essential role of the dynamic vascular ECM and SMCs crosstalk mechanisms in aging and pathologic states. The osteochondrogenic and senescence-associated secretory phenotypes of senescent SMCs is amplified by the age-induced changes in ECM, establishing a fertile inflammatory and oxidative environment predisposing to development of age-related cardiovascular pathologies. Population aging has several unmet clinical needs and represents an opportunity to develop new approaches to delay SMC aging and age-related vascular derangement based on improved understanding of these vascular biology processes.


Maturation of these barriers is essential for the proper functioning of the GIT. Maturation, particularly of the immunological barrier, involves stimulation by bacteria. Segmented filamentous bacteria (SFB) which are anaerobic, spore-forming commensals have been linked to immune activation. The presence and changes in SFB abundance have been positively correlated to immune markers (cytokines and immunoglobulins) in the rat ileum and stool samples, pre- and post-weaning. The abundance of SFB in infant stool increases from 6 months, peaks around 12 months and plateaus 25 months post-weaning. Changes in SFB abundance at these times correlate positively and negatively with the production of interleukin 17 (IL 17) and immunoglobulin A (IgA), respectively, indicating involvement in immune function and maturation. Additionally, the peak in SFB abundance when a human milk diet was complemented by solid foods hints at a diet effect. SFB genome analysis revealed enzymes involved in metabolic pathways for survival, growth and development, host mucosal attachment and substrate acquisition. This narrative review discusses the current knowledge of SFB and their suggested effects on the small intestine immune system. Referencing the published genomes of rat and mouse SFB, the use of food substrates to modulate SFB abundance is proposed while considering their effects on other microbes. Changes in the immune response caused by the interaction of food substrate with SFB may provide insight into their role in infant immunological barrier maturation.The microbiological, physical, chemical, and immunological barriers of the gastrointestinal tract (GIT) begin developing  It is widely accepted that, amongst other factors, the microbial consortia in all regions of the body contribute to maintaining homeostasis and good health –4. TheseClostridiaceae family. SFB possess a unique holdfast structure which facilitates their attachment to the ileal mucosa. During the lifecycle of SFB, the segmented filaments divide and elongate, forming viable intracellular offspring or spores in adverse conditions (Segmented filamentous bacteria (SFB) were discovered attaching to the ileal mucosa in invertebrates  and healnditions . The clanditions , 20. In nditions , 19. Stunditions  and a nenditions –27, thounditions , 28–30. nditions .Additionally, the presence of SFB is variable; their abundance in the ileum of infants increases at weaning from 6 months, peaks around 12 months and plateaus until 25 months post-weaning , 31, 32.In vitro studies were carried out initially and proved challenging as SFB did not grow outside the ileum . The genome reportedly lacks genes for biosynthesis of most amino acids. Amino acid transporters and permeases found in the genome imply SFB uptake amino acids possibly from dietary sources and host protein degradation by proteases secreted by SFB. The absence of these important genes could explain their commensal nature . SF. SFCandidization . Once thdization . This obeir host .via Cesarean-section, it is unclear how SFB are present in the infant GIT. SFB spores could also be passed from the mother to the embryo via the placenta and may be the origin of SFB in infants born via Cesarean-section if SFB are even present in these infants. This theory, however, has no reported evidence.The origin of SFB in the GIT is thought to be via vertical transmission, as with other GIT microbes, from the mother to the fetus. The presence of SFB in dormant stages suggests that their spores found in maternal feces may seed the infant during vaginal birth . In the In postnatal life, SFB are present in the ileum of healthy weanling rodents . They haThe discovery and characterization of SFB in the ileum of healthy rodents drew interest due to their reported influence on markers of the GIT immune system. Later detection of SFB in the feces of healthy infants and adults suggests that SFB form part of the normal GIT microbiota and, like rodents, may also influence the GIT immune system. Knowledge of the role of SFB in humans is still scarce, and a time-course study elucidating the temporal profile of SFB at the crucial weaning stage in infants has yet to be attempted.A comparative 16S rRNA gene analysis of SFB in healthy humans feces, mice ilea and chicken ilea indicated similarities in the abundance change of these microbes at similar stages of development . The simThe discovery of SFB in the ileum of vertebrates prompted investigations of their role in the GIT. Studies on how SFB interact with the immune system indicate that SFB do not appear to cause ill-effects in healthy vertebrates.Studies on SFB have investigated their relationship with IgA, the most abundant immunoglobulin occurring in the body. IgA acts to block excessive bacterial adherence or translocation, mediates the neutralization of toxins and viruses, and removes unwanted macromolecular structures on the epithelium in the GIT . IgA in Morganella morganii  from SFB-monocolonized mice to form the genomic co-assembly “SFB-co.” A second co-assembly, “SFB-mouse-SU,” which was closely related to their SFB was also assembled using the published SFB mouse genome [SFB-mouse-Yit (AP012209)]  . SNPs oc012209)] . Some ofe change . These me change , 95. Thee change  which inFinotti et al.  also seq+ cells when compared to SFB-negative NOD mice. The SFB-positive NOD mice also did not develop diabetes though levels of insulitis, a marker for type 1 diabetes, were similar to those in SFB-negative NOD mice. This result implies that SFB colonization may not block the trigger of diabetes but might modulate the progression of the disease . Results from the published rat and mouse SFB genomes revealed the presence of carbohydrate, amino acid, protein, vitamin and mineral permeases, import/export transporters and ABC-type transporters , which are lacking in rat and mouse SFB. This observation may demonstrate physiological or dietary differences of the hosts, or host microbial community, as some gut microbes can synthesize biotin while others cannot.An analysis of the SFB rat genome also indicated the presence of an N-acetylglucosaminidase family protein. N-acetylglucosaminidases are essential enzymes involved in the hydrolysis of complex oligosaccharides and their presence in the genome could point toward the ability of SFB to metabolize these kinds of carbohydrates. Analysis of the draft genome of human SFB from ileostomy patients, revealed the presence of one tentative extracellular N-acetylglucosaminidase, nine glycoside hydrolases representing six different families, as well as several cell surface-bound and extracellular proteases . AnalysiClostridium class XIVa, could utilize simple carbohydrate fermentation products from anaerobes such as some Streptococcus spp in a cross-feeding manner to produce butyrate   . They prThe scarce knowledge on SFB is unsurprising, considering most studies have focused mainly on the effects of SFB presence and absence on the GIT immune system. Therefore, this new avenue of utilizing diet to decipher any influence on SFB could increase the understanding of the suggested role of these unique commensals in small intestine immune barrier maturation.LO, RA, NR, and WM contributed to the conception of the review. The draft manuscript was prepared by LO. EA and NR contributed to the genomics portion of the review. All authors contributed to the preparation of the manuscript.LO was supported by a PhD Fellowship from the Riddet Institute Centre of Research Excellence, funded by the Tertiary Education Commission.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.


A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis. A notable feature of the skeleton is its plasticity in response to changing biophysical environments. Remodeling of the skeleton under high mechanical load offers the ability to develop strength through hypertrophy to withstand strain. Repair of the skeleton is greatly influenced by its strain environment. This review presents the influences of some biophysical forces on skeletal tissues and cells, notably skeletal-derived mesenchymal stem cells (MSCs), and emphasizes physically enhanced morphogenesis in the context of repair. The review takes a distinctly translational approach. In vitro and in vivo experiments provide complementary opportunities for examining the responses of mesenchymal cells. In vitro models permit the detailed examination of cellular responses including signal transduction, while in vivo models allow observation of cell differentiation in a developmental process such as endochondral bone formation. In describing together these cell and tissue responses to biophysical stimuli, the potential of how these responses translate to the clinic is pointed out. The review examines external electromechanical stimulation of MSCs from a particular point of view. Because of the intrinsic coupling of mechanical strain, fluid flow, and electrical phenomena, it is extremely difficult to isolate the effects of specific biophysical phenomena on cultured cells or tissues. The application of external electrical or electromagnetic fields, however, can explore the effects of electrical stimuli on proliferation and differentiation in the absence of mechanical loading. The focus is on modulation of MSC-mediated morphogenesis by external biophysical stimuli and the contributions of both in vivo models describing developmental processes and in vitro models describing cellular responses, and how they can be interpreted together to inform translational efforts and clinical applications, notably in the context of repair.Skeletal tissues and MSCs exist in a biophysically rich microenvironment that provide cells with many mechanical, electrical, and biochemical cues. In turn, cells have evolved an array of organelles and transduction pathways for sensing and responding to physical signals to meet their physiological requirements. These mechanisms include direct mechanosensing, recognition of fluid flow patterns, and electrokinetic events by cell deformation, membrane shape changes, adhesion molecules, cytoskeletal signal transmission, and mechanosensitive transmembrane ion channels. Intracellular signaling pathways transduce the sensed signals, eliciting responses usually composed of the synthesis of ECM molecules to reinforce or repair local structures to meet the demands of the environment. Cells express genes that encode for structural and signaling molecules that remodel the ECM and provide paracrine signaling, respectively, ultimately leading to changes in cell proliferation, differentiation, and morphogenesis ,3. ExpreThe adoption of specific lineages by MSCs is dependent, in part, upon the microenvironment and the cytokines to which MSCs are exposed. The mechanical properties of native tissue stem cell niches, in vitro substrates, and external mechanical stresses in vivo have major effects on MSC differentiation. MSCs adopt varying morphologies in response to microenvironments of varying mechanical properties and to external mechanical stresses. The activation of mechanosensitive membrane receptors and intracellular messengers, such as the mitogen-activated protein (MAP) kinases by mechanical environments, are important transduction pathways of mechanical signals that influence differentiation and phenotypic expression of MSCs . The stiIn addition to biochemical regulation, biophysical signaling in response to hydrostatic pressure, fluid flow and accompanying shear stress, substrate strain and stiffness, substrate topography, and electromagnetic fields have induced chondrogenic and osteoblastic differentiation of MSCs in vitro . Matrix Physiologic loading of the musculoskeletal system gives rise to strain-associated biophysical stimuli such as deformational loading, hydrostatic pressure, fluid flow, electrokinetic phenomena, and osmotic loading, that modulate cell activities responsible for tissue remodeling, repair, and maintenance . BiomimeCell Sensing-Biophysical Transduction: Primary cilia are sensory organelles that extend into the extracellular milieu and have been shown to play a critical role in chemical and mechanical induction of stem cell differentiation . Os. Os66]. Measurements of chondrogenesis on day 8 of ossicle development have demonstrated that exposure to PEMF during the mesenchymal or chondrogenic phases stimulate indices of chondrogenesis similarly  67]. Th. Th67]. These observations suggest several effects of PEMF in this developmental model of endochondral bone formation. Cartilage matrix proteoglycan appears earlier in the developmental process and accumulates to a greater amount in implants exposed to PEMF. Chondrogenesis is concluded and cartilage matrix is resorbed at a time appropriate to the onset of calcification and bone formation. The amount and maturation of bony trabeculae are increased in PEMF-exposed ossicles. Stimulation during the chondrogenic stage only, while sufficient to increase cartilage formation, is insufficient to increase trabecular bone formation. Increasing chondrogenesis without stimulating the early progenitor cell pool does not result in an increased amount of bone. Conversely, PEMF exposure during the mesenchymal stage increases chondrogenic differentiation, cartilage ECM formation, calcification, and trabecular maturation to a degree not observed with stimulation of other stages of endochondral bone formation. This localizes the locus of response to cells in the mesenchymal stage that is competent to respond to electromagnetic field stimulation and to subsequently result in enhanced chondrogenesis and more mature trabecular bone formation.Clinical Translation: PEMF exposure enhances cartilage and bone formation but, unlike some growth factors, does not disorganize endochondral ossification. These observations have supported the use of PEMF to enhance bone repair in clinical situations, prominently in fracture non-unions. Controlled studies have demonstrated the efficacy of PEMF in enhancing deficient bone repair. A recent review has focused on the role of signal transduction in PEMF efficacy and has described controlled studies of PEMF-stimulated bone repair. Anabolic effects of PEMF on articular cartilage are described as well  thymidine incorporation and cell replication [Internally or externally manipulated cells, including but not limited to MSCs, are currently under significant FDA scrutiny due in part to the dearth of adequately powered, placebo-controlled studies demonstrating their efficacy , unprovelication . Therefolication . This islication .The study of mechanobiology and electrobiology in orthopedics—in both basic and translational science—can also inform therapies and pharmaceutical interventions in clinical medicine . For insThis review has integrated in vitro and in vivo evidence of effects of biophysical forces upon MSCs that may be useful in advanced therapeutics for tissue repair. The physical microenvironment of MSCs has been described as well as the responsiveness of the cells to mechanical and strain-associated forces. Using MSCs in a therapeutic context to effect repair requires understanding of their complex communication mechanisms. The “language” of the MSCs most likely involves a complex of biochemical and biophysical signals that are integrated with each other and, in a developmental analogy, may require the receptivity of the MSCs to respond to extracellular signaling patterns. Therapeutic biophysical signals will have to be tuned to maximal efficiency to achieve optimal dosing and utilize the incredible promise of appropriately harnessed MSCs in the context of repair.


In particular, ISR can modulate metastasis via transcriptional reprogramming, in the help of essential transcription factors. In this review, we summarized the current understandings of ISR in cancer metastasis from the perspective of transcriptional regulation.As a central cellular program to sense and transduce stress signals, the integrated stress response (ISR) pathway has been implicated in cancer initiation and progression. Depending on the genetic mutation landscape, cellular context, and differentiation states, there are emerging pieces of evidence showing that blockage of the ISR can selectively and effectively shift the balance of cancer cells toward apoptosis, rendering the ISR a promising target in cancer therapy. Going beyond its pro-survival functions, the ISR can also influence metastasis, especially  Development of secondary lesions in organs or tissues that are physically disconnected with the original primary cancer is termed metastasis. As a systemic disease, metastasis requires cancer cells to leave their primary organ, circulate in the bloodstream, endure the pressure of the vasculature, adapt to the new microenvironment in a secondary site, survive the hostile battle against immune cells, and finally repopulate in the new organ . Once deeukaryotic translation initiation factor 2) (The integrated stress response (ISR) is a conserved network of signaling pathways that helps the organism to adapt to an ever-changing environment and maintain the integrity and health of the host , 10. In actor 2) , 15. Upoactor 2) . ThroughThe formation of clinically detectable metastasis is the ultimate, end result of a series of stochastic events that first allow cancer cells to disperse and survive in distant sites and later to grow as secondary tumors. The sequence of metastasis steps starts with the departure of cancer cells from the primary tumor and ends in the formation of clinically detectable macro-metastases in the target organs. Apparently, this is a multi-step, long-term adventure for cancer cells. In general, it comprises steps of local invasion , entry into the circulation, travel along the vasculature, arrest at secondary sites, extravasation, and colonization (metastatic outgrowth) .Invasion represents the very first step and a pre-requisite to metastatic dissemination. Cancer cells are required to take a plastic phenotype to complete an invasive transition. A diverse set of factors and molecular circuits can equip the cancer cells of plasticity and trigger this transition. Originally discovered as an essential transdifferentiation program in development and tissue repair, epithelial-mesenchymal transition (EMT) is known as the key mechanism in promotion of cancer invasion. While cancer cells at the boarder of cancer-normal tissue can invade in a single-cell migration or collective migration manner, they usually display a mesenchymally transdifferentiated cell state, or at least a partial (hybrid) EMT . In addiDissemination comes after invasion. After entering into the bloodstream, tumor cells must circulate and survive the hostile environment before they can extravasate and form secondary tumors. Circulating tumor cells (CTCs) represent an intermediate stage of metastasis . While sOnce the cancer cells exit the bloodstream, they may begin to divide and attempt to complete the last step of metastasis, colonization. Colonization can be divided into steps: formation of micro-metastasis, latency in the distant organ, re-activation of growth in the latent micro-metastases, and a final, life-threatening, aggressive overtaking of the target tissue . In mostMetastasis is a highly inefficient process. Over a million cancer cells can be released by the primary lesion into the circulation every day, but only a very minor portion of them is capable of colonizing a distant organ, even fewer can flourish into clinical detectable macro-metastasis . For lonThe metastatic cascade progresses in biological environment that is drastically different than where it initiates at the first place. Therefore, metastatic tumor cells will inevitably encounter numerous stresses that force them to develop circuits or pathways to obtain improved aptness along the metastatic marathon. It has been proposed that instead of behaving as traditional driver oncogenes, the so-called “metastasis adaptiveness genes” can increase the metastatic potential and successful rates by relieving stresses that are not encountered in physiological conditions . Thus, oThe ISR responds to a variety of different stress conditions that interfere with the cellular homeostasis Figure 1The link between ISR and cancer has been long appreciated. Not surprisingly, as a pathological process, which inevitably interferes with normal homeostasis, cancer development enlists a great number of different types of stresses. Oncogene activation, including cancer-specific mutation or overexpression, could elicit stresses on transformed cells that normal cells usually do not encounter. For instance, mutations in tumor suppressor genes, such as PTEN, or the over-production of oncogenes, such as c-MYC, results in increased protein synthesis, which can saturate the proteostasis machinery and activate the ISR , 36. ForAberrant cell survival and reduced cell death are hallmarks of cancer cell. For long, the role of ISR in cancer development has been largely linked to and explained by the function of protein translation regulation on cell death/survival balance. Indeed, the ISR kinases have been implicated in cancer regarding cell death and proliferation. Activation of the ISR by PERK promotes tumor initiation and progression . Consistvia translation-independent mechanisms. Metastasis, as a complicated, multi-step process, requires the many faces of the ISR to support and facilitate cancer cells to survive this challenging journey. In particular, the role of the ISR in transcriptional reprogramming has been increasingly appreciated  and the Zhejiang Provincial Natural Science Foundation of China .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 nursing field occupies the largest secion of the cardiovascular healthcare services. Despite this, the roles of nursing within the cardiovascular healthcare system has not been well displayed. The authors searched PubMed and Embase  and created a narrative review of recent publications regarding the role of nursing in the management of geriatric cardiovascular disease (CVD). Patients with geriatric CVD, which includes mainly myocardial ischemia and heart failure, were enrolled. Nursing can improve the outcomes of myocardial ischemia and heart failure. It plays a pivotal role in the recovery, rehabilitation, and outcomes of geriatric CVD, especially for chronic heart diseases. Taken together, this paper compiled is focused on the current status of cardiovascular nursing and may facilitate future treatment and rehabilitation in geriatric CVD. Cardiovascular disease (CVD) remains a primary cause of mortality for people all over the world . AccordiIn the nursing work of geriatric CVD, effective prevention of risk factors in nursing work is of great clinical significance to improve the quality of nursing and the early rehabilitation of geriatric CVD patients. As nurses have the most contact time with patients, they should not only be familiar with the characteristics of elderly cardiovascular disease, but they also acquire knowledge of the mental aspect of nursing, considering the social roles of the elderly.China is now undergoing unprecedented economic growth and globalization, and this has resulted in an increase in the prevalence of chronic conditions, particularly CVD . CVD makThis narrative review is aimed at discussing the roles of nursing in the management of geriatric CVD. Firstly, we introduce the background of CVD and cardiovascular nursing, including the epidemiology and therapeutics of CVD as well as the current status of nursing. Secondly, we review the roles of nursing in the management of CVD such as heart failure and myocardial ischemia. Thirdly, we talk about the concept of nursing education. Finally, we discuss home- and clinic-based nursing, cardiac rehabilitation, and individual care. This article highlights the recent advances and provides an elaborate picture of cardiovascular nursing, which might be helpful in nursing care and therapy for CVD.The symptoms of heart failure are characterized by shortness of breath, fluid retention, poor oxygen delivery, and impaired function of the heart itself . The preIn total, 127 patients with reduced ejection fractions (EFs) were prospectively allocated to standard care or intervention programs (1:2) at random from 2011 to 2013. Ortiz-Bautista et al.  found thHF may influence a patient's quality of life to a great extent. Rorth et al.  found thMyocardial ischemia is referred to the insufficient flow of the coronary artery and is an early pathological stage of CVD, such as myocardial infarction and acute coronary syndrome . After tPsychological nursing used computed tomography angiography (CTA) technology-based nursing methods for patients with CHD. Systolic blood pressure, heart rate, diastolic blood pressure, self-rating anxiety scale, and the self-rating depression scale scores of patients in the observation group were notably lower than controls . Seidl eThere is no standardized protocol for HF education programs. Researchers and nursing staff are still exploring the best form of education. Breathett et al. added a novel tablet application to nurse practitioner (NP) education. They found that the addition of novel tablet applications may contribute to better patient satisfaction and teaching effects for HF patients . AddictiCardiosurgery nurses performed preoperative education for inpatients. They found that nurse-led preoperative education is helpful for reducing preoperative anxiety and postoperative cardiovascular/mortality complications, whereas it fails to reduce the possibility of second admissions and length of admission . Awoke aMaru et al. enrolled 611 patients with subclinical cardiovascular diseases (without chronic heart failure) . In totaCardiac rehabilitation improves prognosis after an acute AMI, however, the optimal method of implementation is unknown. In total, 217 patients after an AMI received tailored care through a nurse-led cardiac rehabilitation program, and this achieved better control of total cholesterol, low-density lipoprotein (LDL) cholesterol, and systolic blood pressure. This suggests that a tailored, nurse-led cardiac rehabilitation program improves risk factor management in post-AMI patients.The elderly are usually faced with several major comorbidities/risk factors of CVD . The curIn the nursing work of geriatric CVD, effective prevention of risk factors in nursing work is of great clinical significance to improve the quality of nursing and the early rehabilitation of geriatric CVD patients. As nurses who have the most contact time with patients, they should not only be familiar with the characteristics of elderly cardiovascular disease, but they should also have knowledge of mental nursing, considering the social roles of the elderly. Nurses should strengthen the study of etiology, pathogenesis, drug indications, and adverse reactions of CVD to improve the levels of professional technology. They should also actively communicate with patients, establish a relationship of mutual trust and understanding, and carry out targeted psychological nursing, illness nursing, diet nursing, and discharge guidance according to elders' different conditions and personality characteristics so as to improve the quality of nursing and the recovery rate of geriatric CVD patients.Though this narrative illustrates the most recent advances of nursing in the management of geriatric cardiovascular disease, there remain limitations and hope that further research/works can improve. Firstly, the authors failed to make a systematic review (evidence-based search) and only make a narrative review summary. Secondly, the authors failed to provide a comprehensive review: parts of the content are not analyzed in great detail, and this is possibly due to the length limitation of this narrative article and journal requirements.CVD remains the main killer for people throughout the world , 29, 30.TL, XW, and ZM: conceptualization. CZ and CX: writing – original draft. XT, JX, GH, and TL: writing – review and editing. All authors contributed to the article and approved the submitted version.This study was supported by Key Research Project of Medical Science of Health and Family Planning Commission of Hebei Province (ZD20140476).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.


Attention deficit hyperactivity disorder (ADHD) is one of the most common syndromes of childhood. While in the past, ADHD was assumed to be a condition that disappears with maturation and is non-existent in adulthood, it is nowadays understood that ADHD persists into adulthood. Although there is a discussion about the actual percentage of children with ADHD who will still suffer from the disorder in adulthood, there is little doubt that it is a substantial proportion. Data from epidemiologic and follow-up studies indicate a persistence of ADHD across adolescence into adulthood in one to two thirds of diagnosed children with ADHD. The key defining symptoms of ADHD are inattention, hyperactivity and impulsivity, however, motor symptoms of hyperactivity/impulsivity were shown to be less dominant in adult ADHD, whereas attention deficits were found to become more pronounced in adults with ADHD. These core symptoms are pervasive and lead to severe functional impairments of affected adults. Besides these core symptoms, ADHD in adults can produce a wide range of additional cognitive deficits as well as motivational, affective, and social symptoms which can affect nearly every aspect of real-life functioning. In this context, it has to be considered that typical symptoms of ADHD may affect various domains of real-life functioning at the same time. For example, impulsivity of an adult with ADHD may have a negative impact on his or her social relationships, food choice and consumption, risk behaviour, handling of money, etc. Conversely, a specific domain of real-life functioning, such as driving a motor vehicle, may at the same time be adversely affected by various symptoms of ADHD, including impulsivity, inattention, distractibility and lack of flexibility, for instance. High rates of comorbidity further contribute to the impairment in real-life functioning. Real-life functioning is a complex and resource demanding process which requires the integrity of a number of abilities in a dynamic environment with constantly changing requirements. Such abilities include, among others, cognition, self-awareness, coping with stress and flexibility/adaptability. Typical domains of real-life functioning comprise among others social relationships, parenting, diet, social media use, mobility such as driving a motor vehicle, financial planning and decision-making, risk-taking, and vocational functioning.As real-life functioning is typically impaired in adults with ADHD, this special issue has been put together with the goal of highlighting the significance of real-life functioning of adults with ADHD and the problems they experience. Furthermore, the prerequisites of successful everyday functioning  and the related concepts  are considered in the current issue. Various scholars who are experts in their fields contributed to this endeavour by providing their up-to-date applied or fundamental research results. The result is a comprehensive overview of present research activities examining the impact of ADHD on real-life functioning in adults.Guo and colleagues present data about the neuropsychological functioning of individuals at clinical evaluation of adult ADHD.Diaz Orueta and colleagues systematically review the literature regarding cognitive functions of adults with ADHD.Butzbach and colleagues study metacognition in adult ADHD by examining the subjective and objective perspectives on self-awareness of cognitive functioning.Asadi and colleagues examine unique predictions of general risk-taking behaviour in adult ADHD.Koerts and colleagues discuss financial judgement determination in adults with ADHD.Barra and colleagues present a study on the role of stress-coping strategies for life impairments in ADHD.Godfrey and colleagues examine public perceptions of adult ADHD as indications of stigma.Young and colleagues review the literature on ADHD and offending.Fuermaier and colleagues study the nature of work-related problems and impairments of adults with ADHD and explore the association to ADHD symptoms and neuropsychological test performance.Werling and colleagues investigate screen media use before, during and after the COVID-19 lockdown in ADHD.Becke and colleagues discuss a new validity index embedded in the Conners’ Adult ADHD Rating Scales and provide information about its development and validation.Harrison and colleagues perform a comparison of the self-report patterns of analogue versus real world malingerers of ADHD.Fuermaier and colleagues investigate feigning of ADHD and stimulant misuse among Dutch university students.Mucci and colleagues perform a naturalistic review of the literature about ADHD treatment across the lifespan.Young and colleagues review key research in the literature on the assessment and treatment of substance use in adults with ADHD.Tamburin and colleagues explore whether cognitive dysfunction differs in high-dose benzodiazepine/Z-drug users with and without adult ADHD and the impact of cognitive deficits and adult ADHD on quality of life in this substance-use disorder.Faltraco and colleagues examine circadian gene expression in ADHD and the influence of norepinephrine, dopamine, atomoxetine and remdesivir.We hope that this special issue will reflect the wide range of scientific efforts in this exciting field and inspires all those who work in the field of adult ADHD, or plan to do so.