Despite salvage surgery being a key treatment option for recurrent oropharyngeal squamous cell carcinoma, it is unclear how human papillomavirus (HPV) status affects survival rates. The aim of this study was to evaluate how salvage surgery impacts patient survival in the setting of HPV oropharyngeal cancer that recurred within the head and neck region. This scoping review of 32 studies found that only 18.8% of these articles evaluated survival data specific to salvage surgery patients, and 4 studies inconsistently reported survival endpoints, such as overall survival. These findings suggest that future studies can improve upon survival reporting to guide clinical management decisions for HPV-positive recurrent oropharyngeal cancer.Although HPV status is known to provide an improved prognosis in initial treatments of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), it is unclear how it affects patients who receive salvage surgery (SS), which has historically poor survival rates. The purpose of this study was to evaluate the role of SS for patients with locoregional recurrence (LRR) of HPV-positive OPSCC and its impact survival rates. We conducted a scoping review of literature through October 2022 and included 995 individuals. Survival endpoints, such as overall survival (OS), Kaplan–Meier curves, and median post-recurrence survival, were analyzed in addition to demographics. Of all studies, 18.8% (6/32) reported any survival data for SS patients, with the most prevalent reporting 2- and 5-year OS in two studies. Median post-recurrence survival was not reported for SS. These findings reveal the limited and unpredictable reporting of survival-specific data on SS for HPV-positive OPSCC. With limited survival assessment, it is difficult to assess the potential advantages and disadvantages of this therapy to guide clinical decision-making.  The prevalence of human-papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) continues to increase in the United States and internationally ,2. PatiePrevious studies have either failed to address the role of HPV status in recurrent OPSCC or acknowledged the lack of strong evidence available ,6,8,9. IThe primary aim of this study was to evaluate the impact of SS treatment on overall survival, disease-specific survival, progression-free survival, and recurrence-free survival outcomes for patients with HPV-positive OPSCC and to secondarily assess an association between patient characteristics and survival outcomes. Upon initial evaluation of the literature, it was discovered that cancer survival rates were inconsistently reported. Therefore, a scoping review was conducted. The objective of this review is to summarize the reporting of survival outcomes for adults (≥18 years) with HPV-positive OPSCC who received SS for recurrent disease and highlight the clinical importance of the current limitations in the literature.This systematic scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines  and follThis review sought to investigate the reporting of survival outcomes for adults (≥18 years) with HPV-positive OPSCC who received SS for recurrent disease. Additionally, we wanted to highlight the clinical importance of the current limitations in the literature.With the help of an academic librarian, a search strategy was developed and was executed by the two primary authors, A.N.T. and S.R.S. A systematic search was conducted with the PubMed , SCOPUS (Elsevier), and CINAHL (EBSC) databases from the inception through 10 October 2022, using keywords related to oropharyngeal neoplasms, recurrent disease, HPV, and salvage therapy. The PubMed search was adapted for the other two databases by replacing MeSH terms with the appropriate subject headings, when possible, and maintaining similar keywords. This strategy is detailed in the . AdditioThis review aimed to identify all published reports relevant to adults (≥18 years) with HPV-positive OPSCC. The population of interest was surgically salvaged for recurrent disease. This scoping review considered randomized controlled trials, non-randomized controlled trials, prospective and retrospective cohort studies, prospective and retrospective chart reviews, case–control studies, and case series studies. Review articles were assessed but not included in the reporting of quantitative data to avoid redundancy. Other exclusion criteria were non-human studies, non-English language, study protocols, and incomplete or inaccessible articles. There was no limitation for the time range of included publications.This review was conducted in compliance with PRISMA-ScR scoping review methods . The iniData extraction from the 32 included reports was first pilot tested, where both reviewers (A.N.T. and S.R.S.) independently extracted from ten articles, with over 90% agreement. All discrepancies were discussed, and adaptations were made to the extraction template. One author (A.N.T.) extracted the remaining reports. The data extracted from reports included author; year of publication; study design; aims of the study; key findings relevant to scoping review; patient demographics, such as age, gender, race, and risk factors; OPSCC characteristics; and survival parameters, which included overall survival, post-recurrence survival, cancer-specific survival, disease-free survival, progression-free survival, and Kaplan–Meier (K-M) survival curves.All the included reports were critically appraised to assess the level of evidence using the Oxford Center for Evidence-Based Medicine criteria . The risReview results are presented through descriptive statistics (frequency (%), mean/median, and range/95% confidence interval (CI)) of included studies and a narrative summary of findings. Implications of the analysis are then discussed.The goal of this review was to evaluate commonly reported survival outcomes, such as overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), disease-free survival (DFS), and relapse-free survival (RFS).OS is the percentage of patients that are still alive for a specified time after receiving a diagnosis or treatment. PFS is the length of time that a patient lives with a disease that does not worsen. DSS rate is the percentage of patients who have not died from a defined disease in a certain period. DFS is the length of time that a patient survives without signs or symptoms of his/her disease. DFS and PFS are markers that can determine the efficacy of a new treatment. Definitions are derived from the National Cancer Institute . AdditioIn this study, patients were defined as having recurrent disease if the included studies reported their disease as recurrent or persistent. Patients in six of the included studies were labelled with persistent cancer seemingly based on the discovery of disease within <6 months of treatment. We did not view this distinction to warrant a separate category, so all patients documented with persistent or recurrent disease were grouped as recurrent. Recurrence refers to locoregional recurrence (LRR) and does not include distant metastasis. Time to recurrence was not routinely reported as a predictive variable of interest in the included studies.SS, as defined in this study, was any surgical approach utilized for recurrent HPV-positive OPSCC. There was considerable variation in how SS was defined by the included studies, and some did not explicitly indicate which surgical approach was utilized. Other studies defined SS with the following methods: primary tumor resection with or without neck dissection (ND), ND, surgery with flap reconstruction, transoral robotic surgery (TORS), transoral laser microsurgery (TLM), open approach, total laryngectomy with or without glossectomy, mandibulectomy, mandibulotomy, and tonsillectomy.2 and I2 statistics. If there was high heterogeneity (I2 > 50%), the random-effects model was used; if heterogeneity was low, then a fixed-effects model was considered allowable [Meta-analysis of single means  for age was performed by Comprehensive Meta-Analysis (version 3) . Meta-analysis of proportions  was performed using MedCalc 20.110  and was expressed as a percentage with 95% confidence intervals. Each measure was weighted according to the number of patients affected. The weighted-summary proportion was calculated by the Freeman–Tukey transformation . Heterogllowable .The search for surgical salvage in patients with HPV-positive OPSCC encompassed 2264 articles, of which 26 were included ,43,44,45Most of the studies presented detailed demographics for subjects with a primary diagnosis of HPV-positive OPSCC ,49,50,51Analysis of the 32 included articles demonstrated considerable variability in survival assessment for our study’s population of interest . A notewUnique to surgically salvaged patients, there was a paucity of evidence for survival endpoints, such as OS, DFS, and PFS. Twelve studies did not provide a numerical assessment of these variables, and the bulk of the remaining articles limited their evaluation to patients with a primary diagnosis of HPV-positive OPSCC or documented recurrence. A total of four articles calculated numerical values for survival endpoints  13,14,3,37. HoweIn addition to the numerical parameters, survival was graphically appraised through K-M curves. As exhibited by As a cancer treatment with curative potential, SS is a favorable option for patients with relapsed disease . HoweverSalvage surgery is inherently more dangerous and carries more complications than its primary surgery counterpart because of fibrotic tissue planes, advanced disease, and patients who are infirm and malnourished from prior treatments ,53. OptiIn order to optimize the survival outcomes of SS, it is important to recognize that not all subjects are good candidates for surgical intervention—both from a medical standpoint and from an anatomic standpoint . CarefulIn this scoping review of HPV-positive recurrent OPSCC SS patients, the literature demonstrated a scarcity of survival variables, with the most robust reporting from two studies that evaluated OS at 2 and 5 years . This waDespite their frequent use among the included studies, K-M curves had a limited benefit in expanding the knowledge of SS survival projections for HPV-positive recurrent OPSCC. Out of 32 studies, only 6 published K-M curves for surgically salvaged patients ,30,31,37As further evidence of reporting insufficiency, zero studies documented median post-recurrence survival (PRS) for surgically salvaged patients with recurrent HPV-positive OPSCC. Instead, four studies reported median PRS for those patients with any treatment modality ,30,35,42To improve clinical decision making, the focus of this study was to emphasize the underreporting of survival data for the growing population of HPV-positive recurrent OPSCC SS patients. Survival endpoints, such as the 2-year PFS and DFS, would be a helpful tool when considering SS treatment for patients ,56. It iGiven the distinct nature of HPV-positive and -negative oropharyngeal cancers, we recommend that future studies consistently record HPV status to distinguish between the two patient groups and not aggregate the data as one population. Furthermore, with a similar trend of limited survival reporting for HPV-negative patients, direct comparisons between surgically salvaged HPV-positive and -negative patients could reveal whether HPV status is a reliable prognostic factor.With 75% of the articles being retrospective chart or cohort studies , this reIt has been over 20 years since Goodwin concluded that SS was justified in recurrent UADT cancer , yet the


Panic disorders (PD) are associated with suicidality. The link between PD and suicide has been suggested to be depression; however, this remains controversial. Comprehensive research on the history of suicide attempts (SAs) in patients with PD is scarce.This study investigated the characteristics and pharmacological short- and long-term treatment responses of patients with PD, with or without SAs. Moreover, a network analysis was conducted to investigate the central symptoms and their connection to suicidality among SA-related variables with and without SAs.We investigated the characteristics of SAs in patients with PD using PD-related scales, magnetic resonance imaging, and network approaches. A total of 1151 subjects were enrolled, including 755 patients with PD (97 with SA and 658 without SA) and 396 healthy controls. Suicide and PD-related scales were also administered.Our results revealed that the scores of all symptom severities were significantly higher in the PD+SA group than in the PD-SA group. Multiple linear regression analysis revealed that short- and long-term pharmacological treatment responses were significantly poor in the PD+SA group. Network analysis showed that fear of cognitive dyscontrol (FCD) was the strongest central symptom among strength, expected influence (1 and 2 step), randomized shortest path betweenness, and eigenvector centrality measures in PD+SA, whereas depression was the central symptom in PD-SA.Image:Image 2:Image 3:Our results suggest that SA history could be associated with high symptom severity and poor pharmacological treatment response in patients with PD and that FCD is the central symptom in the PD+SA network.None Declared


Aging is a biological process determined through time-related cellular and functional impairments, leading to a decreased standard of living for the organism. Recently, there has been an unprecedented advance in the aging investigation, especially the detection that the rate of senescence is at least somewhat regulated via evolutionarily preserved genetic pathways and biological processes. Hematopoietic stem cells (HSCs) maintain blood generation over the whole lifetime of an organism. The senescence process influences many of the natural features of HSC, leading to a decline in their capabilities, independently of their microenvironment. New studies show that HSCs are sensitive to age-dependent stress and gradually lose their self-renewal and regeneration potential with senescence. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally inhibit translation or stimulate target mRNA cleavage of target transcripts via the sequence-particular connection. MiRNAs control various biological pathways and processes, such as senescence. Several miRNAs are differentially expressed in senescence, producing concern about their use as moderators of the senescence process. MiRNAs play an important role in the control of HSCs and can also modulate processes associated with tissue senescence in specific cell types. In this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors, which affect HSCs function during aging. In addition, we investigate the particular miRNAs regulating HSCs senescence and age-associated diseases.Video AbstractThe online version contains supplementary material available at 10.1186/s12964-023-01117-0. Senescence is an unavoidable process. As the older population grows, decreasing aging and potentially age-related disorders require minimizing or controlling senescence. Stem cell therapy has become a promising method for intervening in aging frailty and aging-related disorders . SomaticHSC regulates the hematopoietic system, which produces new blood cells continuously throughout life. Bone marrow (BM) is their primary habitat, although they may also be found in the spleen, thymus, and lymph nodes , 8. TheyMicroRNAs (miRNAs) are a group of short non-coding RNA (about 22 nt) that can control the expression of several protein-coding mRNA transcripts by connection to the 3' UTR of target transcripts and inhibiting their translation into the encoded protein or activation of their instability and cleavage of mRNA . NumerouIn this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors that affect HSCs function during aging. In addition, we discuss the roles of the particular miRNAs regulating HSCs senescence and age-associated diseases.Caenorhabditis elegans was used to describe this conserved family of miRNAs throughout evolution. Similarities between let-7 in C. elegans and the mouse are observed by Nishino and coworkers, are intriguing. Hypodermal stem cells (seam cells) of C. elegans are strongly stimulated in let-7 near the end of their differentiation process, and impairment of let-7 activity results in the ongoing proliferation of these cells [MiRNA genes are transcribed through RNA polymerase II (pol II) and may be synthesized either from their genes or from a segment of sequences in protein-coding genes. MiRNAs are derived from longer ds-RNAs named pri-miRNAs, which may be produced from intergenic regions, exonic or intronic sequences, or as polycistronic transcripts (including many hairpin structures in a single RNA transcript) , 32. These cells . Furtherse cells . Blood tse cells .Fig. 2MaMechanisms that cause cellular senescence might be intrinsic alterations such as telomere friction, proteostasis changes, epigenetic viewpoint changes, DNA damage, mutational load, and mitochondrial failure. Foreign modifications may also vary from small niche-macroenvironmental changes to systemic level changes to larger-level environmental insults such as irradiation, pathogen, and reactive oxygen exposure –53 Tabl.Table 1Ap53 activity affecting HSCs numbers, proliferation capability, and hematopoiesis in aged organisms, support a model in which aging is caused by a reduction in tissue stem cell regenerative function [Similar processes occur during the maturation of blood cells in both mice and humans. Therefore, it is likely that the exact mechanisms that induce stem cell senescence in mice also do so in humans . The confunction , 65–67. function . In addifunction .Fig. 3ThMetabolic processes are an organism's chemical reactions that keep it alive. Quiescence to reduce stress damage, proliferation, and self-renewal to maintain progenitor pools, and lineage specification for tissue regeneration represent metabolically distinct stem cell appreciations of different energy sources. The primary purposes of metabolism are included: proteins, fatty acids, nucleic acids, and some carbohydrates, as well as the removal of nitrogenous wastes. Hydrocarbons and energy in the form of ATP, and dwindling cofactors from catabolic productions are substrates for the anabolic production of non-renewable macromolecules. Metabolic circulation supplies energy and activates master genetic programs that control cells behaviour –72. To pNumerous molecular and cellular essential pathways have been identified as factors in the decline of HSC function with age. Mechanistically, however, it may be possible and beneficial to communicate these multiple aging pathways separately, leading one to conclude that they are, in fact, highly related and connected. While it's implausible to reversed any of the cellularly fundamental causes of aging, number of them have the potential to be intervened on and thus could be a target for pharmacological study . DownstrStem cell lineages in various organs and tissues become more susceptible to DNA damage as we age , 91. AnoEpigenetics examines how changes in gene expression may be passed down from generation to generation to affect cellular phenotype independent of DNA sequence. In a broader sense, the word refers to the mechanism of genomic control that is not based on the sequence of nucleotides –110. TheDuring each stage of differentiation, a unique miRNA signature is produced by HSCs. By regulating the expression of the master pluripotency genes and early organogenesis, miRNAs have been shown to play a role in maintaining "stemness" and priming differentiation. MiRNAs constitute an additional regulatory mechanism in HSCs, influencing transcription patterns and transcript consistency. There is evidence that miRNAs can direct primary somatic cells back to a pluripotent state . NumerouResearchers showed that the miRNA-212/132 cluster is increased in HSCs and is upregulated in aging. The miRNA-132 and miRNA-212 overexpression and elimination of these miRNAs result in inappropriate hematogenesis with increasing age. Mice with miR-132 overexpressed in their BM had rapid HSC cycling and depletion. Mice, in whom this cluster of miRNAs had been genetically eliminated, had HSCs with altered cycle, function, and survival in response to growth factor deficiency. In this study, researchers demonstrated that miR-132 targeted the transcription agent FOXO3, an established senescence-related gene, to exert its effect on senescence HSCs. Furthermore, by regulating FOXO3 expression, these miRNAs help maintain a preserving balance in HSCs' production .miR-125b, which regulates HSC survival, is highly expressed in the early compartment and is regulated by DNA and histone methylation in tumor settings. miR-125b expression rates are lowered in HSC populations with aging. A higher frequency of the CD150low "lineage balanced" and CD150neg lymphoid-biased HSC subsets is seen when miR-125b expression is elevated, suggesting that miR-125b confers a more stress resistant, anti-apoptotic scenario to the HSCs, influencing the composition of the HSC compartment. It is interesting to note that the frequency of these HSC subsets is reduced in aging animals, suggesting that the miR-125b deregulation is involved in the variations of the CD150 compartments frequency –129.MiR-33 is downregulated in HSCs and strongly expressed in MPPs in super-p53 (sp53) animals with an extra copy of the p53 gene. After transplantation, miR-33 transduced sp53 HSC shows extraordinary regeneration capabilities but drastically reduces recipient survival. In addition, high levels of miR-33 inhibit tumor-derived cell lines' apoptotic response, cause murine embryonic fibroblasts (MEFs) to undergo a neoplastic transformation, and promote MEFs' anchorage-independent proliferation. Downregulation of p53 by miR-33 is associated with its binding to two conserved domains in p53's 3′UTR. To prevent and treat hematological diseases, understanding the role of miR-33 in controlling HSC self-renewal through p53 is crucial .Myelodysplasia, chronic myelogenous leukemia (CML), polycythemia vera, and leukemia are all clonal hematopoietic diseases that are more common in the elderly and may be caused by the genetic and epigenetic abnormalities that become more common in HSC clones as we age. Some researchers believe that changes in the BM microenvironment that occur with age have a role in the selection of senescence human HSC clones . For insResearchers found that miR-146a deficiency contributed to age-related inflammation in individuals with acute myeloid leukemia (AML). Loss of miR-146a in young miR-146a-null mice enhanced senescence of HSCs and inflammation, and senescence-related AML developed earlier than in wild-type animals. An undeveloped subset of resting HSCs was eliminated after miR-146a inhibition. DNA methylation and transcriptome profiling implicated NF-κB, IL-6, and TNF as potential drivers of HSC dysfunction. This resulted in an inflammatory signaling relay leading to increased IL-6 and TNF release from mature miR-146a myeloid and lymphoid cells. Single-cell measurements of miR-146a HSC involvement and subpopulation creation were restored and when inflammation was reduced by targeting IL-6 or TNF, the incidence of hematological malignancy has reduced miR-146a in mice. Loss of miR-146a alters HSC function through cell-extrinsic inflammatory signals and greater cell-intrinsic sensitivity to inflammation, as shown by miR-146a/ HSCs' heightened sensitivity to IL6 induction. Consequently, HSC inflammation contributes to the formation of AML through cell-extrinsic and -intrinsic pathways regulated by the miR-146a loss .The miR-146a has a crucial role in dampening the inflammatory response. The miR-146a depletion leads to fatigue of HSCs and the development of hematological tumors, reduction in the number and quality of HSCs, and an increase in myeloproliferative neoplasms. The internal problem with miR-146a-defective HSCs, and the extrinsic efficiency of lymphocytes and non-hematopoietic cells contribute to the cellular environment's insufficiency. This contains the miR-146a, the signaling protein TRAF6, the transcription factor NF-κB, and the IL-6 along a molecular axis. Using a mouse model of chronic inflammation, researchers found miR-146a to be a crucial regulator of HSC homeostasis and established a mechanical connection between chronic inflammation, BM failure, and the development of myeloproliferative neoplasms. Myelodysplastic syndromes (MDS) are a hematological malignancy of older persons (median age 70 years) that always exhibited reduced expression of miR-146a, making miR-146a-defective mice an excellent model to investigate the etiology of MDS. It concludes by suggesting that chronic inflammation could be to blame for the age-related decline in HSC activity .Distinct types of hematologic malignancy may be identified by the abnormal growth of lymphocytes, which are known as lymphoproliferative disorders. Transplantation of autologous HSCs is a crucial component of treatment for lymphoproliferative conditions. Existing miRNAs in the hematopoietic niche that target cytokines and signaling pathways may have a significant regulatory role in the mobilization of HSC. Furthermore, miRNAs may influence CD34 + cell mobilization efficiency. Next to the first apheresis, a negative relationship was detected among hsa-miR-146a-5p and the quantity of total CD34 + cells. Compared poor mobilizers, excellent mobilizers had a lower hsa-miR-146a-5p rate on the day of the first apheresis, as determined by GITMO criteria. Potentially boosting HSC mobilization efficiency, Hsa-miR-146a-5p .miR-126 has been determined as an essential modulator of HSCs. Reduced levels of miR-126 caused an increase in HSC cycling, which led to a dramatic increase in the HSC compartment and a corresponding reduction in lymphoid capacity. This functional stem effectiveness is also at odds with AML stem cells due to miR-126's control of normal HSC cycling. In AML stem cells, miR-126 protects quiescence and promotes antineoplastic resistance by targeting the PI3K/AKT/mTOR signaling pathway, as shown by a combination of transcriptome and proteome analysis. These characteristics, except retained complete reconstitution capacity, are again indicative of HSC senescence: development of the HSCs and reduced lymphoid output, and miR-126 is linked as a significant mediator of HSC senescence , 136.Incorrect quiescence, self-renewal, and differentiation are seen in aged HSCs. As miRNAs can regulate these processes, they may restore homeostasis to a more 'youthful' state. As a result, miR intermediacy presents a promising strategy for revitalizing HSCs. The mTOR inhibitor rapamycin and calorie restriction are two examples of therapies shown to delay senescence. In the latter case, no proof exists that HSCs can be kept young via nutritional therapies. However, rapamycin may have beneficial effects on HSCs that have reached senescence. The serine/threonine protein kinase mTOR, which regulates cell growth, metabolism, and autophagy, is inhibited by rapamycin. Genes in the mTOR pathway are also targeted by miR-21, miR-22, miR-99, miR-125a/b, and miR-155 , 137 (TaDuring senescence, HSCs undergo an ongoing disorder of function accompanied by a decreased regenerative capability. Understanding the many biochemical processes driving the malfunctioning of senescence HSCs is a critical focus of biomedical research. The average age of the general population is increasing as new health care advances. If molecular therapies that regenerate senescence HSCs are discovered, it might reduce the burden of age-related disorders while opening up new avenues for regenerative blood disease therapy. Numerous studies on the role of miRNAs in aging stem cells have revealed that changes in miRNA expression and their mRNA targets with age within a cellular environment play a critical role in cellular aging and the age-related phenotype. The progress in the comprehension of the miRNAs functions in aging might propose novel curative modalities. However, the role of miRNAs in senescence HSCs is still poorly understood. With the ongoing deepening of HSCs senescence investigation and the continuous progress of miRNAs as anti-aging techniques, the clinical usage of miRNAs in HSCs delaying human aging would gradually come to fruition.


Smoke-free policies are essential to protect people against tobacco smoke exposure. To successfully implement smoke-free policies that go beyond enclosed public places and workplaces, public support is important. We undertook a comprehensive systematic review of levels and determinants of public support for indoor (semi-)private and outdoor smoke-free policies.In this systematic review and meta-analysis, six electronic databases were searched for studies (published between 1 January 2004 and 19 January 2022) reporting support for (semi-)private and outdoor smoke-free policies in representative samples of at least 400 respondents aged 16 years and above. Two reviewers independently extracted data and assessed risk of bias of individual reports using the Mixed Methods Appraisal Tool. The primary outcome was proportion support for smoke-free policies, grouped according to location covered. Three-level meta-analyses, subgroup analyses and meta-regression were performed.14,749 records were screened, of which 107 were included; 42 had low risk of bias and 65 were at moderate risk. 99 studies were included in the meta-analyses, reporting 326 measures of support from 896,016 individuals across 33 different countries. Support was pooled for indoor private areas : 66–79), indoor semi-private areas , outdoor hospitality areas , outdoor non-hospitality areas , outdoor semi-private areas  and outdoor private areas . Subcategories showed highest support for smoke-free cars with children , playgrounds  and school grounds . Non-smokers and ex-smokers were more in favour of smoke-free policies compared to smokers. Support generally increased over time, and following implementation of each smoke-free policy.Our findings suggested that public support for novel smoke-free policies is high, especially in places frequented by children. Governments should be reassured about public support for implementation of novel smoke-free policies.10.13039/100002129Dutch Heart Foundation, 10.13039/501100014780Lung Foundation Netherlands, 10.13039/501100004622Dutch Cancer Society, 10.13039/501100003092Dutch Diabetes Research Foundation and 10.13039/501100012028Netherlands Thrombosis Foundation. Smoke-free policies can protect people against the harmful effects of tobacco smoke exposure. When implementing such policies, information on public support is essential to policy makers. We identified any existing or planned systematic reviews investigating public support for smoke-free policies in indoor (semi-)private and outdoor (semi-)private areas, i.e., “novel” smoke-free policies. Google Scholar was searched on 23 January 2020 using the terms: “systematic review”, “meta-analysis”, “smoking”, “policy”, “regulation”, “legislation”, “law”, “outdoor”, “private”, “support”. We identified five systematic or scoping reviews focusing on support for specific smoke-free locations, or within specific countries showing high or increasing levels of support for outdoor smoking regulations, smoke-free multi-unit housing and smoke-free cars.Our systematic review and meta-analysis provides the first comprehensive overview of support for smoke-free policies that go beyond smoke-free indoor public places and workplaces without any language or geographic restrictions. Overall, the findings from over 100 studies of which 99 could be included in meta-analysis, indicate that public support for novel smoke-free policies is generally high, particularly in areas where children are commonly exposed to tobacco smoke.Smoke-free policies can benefit health and more and more countries are implementing smoke-free policies in novel places. Governments should be reassured by the considerable public support for implementation of smoke-free policies in (semi-)private areas and outdoor public places.,Exposure to second-hand smoke (SHS) poses a major burden to population health globally. Each year, 1.2 million deaths and 36.3 million disability-adjusted life years (DALYs) are attributed to SHS exposure.Public support is important for policymakers to consider implementing novel smoke-free policies and to maximise compliance.Therefore, the primary objective of this study was to systematically review evidence on the levels and determinants of public support for smoke-free policies covering outdoor places or (semi-)private places, henceforth referred to as ‘novel smoke-free policies’. To our knowledge this is the first comprehensive overview of support for novel smoke-free policies that is not limited to a specific smoke-free place or geographic region. Our secondary objective was to identify which personal and country-level characteristics are associated with public support for these policies.We undertook a systematic review and meta-analysis in accordance with our peer-reviewed review protocol.Eligible studies investigated support for smoke-free policies in indoor private places , indoor semi-private places , outdoor semi-private places , outdoor hospitality places , or outdoor non-hospitality places . Policies could already have been in place, were planned, or were hypothetical . Studies were only eligible when support was assessed in a population aged 16 years or above, representing the majority of a population affected by the policy . Studies were excluded if: 1) fewer than 400 participants were included; this limit is based on survey sample size calculations to ensure a margin of error of 5%,Three authors independently performed the data extraction , and cross-checked one another. The following information was extracted: first author’s name, publication year, type of publication, study design, location of the study, description of the policy, policy information , observational period, selection of participants , method of data collection, definition of support, method of assessment , statistical analysis (if applicable), numbers and percentages of missing values and non-response (if applicable), techniques for handling missing data, level of support , personal characteristics , any conflict of interest reported by the authors and funding sources. Furthermore, information was extracted regarding whether the degree of support was for a hypothetical scenario or for a policy that was (about to be) implemented. For reports including pre- and post-implementation support, information was sought on all measurement points.,Country income level according to World Bank classifications and information on traditional comprehensive smoke-free legislation in place according to WHO was sought externally for each report.The Mixed Methods Appraisal Tool (MMAT)not in favour of the policy outcome estimates were reversed. If Likert scales were used, all answer options that were more positive than neutral were combined to indicate support. Policies were categorised by the places that they cover: 1) indoor private places, 2) indoor semi-private places, 3) outdoor private places, 4), outdoor semi-private places, 5) outdoor hospitality places, and 6) outdoor non-hospitality places. When multiple estimates per category were presented , the average support across the category was calculated. For studies based on the same samples a hierarchy of criteria was used to include one of them; the included study was most representative of the general population, had the lowest risk of bias, was based on the largest sample size. If relevant data were missing, corresponding authors were contacted.Reported support was expressed as the proportion of the surveyed population endorsing the smoke-free policy. When studies reported the proportion that was All analyses were conducted with R V.3.6.5 . Support reported as proportions ranging between 0 and 1 did not meet the normality assumption, and therefore logit transformations were applied.If the Likert scale ranged between 0 and a maximum score, the mean score was divided by the highest scale value. For ease of interpretation, proportions were converted to percentage support. We assumed support was related to country of residence and thus violated the meta-analysis independence assumption if multiple studies from a single country were included. Hence, a three-level meta-analysis was conducted to account for within-study, between-study and country-level clustering.Subgroup analyses were conducted by gender , smoking status , parental status (parents vs. others), and age group (youngest age group vs. oldest age group reported). Log odds ratios (ORs) were pooled; if ORs were not reported the following formula was used:Finally, pooled log ORs were back-transformed to ORs for ease of interpretation.In addition to the subgroup analysis three-level meta-regression analysis was conducted. Variables of interest were: calendar year in which the study was conducted, country income level (high- vs. low- and middle-income (LIMC)), and the comprehensiveness of traditional smoke-free policies in place .no or can’t tell on at least one of the MMAT criteria). As appropriate for proportional data, publication bias was assessed using funnel plots of study size against log odds.,Finally, a sensitivity analysis to explore the impact of risk-of-bias of individual studies on the findings was performed by repeating the meta-analyses separately for studies with low risk of bias and studies at higher risk of bias  assessed support for hypothetical scenarios, i.e., support for smoke-free places not yet in place without referring to concrete plans for implementation or actual implementation see .22, 23, 27 assessedRisk-of-bias assessment of individual reports is reported in ,,,Eight reports were not included in meta-analyses: three because public support estimates from the same study population in more recent years were available,In total, data from 896,016 participants were included in the meta-analyses. Some studies provided multiple estimates of public support for policies covering different places, therefore the total number of observations was 1,938,700. Support was highest for policies making cars carrying children smoke-free , followed by playgrounds  and school grounds . For all subcategories except outdoor private areas, we found a mean pooled support higher than 50%. Places with relatively low levels of support included: parks and beaches , outdoor hospitality places  and outdoor private places .Heterogeneity was assessed within (level 1) and between (level 2) studies, and between countries level 3, . OverallSupport was almost uniformly significantly higher among non-smokers and former smokers than among current smokers with ORs ranging between 2.45 and 6.13 . Non-smoMeta-regression analyses indicated no significant associations between question type, study year, and number of indoor public places covered by smoke-free legislation and support for novel smoke-free policies . People ,,,,,,,,,,,,,We identified 12 studies that evaluated support for smoke-free policies before and after implementation . Only onIs the risk of non-response bias low?”. Funnel plots of sample size against log odds were not suggestive of publication bias private places. Support was particularly high for smoke-free places where children are commonly exposed to tobacco smoke, such as cars carrying children, playgrounds, and school grounds. Except for outdoor private areas, support was 50% or higher for all places evaluated. Non-smokers and ex-smokers were more in favour of smoke-free policies than smokers.Strengths of the study include the comprehensive search in six databases, and the absence of any language restriction. With 107 reports included covering data from 33 different countries, the body of existing literature describing support was substantial. Data from 99 studies were pooled for 15 different areas of smoke-free policies, and we accounted for potential clustering at country-level by applying a three-level meta-analysis. Hence, we accounted for variance at participant, study, and country level. In addition to the meta-analysis we conducted subgroup analyses, meta-regression, and sensitivity analyses, providing additional insight in the patterning of public support for novel smoke-free policies. Sensitivity analyses generally showed no meaningful differences in support between lower and higher risk-of-bias studies, suggesting that the evidence is robust.A limitation of this study is that generalisability to other countries from which no surveys were available may be limited. Although there was no indication for publication bias, countries included might be subject to bias, as it is likely that countries planning for novel ways to reduce negative harms of tobacco among the population are more likely to survey support for such policies. This is reflected by the large number of studies from the USA where traditional smoke-free policies are already commonplace, and the low proportion of studies from LMICs, where governmental actions regarding tobacco are commonly more limited. Thirteen reports with 69 estimates in our systematic review were from 11 LMICs. The majority of estimates included in the meta-analysis (33%) however, were from one country . Other limitations of this study concern the different ways in which support was assessed. We did take into consideration the type of answer categories, and did not find large differences when participants were asked if they supported smoke-free policies with a yes-no question or on a Likert scale. Some papers reported proportion not in favour of a policy and outcome estimates were reversed. Although for one study this led to the reported outcome including neutral and positive answers, potentially overestimating support, any bias resulting from this will be very limited. Negative or positive framing of a question might also influence the response.,,,,,,,,Previous studies have shown strong increases in support for novel smoke-free policies over time,Public support is an essential element facilitating policy implementation. We identified highest levels of support for places where children are frequently exposed to tobacco smoke. For example, support for smoke-free cars when driving with children was much higher (86%) compared to a generic policy making cars smoke-free (57%). Similarly, support for smoke-free playgrounds (80%) was higher compared to support for smoke-free parks and beaches (53%). On average, support was highest for indoor private places; this was primarily driven by the high level of support for smoke-free cars carrying children. Apart from that, support was generally higher for semi-private places compared to private places. For example, support for smoke-free regulations in multi-unit housing (76%) was higher compared to private housing (59%).,Of all places evaluated in our study, the highest level of support was found for smoke-free cars: eight out of ten participants were in favour of cleaning the air in cars when children are present. This is in agreement with a previous brief review of support for smoke-free cars, which included studies up to 2008.,,A similarity between the places with highest support was their link with children, suggesting the effectiveness of approaching tobacco control as a child health issue.,The large number of reports included enabled us to evaluate differences in support between population subgroups. Perhaps unsurprisingly, higher levels of support were found among non-smokers and former smokers compared to current smokers.,The results presented in this paper indicate that the majority of the surveyed population is in favour of smoke-free environments beyond places currently being legislated. The consistent high level of support for smoke-free policies in cars carrying children in particular, indicates momentum for increased implementation of regulation in this area. Support was consistently high not only for cars carrying children but for all places where children often go. Framing smoke-free policies as a children’s rights or child health issue as part of a broader smoke-free or tobacco-free generation initiative can provide a good starting point for implementing novel smoke-free policies.Support for novel smoke-free policies is generally high across countries, especially for policies in places where children are present. This indicates that there is substantial momentum for policy-makers to take the next step in protecting the public, and children in particular, from the harmful effects of tobacco smoke exposure by expanding smoke-free policies.JVB secured funding for this work. NWB, FJMM, AzS, AB, FJvL and JVB designed the study and wrote the protocol paper. NWB, AsS and EL contributed to the search, study selection, data extraction and risk of bias assessment. NWB conducted the data analyses and created the figures. JVB supervised the review process. NWB, FJMM and JVB verified the underlying data. NWB, FJMM and JVB drafted the manuscript, AzS, AB and FJvL provided feedback. All authors interpreted the analyses, read and approved the final manuscript, had full access to all the data in the study and had final responsibility for the decision to submit for publication.All datasets generated and analyses are available in the article and the NWB was funded by the Smarter Choices for Better Health Programme from Erasmus University. JVB is PI of a research project to tailor a National Smoking Cessation Programme for (future) parents funded by the Erasmus Initiatives Smarter Choices for Better Health Programme and the Dutch Ministry of Health, Welfare and Sports payed to Erasmus MC. JVB is member of the National Taskforce Smokefree Start, a collaboration of professional organisations involved in the care of pregnant couples, parents, and children aimed at supporting a smoke-free start. This Taskforce is supported by the Trimbos Institute and the Dutch Ministry of Health, Welfare and Sports. Fees for participation in the Taskforce are paid to Erasmus MC. JVB chairs the Taskforce Smokefree Erasmus MC which aims to support a smoke-free hospital environment and optimise smoking cessation support for patients and employees. JVB is a committee member for the national multidisciplinary guideline on tobacco addiction treatment and smoking cessation support.


This facial and dental regional anesthesia task trainer is designed for teaching emergency medicine (EM) residents and medical students; however, it can be used by other specialties including plastic surgery, otolaryngology, oral surgery, and dentistry.While the opioid epidemic remains a public health crisis, emergency departments (EDs) continue to treat patients who require painful facial procedures or who present with severe dental pain. There is increasing interest and renewed use of regional anesthesia for procedural anesthesia and as an effective non-opioid analgesic. Although many nerve blocks are now being taught using ultrasound guidance, regional anesthesia of the face and mouth is still performed using landmark-based techniques. To date, there are no commercially available task trainers for teaching regional anesthesia of the face and mouth. Therefore, a low-cost, feedback-enhanced, partial task trainer was created for teaching regional anesthesia of the supraorbital, infra-orbital, mental, and inferior alveolar nerves.By the end of this educational session, learners should be able to:Describe and identify relevant anatomy for supra-orbital, infra-orbital, mental, and inferior alveolar nerves.Successfully demonstrate supra-orbital, infra-orbital, mental, and inferior alveolar nerve blocks using a partial task trainer.Using inexpensive and commonly found materials, we were able to successfully modify an existing airway task trainer in order to create a feedback-enhanced partial task trainer for teaching supra-orbital, infra-orbital, mental, and inferior alveolar regional anesthesia. When the needle is inserted in the correct nerve location by the learner, the task trainer provides positive feedback in the form of an audible alert. This innovative task trainer has been used to teach post graduate year (PGY) 1–4 resident learners as part of a standard emergency medicine residency didactics curriculum. After a brief introductory didactic session, participants are given the opportunity for hands-on skills practice using the task trainer under faculty supervision.An existing airway task trainer was successfully modified in order to create a feedback-enhanced, partial task trainer for teaching supra-orbital, infra-orbital, mental, and inferior alveolar regional anesthesia. Learners were asked to complete a post-session survey to assess the educational value of the station and the task trainer.Twenty-one residents  participated in a didactic session and all completed a brief post-session survey. Many participants  had never previously performed any of these nerve blocks. On average, participants rated their comfort performing these specific nerve blocks before the session to be 1.96 on a 5-point Likert-scale . Following the session, participants’ comfort level increased to 3.67 on the same scale. Participants rated the usefulness of the feedback-enhanced task trainer to be a 4.71 on a 5-point scale .Using inexpensive and commonly available materials, we were able to successfully modify an existing airway task trainer in order to create a feedback-enhanced partial task trainer for teaching regional anesthesia of the face and mouth. Learners reported that the educational session greatly increased their confidence in performing supra-orbital, infra-orbital, mental, and inferior alveolar nerve blocks. Additionally, they found the feedback-enhanced partial task trainer to be extremely helpful for teaching appropriate landmark identification. Our model was successfully used to teach facial and dental nerve block techniques which are able to provide both procedural anesthesia and non-opioid analgesia. Future studies could investigate whether this educational session and model leads to increased competence and/or increased performance of facial nerve blocks in the clinical setting.Nerve blocks, regional anesthesia, dental emergencies, facial trauma. Learner Audience:Interns, Junior Residents, Senior ResidentsTime Required for Implementation:The task trainer can be assembled in approximately 30 minutes if a preexisting airway task trainer is available for modification. We recommend each educational session, although flexible, be scheduled for 45 minutes to allow for a brief didactic session and demonstration followed by hands-on practice. Given that learners may not regularly perform all of these specific nerve blocks in the clinical setting, we recommend including this educational session on an annual or bi-annual basis as part of a standardized didactics curriculum.Recommended Number of Learners per Instructor:We recommend a ratio of 1 task trainer for every 4 to 5 learners with a maximum instructor to learner ratio of 1:10.Topics:Nerve blocks, regional anesthesia, dental emergencies, facial trauma.Objectives:By the end of the educational session, learners should be able to:Describe and identify relevant anatomy for supraorbital, infra-orbital, mental, and inferior alveolar nerves.Successfully demonstrate supra-orbital, infraorbital, mental, and inferior alveolar nerve blocks using a partial task trainer.Simulation-based medical education is a widely accepted, effective, and popular modality for teaching both cognitive and procedural skills. Built upon a wide array of educational theories and literature, simulation is an active teaching strategy that not only enhances learning by providing a contextual framework, but also allows learners to process and use knowledge in an engaging way. As described by Bloom’s TaxonomySimulation also provides learners with a consistent and safe environment for practice and learning. Whereas the clinical environment is highly variable and instructors cannot guarantee that learners will encounter certain pathology or cases, simulation-based medical education can ensure that all learners are exposed to requisite experiences. Additionally, simulation provides learners with the opportunity to learn and practice skills without introducing additional risks to patients or themselves.While simulation can be used to teach a wide variety of skills and concepts, it is the ideal modality for teaching low frequency or high-risk procedures. Given the importance of providing anesthesia and appropriate analgesia, coupled with the numerous indications for blocks of the supra-orbital, infra-orbital, mental, and inferior alveolar nerves, it is critical that emergency physicians gain experience and comfort performing these blocks. By integrating a positive-feedback mechanism, our task trainer allows learners to perform deliberate practice, either independently or with faculty supervision, while ensuring that they correctly perform the procedure.Moskovitz J, Sabatino F. Regional nerve blocks of the face. Emerg Med Clin North Am. 2013;31(2):517–527. doi:10.1016/j.emc.2013.01.003https://www.aliem.com/pem-pearls-regional-facial-nerve-blocks/PEM Pearls: Regional Facial Nerve Blocks: http://www.emdocs.net/facial-nerve-blocks/EMDocs: Facial Nerve Blocks https://www.downeastem.org/nerve-blocks-of-the-face-and-mouthDowneast EM: Facial Nerve Blocks https://www.aliem.com/pem-pearls-regional-facial-nerve-blocks/PEM Pearls: Regional Facial Nerve Blocks: http://www.emdocs.net/facial-nerve-blocks/EMDocs: Facial Nerve Blocks https://www.downeastem.org/nerve-blocks-of-the-face-and-mouthDowneast EM: Facial Nerve Blocks The task trainer must be created and tested prior to the educational session to ensure that all electrical connections are working properly and safely secured. We recommend that the instructor spend the first 15 minutes of the 45-minute session reviewing the common indications for these specific nerve blocks, relevant anatomy and landmarks, complications, anesthetic dosing, and appropriate insertion techniques. The instructor should then demonstrate each of these nerve blocks on the task trainer. Following the introduction, learners should practice each of these nerve blocks on the feedback-enhanced task trainer, with the instructor providing feedback and answering questions. At the conclusion of the educational session, the instructor provides a brief recap of the high-yield learning points, as guided by the learning objectives.The feedback-enhanced task trainer is made by using inexpensive and commonly available materials that modify an existing airway task trainer. Many commercially available airway task trainers can be substituted for the base.https://www.laerdal.com/us/doc/92/Laerdal-Airway-Management-TrainerAirway Trainer: https://www.amazon.com/365-Everyday-Value-Aluminum-Foil/Roll Standard Kitchen Aluminum Foil: https://www.walmart.com/ip/Unique-Bargains-10-Pcs-20-Double-ended-Alligator-Clips-Test-Lead-Jumper-Wire-50cm-5-Color/4558611320-inch Double Ended Test Lead Jumper Wire with Alligator Clips: https://www.amazon.com/Electric-Buzzer-Physics-Circuits-Continuous/3-24v Piezo Electric Buzzer: , depending on local purchasing agreements and existing simulation resources. However, the overall task trainer will cost more if a new airway task trainer is purchased separately.Identify the airway trainer to modify.Remove the simulated skin that covers the facial structures.Identify the proper anatomical target zones for the nerve blocks.Cut a 2’ long strand of electric wire for each target zone you wish to create . Double this number if you would like bilateral target zones. You may wish to use one color electric wire for the right-sided target zones and another color for the left-sided target zones.For each strand of electric wire, use a wire cutter to remove 1cm of insulation from each end.For each target zone, mold a sheet of aluminum foil around the exposed end of a strand of electric wire.Mold and attach the aluminum foil target to the correct anatomical location on the simulated skull using electrical tape.Repeat steps 5–7 for each target zone. The size of the aluminum foil target can be adjusted for each anatomical location and for the desired level of difficulty. On average, the foil target should be approximately 2–3cm by 1cm, however smaller targets can be used to increase the level of difficulty.Secure the electric wire strands to the simulated skull using electrical tape. It is optimal to tape the right sided strands together into one “cord” and the left sided strands together into a separate “cord.”Bring each “cord” to the back of the simulated skull, or wherever they will exit the skin of the airway trainer you selectedCarefully return the simulated skin to its original position, bringing it up and over the target zones. Alternatively, you may wish to leave this until the final step to ensure that all electrical connections are working properly.Twist the exposed distal ends of the electrical wire togetherAttach one end of an alligator clip #1 to this bundle of exposed ends. Secure with electrical tape.Attach the other end of alligator clip #1 to one end of the piezo electric buzzer.Attach one end of alligator clip #2 to the other end of the piezo electric buzzer.Attach the other end of alligator clip #2 to one electrode of the 9V battery.Attach one end of alligator clip #3 to the other electrode of the 9V battery.Connect the needle and syringe.Either connect the other end of alligator clip #3 directly to the needle, or you may connect it to another strand of electrical wire that is then connected and secured to the needle after the distal edges of insulation have been removed.Test the model by inserting the needle into one of the target zones. You may need to experiment and adjust the connections of the buzzer and/or battery to ensure that current is flowing in the correct directions.Reassemble the airway trainer to hide unnecessary electrical components.This innovative partial task trainer has been successfully used as part of a simulation-based didactics program for PGY 1–4 EM residents. Following the session, learners were asked to complete a post-session survey. The survey contained basic demographic and procedural experience questions, Likert-type questions, and an open-response question. Twenty-one residents  participated in the didactic session and all completed the post-session survey. Many of the participants  had never previously performed these nerve blocks. On average, participants rated their comfort performing these specific nerve blocks before the session to be 1.96 on a 5-point Likert-scale . Following the session, participants’ comfort increased to 3.67 on the same scale. Participants rated the usefulness of the feedback-enhanced task trainer to be a 4.71 on a 5-point scale  and many provided additional positive comments, without recommendations for alterations or modifications.Using inexpensive and commonly available materials, we were able to successfully modify an existing airway task trainer in order to create a feedback-enhanced partial task trainer for teaching regional anesthesia of the face and mouth. Learners reported that the educational session greatly increased their confidence in performing supra-orbital, infra-orbital, mental, and inferior alveolar nerve blocks. Additionally, they found the feedback-enhanced partial task trainer to be extremely helpful for teaching appropriate landmark identification. Our model was successfully used to teach facial and dental nerve block techniques which are able to provide both procedural anesthesia and non-opioid analgesia. Future studies could investigate whether this educational session and model leads to increased competence and/or increased performance of facial nerve blocks in the clinical setting.


Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids (SLIPPERS) is a rare variant of the CLIPPERS spectrum with less than ten reports published so far. There is ongoing discussion regarding whether SLIPPERS is a disease entity on its own or just an acronym encompassing many underlying diagnoses, such as sarcoidosis, vasculitis and anti-glial fibrillary acidic protein (GFAP)-associated disease. A 40-year-old woman presented with episodes of language and attention impairment. Magnetic resonance imaging (MRI) revealed T2/FLAIR hyperintense lesions in the subcortical white matter associated with a micronodular, curvilinear perivascular contrast-enhancement. Alternative diagnoses were excluded. There was a remarkable response to steroids. A relapse occurred after six years, and the biopsy showed perivascular T-cell lymphocytic infiltrate, without granulomas, vasculitis, or neoplasia. There was complete resolution of the relapse after steroids. This case represents the longest reported follow-up of a patient diagnosed with SLIPPERS, and brain biopsy after 6 years did not suggest alternative diagnoses. This report contributes to the discussion regarding the possibility that exclusive supratentorial CLIPPERS-like pathology might be an isolated disease entity, but more biopsy-proven cases with a longer follow-up are needed to support this hypothesis. Recently, GFAP astrocytopathy has been characterized and might correspond to a significant number of cases previously diagnosed as CLIPPERS or SLIPPERS. Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) presents as idiopathic steroid-responsive T-CD4 lymphocyte infiltrates associated with pontine perivascular gadolinium-enhancing punctate lesions . Few casHere we report clinical, radiological, and pathological features of a well-documented case fulfilling the proposed criteria for SLIPPERS with a six-year follow-up. In this case, the biopsy was compatible with previous findings in SLIPPERS and excluded common differential diagnoses like CNS vasculitis and granulomatous diseases.This is a retrospective report of a patient evaluated in a specialized neuroimmunology center in Brazil. Informed consent for publication was obtained for the patient. All ancillary tests were performed for the regular follow-up at the discretion of the attending physician. Brain MRI was evaluated by a neuroradiologist. Pathological specimens were evaluated by experienced neuropathologists.A 34-year-old woman with a past medical history of vitiligo presented with episodes of speech/language impairment for the last six months. Family history was significant for a sister diagnosed with Sydenham chorea. Neurological examination demonstrated only brisk reflexes on the left-side.3, and normal protein and glucose levels. Protein electrophoresis demonstrated an increase in CSF IgG levels. Oligoclonal bands were absent. Chest and abdominal computed tomography scans revealed no abnormalities. Serum ANA, Rheumatoid Factor, Anti-Ro, Anti-La, Anti-RNP, anti-dsDNA, Anti-Sm, ANCA, ASCA, C3, C4, ACE, AgHBs, Anti-HCV, HIV serology, HTLV serology, and FTA-abs were normal.Magnetic resonance imaging showed bilateral T2/FLAIR hyperintense lesions in the frontal subcortical white matter associated with a micronodular, curvilinear perivascular pattern of contrast-enhancement . CerebroThe patient received 1 g/day of methylprednisolone for 5 days, considering a possible diagnosis of SLIPPERS and the absence of infection. The administration of high-dose steroids led to complete clinical and radiological improvement after 3 months . We did Two years after disease onset, the patient became pregnant. Pregnancy and delivery occurred without maternal or neonatal complications. No neurological symptoms occurred during this period, as well as during the puerperium.Six years after the disease onset, she presented with cognitive impairment, particularly in attention, associated with headache. Magnetic resonance imaging revealed new areas of nodular, perivascular T2/FLAIR hyperintensities in the frontal subcortical and deep white matter with areas of nodular and linear contrast enhancement . ConsideThis case represents the longest reported follow-up of a patient diagnosed with SLIPPERS, and a brain biopsy after 6 years of disease onset did not suggest any alternative diagnoses. This report contributes to the discussion regarding the possibility that exclusive supratentorial CLIPPERS-like pathology might be an isolated disease entity, but more biopsy-proven cases a with longer follow-up are needed to support this hypothesis.We also discuss characteristic neuroimaging findings, possible differential diagnoses and the possibility of relapses in this pathology. Of note, this was the first report of a successful pregnancy in a patient diagnosed with SLIPPERS, and they did not show worsening or relapse during pregnancy or puerperium.In the original CLIPPERS series, all patients’ MRIs exhibited a distinct pattern of punctate and curvilinear enhancement peppering the pons and extending variably into the medulla, brachium pontis, and mid-brain. In some cases, a milder radial pattern of identical enhancing lesions extended into the basal ganglia and inferior cerebellar white matter, corpus callosum, and spinal cord. Lesions became fewer and smaller as distance from the pons increased . HoweverDiagnostic criteria proposed for CLIPPERS require enhancing lesions predominating in the pons . HoweverSLIPPERS is very rare and to the best of our knowledge, only six cases of exclusive supratentorial lesions have been reported . The appSince its first description in 2016, autoimmune GFAPastrocytopathy has been increasingly recognized as a cause of autoimmune meningoencephalitis with particular neuroimaging and pathologic findings . AutoimmCLIPPERS neuropathology demonstrates extensive lymphocytic inflammation (T cells predominance) with perivascular predominance and parenchymal diffuse infiltration, associated with an absence of myelin loss or focal secondary myelin loss ; there iEven in patients diagnosed with CLIPPERS/SLIPPERS, long-term follow-up is required for necessary diagnostic revision at each new attack and the GFAP antibody test is advised for differential diagnosis, particularly when the patient presents with linear perivascular radial gadolinium enhancement.Little is known about the long-term outcomes of SLIPPERS. However, our case demonstrated that patients could present relapses several years after disease onset. Moreover, almost 60% of patients with CLIPPERS show relapses . AlthougPregnancy can ameliorate autoimmune diseases such as rheumatoid arthritis but can also exacerbate or have no effect on other conditions such as lupus erythematosus . The disOur report has limitations that must be addressed. First, the comprehension of the pathophysiology is limited and the concept that SLIPPERS represents part of the clinical spectrum of CLIPPERS is based on radiological and pathological findings. Also, multiple autoimmune and neoplastic disorders can present the radiological and pathological findings of SLIPPERS, reinforcing the importance of long-term follow-up in case reports of the disease to evaluate alternative diagnoses.Recently, GFAP astrocytopathy has been better characterized and might correspond to a significant number of cases previously diagnosed as CLIPPERS or SLIPPERS. Unfortunately, we were not able to test for anti-GFAP antibodies due to unavailability of antibody testing at the initial presentation and difficulties in access to antibody research during relapse. This is an important limitation as clinical and radiological aspects of this case may overlap with anti-GFAP and biopsy findings in GFAP astrocytopathy have not been extensively documented. Furthermore, a single case report has limited generalizability and lacks predictive value for disease progression estimates.We reported the longest follow-up in a biopsy-compatible SLIPPERS case. This case highlights the necessity to investigate and exclude potential alternative diagnosis, particularly CNS vasculitis, hematologic malignancies and granulomatous diseases, in an expanding list of differential diagnoses. Recently described GFAP astrocytopathy may correspond to a significant number of cases previously diagnosed as CLIPPERS or SLIPPERS, and testing for GFAP-antibodies is advised even in long-term or relapsing disease. Case series with a longer follow-up and testing for anti-GFAP antibodies could help us understand if SLIPPERS is a disease entity on its own and provide guidance for treatment and follow-up of these cases.


Currently, hidden blood loss (HBL) has been paid more and more attention by spine surgeons. Simultaneously, it has been the effort of spine surgeons to explore more advantages of minimally invasive surgery. More and more articles have compared unilateral biportal endoscopic lumbar interbody fusion (BE-LIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). But so far, there is no HBL comparison between BE-LIF and MIS-TLIF. This study aims to compare the surgical invasiveness, hidden blood loss, and clinical outcome of BE-LIF and MIS-TLIF and to provide insight regarding minimally invasive surgery for lumbar degenerative disease (LDD).We enrolled 103 eligible patients with LDD who underwent BE-LIF (n = 46) and MIS-TLIF (n = 57) during August 2020–March 2021. We collected data, including demographics, perioperative haematocrit, operative and postoperative hospital times, serum creatine kinase (CK) and C-reactive protein (CRP) levels, and hospitalization costs. Total and hidden blood loss was calculated. Clinical outcomes were assessed using a visual analogue scale (VAS) score for back and leg pain, Oswestry Disability Index (ODI), modified MacNab criteria, fusion rate, and complications.Basic demographics and surgical data were comparable. The CRP and CK levels were generally lower in the BE-LIF than in the MIS-TLIF group, especially CRP levels on postoperative day (POD) three and CK levels on POD one. True total blood loss, postoperative blood loss, and hidden blood loss were significantly reduced in the BE-LIF group compared with the MIS-TLIF group. Postoperative hospital times was statistically significantly shorter in the BE-LIF group. The VAS pain and ODI scores improved in both groups. At three days and one month, the VAS lower back pain scores were significantly better after BE-LIF. Clinical outcomes did not otherwise differ between groups.Compared with MIS-TLIF, BE-LIF has similar medium and short-term clinical outcomes. However, it is better regarding surgical trauma, early lower back pain, total and hidden blood loss, and recovery time. BE-LIF is an adequate option for selected LDD. Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is commonly used to treat lumbar diseases, including spinal stenosis and spondylolisthesis . CompareSpinal endoscopic techniques have been successively applied to lumbar intervertebral fusion surgery . RecentlThis retrospective cohort study included 103 (46 BE-LIF and 57 MIS-TLIF) patients with clinically and radiographically diagnosed single-segment lumbar degenerative diseases admitted during August 2020–March 2021. During the study period, 21 (eight BE-TLIF and 13 MIS-TLIF) of 103 patients were excluded for the following reasons: lost to follow-up (two BE-TLIF and three MIS-TLIF), coagulation disorders or anaemia (four BE-TLIF and six MIS-TLIF), and incomplete data (two BE-TLIF and four MIS-TLIF). Therefore, the clinical data for comparative analysis came from 38 BE-TLIF and 44 MIS-TLIF patients.The inclusion criteria were: age ≥ 40 and ≤ 75 years; lower back and lower limb radiation pain ≥ 5 on the visual analogue scale (VAS); and/or neurogenic intermittent claudication not responding to appropriate conservative treatment for over six months; defined single-segment lumbar degeneration or isthmic spondylolisthesis (below Meyerding grade II), lumbar spinal stenosis with spondylolisthesis or instability or lumbar disc herniation with spinal stenosis; and follow-up over one year with sufficient clinical data.The exclusion criteria were: anaesthesia contraindicated for poor condition; spondylodiscitis, active infection, fractures, or spondylolisthesis (higher than grade II); previous lumbar procedures; cognitive or psychological unfitness for participation; and haematologic-related diseases.All procedures were performed by the same surgical team from our hospital. The choice of surgical method is a decision made by the patients and their families after the surgeon fully and thoroughly explains the details, advantages and disadvantages, total cost and social medical insurance policy of the different surgical methods. This study was approved by the Medical Ethics Committee of our institution and was performed according to the Declaration of Helsinki. Written informed consent was obtained from all participants.Patients were placed prone after general anaesthesia. The target intervertebral space was identified with G-arm fluoroscopy and marked. After routine disinfection and draping, two 1-cm transverse incisions were made at the medial edge of the upper and lower pedicles in the ipsilateral target space. The soft tissues on the laminar and facet joint surfaces were peeled off with a periosteal stripper, and the skin dilator was used to gradually expand and to establish observation and surgical channels Fig. a. The loThe procedure was performed according to the routine MIS-TLIF technique described in previous reports , 13. AftBoth groups followed the same postoperative protocol. Antibiotics were routinely administered. Once the drain was removed according to volume on postoperative day (POD) two or three, patients were encouraged to wear an orthosis to mobilize and to continue protective use for three months. The patients were informed of perioperative precautions and instructed to perform functional rehabilitation. They were instructed to return at one, three, and 12 months after discharge; clinical follow-up was also conducted regularly by telephone or email.Patients were followed for at least one year. The demographic information of the two groups was recorded preoperatively, including age, gender, body mass index (BMI), diagnosis, and surgical segment. Perioperative data included operative time, perioperative TBL, HBL, and postoperative hospital stay and hospitalization costs. CK and CRP levels were recorded preoperatively and on PODs one, three, and five. Clinical efficacy was evaluated using the VAS and Oswestry Disability Index (ODI) scores of lower back and leg pain preoperatively and three days, one month, three months, and one year postoperatively. The modified MacNab score at one year was used to evaluate patient satisfaction. Perioperative complications were recorded. At one year, radiography and computed tomography (CT) were performed, and fusion rates were assessed by two radiologists according to the Bridwell grading system, with grades I and II defined as spinal fusion.pre–HCTpost)/HCTave . PBV was calculated according to Nadler et al. [3+k2×weight (kg) + k3 . HBL was calculated using the method of Sehat et al. [Haematocrit (HCT) changes can reflect TBL . TBL wasOD three , 17, andr et al. : PBV = kStatistical software SPSS 27  was used for data analysis. Measurement data are presented as means ± standard deviations. Repeated-measures analysis of variance (ANOVA) was performed to determine differences in repeated measurements, such as serological markers (CRP and CK) and clinical outcomes (VAS and ODI) between the two groups, and changes in each group over time. Normally distributed variables were assessed using the Student’s T-test, while non-normally distributed variables and ranked data were evaluated using the non-parametric Mann-Whitney U test, such as modified MacNab criteria. Categorical data were analysed with using the chi-square test or Fisher’s exact test. Significance was assessed at P < 0.05.Procedures were successful in all patients, and follow-up lasted for more than 12 months. One BE-LIF case is presented in Fig. The mean operative time was longer for the BE-LIF group than for the MIS-TLIF group . Hospitalisation costs were significantly greater for the BE-LIF group (66813.68 ± 3734.79 RMB) than for the MIS-TLIF group . The postoperative hospital stay was significantly shorter for the BE-LIF group  than in the MIS-TLIF group . Higher prices and an inadequate Chinese social-medical insurance system related to BE-LIF surgery have somewhat limited its development.post). If the patient has not yet hemodynamically stabilized, fluid shifts may be incomplete, resulting in low values for calculated TBL and HBL. This factor did not affect the results of our two groups, because the HCTpost values of both groups were collected on the same day after surgery. Third, the case number was small and follow-up time short; thus, a prospective randomized controlled trial with longer follow-up and larger sample size is still needed to further evaluate this technique.Some limitations of our study should be mentioned. First, this is a single-centre, retrospective cohort study, and inherent selection bias is inevitable. We did our best to balance the two groups at the beginning of the study, and they did not differ based on basic demographics. Second, we calculated true TBL using HCT at three days postoperatively (HCTCompared with MIS-TLIF, BE-LIF has similar medium and short-term clinical efficacy and fusion rates. However, BE-LIF is favourable regarding surgical trauma, early postoperative lower back pain, total and hidden BL, and recovery time. These advantages make it an effective option for selected lumbar degenerative diseases. Further studies with large samples and long-term follow-up are needed.


Cross-frequency coupling (CFC) mechanisms play a central role in brain activity. Pathophysiological mechanisms leading to many brain disorders, such as Alzheimer’s disease (AD), may produce unique patterns of brain activity detectable by electroencephalography (EEG). Identifying biomarkers for AD diagnosis is also an ambition among research teams working in Down syndrome (DS), given the increased susceptibility of people with DS to develop early-onset AD (DS-AD). Here, we review accumulating evidence that altered theta-gamma phase-amplitude coupling (PAC) may be one of the earliest EEG signatures of AD, and therefore may serve as an adjuvant tool for detecting cognitive decline in DS-AD. We suggest that this field of research could potentially provide clues to the biophysical mechanisms underlying cognitive dysfunction in DS-AD and generate opportunities for identifying EEG-based biomarkers with diagnostic and prognostic utility in DS-AD. Brain function and cognition rely on the precise coordination of neural activity within and across brain areas. Yet, how neural networks achieve this precise coordination is part of a long-standing debate in neuroscience, and much remains to be understood about how brain function emerges from different patterns of neuronal communication in both health and disease.Early research efforts were often devoted to investigating the functional properties of frequency bands in isolation; however, many recent studies have focused on exploring how distinct brain rhythms could interact with each other to support information processing and communication within the brain -3. EmergIndividuals with Down syndrome (DS) are at a greater risk of developing early-onset dementia, which is driven by the near-universal presence of AD-type pathology in DS brains by 40 years of age , 21. EstHere, we briefly review some of the basic physiological mechanisms underlying neural oscillations, and how dynamic interactions between different brain rhythms can be studied by analysis of CFC in both health and disease. We then review preclinical and clinical studies aimed at investigating electrophysiological alterations that may be associated with AD progression. Particular focus was given to studies on the potential use of theta-gamma PAC as a biomarker of cognitive decline in AD. We argue that PAC analysis has great potential as an adjuvant tool for evaluating clinical changes in brain network dynamics associated with early stages of AD in the DS population, as well as in preclinical and clinical research aimed at exploring electrophysiological mechanisms associated with the progressive neurodegenerative processes in DS-AD. We conclude by speculating that this line of investigation could also provide an opportunity for the identification of non-invasive, EEG-based biomarkers with diagnostic and prognostic utility in DS-AD.Brain oscillations result from rhythmic fluctuations in the electrophysiological activity of single neurons, local assemblies of neurons, and/or several spatially distributed neuronal assemblies . The priSynchronous activity of neural networks generates rhythmic voltage oscillations at multiple frequencies, which are conventionally classified as ultraslow (<1 Hz), delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta 12-30 Hz), slow gamma (30-80 Hz), fast gamma (80-200 Hz), and ultra-fast gamma (200-600 Hz) oscillations . Switche Hz, slowTiming in neural networks is mainly determined by the activity of gamma-aminobutyric acid (GABA) inhibitory interneurons . The timCoherence may reflect coupling between spikes in one region and the LFP within either the same or a different region , as well as phase relationship between neural oscillations at two different brain regions , 35. ForWhile “communication through coherence” contemplates coupling between oscillatory activity at the same frequency, more complex patterns of network organization can arise from mechanisms by which oscillators across different frequency bands can be nested within each other , 5.Because brain rhythms coexist in different frequency bands, their physiological role in cognitive functions cannot be fully appreciated in isolation. Therefore, it is critical to understand the production of CFC, i.e., how different brain rhythms interact with each other. Neural oscillations can be hierarchically organized in such a way that the phase or amplitude of a slower oscillation modulates the phase or amplitude of a faster one via phase-phase, amplitude-amplitude, or phase-amplitude coupling , 8, 37. CFC has been associated with multiple brain and behavioral states. For example, in awake rats, it was found that the amplitude of high frequency oscillations was modulated by the phase of ongoing theta rhythm, both within and across striatal-hippocampal circuits, and that the strength of such CFCs dynamically changed according to the rodent’s behavioral performance . In addiAs aforementioned, the coupling between theta phase and gamma amplitude (theta-gamma PAC) is the best-studied modality of CFC , 7. It din vitro studies showing that theta-burst stimulation (TBS), which consists of multiple pulses at 100 Hz repeated in 5 to 7 Hz inter-burst-intervals , effectively induces LTP [vivo studies have shown that phase-locked high-frequency bursts of transcranial magnetic stimulation (TMS) caused an LTP-like increase in motorcortical excitability [The initial idea of a phase-dependent mechanism supporting memory performance stemmed from studies showing theta phase-dependent modulation of synaptic strength and efficacy by using hippocampal long-term potentiation (LTP) and depression (LTD) recordings , 51. Thiuces LTP , 53. In tability , 55.The strength of phase-to-power interaction between theta and gamma oscillations may change according to task demand, and it may also predict behavioral performance . For exaGiven the potential functional role of theta-gamma PAC in brain activity, special focus has been given to studying the underlying network substrates that give rise to the oscillatory activity at these frequencies . Theta aIn the hippocampus, gamma oscillations are generated by two main mechanisms: reciprocal interactions within the highly interconnected GABAergic interneuron network (interneuron network gamma or ING) and feedback loop between excitatory principal neurons and local interneuron networks  , 65. AmoA receptor agonist) into MS also affected theta-gamma PAC and reduced the probability of successful memory retrieval [Both cholinergic and GABAergic inputs from the medial septal nucleus (MS) contribute to hippocampal theta rhythm generation , 70-72. etrieval . In addietrieval , 76. Recetrieval  providedetrieval .vis-à-vis non-invasive, scalp-EEG recordings in clinical setting.The question of whether findings from preclinical electrophysiological studies in animal models can reliably be translated into clinically relevant work is a contentious issue. This is especially true when one considers that brain rhythms are mostly studied by LFP recordings in preclinical research In spite of clear interspecies differences in anatomy and physiology, compelling evidence has shown that the relatively well conserved similarities in brain structure and function between rodents and humans can reasonably support translatability of EEG measures of brain activity across these species. Particularly, the notion that hippocampal theta- and gamma-range responses in humans share many similarities with those in rodents is supported by findings from intracranial EEG recordings in patients with epilepsy surgically implanted with electrodes -81. HippBeyond the hippocampus, evidence from non-invasive scalp-EEG recordings in human subjects suggests increased cortical theta oscillations in different cortical structures during cognitive tasks ), synaptic loss  PET), neurodegeneration , and neurofilament light (NfL) concentration in CSF and blood), and inflammation  and translocator protein (TSPO)) [Given that definitive diagnosis of AD still requires nifested -101. Bio (TSPO)) , 103. AlA particularly promising new approach in the field of AD biomarkers focuses on the monitoring of electrophysiological brain activity and has received growing acceptance as a validated surrogate marker for cognition in the past several years , 99, 104A wide range of brain rhythms has been found to be altered in EEG recordings from subjects with AD. For example, spontaneous EEG recordings from individuals with AD have showed increased power in delta and theta frequency bands and decreases in power of alpha and beta oscillatory activities, which suggest a shift of the power spectrum from faster to slower frequencies , 106-109Recently, EEG markers based on measures of signal complexity (epoch-based entropy) and synchrony (bump modeling) were showed to automatically and efficiently discriminate patients with AD from those with subjective cognitive impairment, MCI, and other pathologies . Yu and A growing body of evidence suggests that decreased functional connectivity between brain areas may be one of the earliest signatures of AD , 122. DaDS results from the trisomy of chromosome 21 and is associated with a variety of cognitive comorbidities, such as intellectual disability and AD . The vasAPP), which is located on chromosome 21, is associated with increased susceptibility to AD [APP may also increase Aβ aggregation, deposition of plaques, and worsen AD-related cognitive impairments [The molecular pathophysiology of DS-AD is not well defined. There is general acknowledgment that the extra copy of the gene encoding for amyloid precursor protein , while this parameter only slightly decreased with age in the controls  [Electrophysiological findings in persons with DS and AD are also consistent with those in individuals with AD without DS . A crossference) . Given tference) , 154, itference) , 156. Inference) -159. Impference) . This obference) , 154, whference) , 160. Inference) .In sum, electrophysiological findings in persons with DS corroborate evidence from studies supporting the well-accepted notion in the AD research community that slowing of brain rhythm may be associated with the level of cognitive deterioration, and hence may serve as a biomarker to predict the onset of dementia , 161. YeApp, such as the Ts65Dn mouse model of DS [40 and Aβ42 monomers and soluble Aβ oligomers [Many AD-relevant phenotypes can be observed in mice overexpressing el of DS . The Ts6el of DS . This moel of DS , 168, thligomers -171. Solligomers -174. Theligomers -178, enhligomers . Importaligomers -183.App gene dosage and reduced retrograde axonal transport of nerve growth factor [The Ts65Dn mouse also shows progressive, age-related degeneration of basal forebrain cholinergic neurons , 184. Thh factor , 190. Thh factor , 192, anh factor -195.Decline in cholinergic signaling may contribute to AD-related brain electrical activity alterations , 196, giThere is growing evidence that the activity of interneurons, as well as the oscillatory network activities they regulate, are impaired in AD , 203. FiApp and increased levels of Aβ peptides have also been found to impair gamma oscillations in both in vitro and in vivo preclinical studies [A decrease in rhythmic bursting activity of septo-hippocampal PV interneurons has been observed following hippocampal Aβ injections, which correlated with decreased theta power and impaired recognition memory performance in rats . Overexp studies , 209. Su studies , 211. Th studies , 211-214 studies , 215-224 studies , 128.Inhibitory circuit dysfunction has been implicated as a contributing mechanism to DS pathophysiology . FindingMouse models of DS also showed altered hippocampal theta-phase modulation of low and high gamma amplitude during rest and behavioral performance , 163. ReAlthough preclinical studies have shed some light on the potential links between PAC alterations and brain phenotypes associated with cognitive deficits in DS, the underlying mechanisms leading to these pathophysiological processes remain to be further elucidated.Despite of growing preclinical and clinical evidence supporting the use of EEG to probe the effects of AD pathology on neurophysiological parameters, currently applied diagnostic criteria do not yet support the application of EEG-based biomarkers in AD clinical practice -232. A sEven with the limitations of preclinical experimentation (as discussed below), animal models have been employed in the study of the association between AD pathology and its neurophysiological effects (as measured by EEG) on brain oscillations and network dynamics . ImportaElectrophysiological technology has great appeal as a biomarker for several reasons. This technique is generally non-invasive, low-cost, widely available, and ease to deploy (including training requirements for staff) in both clinical practice and clinical trials. In contrast, other approaches, such as CSF and neuroimaging biomarkers, demand higher technical expertise and have operational limitations , besides being considered “more than minimal risk” by regulatory agencies . Additionally, EEG recordings may also be better tolerated by persons with intellectual disability than other investigative modalities , 234.Compared to other technologies that also measure brain function, such as functional MRI (fMRI), EEG is less sensitive to motion, and it is far less expensive. In addition, while fMRI records blood oxygen level-dependent (BOLD) responses, and thus provides an indirect measure of neuronal activity, EEG captures neuronal activity at its natural high-temporal resolution, and thus may provide better accuracy than fMRI in detecting early changes in brain dynamics associated with AD-related cognitive decline.EEG-based biomarkers may also have the potential to aid in advancing the development, clinical implementation, and monitoring of novel drug candidates against AD. Recently, a double-blind, placebo-controlled trial used EEG-derived measures to evaluate the safety, tolerability, and efficacy of the glutaminyl cyclase inhibitor PQ912 in patients with MCI or mild dementia due to AD . AccordiThe utility of EEG recordings as a potential longitudinal measure of treatment efficacy has been explored for decades. For example, EEG spectral analysis showed a power decrease in delta  and thetThere are many limitations that still need to be addressed before considering the general application of EEG-based biomarkers such as PAC as an adjuvant tool for detecting DS-AD. A partial list of the necessary steps to achieve this goal is provided in the following paragraphs.First, further biological validation is needed by larger studies, as well as by studies involving different animal models, given that there is currently no animal model that faithfully reproduces the whole phenotypic spectrum of DS. In addition, how well animal models of DS can mirror PAC alterations in the DS clinical setting also remains to be determined.Second, correlations of EEG findings with well-established AD biomarkers , as well as with markers of cognitive function, should be considered in future preclinical and clinical studies. The longitudinal investigation of changes in EEG-based biomarkers and cognitive outcome measures may provide key information on time sequence of transition from cognitive health to cognitive impairment and decline.Third, standardization of operating procedures for EEG recording and data analysis will be needed to enable valid comparisons between basic and human research laboratories, as well as with clinical centers. For example, changes in PAC strength depend on cognitive demands  and perf42, NfL, and phosphorylated-tau) have been suggested to directly provide in vivo evidence of AD pathology, topographical markers  characterize downstream brain changes generally induced by AD pathology [Fourth, because of the phenotypic variability in DS-related cognitive traits and the presence of potential confounding factors (such as DS-related comorbidities), it is likely that a combination of biomarker modalities will turn out to be a more effective way to discriminate between DS and DS-AD. While pathophysiological markers  for the diagnosis of AD may be an important step toward the identification of individuals at the preclinical or prodromal stage of the disease, especially in the most susceptible populations as the case of DS.Identifying individuals with DS at the very earliest stages of AD is vital for maximizing the efficacy of therapeutic interventions to mitigate cognitive decline due to AD. In addition, early identification of individuals with DS at risk of developing AD would allow them to be recruited in intervention trials aimed at testing disease-modifying drugs whose therapeutic goals are to prevent or slow AD-related cognitive decline. EEG-based markers might also prove to be useful in clinical routine practice to monitor therapy efficacy not only in people with DS-AD, but also in those with AD in the general population. Yet, it remains to be determined how EEG-based biomarkers are associated with other biomarkers of DS-AD, as well as with the onset of AD-related signs and symptoms. Although much work remains to be done, we encourage a continuous debate on the potential utility of PAC measures, not only as an EEG-based biomarker or surrogate marker, but also as a tool for studying the pathophysiological processes underlying DS-AD.