Ageing of the global population represents a challenge for national healthcare systems and healthcare professionals, including medico-legal experts, who assess personal damage in an increasing number of older people. Personal damage evaluation in older people is complex, and the scarcity of evidence is hindering the development of formal guidelines on the subject. The main objectives of the first multidisciplinary Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People were to increase knowledge on the subject and establish standard procedures in this field. The conference, organized according to the guidelines issued by the Italian National Institute of Health (ISS), was held in Bologna  on June 8, 2019 with the support of national scientific societies, professional organizations, and stakeholders. The Scientific Technical Committee prepared 16 questions on 4 thematic areas: (1) differences in injury outcomes in older people compared to younger people and their relevance in personal damage assessment; (2) pre-existing status reconstruction and evaluation; (3) medico-legal examination procedures; (4) multidimensional assessment and scales. The Scientific Secretariat reviewed relevant literature and documents, rated their quality, and summarized evidence. During conference plenary public sessions, 4 pairs of experts reported on each thematic area. After the last session, a multidisciplinary Jury Panel (15 members) drafted the consensus statements. The present report describes Conference methods and results, including a summary of evidence supporting each statement, and areas requiring further investigation. The methodological recommendations issued during the Conference may be useful in several contexts of damage assessment, or to other medico-legal evaluation fields. The number of people aged 65 years and over (older people) is increasing worldwide, particularly in North America and Europe . Among tThis scenario represents a challenge for national healthcare services and for healthcare professionals, including Medico-Legal experts. Indeed, the latter assess the personal damages resulting from traumatic injuries in an increasing number of older people, especially in the legal framework of third-party motor liability .The ascertainment and evaluation of personal damage are complex issues from both clinical and medico-legal standpoints . The assThe impact of the abovementioned assessment issues on the daily practice of medico-legal experts was confirmed by interviews with experts in personal damage assessment carried out in December 2017, and represents the starting point of the Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People.The aim of a consensus conference is to produce recommendations through “the analysis of the available evidence on specific controversial subjects for which there is no shared opinion, and often leading to non-standard practices in the clinical, organisational, and managemental aspects of healthcare” . In fielImprove knowledge on the subjectDefine standard medico-legal assessment proceduresAgree upon a common terminologyIdentify qualitative indices, andSuggest areas requiring further investigationThe Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People focuses on the medico-legal assessment of personal damage (both as unbiased ascertainment and rating) in the elderly person. The consensus conference aims to:The consensus conference target audience includes Legal Medicine experts and Geriatricians, and insurance and law professionals in the field of personal damage, as well as the lay public. Also, the consensus conference’s recommendations can help all physicians  who take care of older people.The consensus conference was held in Bologna  on June 8, 2019. This report describes the Conference methods, presents the summary of evidence, and the statements/recommendations formulated by the Jury Panel, which also pointed out limitations and areas requiring further investigations.The consensus conference, promoted and endorsed by several Italian Scientific Societies and Institutions (see Appendix The organization of the consensus conference was a 2-year long process (May 2017–May 2019), preceded by a 5-month evaluation period during which the feasibility of the project was assessed (December 2016–April 2017). The early phases of conference organization involved the constitution of (1) the Promotion Committee, which promoted the conference, appointed the Scientific Technical Committee (STC) members, identified the field experts, and solicited questions concerning selected topics; (2) the STC, which selected the members of the Scientific Secretariat, prepared the questions, and drafted the guidelines for the literature review and the preparation of conference presentations; and (3) the Scientific Secretariat (including a literature review expert) was in charge of reviewing the scientific literature and preparing summary documents containing the information collected during the review.Consensus Conference Promoters identified 8 field experts , responsible for providing the Jury Panel with the summary of evidence and presenting it during the Conference. To constitute a multidisciplinary and multiprofessional Jury Panel, multiple stakeholders  were asked to designate a representative who would sit on the Jury Panel. The Jury Panel also included a nursing professor with an interest in geriatric research, a methodologist specialized in searching for and assessing evidence, and a representative of elderly people’s associations. The Conference organogram is presented in Appendix Evidence that traumatic injury outcomes are different between older and younger people and its relevance for the assessment of personal damage Pre-existing status reconstruction and evaluationMedico-legal examination proceduresMultidimensional assessment and scalesThe 16 consensus conference questions addressed the following 4 thematic areas:All questions focused on personal damage assessment in older people. Starting from questions, a systematic literature review for each thematic area/topic of the conference was carried out. To deal with the great variability of possible clinical conditions, the necessity of also including theoretical/doctrinal documents, the existence of a considerable amount of literature, and the difficulty of identifying documents inherent to the medico-legal practice, the systematic review followed some general criteria. First, a hierarchical search strategy favouring the selection of the most recently published systematic reviews was applied. Non-systematic reviews were included when systematic reviews were not available. Primary studies were included if no reviews were available on a specific topic, or if primary studies were more recent than systematic reviews on the same topic. Then, for questions concerning clinical practices and medico-legal technical aspects, the search focused on available guidelines, narrative review, and grey literature.In particular, for the first thematic area, only reviews discussing trauma outcomes in general or major trauma outcomes were included, excluding those that did not analyze associations between outcomes and age ≥ 65 years. For questions on pre-existing status, only reviews investigating the role of the pre-injury status on trauma outcomes in older people and theoretical/doctrinal documents were included. For questions concerning examination procedures, when reviews were not available, observational studies were included. For questions concerning the multidimensional assessment, guidelines, evidence-based synthesis, health technology documents, documents by scientific societies, and primary studies on the functional status assessment tools validated in Italian were included. Also, experts were asked to recommend additional documents, which were included only if they matched the above-mentioned criteria.https://dejure.it) database. This search led to a list of 10 relevant documents. The CISMeF (www.chu-rouen.fr/cismef), Cochrane Library (www.cochranelibrary.com), and NHS Evidence (www.evidence.nhs.uk) databases were also used for the literature search. For grey literature retrieval, webpages of scientific societies, point-of-care evidence-based medicine websites (UpToDate), as well as Google and Google Scholar search engines were used. This search produced 10 relevant documents, to which 1 document recommended by an expert was added.A first round of literature search was performed between July and August 2018, using the PubMed and EMBASE databases ; the search led to the identification of 3924 documents, most of which were of little or no relevance to the Conference questions. Therefore, at the beginning of 2019, a second round of literature search, that included documents published until the end of 2018, was performed. The new search led to the identification of 5437 articles, 29 of which were included in the review. Theoretical/doctrinal documents and court rulings were identified from the list of non-indexed journals of Legal Medicine that publish articles on the topic, and the DeJure , main measured outcomes, follow-up duration, and main findings with reference to the questions. Similarly, the Scientific Secretariat prepared summary tables for the theoretical/doctrinal material and other included documents. The experts and Jury Panel members were provided with the reviewed documents, together with the summary tables of the results of the quality assessment (see below), ahead of consensus conference. The experts used a further 20 non-reviewed documents during their presentations of summary of evidence.AGREE II  [AMSTAR 2 [Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields [The following tools were used for the evaluation of documents included in the revision: version) , for guiAMSTAR 2  for systf Fields  for primOverall, the quality of the observational studies was good, while that of systematic and non-systematic reviews was poor ; one of the guidelines was of high quality, while the other was of average quality Table . TheoretThe consensus conference was held on June 8, 2019, in Bologna . The invited audience included field experts and citizens.During the morning sessions, the experts presented a summary of the literature before the Jury Panel and the audience. For each session, the speakers were a medico-legal expert and a geriatrician giving a 40-min-long oral presentation, followed by 30 min of discussion. After the last session, the Jury Panel gathered in a secluded place to discuss the evidence presented and to draft a preliminary consensus document including the answer to each question  that was publicly presented by the Jury Panel’s Chair at the end of the Conference.The final version of the consensus document was drafted during the months following the conference, and finally approved on February 29, 2020. The agreement on the Jury Panel statements was reached through a two-round Delphi-like method . AccordiTwo reviews suggest that after traumatic injuries older people, regardless of injury type, have a lower quality of life, longer recovery times, less probability to regain independence in activities of daily living, and a reduced functional status , 30. GooSeveral reviews found a direct association between ageing and mortality after major traumas –27, 30. In conclusion, several studies show that the elderly population experience worse outcomes with regard to mortality, complications, functional status, and quality of life compared to a younger population. Different factors, including the pre-existing functional status, contribute to an increased risk of post-traumatic unfavourable outcomes and mortality in older people. However, further studies are required to better understand the role of these factors and their interactions with age.an  and the quantum (methods for damage ascertainment and rating criteria). Concerning the causation, these lines of evidence provide an empirical unbiased basis to establish that, on average, injury outcomes are more severe in a specific group of older people compared to the reference group composed of younger people . In addition, these lines of evidence provide objective support in explaining the particular severity of the outcomes in that specific older person undergoing a medico-legal assessment . In this assessment, the evidence of the harmful mechanism has a key role, and should always be assessed in the ascertainment of causation [evidence-based medicine [quantum, the criteria used in current rating methods depend upon decisions not stemming from empirical evidence, but available evidence might support these decisions in a concrete manner.According to experts’ opinions, available evidence is relevant to the evaluation of personal damage with regard to the ausation . The undmedicine . With reQuestions and Jury Panel statements/recommendations are reported in Table The available literature on this topic consists mainly of theoretical/doctrinal contributions.According to the doctrine, the reconstruction of the pre-existing status of the injured party is essential , 56, 65.In order to reconstruct the pre-existing status, several studies recommend the need to investigate, besides pre-existing diseases and therapies, the following aspects: what the person was able to do beforehand ; clinicaSome authors believe that the reconstruction of pre-existing status should only rely on objective information: ongoing treatments, General Practitioner’s opinion, laboratory and diagnostic tests, family context, and personal autonomy  . Others According to some authors, the evaluation should not only rely on standard ratings but should consider the actual negative impact of the injury on the general homeostatic balance of the person , includiQuestions and Jury Panel statements/recommendations are reported in Table A search of the literature did not provide results on the topic, partly because an unambiguous definition of clinical stability is still lacking . Some stSeveral observational studies found that the time needed for a medical examination increases with ageing and in the case of elderly patients , 47, 51.Several observational studies showed that accompanying family members and/or caregivers play a key role in the examination process of elderly patients, especially with regard to female patients ; patientFamily members and caregivers usually have an encouraging attitude during the medical examination , 42, thuAccording to the only available review , the firQuestions and Jury Panel statements/recommendations are reported in Table The multidimensional assessment (MDA)  can identify factors influencing the health and functional status of the older person even when the patient has poor self-perceived health conditions . AlthougMultidimensional assessments have long been used for the epidemiological study of disability , 77 and Clinical status (comorbidity): Cumulative Illness Rating Scale; Charlson IndexFunctional status: Basic Activities of Daily Living-BADL  and Instrumental Activities of Daily Living-IADL Cognitive status: Short Portable Mental Status Questionnaire, Mini Mental Status Examination, Clock Drawing testAffective status: Geriatric Depression Scale (15- or 5-item version)Social interactions: Oslo-3 Social Support ScaleIndependently of the specific purpose of an MDA, there is international consensus on the minimum set of domains that should be assessed , and on Some authors suggest using a smaller set of domains  .When specific alterations are found, a II level assessment should be performed .Four-Meter Gait Speed test Get-Up and Go test , 20Short Physical Performance Battery , 13, 14Grip Strength In some cases, a functional assessment with physical performance measurements, which better define the functional status, may be useful ; the mosIn literature, several frailty assessment methods are reported; the “physical frailty” and the “cumulative deficit frailty” are the most cited conceptual frameworks . The fraThe abovementioned tools have been routinely used for decades in geriatric practice. They provide a quantitative assessment of the patient status resulting in a discrete score that allows an accurate comparison between different examinations, when available.Additional tools for the evaluation of older patients that are validated in Italian are available , 41, 46,Questions and Jury Panel statements/recommendations are reported in Table unicum, without taking into account the heterogeneity of the elderly population with regard to several critical factors: global health conditions, frailty, odds of recovery, and social relationships and social capital. Even the most used assessment tools are generally not adequate for the older population. Further studies that consider these factors and investigate the relations between injury outcomes and pre-injury conditions are required. Also, additional studies are needed to validate, in the medico-legal context, the evaluation tools used to assess functioning of older people and the usefulness, for the purposes of personal damage assessment, of the frailty scales and the bio-psycho-social model issued by the World Health Organization [Most of the available studies on traumatic injury outcomes consider the older person as an nization . The latFinally, some members of the Jury Panel required an in-depth discussion of the most appropriate criteria for the monetary quantification and settlement of personal damage in older people, considering, in addition, the possible settlement by an annuity. On the contrary, other Jury Panel members expressed their disagreement on the inclusion of compensation settlement issues, or, in any case, for the mention of possible annuity compensation, in the present report.The consensus conference referred to personal damage assessment, with a focus on third-party liability. Nevertheless, for the medico-legal discipline unity, the methodological recommendations issued during the Conference may be useful to other contexts of damage assessment, or to other medico-legal evaluation fields.


Flaviviridae family, is a current issue worldwide,particularly because of the congenital and neurological syndromes associatedwith infection by this virus. As the initial clinical symptoms of all diseasescaused by this group are very similar, clinical diagnosis is difficult.Furthermore, laboratory diagnostic efforts have failed to identify specific andaccurate tests for each virus of the Flaviviridae family due tothe cross-reactivity of these viruses in serum samples. This situation hasresulted in underreporting of the diseases caused by flaviviruses. However, manycompanies developed commercial diagnostic tests after the recent ZIKV outbreak.Moreover, health regulatory agencies have approved different commercial tests toextend the monitoring of ZIKV infections. Considering that a specific andsensitive diagnostic method for estimating risk and evaluating ZIKV propagationis still needed, this review aims to provide an update of the main commerciallyapproved serological diagnostics test by the US Food and Drug Administration(FDA) and Brazilian National Health Surveillance Agency (ANVISA). Additionally,we present the technologies used for monoclonal antibody production as a toolfor the development of diagnostic tests and applications of these antibodies indetecting ZIKV infections worldwide.Zika virus (ZIKV), an emerging arthropod-borne virus (arbovirus) of the Flavivirus genus,Flaviviridae family, that belongs to the arbovirus group, whichcomprises viruses that share a cycle of transmission via arthropod vectors, mostcommonly mosquitoes, ticks and flies [Flavivirus genus are also some of the most globally relevantviruses in relation to vector-borne diseases, causing worldwide morbidity andmortality, including Dengue virus (DENV) subtypes 1, 2, 3, and 4 and Yellow Fevervirus (YFV). ZIKV transmission primarily occurs through the bite ofAedes mosquitoes infected with the virus. One of the mostalarming features of ZIKV is that it can be transmitted vertically from mother tofetus during pregnancy or at the time of birth, which differs from otherflaviviruses [Zika virus (ZIKV) is an RNA virus of the nd flies ,2. OtherMost people infected with ZIKV have no symptoms, and when present, the symptoms aremild, such as headache, skin rash, fever, joint pain, muscle ache, retro-orbitalpain and conjunctivitis . It is iZIKV was isolated for the first time in 1947 in the Ziika forest near Lake Victoriain Uganda ,9. InlaSubsequently, a small outbreak in the Northeastern Brazil was described in 2015, and in ZIKV can be grouped into two main strains: African and Asian. Phylogenetic analyzisindicate that ZIKV originated in Africa and then spread to Asia, the Pacific islandsand throughout the Americas. The introduction of ZIKV in the Americas was probablydue to a single introduction of an Asian strain between May and December 2013, morethan 12 months before the detection of ZIKV in Brazil . Some stThe structure of ZIKV is very similar to that of other flaviviruses. The structuralproteins include the envelope protein (E), capsid protein (C), membrane precursor(prM) and membrane protein (M). ZIKV protein E is the main viral protein involved incell receptor binding and entry and, therefore, is considered to be one of the majordeterminants of ZIKV pathogenesis . EachmoThe nonstructural protein 1 (NS1) protein is also considered an important antigenicmarker of ZIKV and other flaviviruses. NS1 is a glycoprotein that exists as amembrane-associated dimer after translocation to the lumen of the endoplasmicreticulum of virus-infected cells. As the genetic material and viral replicationcomplex are also located in the endoplasmic reticulum, this host cell organelle isessential for flavivirus RNA replication . In addiThe incidence of ZIKV in the Americas peaked in 2016 and decreased substantially overthe course of 2017 and 2018, with a slight increase in 2019 . ZIKV trEpidemiological data contribute to assessing the incidence of infections and theircontext and complexity, assisting in the setting of goals and selection of necessaryinterventions . NonetheOverall, inadequate diagnosis can interfere with the risk estimation, propagation,and determination of the true impact of ZIKV infection on other arboviruses and,consequently, on an efficient response from public health agencies. Accordingly,this review aims to provide an update of the main commercial serological diagnostictest approved by the US Food and Drug Administration (FDA) and Brazilian NationalHealth Surveillance Agency (ANVISA). This review also aims to present the advantagesof monoclonal antibodies as tools for diagnosis, their recent applications in thedetection of ZIKV infections and other perspectives regarding ZIKV diagnosis.The most appropriate diagnostic test for the detection of viral infections isdependent on the stage of the disease, which is divided into acute and convalescentphases. The acute phase is characterized by the early stages of infection whenviruses replicate in infected cells and the host develops viremia. After the onsetof clinical manifestations, there is an initial response to the infection by theproduction of IgM antibodies against the virus; this immune response is alsoconsidered part of the acute phase. The convalescent phase occurs in the late stagesof infection, and a more specific and persistent IgG antibody response against thevirus develops ,28. The Although IgM levels vary, they are generally positive from the fourth day after theonset of symptoms until up to 12 weeks, and the levels may persist for even longer.The IgG response develops shortly after the IgM response, and it has been shown thatIgG levels remain high for at least 2 years after infection . When paZika virus shares approximately 55.6% amino acid sequence identity with DENV, 46.0%with YFV, 56.1% with Japanese Encephalitis virus (JEV) and 57.0% with West Nilevirus (WNV) . This laFlaviviridaefamily. In addition, similar clinical manifestations, and even the presence of manyasymptomatic patients, make it even more difficult to accurately diagnose ZIKV.Although ZIKV and DENV show approximately 41% to 46% differences in envelope proteinamino acid sequence , the simPublic health surveillance monitors infectious diseases in the population. Thus,diagnostic tests has a strong role in providing accurate results that allow pathogenoccurrence identification so that measures can be executed to control and preventthem from reappearing. Particularly, serological test is a way to better understandthe expansion of the infection through the population, allowing a serosurveillanceon a herd level. Tests should be easy to use and provide a rapid result to have apositive impact on care . The dynGiven the necessity of establishing strategies for the control and dispersion ofZIKV, the Centre for Disease Control and Prevention (CDC) has establishedrecommended guidelines for ZIKV diagnosis. The diagnostic tools consist of reversetranscriptase reaction assays followed by real-time polymerase chain reaction(RT-qPCR), ZIKV IgM antibody capture immunoenzyme assays (MAC-ELISAs) and platereduction neutralization tests (PRNTs) ,49.The RT-PCR assay is only applicable during the acute phase of infection, when viralRNA is still detectable in body fluids, and the persistence of viral RNA variesaccording to the biological material examined. The sensitivity of the RT-PCR assayis very important to avoid false negative results . Up to tMAC-ELISA is a serologic test used for qualitative detection of IgM antibodies in theserum or cerebrospinal fluid. Nonetheless, the results can be difficult to interpretdue to the possible non-specific reactivity of antibodies. Consequently, testsdetermined to be positive, equivocal or inconclusive should be confirmed by PRNT, aserological test based on the ability of specific antibodies present in the serum ofpatients to neutralize viruses by preventing plaque formation in a cell monolayer.PRNT is currently considered the "gold standard" for differential flavivirusserodiagnosis due to its high specificity. However, this assay has a high cost,requires highly specialized laboratories with adequate equipment to maintain cellculture, and special regulations for working with the active virus; it is alsodifficult to perform, and 5 to 10 days are required to obtain results ,52.Among the available serological commercial tests, the tests developed by Euroimmun AG(Germany) and InBios (USA) are noteworthy. The Euroimmun assay was the firstcommercially available serological test for ZIKV detection, and it has beenextensively evaluated in the literature -56. The The InBios assay, also known as the ZIKV Detect 2.0 The IgM Capture ELISA kit, is anassay based on capture ELISA for qualitative detection of IgM antibodies againstZIKV using the viral envelope protein as an antigen. This assay was the firstcommercial serological test to receive FDA marketing authorization in the USA,granted in May 2019 . GrangerThe ADVIA Centaur Zika test was the second Zika diagnostic test that the FDA hasallowed to be marketed in the USA for detecting ZIKV IgM antibodies. The third andlast authorized test to be marketed was LIAISON XL Zika Capture IgM Assay II.Previously, these tests had only been authorized for emergency use under the FDA’sEmergency Use Authorization (EUA) authority. A unique serological test that is stillunder the FDA’s EUA is DPP Zika IgM Assay System from Chembio Diagnostic Systems. In BrazMonoclonal antibodies (MAbs) are products of individual B-cell clones. They havebroad applicability in therapies and drug targeting, and have a profound impact onthe immunodiagnostics of infections. MAbs interact with a single antigenicdeterminant, allowing for specific reactivity and accurate identification of theorganism of interest. This feature confers a great advantage to MAbs versuspolyclonal antibodies, which have different epitope specificities and affinities,64. MoreRegarding MAb production, advances in molecular biology and genetic engineering overthe years have led to different methods of producing and modifying these antibodies,as opposed to the traditional technique of hybridoma production. Some of these MAbsare produced through cell-free libraries, combinatorial synthetic libraries,affinity maturation, and production in transgenic animals and plants, as well asseveral other technologies, allowing for great robustness and interaction efficiencywith a specific target . The development of MAbs has been mainly focused on the development of therapies forcancer, autoimmune diseases, and inflammatory conditions. However, the applicationof MAbs for infectious diseases still has limitations . One of Despite the worldwide effort to facilitate flavivirus diagnostics, no fully validatedserological test shows good sensitivity and specificity without the interference offalse positive or negative results and is also robust and rapid. Accordingly, thesearch for MAbs that specifically recognize each virus of this family is extremelyrelevant and has been addressed by many researchers. Among the tests referred in The MAb developed by Balmaseda et al.  isderivin vivo immunization throughthe selection of combinatorial libraries of human antibodies displayed onfilamentous phage surfaces against a target antigen, allowing for rapid andeconomical MAbs generation [In addition to the methodologies for MAb obtention, phage display has emerged as oneof the main alternatives for the generation of human recombinant MAbs. Phage displayenables to select human MAbs without neration . The phaneration . Therefoneration  identifiPhage display is also considered an important tool for mapping the epitopes ofmonoclonal antibodies. In this regard, Ravichandran et al.  exploredThe abovementioned techniques include different antibody formats, such as wholeantibodies, fragment antigen binding (Fab) or single-chain variable fragments(scFv). Each of these formats has advantages and disadvantages based on the desiredapplication. For diagnostic methods, such as immunohistochemistry, the lack of Fcensures the reduction of non-specific binding in addition to a good tissuedistribution . Given tOther innovative methodologies have been applied for the development of serologicaldiagnostics with the potential to outperform conventional methodologies in terms ofspeed and sensitivity. The reporter virus neutralization test (RVNT) represents avery promising alternative to the PRNT. RVNT uses luciferase-labelled ZIKV and DENV,and neutralizing antibodies can be quantified within 24 h instead of the typical7-day period required for plaques to be visible with the PRNT method . Wang etIn addition, Kareinen et al.  developeZIKV infections constitute a major public health problem in Brazil and around theworld, mainly due to the magnitude of its complications, and there are still majorchallenges in our understanding of ZIKV infection mechanisms. Among them, the lackof complete understanding regarding the risk of complications according to differentstrains of the ZIKV, possible environmental, genetic or other cofactors that mayincrease the risk of complications and the lack of knowledge of the role ofasymptomatic infections and other modes of transmission play in the general dynamicsof circulation. This scenario makes it difficult to fully characterize the damagethat ZIKV infections can cause. Despite the great advances in serological assays in the last years, the incompleteknowledge about the pre-existing immunity for other flavivirus of the population inendemic countries, may impose difficulties in diagnosis . Some imAedes aegytpi, updatingsurveillance protocols and responding to ZIKV infections and its resultingcomplications. Moreover, for the first time, the Ministry of Health has organized anetwork of integration between managers, researchers and civil society to cope withthe disease: Renezika. The creation of this network has demonstrated the ability ofthe Brazilian scientific community to respond to major international health problemsand to propose relevant activities such that future emergencies can be preventedwith rapid and effective action.Since the beginning of the ZIKV epidemic, many efforts from health care organizationsaround the world have been applied to the development of plans for ZIKV control. In2016, the WHO implemented the Zika Strategic Response Plan, which involves four mainobjectives to support governments in preventing and managing the complicationscaused by this virus and mitigating the socioeconomic consequences, includingdetection, prevention, care and support, and research . In BrazDespite the limitations in flavivirus serological assays due to highcross-reactivity, many advancements have been made in ZIKV diagnosis, even with thedecrease in the number of infected patients. Investment in the development ofinnovative methodologies to obtain immunobiological products quickly and effectivelyrepresents a crucial factor for the advancement of public health systems worldwide.Contemporary molecular biology and molecular immunology technologies, such asantibody engineering and phage display, allow for the possibility of producing aspecific human antibody with relatively high affinity to a target molecule in vitrowithout in vivo immunization. The application of these biomolecules in innovativetechnologies, such as biosensor chips, with potential application in POC diagnosismay enable increased epidemiological control efficiency. These tests may ensureaccurate evaluation of ZIKV infection rates, contributing to the development ofefficient public policies to combat this infection.


The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies. More than 200 years ago, James Parkinson described some of the clinical symptoms of the disease that, later, was named as Parkinson’s disease (PD) in “Essay on the Shaking Palsy” . ClinicaLBs inclusions contain high levels of aSyn phosphorylated at serine 129 (pS129). In addition, it is estimated that 10 to 30% aSyn in LBs is truncated in the N- or C-terminal regions . In the Detailed observations of aggregated aSyn in post-mortem brain tissue from patients at different clinical stages of PD form the basis for the hypothesis that Lewy pathology can progress, as disease progresses, through interconnected brain regions ,13,14. TIn this review, we focus on selected studies supporting the prion-like behavior of aSyn and on the molecular mechanisms involved in the spreading of pathology during disease progression. Further clarification of these concepts will assist in the development of new therapeutic strategies aimed at preventing disease progression in synucleinopathies. SNCA gene and is composed of three distinct domains, which are defined on their amino acid composition: The N-terminal lipid-binding domain, an amyloid-binding central region (NAC), and a C-terminal disordered region . T. T186]. Another mechanism involved in the release of aSyn assemblies is through their association with exosomes . ExosomeTunneling nanotubes (TNTs) represent a novel type of intercellular communication machinery . These mPassive diffusion , conventThe reasons for aSyn secretion still remain an open question in the context of the prion-like spreading hypothesis. Technical questions relate to the low levels of aSyn and extracellular vesicles that are secreted by cultured cells to the media, and the detection of different types of aSyn species that might be present in the media. The identification of the molecular mechanisms and proteins responsible for the recognition and secretion of aSyn assemblies may, ultimately, support the development of novel approaches to prevent disease progression, but such research is only in its infancy.Emerging evidence supports the concept that cell-to-cell transmission and disease-selective strains underlie disease progression and heterogeneity in synucleinopathies. aSyn propagation is coincident with the progression of PD pathology throughout the brain. Our current understanding of this phenomenon is that aSyn pathology spreading may not be the main driving factor in PD. However, it is not yet well understood how aggregated aSyn can transfer from cell-to-cell to induce synaptotoxicity and neurodegeneration. Additionally, it should be determined if endogenous aSyn pathology spreads between cells. Additional studies of the aggregation process are necessary in order to understand the precise mechanism of aSyn propagation in the brain.Although several studies use in vivo models to address the prion-like properties of exogenous aSyn strains, self-propagation of the endogenous protein remains to be shown. Furthermore, the different mechanisms described to be involved in aSyn cell-to-cell spreading were observed using in vitro models, but whether these mechanisms occur in the brain of PD patients is still unknown. Overall, several studies suggest that aSyn seeds can be transferred through various cell types, inducing the aggregation of the endogenous protein. Regardless, the different factors promoting progressive cell-to-cell transfer of aSyn need to be investigated. In the future, it will be important to understand the exact contribution of different aSyn species to the prion-like spreading of PD pathology, by elucidating their transfer and seeding properties, as well as their toxic effects on recipient cells. Clarification of these questions might support the development of novel types of interventions for PD.Moreover, it remains unclear whether and how familial PD-associated aSyn mutants propagate throughout the brain, as they present distinct aggregation kinetics and different physicochemical properties. Since most studies do not use patient-derived aSyn assemblies, it is uncertain the extent to which experimental models recapitulate the cell-to-cell transmission in PD.C oligomers are being developed after the observation that only oligomers, not monomers, are infectious. However, considering the limited availability of human brain material, it is indispensable to develop new methodologies that enable the production of sufficient amounts of disease-specific aggregates for research.The spreading of aSyn pathology  in the nervous system is defined by several factors. These factors should differently influence the spread of pathology among strains, thereby causing distinct disease entities. Therefore, it may be necessary to use disease-specific aggregates in experiments in order to identify therapeutic targets that may be unique among these diseases. In prion disorders, approaches targeting PrPThe development of new therapeutic strategies has been slow and difficult due to the plethora of possible targets that may be tackled in synucleinopathies. This includes aSyn production, aggregation, toxicity, degradation, and spreading. The use of receptor blocking strategies to inhibit aSyn internalization, or of strain-specific antibodies to decrease the levels of extracellular aSyn, may delay the spreading of pathology, but this also needs to be investigated further.In total, a deeper understanding of the molecular mechanisms underlying aSyn aggregation and intercellular propagation is important for understanding the pathogenesis of PD and related synucleinopathies, to identify new disease targets, and to develop novel therapeutic strategies to halt disease progression.


Senescent cells are unable to divide and, thus, they possess a barrier for transmission of mutations for the next generations of cells. However, senescent cells remain alive and reportedly accumulate in tissues with age and, noteworthy, exhibit increased secretion of inflammatory cytokines, chemokines and growth factors . SASP appears to be beneficial early in life by contributing to embryonic development, wound healing and suppression of malignancy, but deleterious for aging organisms promoting sterile inflammation and leading to age-related disorders, including cancer. This is consistent with the theory of antagonistic pleiotropy of aging, which implies the contribution of pleiotropic genes that have evolved to maintain fitness in youth when selection is strong, but they become harmful when selection weakens with age and reproductive period is over (Reviewed in ).Spalax and African underground rodents  spend their lives in deep underground nests, in an environment with low oxygen and high carbon dioxide contents [However, a huge variety of species, living in various ecosystems and forced to adapt to environmental stress in order to survive and maintain reproduction, contributed to the selection of traits that are more likely to be an exception than the rule in the wild. Among mammals, the underground blind mole rat of Mediterranean region contents ,3. For aSpalax, the Mediterranean blind mole rat. Spalax is one of the “champions” of longevity, which lives in captivity for ~ 17-20 years and does not exhibit an obvious aging phenotype, while maintaining physical and digging activity without signs of sarcopenia, frailty, hair loss and other signs of aging. Our recent report demonstrated a unique mechanism of cellular senescence in Spalax fibroblasts, which, like senescent human and mouse fibroblasts, showed proliferative arrest, SA-β-Gal-positive staining and increased expression of p21 and p53; however, signs of cellular senescence in Spalax were not accompanied by the secretion of the canonical inflammatory factors  both after replicative senescence and etoposide-induced senescence [Spalax cultured cells: down-regulation of mRNA expression of pro‐inflammatory SASP representatives was also found in aging Spalax tissues. These results strongly support the notion that suppressed inflammatory response is a general Spalax evolutionary strategy that does not follow the theory of antagonistic pleiotropy of aging.We focus on studying the molecular mechanisms of hypoxia tolerance, cancer resistance, and aging in nescence . NoteworSpalax during senescence is transient . Since A repair ,6) and d of SASP , and inh of SASP . In our stimulus .Spalax seems to be very important. These strategies were developed and fine-tuned by evolutionary forces during millions of years facilitating longevity, healthy aging and reduced cancer risk (Thus, the uncoupling of inflammatory phenotype and cellular senescence provides an opportunity for independent study of these phenomena and creates a unique approach to the development of new inflammation inhibitors that can potentially be used to suppress inflammaging in the elderly and to inhibit of the cytokine storm in patients with the emerging COVID-19. In this context, the elucidation of the molecular mechanisms restraining the inflammatory response in cer risk .


The spread of the novel coronavirus (SARS-CoV-2) has resulted in the mostdevastating global public health crisis in over a century. At present, over 7million people from around the world have contracted the Coronavirus Disease2019 (COVID-19), leading to more than 400,000 deaths globally. The global healthcrisis unleashed by the COVID-19 pandemic has been compounded by political,economic, and social crises that have exacerbated existing inequalities anddisproportionately affected the most vulnerable segments of society. The globalpandemic has had profoundly geographical consequences, and as the current crisiscontinues to unfold, there is a pressing need for geographers and other scholarsto critically examine its fallout. This introductory article provides anoverview of the current special issue on the geographies of the COVID-19pandemic, which includes 42 commentaries written by contributors from across theglobe. Collectively, the contributions in this special issue highlight thediverse theoretical perspectives, methodological approaches, and thematic focithat geographical scholarship can offer to better understand the unevengeographies of the Coronavirus/COVID-19. The world is again in crisis. As the coronavirus (SARS-CoV-2) and its accompanyingdisease (COVID-19) have spread globally since December 2019, hundreds of thousandshave died, millions more have been infected with the virus, and entire economieshave come to a screeching halt amid government-imposed lockdowns. The COVID-19pandemic is, first and foremost, a global public health crisis, yet its impactsextend far beyond the realm of epidemiology alone. We are also witnessing apolitical, economic, and social crisis the likes of which the world has not seensince the 1918 influenza pandemic and the Great Depression .Border closures have restricted international travel ; quarantAt the same time, there has been a tremendous outpouring of mutual aid and socialsolidarity to assist those in immediate need . Health Although the precise origins of the SARS-CoV-2 virus are currently underinvestigation . In the Within a relatively short period of time, the COVID-19 pandemic has become a trulyglobal event with consequences that span every facet of daily life in ways that areprofoundly geographical. The spread of the disease demanded a spatialized responsethat recognized the vectors and clustering of diffusion within localized settings aswell as across space and borders. Spatial modeling has been an essential part of theepidemiological toolkit guiding public health and government policy responses, andmaps and charts that compare places have become key media for enhancing publicunderstanding of the pandemic. Measures put in place to contain, delay, and mitigatethe diffusion of the disease have radically disrupted society and economy,transforming socio-spatial relations and socionatures, delimiting mobility andaccess, reconfiguring the production of space and territory, and alteringperceptions of place. In turn, these changes have profoundly transformed thefamilial spaces of home, modes of living, and the geographies of everyday lives;relations to public space and nature; the operations of work and the space economy;the geopolitical landscape; and the global dynamics of capital accumulation.The measures adopted in response to the COVID-19 pandemic and their effects have beenfar from universal—varying between and within countries depending on politicalregime and capacity to respond—which has led to differences in approaches taken aswell as differential infection rates and deaths . GovernmGeography as a discipline and practice has also been transformed. University campuseshave closed, academics are working from home, teaching has moved online, in-situfieldwork has halted or shifted to the use of virtual methods where possible, andseminars, workshops, and conferences have been canceled or converted into virtualevents. There has been enormous pressure to deliver existing classes andcommitments, and support students and colleagues, in new ways, while also copingwith changing conditions (such as working from home while providing childcare andhome schooling). The pandemic and its consequent economic impacts are highlightingand exacerbating underlying crises and chronic problems in higher education in manycountries across the globe. Even those universities with large endowments have beenbreathtakingly swift to cut academic staffing costs. Not surprisingly, the presentcrisis is affecting university employees unequally—with precarious faculty and staffin many universities experiencing the most hardship as their pay and work conditionsdeteriorate significantly and some lose their jobs altogether. A whole generation ofstudents and scholars is facing limited future career prospects. Moreover, many ofour research partners are also struggling, including collaborators in the artssector, non-governmental organizations, and community services.Dialogues in Human Geographydecided to temporarily pause the refereeing of new papers for 6 weeks and grantedautomatic extensions for those who had already agreed to peer review manuscriptscurrently within the system. At the same time, there has been a desire by many torespond intellectually and constructively to the current global crisis. This hasdemanded a quick response to an unfolding set of interrelated events, in contrast tothe often slower and more reflexive scholarship that is more typical in the academy.Indeed, geographers and other scholars are already producing intellectual andempirical analyses of COVID-19. Some are actively working with government,policy-makers, and communities, undertaking epidemiological modeling, helping withdata infrastructures, advising on interventions and recovery strategies, andvolunteering to help the vulnerable. Many geographers are also activists and keymembers of solidarity networks and grassroots groups that have been formulated toaddress already existing inequalities that COVID-19 has exacerbated as well as newinequalities caused by the pandemic.To avoid placing additional pressure on our academic peers during the initial stageof the pandemic, the editorial team at Some scholars have expressed concerns that fast, not-fully-considered work mayconstitute academic disaster voyeurism; weak, underdeveloped scholarship; neoliberalopportunism through rapid publication; or reproduces and deepens gendered, classed,and other inequalities within the academy given the differential ability tocontribute. We share those concerns and believe they deserve consideration . At the same time, giventhe scope, extent, and impact of the current crisis, there is undoubtedly a need torespond in the here-and-now, drawing on the deep well of theoretical and appliedexpertise across the full breadth of the discipline. For geographers not to respond,or to wait until the crisis has passed before examining its processes and impacts,would be to forgo practicing public and engaged geography of the here-and-now. Itwould deny our ability, and arguably abdicate our responsibility, if we did not useour skills in geographical scholarship to help bear witness and make sense of whatis happening and to help cultivate new critical publics. Moreover, it would leaveinterventions in the contemporary world to the preserve of politicians, journalists,civil servants, and academics in other fields. It would also consign geography toonly being historical rather than analyzing or being applied in the present, which,in an increasingly disrupted world, is an untenable stance . So howeveruncomfortable or disastrous our present is, or whether we are all able to contributeequally, we believe it is important for geographers who feel they have something tooffer to respond as best they can within their own circumstances.Dialogues in HumanGeography—together with recent editorials and articles in othergeography journals . The interruption andslow-down in economic activity has, Creighton Connolly, Harris Ali, and Roger Keil highlight urban life andurbanization as key factors giving rise to the pandemic through shiftingurban-ecological dynamics, dense networks, interdependent infrastructure, andinter-urban connectivity, while also being key sites for mitigating measures.Drawing on examples from Sub-Saharan Africa, Brandon Finn and LindsayKobayashi argue that understanding how public health interventionsproduce durable autocratic urban governance and reproduce structural inequalitiesbetween social classes requires a historical understanding of similar deployments inpast pandemics. Taking a different tack, Michele Acuto contends thatgeographers can make better sense of the urban realm in the crisis by conjoiningplanetary urbanism with world political systems and taking a fuller account of thedynamics of global urban governance. Focusing specifically on housing, and usingAustralia as an example, Sophia Maalsen, Dallas Rogers, and Leo PattersonRoss note that the pandemic has rendered visible long-term, systemicissues and created a new suite of problems that need redress. UlisesMoreno-Tabarez makes clear that the pandemic is not simply an urbanphenomena, and again reiterates the need for historical contextualization, unpackinghow the legacies of slavery and colonialism continue to haunt Afro-Indigenousruralities in the Costa Chica region of Guerrero, Mexico, during the crisis.Ayona Datta calls attention to the ways in which smart technologieshave been repurposed in India to track and manage the pandemic. She notes that 45out of 100 smart cities in India have renamed their Integrated Command and ControlCentres (ICCC) as ‘COVID-19 war rooms’ and a number of contact tracing andquarantine apps have been deployed, including ones that use selfies and facialrecognition to monitor movement. Likewise, Bei Chen, Simon Marvin, and AidanWhile document the accelerated development of urban robotics, autonomoussystems, and artificial intelligence for urban epidemic control in China, and warnof the potential to extend state surveillance and control. For digital platformcompanies, the repurposing and extension of their technologies and embedding intothe monitoring and lifting of restrictions is, as Jonathan Cinnamoncontends through his analysis of Google Maps data, a key means to strengthen theireconomic and political position, offsetting declining advertising revenues anddefraying regulation. Similar themes are explored by Ryan Burns whoexamines the transition to online education, arguing that rather than challengingthe neoliberalization of education, such a move risks further deepening its reformsand embedding a pernicious techno-utopian imaginary and solutionism within thesector.As the COVID-19 crisis has unfolded, there has been a turn to digital technologies tohelp implement response measures and mitigate the effects of these measures.ChrisBrunsdon, a member of the COVID-19 modeling team providing analysis tothe National Public Health Emergency Team that is guiding the Irish governmentresponse to the pandemic crisis, discusses technical issues with epidemiologicalmodeling, while recognizing the need for a perspective informed by critical datastudies. The data informing these models has been presented to the public usinginteractive dashboards. Philip James, Ronnie Das, Agata Jalosinska, and LukeSmith describe their work repurposing the Urban Observatory forNewcastle, UK, to provide real-time insights into the impacts of lockdown policy onurban governance. The use of dashboards is critiqued by Jonathan Evertswho argues that they present constrained and tailored views of the unfoldingpandemic and obscure localized variances and socio-spatial inequalities, potentiallywidening them. Similarly, Peter Mooney and Levente Juhász question thedesign and efficacy of web-based maps and raise concerns about the extent to whichthey have been co-opted into the ‘infodemic’ of misleading and politicized dataanalytics about the pandemic. Jeremy Brice uses the common ‘flatten thecurve’ chart and the popular Financial Times graph comparing deathrates across countries to argue that data representations actively produce possiblepandemic futures through biopolitical and geopolitical registers and render otherdata as counterfactual. Drawing on an analysis of Twitter data concerning theunsubstantiated rumor that COVID-19 is a Chinese bioweapon that escaped from a labin Wuhan, Monica Stephens explores how misinformation and conspiracytheories are established, circulate, and grow, forming part of the infodemic enabledby social media and 24/7 news cycles. Relatedly, Kaya Barry exploreshow representations and diagrammatic instructions of COVID-19 are informing andshaping how individuals enact specific spatial, mobile, and bodily practices and canaccentuate public feelings of uncertainty, emergency, or threat.Data-driven technologies and the use of charts, dashboards, maps, and models havebecome a key means by which spatialized knowledge about COVID-19 is understood andcirculated within expert groups and the wider public as well as informingdecision-making about counter-measures and when they should be applied. Gwendolyn Blue and Melanie Rock explain thatgenomic science has become the dominant approach to understanding zoonotic disease(i.e. infectious pathogens capable of crossing the species barrier) and itstransmission. They contend that this de-emphasizes other knowledges and localcontext, and argue for the inclusion of more-than-human accounts within discussionsof health and disease. One trope of the crisis is that the pause in economicactivity and human mobility has led to a resurgence of nature. Similarly advocatingfor a more-than-human approach, Adam Searle and Jonathon Turnbull arguethat this trope arises from biocultural decontextualization that assumes nature hasan inherent capacity to heal itself. This downplays the need for urgentenvironmental action obscuring that resurgence is a multispecies endeavor thatrequires cultivation, nurture, and care to foster conviviality.The final two commentaries in this special issue concern the relationship between thepandemic and nature. The commentaries in this special issue present a sample of the wide spectrum ofapproaches and perspectives that geographical scholarship is already bringing tobear on understanding the nature and workings of the unfolding COVID-19 pandemiccrisis. They highlight that the COVID-19 pandemic is thoroughly spatial in nature aswell as the value of geographical theory and praxis in providing critical (what ishappening) and normative (what should happen) thinking as well as applied outcomes(making things happen). While much attention is being focused on scientific andtechnological responses to COVID-19, it is clear that the myriad of political,economic, and social crises that have accompanied the public health crisis of thepandemic require critical and reflexive analysis and theoretical insight. Suchscholarship and praxis can expose the socio-spatial processes at play and theirconsequences, and can translate these to shape public discourse and public policywhich have the potential to transform everyday lives.The COVID-19 pandemic has created a global crisis in which the ‘normal’ conditionsand structures of societies have been upended. Much of the rhetoric in 'telling thestory of the pandemic'  is about


After a stroke, physical activity can be key in enhancing the rehabilitation of patients and preventing a secondary stroke. In this commentary, we critically appraise a systematic review which investigated how different types of physical fitness training impact on the mental and physical conditions of stroke survivors. Cardiorespiratory, resistance and mixed training  can improve key outcomes such as the balance and mobility of stroke survivors, but the most suitable type of training depends on the individual needs and aims of the rehabilitation process. More research is needed to understand how the effects of the different types of training vary by considering the time between stroke and intervention onset, stroke severity, and the dose of intervention. Physical activity is recognised as being crucial to prevent the development of several health conditions as well as generally being good for mental and physical health . PhysicaThis commentary aims to critically appraise the methods used within the review by In the review by In the study selection, the authors included randomised controlled trials (RCTs) which assessed the effects of cardiorespiratory, resistance, or mixed training on adult stroke survivors. Studies were excluded if they focused on fitness training based on virtual reality approaches or combined with assistive technologies and the comparison between upper and lower body training without considering a non-exercise control group.Two reviewers independently screened the titles and abstracts of all the retrieved studies, and the full text of those potentially eligible for inclusion. One reviewer performed the data extraction of the included studies with another reviewer validating data entry. Two reviewers independently performed a risk of bias assessment of the included studies using the Cochrane Risk of Bias tool .2 statistic as part of forest plots; where I2 was higher than 50%  further exploration of the causes of variation, also through subgroup and sensitivity analyses, was attempted. Reporting bias was investigated using a funnel plot when meta-analyses were based on at least 10 studies. The quality of the evidence underpinning the different outcomes was assessed using GRADE.Random effects meta-analyses were carried out when studies were considered sufficiently similar, reporting appropriate measures of effects and 95% CIs at the end of intervention (i.e. training period) and at the end of follow-up. Heterogeneity across the studies was reported using the IIn the review by moderate clinical improvements to disability levels . Furthermore, there was a clinically and statistically significant improvement on physical fitness in terms of VO2 peak (moderate-certainty evidence) and on mobility in terms of gait speed and gait endurance (both supported by high-certainty evidence). Physical function measured by the Berg Balance Scale was also improved but the clinical effect was small (moderate-certainty evidence), while clinically and statistically significant effects were found for the 3-metre Timed Up and Go measure (moderate-certainty evidence). No evidence of difference was found for the effects on death by cardiorespiratory training (low-certainty evidence), while not enough data was available to analyse the effects on death or dependence. However, the rates of mortality were very low within both groups.For the effects of the different types of training at the end of the intervention the authors reported the following results. For cardiorespiratory training, the meta-analysis showed Resistance training had positive effects on three physical fitness outcomes specifically related to muscle strength, as measured by a composite measure , paretic knee flexion , and paretic knee extension . Clinically and statistically significant results were also found for resistance training on mobility outcomes related to gait speed (moderate-certainty evidence) and gait endurance (moderate-certainty evidence). On the contrary, the authors did not find statistically significant effects for resistance training on physical function in terms of the 3-metre Timed Up and Go measure (low-certainty evidence), while statistically significant but clinically modest effects were identified for the Berg Balance Scale (low-certainty evidence). The results on the effects on death by resistance training did not identify evidence of difference (low-certainty evidence), while the effects on death or dependence were not explored due to lack of data.2 peak and muscle strength . The results for mobility captured clinically and significantly effects for mixed training on gait speed (moderate-certainty evidence), and on gait endurance (low-certainty evidence). Statistically significant but clinically small effects were found for physical function in terms of the Berg Balance Scale (low-certainty evidence), while for the 3-metre Timed Up and Go measure the results were not statistically significant. Similarly to the other types of training, the authors found no evidence of difference by mixed training on death (low-certainty evidence), and the lack of data did not allow an analysis of the effects on death or dependence.Mixed training showed small positive effects on disability levels (low-certainty evidence). Small positive effects were also found for physical fitness but only in terms of muscle strength, as measured by knee extension (low-certainty evidence). Other effects on physical fitness were not statistically significant, as measured by VOSub-group analysis was conducted to directly compare the different types of training on disability outcomes at the end of intervention, with cardiorespiratory training showing moderate effects  and mixed training showing small effects (with low heterogeneity), while no evidence of difference was found for respiratory training.Due to lack of data, inconclusive effects were found on other outcomes such as cardiometabolic risk factors, quality of life, mood, and cognitive function. No statistically significant results were found for the other timepoint considered besides the end of the intervention .We used the AMSTAR2 to critically appraise the quality of the review . While wDue to the heterogeneity of outcomes assessed in the included studies in the review, it is difficult to indicate which intervention type is better or worse for a specific outcome. Where common outcomes were assessed, such as disability and mobility, on visual inspection there was not a clear statistically significant difference between cardiovascular, resistance, and mixed training. Therefore, for these outcomes all three methods may provide similar levels of improvement. However, for specific outcomes relating to the purpose of the training, such as cardiovascular exercise and VO2 peak, there was a clear clinically significant improvement. Similarly, with resistance training there was a notable clinically significant improvement in strength. However, these outcomes were not assessed in the alternative exercise type and subsequently cannot be compared. Therefore, when there is a specific focus on improving physical fitness or strength the corresponding exercise type should be selected.All three types of training  produced an improvement in balance, with resistance training demonstrating the greatest, but not statistically significant, improvement. Therefore, when deciding on methods for improving balance other factors may be considered such as the environment, patient preference, clinician experience, equipment, and functional purpose . RegardiA wide range of variability in study population and intervention type was reported across studies. Further research would benefit from exploring the impact of cardiorespiratory fitness, resistance, and mixed training dependent on time between stroke and intervention onset, stroke severity, and effects of the dose of intervention. Studies with longer follow-up data are also recommended in order to determine whether and how the benefits of fitness training persist over time.Moreover, we suggest the involvement of patient groups to co-design appropriate and acceptable attention control in future studies. Along similar lines, a better understanding of the effects on patients can be enhanced by using Patient-Reported Experience (PREMs) and Outcome Measures (PROMs).Lastly, this review did not assess the evidence around the cost-effectiveness of the different interventions. As such, the economic evidence base will need to be scrutinised in future reviews to determine, and possibly rank, the interventions in terms of overall costs, resource use, and cost-effectiveness.1)What do you think about the choice of primary and secondary outcomes that the authors decided to investigate?2)In your opinion, what is the main take-away message from this review and why?3)IIf you were asked to update this review, would you apply any changes to its design  and/or its reporting? Why?This research was partly-funded by the National Institute for Health and Care Research Applied Research Collaboration North West Coast (NIHR ARC NWC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.


Drug eluting ureteral stent is an effective means for local drug delivery to the urinary tract. It can potentially solve a variety of upper urinary tract problems, such as stent-related urinary tract infections and discomfort, ureteral stricture, and neoplastic diseases. However, the release of drug elutes on the surface of biostable stents is unsustainable and uncontrollable. With the development of biomaterial science, the emergence of biodegradable ureteral stents (BUSs) provides a new approach for local drug delivery in the urinary tract. The drugs can be continuously released in a controlled manner from a drug-eluting BUS, when the stent degrades. Especially for the delivery of anti-tumor drugs, the stents can obviously improve the therapeutic effectiveness of the drugs by prolonging the contact duration of the drug and tumor cells. In addition, a secondary stent removal procedure can be avoided. The purpose of this review article is to provide an overview of anti-tumor drug-eluting BUSs and discuss the biomaterials and drug delivery systems of BUS that are currently being developed to deliver anti-tumor drugs for upper tract urothelial carcinoma. For patients with low-risk upper tract urothelial carcinoma (UTUC), kidney-sparing surgery is recommended as the preferred treatment by the European Association of Urology (EAU) guidelines . After kWith the rapid development of nanodrug loading technology, many localized cancers can be treated by direct deposition of nanoparticle-based drugs in the target area . Some loThe degradable drug-loaded ureteral stents have been getting more and more attention because of their advantages of no need for cystoscopy, no “forgotten stent” problem, and low incidence of infection and hematuria . The bioin vivo results indicated that the alginate-based stent could effectively facilitate the urinary drainage and exhibited excellent biocompatibility. It is noted that there was a 3.4% insufficient degradation of the stent, which needed a second intervention to remove the fragments. in vivo degraded experiment indicated that this stent exhibited the fastest biodegradation rate than the control group. Moreover, the stent could effectively reduce the bacterial adhesion and showed excellent biocompatibility properties , and gemcitabine, were loaded into the stent. The in vitro anti-tumor experiment indicated that these drug-eluted stents could efficiently suppress the growth of urothelial cancer cell (T24 cells). In addition, all these drug-eluted stents showed minimal toxicity toward the non-cancer cells (HUVEC cells). These results indicated that the impregnated BUSs could be used as proper anti-tumor drug carriers and potentially be an effective intravesical drug delivery system for UTUC therapy. In their next study, the researchers used different membranes to research the permeability of the loaded anti-tumor agents, including single paclitaxel and doxorubicin, and their release from the prepared BUS. The results demonstrated that the release performances of paclitaxel and doxorubicin from the BUS could be kept for a long time in the ex vivo ureter and only a small amount of the drugs can across the different permeable membranes with a permeability of 3% for paclitaxel and 11% for doxorubicin. All these results demonstrated that most drugs in these BUS could remain in the ex vivo ureter tissue, which were effective to suppress the growth of tumor cells and not affect the non-tumor cells -loaded PCL/PLGA nanofiber ureteral stent with adjustable rates of drug release and degradation for local chemotherapy of UTUC. First, the EPI-loaded PCL/PLGA fibers were developed by general electrospinning technique, and the drug was dispersed in the fibers, both the inside and the surface. The nanofibers showed sustained drug release and controlled degradation, and satisfactory anti-tumor effects both toxicity .in vitro and in vivo, with no apparent systemic toxicity (However, early drug release of the fibers was relatively fast, which may affect anti-tumor effects. Emulsion-electrospinning technology was used to generated a core–sheath structured EPI-loaded PCL/PLGA nanofiber capsules. The core–sheath structures of these fibers were confirmed by a confocal laser scanning microscope, and the EPI was loaded in the inner layer of the fiber. The EPI release was more sustained than that of fibers generated by general electrospinning. The nanofiber capsules effectively inhibited the growth of tumor cells both toxicity . Althougtoxicity .Nanoparticle-based drug delivery systems have been widely used as an effective means for local drug-controlled release systems, and have been widely used in various fields of biomedicine . Variousin situ delivery of drugs. First, the dilution and washing of urine reduce the bioavailability of drugs in the urinary tract. In addition, the limited drug exposure time will influence the treatment effect. Furthermore, when drugs enter tumor cells, they will be blocked by high resistance and tight connection of drugs into superficial cells, and by high resistance and tight connection of superficial cells and semirigid and asymmetric urothelial membrane (Because of the particularity of urinary tract diseases, there are many challenges to realize membrane . In ordemembrane .Based on the above technology, the nanoparticles can also be loaded on the BUS to deliver anti-tumor drugs. For example, an anti-tumor drug can be loaded into polypeptide nanoparticles; then, the drug-loaded nanoparticles are mixed with the biomaterials to fabricate ureteral stents by electrospinning. With the degradation of the ureteral stent, the nanoparticles will continuously release drugs; it can extend the exposure time and enhance the penetration of the nanoparticles into the urothelium. When the nanoparticles are phagocytosed by cells, endogenous stimuli cause the structural changes of the nanoparticles, and the drug will be rapidly released in the cells, which could improve the drug delivery efficiency and reduce toxicity .The use of drug-eluting BUS in urology clinical practice not only provides local chemotherapy but also opens new treatment options. Various advancements in biomaterials, design, and drug delivery systems of BUS in this paper are reviewed. With the most appropriate biomaterial, design, and drug delivery technique, an optimal anti-tumor drug delivery stent could be developed in the future. However, there is no ideal stent, and we wish that our review can provide a summary of the technological challenges that need to be overcome in the development of constructing drug-eluted BUS. Future research should focus on how to use nanoparticle-based BUS to deliver local treatment drugs effectively.XW, JT, and BY: conceptualization. HS, ZC, CC, and BY: literature and data review. HS and JW: writing – original draft. XW and JT: writing – review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges. Mitochondria are dynamic ubiquitous organelles with innumerable functions in various cellular and metabolic pathways. Energy production via the oxidative phosphorylation (OXPHOS) represents the most prominent function of mitochondria . ConsistNucleated cells of multicellular eukaryotes contain hundreds to thousands of mitochondria, with numbers varying among different tissues depending on energy demand . UniquelThe term “mitochondrial disorder” refers to a large group of genetically defined disorders, leading to direct defects of the pyruvate root of the OXPHOS . The cliThe concept of mitochondrial disorders was initially described in de novo , were identified  or Kearns-Sayre syndrome  shortly followed by an mtDNA point mutation in entified . With thentified . Mitochoalidated . Mutatioreported . AlreadyThe identification of pathogenic variants in the mtDNA and nDNA guided the beginning of the genetic era of diagnostics in suspected mitochondrial disease. Traditionally, molecular diagnoses of suspected mitochondrial disorders relied upon clinical phenotyping and blood, urine, and skeletal muscle tests evaluating the biochemical evidence of mitochondrial defects. Biochemical screening studies then guided targeted candidate gene sequencing of patient cohorts with similarities in the clinical and biochemical phenotype. The limited association of single genes with recognizable clinical presentations, in combination with the large number of mitochondrial disease genes, often made the sequencing of individual genes a laborious and time-consuming approach. Hence, candidate gene sequencing is effective only for clear clinical phenotypes explained by a low number of distinct pathogenic variants, due to the technique being sensitive enough for variant detection and segregation analysis.In the last decade, the restricted analysis of the genome by conventional candidate gene sequencing methods was overcome with the advent of whole-exome sequencing (WES) and whole-genome sequencing (WGS), both serving to study the genetic background of this disease group . AdvanceACAD9 by NGS in 2010, the number of reported mitochondrial disease genes has duplicated, exemplifying the technology’s diagnostic power  increases the power and sensitivity of detection and interpretation of the large number of VUS identified by DNA sequencing. RNA-seq provides insight into the transcripts of a tissue at a specific time point and is an additional tool following exome sequencing to analyze unsolved cases by high-throughput functional characterization of variants. Of rare disease patients remaining undiagnosed by DNA analysis, by providing evidence for the pathogenicity of variants, RNA-seq allows an additional 17.5% of investigated patients to reach a genetic diagnosis .Despite the potential of such multi-omic approaches to further increase the diagnostic yield, the most commonly used method in current practice for evaluating the pathogenicity of VUS and the impact on OXPHOS remains to be the biochemical examination of tissue biopsies, though we expect this to change in the future.Taken together, despite the major technological advances in diagnostic tools for rare diseases, the lack of genotype-phenotype correlations, the genetic heterogeneity and the presence of VUS in patients with mitochondrial disease imply that the confirmation of a specific diagnosis often remains a challenge.With the increased utilization of sequencing technologies, it is now possible to provide a molecular diagnosis to a large fraction of patients with mitochondrial disease. As a result, mitochondriopathies are meanwhile frequently defined by their genetic cause rather than by biochemical deficiencies.The number of nuclear genes associated with mitochondrial function is estimated to be ∼1500 . So far,Considering the mitochondrial disease gene lists of four different publications released within the last year, the number of disease associated genes varied between 289 and 384: (1) RRM2B  of the proteins encoded by the named genes are not listed . Though RRM2B . For insS defect . Additiourrently , making 1 as disease genes with an associated phenotype and mode of inheritance (status 07/2020)  genes are not yet annotated in OMIM07/2020) . Differe0) (TXN2 . As most0)  OXPHOS subunits, assembly factors, and electron carriers (112/413 genes), (2) mitochondrial DNA replication and expression (104/413 genes), (3) mitochondrial dynamics, homeostasis, and quality control (55/413 genes), (4) metabolism of substrates (57/413 genes), (5) metabolism of cofactors (49/413 genes), (6) metabolism of toxic compounds (10/413 genes), and (7) others/unknown function (26/413 genes) . Novel dxception . Besidesxception . In contxception . In addiMRPL24 (The pathways currently reported in the context of mitochondrial disorders are presumably not yet complete and ongoing research in the field will continue to expand this list, just as knowledge about the localization and function of proteins is equally dynamic. Given the dynamic nature of mitochondrial disease genes, genes such as MRPL24  may not Taken together, the high level of clinical and genetical complexity, in combination with the absence of reliable biomarkers, resulted in the unavailability of a precise biochemical and genetic definition of mitochondrial disorders. No uniform and standardized definitions, regarding the pathogenicity, the presence of an OXPHOS defect, and the mitochondrial localization, have been provided to classify a gene or variant as a cause of mitochondriopathies . MoreoveWith steadily growing utilization and further advancement of sequencing methodologies, the number of pathogenic variants and genes associated with mitochondrial disease will constantly rise. Raising the question of whether a precise definition of mitochondrial disease genes is indeed useful, and whether it is of importance to speak of 270 or 400 genes.For patients with a constellation of symptoms indicating mitochondrial dysfunction in the absence of clear pathogenic variants and biochemical defects, it is recommended to avoid the diagnostic term “possible” mitochondrial disease . InsteadMitochondrial disorders are associated with an increasingly large number of heterogenous clinical and molecular presentations. By moving further into the genomic and multi-omic diagnostic era, the diagnosis of a mitochondrial disease on the basis of conventional biochemical definitions is increasingly being challenged. The function of mitochondria in many cellular activities and pathways contributes to the complexity in defining a single list of mitochondrial disease genes. Therefore, instead of adhering to an overly precise disease definition, the generous inclusion of patients with suspected mitochondrial disease, based on clinical and genetic evidence, into global patient registries appears to be more practicable and also beneficial to the field. The enlargement of global patient registries not only permits psychological support for patients, but also helps to combine clinical and genetic data in order to be able to analyze disease pathomechanisms in greater detail. Within the framework of the associated research studies, the establishment of genetic and biochemical criteria for the specific definition of mitochondrial diseases lends itself to the formation of clear patient groups. Moreover, advancements in diagnostic techniques are further unraveling the underlying causes of mitochondrial disease and will hopefully pave the way for the development of powerful treatments or curative agents for patients.This article was written by LS under the guidance of HP.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The COVID-19 pandemic is the most severe public health crisis in the 21st century. The pandemic not only posed great challenges to people's physical health but also induced wide-ranging impacts on mental health of infected and suspected patients, frontline healthcare workers, and the general public whose normal life was disrupted by the pandemic. In this commentary, we outline the initiatives and coordinated efforts on providing timely mental health services after the pandemic outbreak in China, including understanding the mental health impact of COVID-19, prioritizing and coordinating mental health services along with medical services in the efforts to contain the pandemic, initiating and implementing specific measures to improve mental wellbeing of frontline healthcare workers, and increasing the accessibility of mental health services to the general public. Theses services, along with other coordinated efforts, contribute to the containment of COVID-19 pandemic in China and could be valuable for other countries to take proactive measures to mitigate the mental health impacts of the pandemic now and in the future. The coronavirus disease 2019 (COVID-19) pandemic is the most severe public health threat to people around the world in the twenty-first century. According to the information released by Johns Hopkins University, by 6:30 am, July 31st, 2020, 17,153,442 patients had been infected by COVID-19, of whom 669,701 died due to the infection [As other infectious diseases outbreak such as SARS, MERS and Ebola, the COVID-19 pandemic induced wide-ranging impacts on mental health of confirmed and suspected patients, frontline healthcare workers, and the general public, such as fear, anxiety, depression, insomnia, and suicidal ideality , 4. As rShortly after the outbreak of COVID-19, researchers in mental health, psychiatry, counseling and clinical psychology, public health, social psychology and social work are conducting emergent research on understanding and monitoring the psychological impact of the COVID-19 pandemic on confirmed and suspected patients, frontline healthcare workers, those experienced quarantine, and the general public. By using social media to monitor social emotions during the epidemic, researchers from the Institute of Psychology of the Chinese Academy of Sciences are working on developing effective strategies to provide tailored mental health services to those in need . As reveShortly after the outbreak of COVID-19, the central government prioritized timely mental health services for those being directly and indirectly impacted by the pandemic. The National Health Commission of China released guidelines on providing emergent mental health assistances and psychological crisis interventions during the pandemic . SpecifiIn response to the advocate on providing timely mental health services during the pandemic, professional organizations such as the Chinese Psychological Society and its sub-working committees initiated online programs shortly after the pandemic to train professionals and volunteers to provide psychological assistances and interventions  to people in need. On March 2nd, 2020, president Xi reemphasized the importance of providing timely and continuous psychological counseling, psychotherapy, and other needed mental health services to confirmed and suspected patients, their families, and the general public. This is the first time that the National Health Commission released specific guidelines on mental health services after a public health emergency in China. These guidelines contributed to the coordination of mental health services and resources around the country.Special efforts were initiated and implemented on protecting the mental health of healthcare professionals and their families. Healthcare workers are the backbone in the battle against the COVID-19 pandemic, in response to this public health emergency, more than 42,000 healthcare professionals around the country were sent to help Wuhan and other major cities in Hubei to contain the COVID-19 pandemic in China. With increasing numbers of patients being infected and diagnosed with COVID-19 during the peak period of the pandemic  to the general public.Mental health centers affiliated with leading research universities such as the Six Hospital of Peking University published books and guidelines on assisting the general public to monitor their mental health status and take proactive measures to improve their mental health and enhance resiliency. More than 600 hotlines for mental health services were established since the outbreak. Thousands of online mental health support groups were established to improve people’s mental health with support from registered counsellors. Professional organizations such as the Chinese Psychological Society also leveraged the advanced internet infrastructure and online healthcare platforms to provide online mental health consultation and to increase the accessibility of mental health resources .During the COVID-19 pandemic, governments, professional organizations, research institutes and universities, psychiatry departments and mental health centers across China have swiftly initiated guidelines, mental health services, and campaigns to address mental health needs for healthcare workers, infected/suspected patients and their families, those experiencing quarantine, and the general public , 9. Time