Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.

Presymptomatic Diagnosis and Gene Therapy for Alzheimer’s Disease: Genomic, Therapeutic, and Ethical Aspects—A Systematic Review

Over the past three decades, genomic and epigenetic sciences have identified more than 70 genes involved in the molecular pathophysiology of Alzheimer’s disease (AD). DNA methylation, abnormal histone and chromatin regulation and the action of various miRNAs induce AD. The identification of mutated genes has paved the way for the development of diagnostic kits and the initiation of gene therapy trials. However, despite major advances in neuroscience research, there is yet no suitable treatment for AD. Therefore, the early diagnosis of this neurodegenerative disease raises several ethical questions, including the balance between the principle of non-maleficence and the principle of beneficence. The aims of this research were to present the genomic and ethical aspects of AD, and to highlight the ethical principles involved in its presymptomatic diagnosis and therapy. A systematic review of the literature in PubMed, Google Scholar and Science Direct was carried out to outline the genomic aspects and ethical principles relating not only to the presymptomatic diagnosis of AD, but also to its gene therapy. A total of 16 publications were selected. AD is a multifactorial disease that can be genetically classified into Sporadic Alzheimer’s Disease and Familial Alzheimer’s Disease based on family history. Gene therapy targeting specific disease-causing genes is a promising therapeutic strategy. Advancements in artificial intelligence applications may enable the prediction of AD onset several years in advance. While early diagnosis of AD may empower patients with full decision competence for early decision-making, it also carries implications for the patient’s family members, who are at risk of developing the disease, potentially becoming a source of confusion or anxiety. AD has a significant impact on the life of individuals at risk and their families. Given the absence of disease modifying therapy, genetic screening and early diagnosis for this condition raise ethical issues that must be carefully considered in the context of fundamental bioethical principles, including autonomy, beneficence, non-maleficence, and justice.

Estimating the time interval between transmission generations and the presymptomatic period by contact tracing surveillance data from 31 provinces in the mainland of China

The global pandemic of 2019 coronavirus disease(COVID-19)is a great assault to public health.Presymptomatic transmission cannot be controlled with measures designed for symptomatic persons,such as isolation.This study aimed to estimate the interval of the transmission generation(TG)and the presymptomatic period of COVID-19,and compare the ftting effects of TG and serial interval(S)based on the SEIHR model incorporating the surveillance data of 3453 cases in 31 provinces.These data were allocated into three distributions and the value of AIC presented that the Weibull distribution fitted well.The mean of TG was 5.2 days(95%C:4.6-5.8).The mean of the presymptomatic period was 2.4 days(95%CI:1.5-3.2).The dynamic model using TG as the generation time performed well.Eight provinces exhibited a basic reproduction number from 2.16 to 3.14.Measures should be taken to control presymptomatic transmission in the COVID-19 pandemic.

Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.

指纹光谱特征揭示叶斑病时空动态发展以实现显症前诊断

植物病原菌不断危害农业生产和粮食安全。因此,病害发展早期的动态表征对病变监测和显症前诊断至关重要。高光谱成像(HSI)在跟踪病害初始侵染部位的动态进程以进行显症前诊断方面具有巨大潜力。然而,目前尚无相关文献提取出早期感染阶段活体叶片病变组织的指纹光谱特征(FSS),也没有探究HSI的检测机制。其中FSS是指能够表征特定植物病害的独特、有代表性的光谱特征。在本研究中,基于时序HSI数据分析,提取了接种Bipolaris sorokiniana的大麦叶片的FSS,以表征叶斑病症状发展,实现显症前诊断。还研究了叶斑病早期发展阶段叶片的光谱和生化响应。本文所提取的全波段FSS能够捕捉病变发展过程中褪绿组织和坏死组织的独特特征,从而原位可视化植物-病原菌像素级的早期互作动态进程。进一步,实现了接种后24 h叶斑病的显症前诊断,比传统的聚合酶链反应(PCR)测定或生化测定提前了12 h。为了揭示HSI显症前诊断的机制,还建立了叶片的平均光谱响应与其生化指标(叶绿素、类胡萝卜素、丙二醛、抗坏血酸和还原型谷胱甘肽)之间的定量关系,回归模型在预测集上的Rp2均高于0.84。总体结果表明,HSI反映了活体植物特性的变化,所提取的FSS可成功跟踪叶斑病发生发展的时空动态进程,实现显症前诊断。在其他植物病害上的试验表明,该方法在植物病害早期控制方面具有较大的推广潜力。

Human cancer genetics

The short report will be focused on the genetic basis and possible mechanisms of tumorigenesis, common types of cancer, the importance of genetic diagnosis of cancer, and the methodology of cancer genetic diagnosis. They will also review presymptomatic testing of hereditary cancers, and the application of expression profiling to identify patients likely to benefit from particular therapeutic approaches.

The relationship between controllability, optimal testing resource allocation, and incubation-latent period mismatch as revealed by COVID-19

The severe shortfall in testing supplies during the initial COVID-19 outbreak and ensuing struggle to manage the pandemic have affirmed the critical importance of optimal supplyconstrained resource allocation strategies for controlling novel disease epidemics.To address the challenge of constrained resource optimization for managing diseases with complications like pre-and asymptomatic transmission,we develop an integro partial differential equation compartmental disease model which incorporates realistic latent,incubation,and infectious period distributions along with limited testing supplies for identifying and quarantining infected individuals.Our model overcomes the limitations of typical ordinary differential equation compartmental models by decoupling symptom status from model compartments to allow a more realistic representation of symptom onset and presymptomatic transmission.To analyze the influence of these realistic features on disease controllability,we find optimal strategies for reducing total infection sizes that allocate limited testing resources between‘clinical’testing,which targets symptomatic individuals,and‘non-clinical’testing,which targets non-symptomatic individuals.We apply our model not only to the original,delta,and omicron COVID-19 variants,but also to generically parameterized disease systems with varying mismatches between latent and incubation period distributions,which permit varying degrees of presymptomatic transmission or symptom onset before infectiousness.We find that factors that decrease controllability generally call for reduced levels of non-clinical testing in optimal strategies,while the relationship between incubation-latent mismatch,controllability,and optimal strategies is complicated.In particular,though greater degrees of presymptomatic transmission reduce disease controllability,they may increase or decrease the role of nonclinical testing in optimal strategies depending on other disease factors like transmissibility and latent period length.Importantly,our model allows a spectrum of diseases to be compared within a consistent framework such that lessons learned from COVID-19 can be transferred to resource constrained scenarios in future emerging epidemics and analyzed for optimality.

Demand for longer quarantine period among common and uncommon COVID-19 infections: a scoping review

Background:As one of the non-pharmacological interventions to control the transmission of COVID-19,determining the quarantine duration is mainly based on the accurate estimates of the incubation period.However,patients with coarse information of the exposure date,as well as infections other than the symptomatic,were not taken into account in previously published studies.Thus,by using the statistical method dealing with the interval-censored data,we assessed the quarantine duration for both common and uncommon infections.The latter type includes the presymptomatic,the asymptomatic and the recurrent test positive patients.Methods:As of 10 December 2020,information on cases have been collected from the English and Chinese databases,including Pubmed,Google scholar,CNKI(China National Knowledge Infrastructure)and Wanfang.Official websites and medias were also searched as data sources.All data were transformed into doubly interval-censored and the accelerated failure time model was applied.By estimating the incubation period and the time-to-event distribution of worldwide COVID-19 patients,we obtain the large percentiles for determining and suggesting the quarantine policies.For symptomatic and presymptomatic COVID-19 patients,the incubation time is the duration from exposure to symptom onset.For the asymptomatic,we substitute the date of first positive result of nucleic acid testing for that of symptom onset.Furthermore,the time from hospital discharge or getting negative test result to the positive recurrence has been calculated for recurrent positive patients.Results:A total of 1920 laboratory confirmed COVID-19 cases were included.Among all uncommon infections,34.1%(n=55)of them developed symptoms or were identified beyond fourteen days.Based on all collected cases,the 95th and 99th percentiles were estimated to be 16.2 days(95%Cl 15.5-17.0)and 22.9 days(21.7-24.3)respectively.Besides,we got similar estimates based on merely symptomatic and presymptomatic infections as 15.1 days(14.4-15.7)and 21.1 days(20.0-22.2).Conclusions:There are a certain number of infected people who require longer quarantine duration.Our findings well support the current practice of the extended active monitoring.To further prevent possible transmissions induced and facilitated by such infectious outliers after the 14-days quarantine,properly prolonging the quarantine duration could be prudent for high-risk scenarios and in regions with insufficient test resources.

Asymptomatic and pre-symptomatic infection in Coronavirus Disease 2019 pandemic

With the presence of Coronavirus Disease 2019(COVID-19)asymptomatic infections detected,their proportion,transmission potential,and other aspects such as immunity and related emerging challenges have attracted people’s attention.We have found that based on highquality research,asymptomatic infections account for at least one-third of the total cases,whereas based on systematic review and meta-analysis,the proportion is about one-fifth.Evaluating the true transmission potential of asymptomatic cases is difficult but critical,since it may affect national policies in response to COVID-19.We have summarized the current evidence and found,compared with symptomatic cases,the transmission capacity of asymptomatic individuals is weaker,even though they have similar viral load and relatively short virus shedding duration.As the outbreak progresses,asymptomatic infections have also been found to develop long COVID-19.In addition,the role of asymptomatic infection in COVID-19 remains to be further revealed as the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants continue to emerge.Nevertheless,as asymptomatic infections transmit the SARS-CoV-2 virus silently,they still pose a substantial threat to public health.Therefore,it is essential to conduct screening to obtain more knowledge about the asymptomatic infections and to detect them as soon as possible;meanwhile,management of them is also a key point in the fight against COVID-19 community transmission.The different management of asymptomatic infections in various countries are compared and the experience in China is displayed in detail.