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 r...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 t展开更多
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 ...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 th展开更多
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 strategi...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展开更多
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...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.展开更多
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,patient...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).C展开更多
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...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.展开更多
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,...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 c展开更多
文摘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 t
基金supported by NIH Grants R01NS092651 and R21NS111275-01the Department of Veterans Affairs,BX001148 and BX005899(to PHK)。
文摘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 th
基金the Key Research and Development Project of Zhejiang Province,China(2022C02044)National Natural Science Foundation of China(32171889 and 32071895)+1 种基金the Natural Science Foundation of Zhejiang Province,China(LQ22C130004)the National Key Research and Development Program of China(2018YFD0700501).
基金funded by the Center of Advanced Systems Understanding(CASUS)which is financed by Germany's Federal Ministry of Education and Research(BMBF)by the Saxon Ministry for Science,Culture and Tourism(SMWK)with tax funds on the basis of the budget approved by the Saxon State Parliament.
文摘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
基金the National Natural Science Foundation of China(82041026,81673275,11961071,91846302)the Huai'an Key Laboratory for Infectious Diseases Control and Prevention(HAP201704).
文摘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.
基金the Shanxi health commission for the grant of the special foundation on COVID-19(Grant number:No.6)Shanxi department of science and technology for the grant of the major science and technology project of Shanxi province(Grant Number:202005D121008).
文摘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).C
基金the National Natural Science Foundation of China(82041027)the China Medical Board(20-366)Peking University(PKU2020PKYZX002).
文摘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.
基金provided by the Chicago Biomedical Consortium’s Postdoctoral Research Award,No.085740
文摘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 c
