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1.
Cell Discov ; 8(1): 53, 2022 Jun 06.
Article in English | MEDLINE | ID: covidwho-1878521

ABSTRACT

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.

2.
Dementia (London) ; 21(5): 1714-1733, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1808169

ABSTRACT

PURPOSES: Dementia-friendly initiatives (DFI) are community-based movements aimed to address stigma, exclusion, and discrimination associated with dementia. This study examined the challenges faced and strategies used by DFI prior to and during the COVID-19 pandemic from the perspectives of stakeholders in the USA and China. METHODS: Qualitative interviews with 17 stakeholders involved in DFI from the United States and mainland China were conducted via the Zoom platform. Semi-structured interview questions focused on DFI challenges and strategies prior to and during the pandemic. Thematic analysis was used to analyze the data. RESULTS: Three major challenges prior to the COVID-19 pandemic included low participation of persons with dementia, difficulties in building community collaborations, and limited funding and resources needed to sustain DFI. During the COVID-19 pandemic, challenges included exacerbated difficulties of involving persons with dementia and reduced policy support for DFI. Strategies implemented prior to COVID-19 included partnerships with community organizations to outreach and engage persons with dementia, and coordination of resources and diversification of funding sources to sustain DFI. Strategies during the COVID-19 pandemic centered on the implementation of person-centered technology to support persons with dementia and family caregivers, and the development of new programs that integrated efforts to address the impact of COVID-19. IMPLICATIONS: DFI in the USA and mainland China shared similar challenges for DFI prior to and during COVID-19. During the COVID-19 pandemic, DFI in both countries showed resourcefulness through reliance on technology, community collaboration, and COVID-19-related resources to provide support and services. While it remains critical to advocate to the central government to fund DFI, DFI in both societies need to be open to other funding sources, hire persons with dementia as key staff members of DFI, and demonstrate its effectiveness through rigorous evaluation.


Subject(s)
COVID-19 , Dementia , COVID-19/epidemiology , Caregivers , Humans , Pandemics , Social Stigma , United States
3.
Innovation in aging ; 5(Suppl 1):484-484, 2021.
Article in English | EuropePMC | ID: covidwho-1782235

ABSTRACT

This East Meets West Symposium presents cross-cultural evidence of community-based programs developed to address cognitive health needs of older adults or to support dementia family caregivers. It includes five studies from mainland China, Taiwan, and the U.S.A. The first study explored the adherence to computerized cognitive training to promote cognitive health among Chinese older adults using a qualitative approach. External encouragement, and self-awareness of performance improvement were found influential to older adults’ adherence. The second study spearheaded by American Association of Retired Persons (AARP) in the U.S.A shed further light on technology use in promoting brain health by comparing in-person versus online cognitive training to older Americans during the COVID-19 pandemic. The third study tested the effectiveness of a cognitive health management model for community-dwelling older adults including healthy and mild cognitively impaired (MCI) ones in Shanghai, China. Older adults with MCI who received the management service showed better cognition outcomes compared to their counterparts in the control group. The fourth study focused on a community program named “Carer Café”, developed to support dementia family caregiver in Taiwan. Participants (n=375) reported reduced stress and increased access to service referrals. The last study examined the stakeholders’ perceptions of dementia friendly initiatives (DFI) being implemented in U.S.A, mainland China, and Taiwan to support persons with dementia and family caregivers. The impacts of DFI made, challenges DFI faced, and strategies DFI used during COVID-19 pandemic were discussed. The discussant will comment on each article’s contributions and limitations in the context of literature.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325436

ABSTRACT

The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates membrane fusion to allow entry of viral genome into host cell. To understand its detailed entry mechanism and develop specific entry inhibitor, the in situ structural information of SARS-CoV-2 spikes in different states are urgently important. Here, by using the cryo-electron microscopic tomograms, we observed spikes of inactivated SARS-CoV-2 virions in both pre-fusion and post-fusion states and solved the nanometer resolution structure of in situ post-fusion spike. With a more complete model compared to previous reports, the relative spatial position between fusion peptide and transmembrane domain was discovered. Novel oligomerizations of spikes on viral membrane were observed, likely suggesting a new mechanism of fusion pore formation.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324470

ABSTRACT

The spike (S) protein of SARS coronavirus 2 (SARS-CoV-2) is an ideal target for the development of specific vaccines or drugs. However, treatments targeting viruses with mutant S proteins that have recently emerged in many countries are limited. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered two novel sites (CS-1 and CS-2) in the S protein for cleavage by the protease Cathepsin L (CTSL). Both sites are highly conserved among all SARS-CoV-2 variants of concern. Cryo-electron microscopy structural studies revealed that CTSL cleavage increases the dynamics of the receptor binding domain of S and induces novel conformations. In our pseudovirus (PsV) infection experiment, alteration of the cleavage site significantly reduced the infection efficiency, and CTSL inhibitors markedly inhibited infection with PsVs of both the wild-type and emerged SARS-CoV-2 variants. Furthermore, six highly efficient CTSL inhibitors were found to effectively inhibit live virus infection in human cells in vitro , and two of these were further confirmed to prevent live virus infection in human ACE2 transgenic mice in vivo . Our work suggested that the CTSL cleavage sites in SARS-CoV-2 S are emerging new but effective targets for the development of mutation-resistant vaccines and drugs.

6.
J Emerg Nurs ; 48(2): 159-166, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1670722

ABSTRACT

INTRODUCTION: Establishing intravenous access is essential but may be difficult to achieve for patients requiring isolation for severe acute respiratory syndrome coronavirus 2 infection. This study aimed to investigate the effectiveness of an infrared vein visualizer on peripheral intravenous catheter therapy in patients with coronavirus disease 2019. METHODS: A nonrandomized clinical trial was performed. In total, 122 patients with coronavirus disease 2019 who required peripheral intravenous cannulation were divided into 2 groups with 60 in the control group and 62 in the intervention group. A conventional venipuncture method was applied to the control group, whereas an infrared vein imaging device was applied in the intervention group. The first attempt success rate, total procedure time, and patients' satisfaction score were compared between the 2 groups using chi-square, t test, and z test (also known as Mann-Whitney U test) statistics. RESULTS: The first attempt success rate in the intervention group was significantly higher than that of control group (91.94% vs 76.67%, ꭓ2 = 5.41, P = .02). The procedure time was shorter in the intervention group (mean [SD], 211.44 [68.58] seconds vs 388.27 [88.97] seconds, t = 12.27, P < .001). Patients from the intervention group experienced a higher degree of satisfaction (7.5 vs 6, z = -3.31, P < .001). DISCUSSION: Peripheral intravenous catheter insertion assisted by an infrared vein visualizer could improve the first attempt success rate of venipuncture, shorten the procedure time, and increase patients' satisfaction.


Subject(s)
COVID-19 , Catheterization, Peripheral , Catheterization, Peripheral/methods , Catheters , Humans , SARS-CoV-2 , Veins
7.
Innovation in Aging ; 5(Supplement_1):244-244, 2021.
Article in English | PMC | ID: covidwho-1584706

ABSTRACT

The purpose of this symposium is to highlight the mental health needs and factors associated with mental health among informal caregivers of older adults in Asia. The symposium consists of five papers. The first paper explores the perceived role, needs, and rewards of informal caregiving among caregivers of residents in independent long-term care facilities in South India. The second paper presents a systematic review and meta-analysis on the association between long-term care service use and informal caregiver burden, depression, and health status. The third paper examines the association between caregivers’ characteristics and quality of life among informal caregivers of older adults with cognitive impairment in China. The fourth paper examines the association between coping strategies and caregiver burden and depression among Chinese caregivers of older adults with cognitive impairment. The last paper examines the association between cohort, meaning making, and depression among adult caregivers during the COVID-19 pandemic in Hong Kong. Taken together, these five papers underscore of the mental health needs and protective and risk factors of mental well-being among caregivers in Asia. Findings of those papers inform the development and adaptation of culturally sensitive interventions to improve mental health outcomes among informal caregivers in Asia. The disccuant will comment on the strengths and limitations of these papers in terms of their contributions to the theory, research, and practice on mental health among informal caregivers in Asia.

8.
Innovation in Aging ; 5(Supplement_1):488-488, 2021.
Article in English | PMC | ID: covidwho-1584529

ABSTRACT

To address the exclusion of persons living with dementia (PWD), Dementia Friendly Initiatives (DFI) are being launched to build a friendly and supportive environment for PWD in the U.S.A, mainland China, and Taiwan. This study aims to identify the impact of DFI, the challenges DFI encountered, and strategies used to address such challenges within the COVID-19 context in American and Chinese societies. Individual interviews via Zoom with 9 stakeholders from the U.S.A, 8 from mainland China and one from Taiwan were transcribed for analyses. DFI have shown effectiveness in raising the public’s dementia awareness and engaging PWD in the community. COVID-19 pandemic posed the challenges of serving isolated PWD due to resources and attention shifted to COVID-19 prevention. Person-centered and technology-based means were used to deliver services for PWD during the pandemic. DFI in American and Chinese societies experienced similar sustainability challenges but showed resilience during the COVID-19 pandemic.

9.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294623

ABSTRACT

Cardiovascular disease (CVD) mortality has substantially improved over recent decades. Some evidence indicates this has been paralleled by an increasing proportion of non-cardiovascular mortality in people with CVD. However, the contemporary causes of death across a broad spectrum of CVDs, either alone or in combination, remains unclear. We analysed cardiovascular, infection, cancer and other causes of death prior to the COVID-19 pandemic in 493,280 participants in the prospective UK Biobank study. Studied CVDs included baseline: abdominal aortic aneurysm, atrial fibrillation, coronary artery disease, heart failure, hypertension, peripheral vascular disease, stroke, valvular heart disease and venous thromboembolic disease;we separately considered cardiovascular multimorbidity defined as the total number of these baseline CVDs. Crude mortality rates and Poisson regression analysis were used to quantify the absolute and relative risk of cause-specific death. Associations are reported as incidence rate ratios (IRR) with 95% CIs. During a median follow-up of 10.9 [IQR 10.1-11.6] years per participant, there were 27,729 deaths (20.4% primarily attributed to CVD, 53.6% to cancer, 5.0% to infection and 21.0% to other causes). As the number of co-morbid CVDs increased, the proportion of cardiovascular and infection-related deaths increased, whereas cancer and other deaths decreased. Accrual of multiple CVDs was associated with marked increases in relative risk of infection and cardiovascular death;versus those without CVD, people with three or more CVDs, the relative risk of cardiovascular death increased most (IRR 3.89;95%CI 3.59-4.21), followed by infection (4.41;3.44-5.64), with other (2.01;1.72-2.35) and cancer (1.52;1.35-1.72) being substantially less increased. All studied CVDs except atrial fibrillation were independently associated with increased risk of infection death, with heart failure (2.73;1.60-4.66) and valvular heart disease (3.09;2.38-4.00) posing the greatest risk. In conclusion, causes of death vary substantially between differing baseline CVDs, and according to the number of baseline CVDs, with non-cardiovascular deaths due to cancer and infection making an important contribution. Holistic and personalized care are likely to be important tools for continuing to improve outcomes in people with CVD.

10.
Proc Natl Acad Sci U S A ; 118(48)2021 11 30.
Article in English | MEDLINE | ID: covidwho-1517667

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates membrane fusion to allow entry of the viral genome into host cells. To understand its detailed entry mechanism and develop a specific entry inhibitor, in situ structural information on the SARS-CoV-2 spike protein in different states is urgent. Here, by using cryo-electron tomography, we observed both prefusion and postfusion spikes in ß-propiolactone-inactivated SARS-CoV-2 virions and solved the in situ structure of the postfusion spike at nanometer resolution. Compared to previous reports, the six-helix bundle fusion core, the glycosylation sites, and the location of the transmembrane domain were clearly resolved. We observed oligomerization patterns of the spikes on the viral membrane, likely suggesting a mechanism of fusion pore formation.


Subject(s)
SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Motifs , Animals , Chlorocebus aethiops , Cryoelectron Microscopy , Electron Microscope Tomography , Glycosylation , Protein Domains , Protein Multimerization , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
12.
Signal Transduct Target Ther ; 6(1): 288, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1333906

ABSTRACT

The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Virus Internalization/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Caco-2 Cells , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Mice, Transgenic , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
13.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1066781

ABSTRACT

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.


Subject(s)
COVID-19/metabolism , DNA-Binding Proteins/metabolism , Macrophages/metabolism , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Fibrosis , Gene Expression Profiling , Gene Expression Regulation , Humans , Liposomes/chemistry , Lung Diseases, Interstitial/metabolism , Lung Neoplasms/metabolism , Macrophages/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/virology , RNA, Small Interfering/metabolism , Scleroderma, Systemic/metabolism , Signal Transduction , Transforming Growth Factor beta1/metabolism
14.
Int J Geriatr Psychiatry ; 35(12): 1458-1465, 2020 12.
Article in English | MEDLINE | ID: covidwho-754845

ABSTRACT

OBJECTIVES: Since the novel coronavirus disease (COVID-19) outbreak started in late 2019, the older population has accounted for a large proportion of severe and fatal cases. This study investigated the mental state and attitudes of older Chinese adults during this epidemic. DESIGN: Cross-sectional online surveys on a convenience sample of China's general population at two different time points. Online surveys were disseminated through popular Chinese social media applications. Adults 18 or older living in China during the initial (N = 1148) and second stages (N = 470) were included in the survey. The Worries, Strategies, and Confidence Questionnaire was created to assess worries and awareness of the disease. RESULTS: Combined responses (N = 1618), 76.1% were female and about 7.0% were 60 years or above. In the first wave, older adults were found less likely to worry about being infected by COVID-19 (p < 0.05) and reported less attention paid to protective measures (p = 0.004) than young adults. However, as the disease evolved, older participants in the second wave were more worried than young adults (p = 0.027) and older adults in the first wave (p = 0.001). CONCLUSIONS: During the epidemic of COVID-19, watchfulness of the epidemic among older Chinese adults fluctuated over time. Initially, they were slow to respond proactively, but their worries gradually increased. Health care and social service professionals need to address the vulnerabilities of older adults to this public health crisis.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , China/epidemiology , Cross-Sectional Studies , Disease Outbreaks , Female , Humans , Male , Middle Aged , Surveys and Questionnaires
15.
Curr Res Microb Sci ; 1: 53-61, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-626185

ABSTRACT

A severe form of pneumonia, named coronavirus disease 2019 (COVID-19) by the World Health Organization, broke out in China and rapidly developed into a global pandemic, with millions of cases and hundreds of thousands of deaths reported globally. The novel coronavirus, which was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the etiological agent of COVID-19. On the basis of experience accumulated following previous SARS-CoV and MERS-CoV outbreaks and research, a series of studies have been conducted rapidly, and major progress has been achieved with regard to the understanding of the phylogeny and genomic organization of SARS-CoV-2 in addition its molecular mechanisms of infection and replication. In the present review, we summarized crucial developments in the elucidation of the structure and function of key SARS-CoV-2 proteins, especially the main protease, RNA-dependent RNA polymerase, spike glycoprotein, and nucleocapsid protein. Results of studies on their associated inhibitors and drugs have also been highlighted.

16.
Gen Psychiatr ; 33(3): e100231, 2020.
Article in English | MEDLINE | ID: covidwho-611809

ABSTRACT

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) pandemic has given rise to fear and panic in the public. Although hospitals in China reduced outpatient visits and restricted inpatient admission to lower the risk of transmission of COVID-19, this has significantly affected patients in need of medical attention, for example, patients with emotional disorders. AIMS: This study aimed to compare the beliefs towards COVID-19 among outpatients with emotional disorders (ie, anxiety or depression) with those of family caregivers and the general public and examine factors that shape the beliefs towards COVID-19 among outpatients with emotional disorders. METHODS: Survey data from 570 outpatients with anxiety or depression disorders, 449 family caregivers and 470 general public subjects were collected. Multiple stepwise regression analyses were used to describe participants' level of concern, prevention attitude and positive expectations towards the COVID-19 outbreak. RESULTS: About 70.9% of outpatients had to postpone their mental health treatment; 43.2% of patients admitted that their mental health was adversely affected by the COVID-19 outbreak-these patients tended to be older, male and less educated. After controlling for age and education level, outpatients with emotional disorders had significantly lower levels of concerns but more negative expectations towards COVID-19, compared with family caregivers and the public. Multivariate linear stepwise regression analysis showed that age, education and the perception of the impact of COVID-19 on one's existing mental illness were significantly associated with outpatients' beliefs about the epidemic. CONCLUSION: Outpatients with anxiety or depression disorders were relatively less focused on the COVID-19 outbreak, but the impact of the infection was found to be independently associated with their beliefs towards COVID-19. In addition, outpatients who were older and of low educational levels particularly held more negative beliefs about the epidemic, which may place them at a higher risk for poor mental health.

17.
Cell Res ; 30(4): 343-355, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-30393

ABSTRACT

The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Lipopeptides/pharmacology , Membrane Fusion , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Administration, Intranasal , Amino Acid Sequence , Animals , Betacoronavirus/drug effects , COVID-19 , Cell Fusion , Chlorocebus aethiops , HEK293 Cells , Humans , Mice , Protein Interaction Domains and Motifs , Protein Structure, Secondary , SARS Virus , SARS-CoV-2 , Sequence Alignment , Structure-Activity Relationship , Vero Cells
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