Using the Diabetes Care System for a County-Wide Hepatitis C Elimination: An Integrated Community-Based Shared Care Model in Taiwan.

INTRODUCTION: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care. METHODS: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined. RESULTS: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction. DISCUSSION: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model.

The term "classic invasive lobular carcinoma" of the breast defines breast malignancies of vastly different nature.

PURPOSE: To describe in detail the special features of a previously unappreciated "classic invasive lobular carcinoma" which is confined to the terminal ductal lobular units (TDLUs) and differs considerably from the extensive classic invasive lobular carcinoma, and to suggest specific terminology. METHOD: All invasive breast cancer cases without associated microcalcifications diagnosed in our Institution with the histopathologic diagnosis of classic invasive lobular carcinoma during the years 1996-2019 (n = 560) formed the basis of this study. The cases were prospectively classified according to their imaging biomarkers (mammographic features) and followed up to Dec 31, 2021, to determine long-term patient outcome. An additional 2600 invasive breast cancer cases (diagnosed other than invasive lobular carcinoma) without associated microcalcifications served as a reference group. Detailed histopathologic analysis used large format (10x8 cm) thin section technique and staining methods including hematoxylin-eosin (H&E), E-cadherin, cytokeratin CK 5/6, a transmembrane glycoprotein (CD44) and anti-actin or anti-smooth muscle myosin heavy chain. RESULTS: The imaging biomarkers differentiated two separate disease subgroups, having the same histopathologic diagnosis, classic invasive lobular carcinoma. One of these has the imaging biomarker of extensive architectural distortion with no central tumour mass, occupies the extralobular mesenchyme and has a long-term survival of 56%. The other subgroup forms stellate or circular non-calcified tumour masses usually smaller than 20 mm, which appear to arise in the intralobular mesenchyme, and has a significantly better long-term survival of 84%. CONCLUSIONS: There is a striking difference between the subgross histopathology and the mammographic appearance (imaging biomarkers) of two breast malignancies having the same histopathologic diagnosis, "classic invasive lobular carcinoma". The large difference in the long-term outcome of these two tumour types is even more striking. Using the same specific term, "classic invasive lobular carcinoma", to describe these two separate entities can adversely affect management decisions.

Finding of the optimal preparation and timing of endometrium in frozen-thawed embryo transfer: a literature review of clinical evidence.

Frozen-thawed embryo transfer (FET) has been a viable alternative to fresh embryo transfer in recent years because of the improvement in vitrification methods. Laboratory-based studies indicate that complex molecular and morphological changes in endometrium during the window of implantation after exogenous hormones with controlled ovarian stimulation may alter the interaction between the embryo and endometrium, leading to a decreased implantation potential. Based on the results obtained from randomized controlled studies, increased pregnancy rates and better perinatal outcomes have been reported following FET. Compared to fresh embryo transfer, fewer preterm deliveries, and reduced incidence of ovarian hyperstimulation syndrome were found after FETs, yet there is a trend of increased pregnancy-related hypertensive diseases in women receiving FET. Despite the increased application of FET, the search for the most optimal priming protocol for the endometrium is still undergoing. Three available FET protocols have been proposed to prepare the endometrium: i) natural cycle (true natural cycle and modified natural cycle) ii) artificial cycle (AC) or hormone replacement treatment cycle iii) mild ovarian stimulation (mild-OS) cycle. Emerging evidence suggests that the optimal timing for FET using warmed blastocyst transfer is the LH surge+6 day, hCG administration+7 day, and the progesterone administration+6 day in the true natural cycle, modified natural cycle, and AC protocol, respectively. Although still controversial, better clinical pregnancy rates and live birth rates have been reported using the natural cycle (true natural cycle/modified natural cycle) compared with the AC protocol. Additionally, a higher early pregnancy loss rate and an increased incidence of gestational hypertension have been found in FETs using the AC protocol because of the lack of a corpus luteum. Although the common clinical practice is to employ luteal phase support (LPS) in natural cycles and mild-OS cycles for FET, the requirement for LPS in these protocols remains equivocal. Recent findings obtained from RCTs do not support the routine application of endometrial receptivity testing to optimize the timing of FET. More RCTs with rigorous methodology are needed to compare different protocols to prime the endometrium for FET, focusing not only on live birth rate, but also on maternal, obstetrical, and neonatal outcomes.

Establishment of the fetal-maternal interface: developmental events in human implantation and placentation.

Early pregnancy is a complex and well-orchestrated differentiation process that involves all the cellular elements of the fetal-maternal interface. Aberrant trophoblast-decidual interactions can lead to miscarriage and disorders that occur later in pregnancy, including preeclampsia, intrauterine fetal growth restriction, and preterm labor. A great deal of research on the regulation of implantation and placentation has been performed in a wide range of species. However, there is significant species variation regarding trophoblast differentiation as well as decidual-specific gene expression and regulation. Most of the relevant information has been obtained from studies using mouse models. A comprehensive understanding of the physiology and pathology of human implantation and placentation has only recently been obtained because of emerging advanced technologies. With the derivation of human trophoblast stem cells, 3D-organoid cultures, and single-cell analyses of differentiated cells, cell type-specific transcript profiles and functions were generated, and each exhibited a unique signature. Additionally, through integrative transcriptomic information, researchers can uncover the cellular dysfunction of embryonic and placental cells in peri-implantation embryos and the early pathological placenta. In fact, the clinical utility of fetal-maternal cellular trafficking has been applied for the noninvasive prenatal diagnosis of aneuploidies and the prediction of pregnancy complications. Furthermore, recent studies have proposed a viable path toward the development of therapeutic strategies targeting placenta-enriched molecules for placental dysfunction and diseases.

The challenging imaging and histopathologic features of diffusely infiltrating breast cancer.

PURPOSE: Clinical, imaging and outcome observations indicate that diffusely infiltrating breast cancer, presenting as a large region of architectural distortion on the mammogram and conventionally termed classic infiltrating lobular carcinoma of diffuse type, represents a very unusual breast malignancy. This article aims to draw attention to the complex clinical, imaging, and large format thin and thick section histopathologic features of this malignancy, which challenges our current diagnostic and therapeutic management practices. METHODS: Prospectively collected data from the randomized controlled trial (1977-85) and from the subsequent, ongoing population-based mammography service screening (1985-2019) with more than four decades of follow up in Dalarna County, Sweden provided the database for investigating this breast cancer subtype. Large format thick (subgross) and thin section histopathologic images of breast cancers diagnosed as "diffusely infiltrating lobular carcinoma of the breast" were correlated with their mammographic tumour features (imaging biomarkers) and the long-term patient outcome. RESULTS: This malignancy does not have a distinct tumour mass or focal skin retraction at clinical breast examination; instead, it causes an indistinct "thickening" and eventually shrinks the entire breast. A dominant feature is extensive architectural distortion on the mammograms caused by an excessive amount of cancer-associated connective tissue. Unlike other invasive breast malignancies, this subtype forms concave contours with the surrounding adipose connective tissue, a feature that makes it difficult to detect on mammograms. Women with this diffusely infiltrating breast malignancy have a 60% long-term survival. Its long-term patient outcome is surprisingly poor compared to that expected from its relatively favourable immunohistochemical biomarkers, including a low proliferation index and remains unaffected by adjuvant therapy. CONCLUSIONS: The unusual clinical, histopathologic and imaging features of this diffusely infiltrating breast cancer subtype are consistent with a site of origin quite different from that of other breast cancers. Additionally, the immunohistochemical biomarkers are deceptive and unreliable because they indicate a cancer with favourable prognostic features predictive of a good long-term outcome. The low proliferation index is usually indicative of a breast cancer with a good prognosis, but in this subtype the prognosis is poor. If we are to improve the dismal outcome of this malignancy, it will be necessary to clarify its true site of origin, which will be a prerequisite for gaining a better understanding why current management efforts often fail and why the fatality rate is so unfortunately high. Breast radiologists should be watchful for the development of subtle signs of architectural distortion at mammography. Large format histopathologic technique enables adequate correlation of the imaging and histopathologic findings.

Sex differences in the change of exercise behavior leading to incident metabolic syndrome reduction: A community-based prospective study.

This study was undertaken to assess the role of sex differences in the effects of exercise behavior change on incident metabolic syndrome (MetS) in Changhua County, Taiwan. Using data derived from the Changhua Community-based Integrated Screening (CHCIS), 22,594 eligible residents aged 40 years or older had the screening at least twice from 2005 to 2018. A prospective cohort study was designed to follow up the normal cohort without MetS at baseline to ascertain incident MetS in the light of the criteria of the Epidemiology Task Force Consensus Group. We then evaluated whether there was a sex difference in the outcome of incident MetS attributed to the change in exercise behavior from three (no, irregular, and regular exercise) maintained patterns already defined at baseline to either the enhanced pattern or the reduced pattern by the end of follow-up. We applied Cox proportional hazards regression model stratified by sex for estimating the hazard ratio of any two-group comparison. After adjustment for sociodemographic factors, the number of screenings attended, personal disease history, and other health behaviors, the influence of change in exercise behavior on incident MetS was statistically significant only in men. Specifically, maintaining no exercise showed a lower risk of MetS than maintaining regular exercise 21 % in men. Regarding the change in exercise behavior, men with the enhanced pattern reduced the risk of MetS by 15 % compared with those maintaining regular exercise. The findings suggest that positive changes in exercise behavior reduce the incidence of MetS in men but not in women.

Growth hormone in fertility and infertility: Mechanisms of action and clinical applications.

Secreted by the anterior pituitary gland, growth hormone (GH) is a peptide that plays a critical role in regulating cell growth, development, and metabolism in multiple targeted tissues. Studies have shown that GH and its functional receptor are also expressed in the female reproductive system, including the ovaries and uterus. The experimental data suggest putative roles for GH and insulin-like growth factor 1 (IGF-1, induced by GH activity) signaling in the direct control of multiple reproductive functions, including activation of primordial follicles, folliculogenesis, ovarian steroidogenesis, oocyte maturation, and embryo implantation. In addition, GH enhances granulosa cell responsiveness to gonadotropin by upregulating the expression of gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), indicating crosstalk between this ovarian regulator and the endocrine signaling system. Notably, natural gene mutation of GH and the age-related decline in GH levels may have a detrimental effect on female reproductive function, leading to several reproductive pathologies, such as diminished ovarian reserve, poor ovarian response during assisted reproductive technology (ART), and implantation failure. Association studies using clinical samples showed that mature GH peptide is present in human follicular fluid, and the concentration of GH in this fluid is positively correlated with oocyte quality and the subsequent embryo morphology and cleavage rate. Furthermore, the results obtained from animal experiments and human samples indicate that supplementation with GH in the in vitro culture system increases steroid hormone production, prevents cell apoptosis, and enhances oocyte maturation and embryo quality. The uterine endometrium is another GH target site, as GH promotes endometrial receptivity and pregnancy by facilitating the implantation process, and the targeted depletion of GH receptors in mice results in fewer uterine implantation sites. Although still controversial, the administration of GH during ovarian stimulation alleviates age-related decreases in ART efficiency, including the number of oocytes retrieved, fertilization rate, embryo quality, implantation rate, pregnancy rate, and live birth rate, especially in patients with poor ovarian response and recurrent implantation failure.

Effect of social media use on food safety risk perception through risk characteristics: Exploring a moderated mediation model among people with different levels of science literacy.

Food safety risk (FSR) is becoming a vital issue for public health, and improving public awareness of FSR through social media is necessary. This study aims to explore specific mechanisms of FSR perception; it first categorizes 19 risk characteristics into two variables, dread and efficacy, and then examines how social media use affects perceived FSR through both variables. Additionally, the study explores the moderating effects of source credibility and science literacy on the mechanisms of FSR perception. Based on a nationwide online survey (N = 2,015) of more than six salient food safety issues in China, the study found that exposure to food safety risk information on social media can help improve perceived FSR based on the proposed "dread-efficacy processing model" (DEPM), where dread stimulates perceived risk, while efficacy suppresses risk perception. Moreover, source credibility intensifies the effect of social media use on efficacy appraisal, whereas science literacy exerts a "double-weakening" influence on dread appraisal. Theoretical and practical implications of the findings are discussed.

Evaluating correlates of protection for mix-match vaccine against COVID-19 VOCs with potential of evading immunity.

BACKGROUND: In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination. METHODS: Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 âˆ¼ 11-fold, 2 âˆ¼ 5.5-fold, and 32.5 âˆ¼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant.

Communication in Oncology Outpatient Clinic Settings: Congruence of Quality of Life Assessment between Patient-Physician and Patient-Caregiver Dyads.

Objectives: The aims of this study were to investigate the congruence of HRQOL reports between patient-physician and patient-caregiver dyads and to determine the association of variables, if any, with the congruence between dyads. Methods: This correlational study with a cross-sectional design first approached physicians who provided care for patients with advanced cancer at the participating institution. Then, participating physicians' patients and their caregivers were recruited. All participants were required to independently fill out an HRQOL questionnaire during their outpatient visits. Descriptive statistics, weighted kappa, Wilcoxon signed-rank test, and linear regression were employed for data analysis. Results: A total of 52 patient-physician and 27 patient-caregiver dyads were examined. Patients suffered from considerable problems in all three HRQOL domains: symptom, functioning, and overall HRQOL. The patients' level of agreement was moderate with the caregivers and fair with the physicians. A significant relationship was found between several patient-related variables and disagreement. Conclusion: These patients with advanced cancer experienced a compromised HRQOL, warranting immediate attention. When there are barriers to obtaining a patient's self-report, clinicians may consider caregivers as a reasonable source. Patients with special characteristics need additional attention because their problems may be at a greater risk of being overlooked.

Ranking the environmental factors of indoor air quality of metropolitan independent coffee shops by Random Forests model.

Independent coffee shops are the alternative workplaces for people working remotely from traditional offices but are not concerned about their indoor air quality (IAQ). This study aimed to rank the environmental factors in affecting the IAQ by Random Forests (RFs) models. The indoor environments and human activities of participated independent coffee shops were observed and recorded for 3 consecutive days including weekdays and weekend during the business hours. The multi-sized particulate matter (PM), particle-bound polycyclic aromatic hydrocarbons (p-PAHs), total volatile organic compounds (TVOCs), CO, CO2, temperature and relative humidity were monitored. RFs models ranked the environmental factors. More than 20% of the 15-min average concentrations of PM10, PM2.5, and CO2 exceeded the World Health Organization guidelines. Occupant density affected TVOCs, p-PAHs and CO2 concentrations directly. Tobacco smoking dominated PM10, PM2.5, TVOCs and p-PAHs concentrations mostly. CO concentration was affected by roasting bean first and tobacco smoking secondly. The non-linear relationships between temperature and these pollutants illustrated the relative low concentrations happened at temperature between 22 and 24 °C. Tobacco smoking, roasting beans and occupant density are the observable activities to alert the IAQ change. Decreasing CO2 and optimizing the room temperature could also be the surrogate parameters to assure the IAQ.

Population-based Oral Cancer Service Screening Disrupted by COVID-19 Pandemic: Observational and Simulation Study

BackgroundIt is important for understanding the impact of COVID-19 pandemic on the missing opportunity for the early detection of oral cancer. This study aimed to assess the impact of COVID-19 pandemic on the existing population-based oral cancer (OC) service screening program in Taiwan. MethodsBefore and after COVID-19 pandemic design was used to assess the impact of COVID-19 on the reduction of screening rate, referral rate, and the effectiveness of this OC service screening. Data and analysis after pandemic covered non-VOC period in 2020 and VOC period in 2021 compared to the historical control before pandemic in 2019. ResultsThe screening rate decreased substantially from 26.6% before COVID-19 in 2019 to 16.7% in 2020 and 15.3% in 2021 after pandemic. The reduction of screening rate varied with months, being the most remarkable decline in March (RR=0.61, 95% CI (0.60-0.62)) and June (RR=0.09, 95% CI (0.09-0.10)) in 2021 compared with January. The referral rate was stable at 81.5% in 2020 but it was reduced to 73.1% in 2021. The reduction of screening and referral rate led to the attenuation of effectiveness of advance cancer and mortality attenuated by 4% and 5%, respectively. ConclusionCOVID-19 pandemic disrupted the screening and the referral rate and further led to statistically significant reduction in effectiveness for preventing advanced cancer and death. Appropriate prioritized strategies must be adopted to ameliorate malignant transformation and tumor upstaging due to deference from participation in the screening. FundingThis study was financially supported by Health Promotion Administration of the Ministry of Health and Welfare of Taiwan (A1091116).

Feasibility of Recombinant Human TSH as a Preparation for Radioiodine Therapy in Patients with Distant Metastases from Papillary Thyroid Cancer: Comparison of Long-Term Survival Outcomes with Thyroid Hormone Withdrawal.

BACKGROUND: this study was designed to compare the long-term survival outcomes of patients prepared for radioiodine (RAI) therapy using either thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH) stimulation, by specifically focusing on cases with distant metastases from papillary thyroid cancer (PTC). METHODS: A retrospective analysis was performed on 88 patients with distant metastases from PTC. Fifty-one and thirty-seven patients were prepared for RAI treatment by either THW or rhTSH stimulation, respectively. The primary endpoints were progression-free survival (PFS) and disease-specific survival (DSS). RESULTS: The 10-year DSS rates of patients prepared for RAI therapy using either THW or rhTSH stimulation were 62.2% and 73.3%, respectively. Using multivariate analysis, RAI-avid metastases (p = 0.025) and preparation with rhTSH (p = 0.041) were identified as independent prognostic factors for PFS. Notably, PFS in the group of patients with RAI-avid metastases and preparation with rhTSH was significantly better than that in the other groups (p = 0.025). CONCLUSIONS: Preparation for RAI therapy using rhTSH stimulation is not inferior to THW preparation in terms of long-term survival outcomes experienced by patients with PTC and distant metastasis. Patients with RAI-avid metastases and preparation with rhTSH had the most favorable PFS.

Epidemic Surveillance Models for Containing the Spread of SARS-CoV-2 Variants: Taiwan Experience

ObjectivesTwo kinds of epidemic surveillance models are presented for containing the spread of SARS-CoV-2 variants so as to avert and stamp out a community-acquired outbreak (CAO) with non-pharmaceutical interventions (NPIs), tests, and vaccination. DesignThe surveillance of domestic cluster infections transmitted from imported cases with one-week time lag assessed by the Poisson model and the surveillance of whether, how and when NPIs and test contained the CAO with the SEIR model. SettingsBorder and Community of Taiwan. Main Outcome MeasurementsThe expected number and the upper bound of the 95% credible interval (CrI) of weekly covid-19 cases compared with the observed number for assessing the threshold of a CAO; effective reproductive number (Rt) and the effectiveness of NPIs for containing a CAO. ResultsFor the period of January-September 2020 when the wild type and the D614G period were prevailing, an increase in one imported case prior to one week would lead to 9.54% (95% CrI 6.44% to 12.59%) higher risk of domestic cluster infection that provides a one-week prior alert signal for more stringent NPIs and active testing locally. Accordingly, there was an absence of CAO until the Alpha VOC period of February 2021. However, given level one of NPI alert the risk of domestic cluster infections was gradually elevated to 14.14% (95% CrI 5.41% to 25.10%), leading to the Alpha VOC CAOs of six hotspots around mid-May 2021. It took two-and-half months for containing this CAO mainly with level three of NPI alert and rapid test and partially by the rolling out of vaccination. By applying the SEIR model, the Rt decreased from 4.0 at beginning to 0.7 on 31 July 2021 in parallel with the escalating NPIs from 30% to 90%. Containing a small outbreak of Delta VOC during this CAO period was also evaluated and demonstrated. After controlling the CAO, it again returned to imported-domestic transmission for Delta VOC from July until September 2021, giving an estimate of 10.16% (95% CrI: 7.01% to 13.59%) for the risk of several small cluster infections. However, there was an absence of CAO that resulted from the effectiveness of NPIs and tests, and the rapid expansion of vaccination. ConclusionsAverting and containing CAOs of SARS-CoV-2 variants are demonstrated by two kinds of epidemic surveillance models that have been applied to Taiwan scenario. These two models can be accommodated to monitor the epidemic of forthcoming emerging SARS-CoV-2 VOCs with various circumstances of vaccine coverage, NPIs, and tests in countries worldwide.

The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-CoV-2 in cell culture models

The SARS-CoV-2 pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure dimerization of ACE2, the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in ELISA and whole cell binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, these studies identify fenofibrate as a potential therapeutic agent requiring urgent clinical evaluation to treat SARS-CoV-2 infection. TeaserThe approved drug fenofibrate inhibits infection by SARS-COV-2

Bayesian approach for modelling the dynamic of COVID-19 outbreak on the Diamond Princess Cruise Ship

The outbreaks of acute respiratory infectious disease with high attack rates on cruise ships were rarely studied. The outbreak of COVID-19 on the Diamond Princess Cruise Ship provides an unprecedented opportunity to estimate its original transmissibility with basic reproductive number (R0) and the effectiveness of containment measures. The traditional deterministic approach for estimating R0 is based on the outbreak of a large population size rather than that a small cohort of cruise ship. The parameters are therefore fraught with uncertainty. To tackle this problem, we developed a Bayesian Susceptible-Exposed-Infected-Recovery (SEIR) model with ordinary differential equation (ODE) to estimate three parameters, including transmission coefficients, the latent period, and the recovery rate given the uncertainty implicated the outbreak of COVID-19 on cruise ship with modest population size. Based on the estimated results on these three parameters before the introduction of partial containment measures, the natural epidemic curve after intervention was predicted and compared with the observed curve in order to assess the efficacy of containment measures. With the application of the Bayesian model to the empirical data on COVID-19 outbreak on the Diamond Princess Cruise Ship, the R0 was estimated as high as 5.71(95% credible interval: 4.08-7.55) because of its aerosols and fomite transmission mode. The simulated trajectory shows the entire epidemic period without containment measurements was approximately 47 days and reached the peak one month later after the index case. The partial containment measure reduced 34% (95% credible interval: 31-36%) infected passengers. Such a discovery provides an insight into timely evacuation and early isolation and quarantine with decontamination for containing other cruise ships and warship outbreaks.

Easing social distancing index after COVID-19 pandemic

ContextEasing social distancing (ESD) is a global public health issue in post-pandemic period of COVID-19 and requires a simple index for real time assessment. ObjectiveWe aimed to develop a simple index for ESD to quantify the impacts of social distancing for reducing confirmed infected cases, optimal triage and care of patients for recovery, and critical care capacity for reducing death from COVID-19. Design, Setting, and ParticipantsData on the retrospective cohort of 185 countries with reported numbers on confirmed cases, recovery, and death from COVID-19 were retrieved from publicity available repository. Up to May 31, a total of 5,844,136 confirmed cases, 2,639,961 recovered, and 327,487 deaths were reported globally. Main Outcome MeasuresThe ESD index measured by cumulative number of COVID-19 cases and recovery and case-fatality rate. ResultsWe developed a simple index for the guidance of easing social distancing (ESD). If the ESD index is less than 1, ESD would be considered. The global ESD index declined from 3.87 at peak in March to 1.35 by the end of May, consisting of 56.76% countries/regions (105/185) with the ESD lower than one. Conclusion and RelevanceThis simple ESD index provides a quantitative assessment on whether and when to ease social distancing from local to global community.

Pixatimod (PG545), a clinical-stage heparan sulfate mimetic, is a potent inhibitor of the SARS-CoV-2 virus

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a co-receptor with the ACE2 protein for recognition of the S1 spike protein on SARS-CoV-2 virus, providing a tractable new target for therapeutic intervention. Clinically-used heparins demonstrate inhibitory activity, but world supplies are limited, necessitating alternative solutions. Synthetic HS mimetic pixatimod is a drug candidate for cancer with immunomodulatory and heparanase-inhibiting properties. Here we show that pixatimod binds to and destabilizes the SARS-CoV-2 spike protein receptor binding domain (S1-RBD), and directly inhibits its binding to human ACE2, consistent with molecular modelling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of monkey Vero E6 and human bronchial epithelial cells at concentrations within its safe therapeutic dose range. Furthermore, in a K18-hACE2 mouse model pixatimod demonstrates that pixatimod markedly attenuates SARS-CoV-2 viral titer and COVID-19-like symptoms. This demonstration of potent anti-SARS-CoV-2 activity establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics. Together with other known activities of pixatimod our data provides a strong rationale for its clinical investigation as a potential multimodal therapeutic to address the COVID-19 pandemic.