Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography.

Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.

A novel galactose electrochemical biosensor intended for point-of-care measurement of quantitative liver function using galactose single-point test.

Liver disease has emerged as a healthcare burden because of high hospitalization rates attributed both to steatohepatitis and to severe hepatic toxicity associated with changes of drug exposure. Early detection of hepatic insufficiency is critical to preventing long-term liver damage. The galactose single-point test is recommended by the US FDA as a sensitive means to quantify liver function, yet the conventional method used for quantitation of circulating galactose still relies on the standard colorimetric method, requiring time-consuming and labor-intensive processes, and is confined to the medical laboratory, thus limiting prevalence. To facilitate time- and cost-effective disease management particularly during a pandemic, a pocket-sized rapid quantitative device consisting of a biosensor and electrochemical detection has been developed. An in vitro validation study demonstrated that the coefficient of variation was less than 15% and deviations were between -4 and 14% in the range of 100-1500 µg/mL. The device presented good linear fit (correlation coefficient, r = 0.9750) over the range of 150-1150 µg/mL. Moreover, the device was found to be free from interference of common endogenous and exogenous substances, and deviated hematocrit, enabling a direct measurement of galactose in the whole blood without sample pre-treatment steps. The clinical validation comprising 118 subjects showed high concordance (r = 0.953) between the device and the conventional colorimetric assay. Thus, this novel miniaturized device is reliable and robust for routine assessment of quantitative liver function intended for follow-up of hepatectomy, drug dose adjustment, and screening for galactosemia, allowing timely and cost-effective clinical management of patients.

A Double-blind, Randomized Phase 2 Controlled Trial of Intradermal Hepatitis B Vaccination With a Topical Toll-like Receptor 7 Agonist Imiquimod, in Patients on Dialysis.

BACKGROUND: Patients on dialysis are hyporesponsive to the hepatitis B virus vaccines (HBVv). We examined intradermal (ID) HBVv Sci-B-Vac, with topical Toll-like receptor 7 (TLR7) agonist imiquimod pretreatment in dialysis patients. METHODS: We enrolled and prospectively followed adult patients on dialysis between January 2016 and September 2018. Eligible patients were randomly allocated (1:1:1) into 1 treatment group, topical imiquimod cream followed by ID HBVv (IMQ + ID); and 2 control groups: topical aqueous cream (placebo) followed by ID HBVv (AQ + ID) or topical aqueous cream followed by intramuscular HBVv (AQ + IM). The primary endpoint was the seroprotection rate (hepatitis B surface antibody ≥10 mIU/mL) at 52 weeks. RESULTS: Ninety-four patients were enrolled, among which 57.4% were previous nonresponders. Seroprotection rate was significantly better at week 52 for the IMQ + ID group with 96.9% compared to 74.2% and 48.4% for AQ + ID and AQ + IM groups, respectively (P < .0001). The geometric mean concentration was significantly higher at week 52 for the IMQ + ID group: 1135 (95% confidence interval [CI], 579.4-2218.2) mIU/mL, compared to 86.9 (95% CI, 18.5-409.3) mIU/mL and 7.2 (2.0-26.5) mIU/mL for the AQ + ID and AQ + IM groups, respectively (P < .0001). IMQ + ID vaccination (odds ratio, 3.70 [95% CI, 1.16-11.81]; P = .027) was the only factor independently associated with higher 52-week seroprotection rate. Adverse reaction was infrequent. CONCLUSIONS: Pretreatment with topical imiquimod before ID HBVv Sci-B-Vac was safe with favorable seroprotection in dialysis patients. CLINICAL TRIALS REGISTRATION: NCT02621112.

Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys.

The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2=6.9h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1-0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100µg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.

Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome.

The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.

Deep-learning-enabled protein-protein interaction analysis for prediction of SARS-CoV-2 infectivity and variant evolution.

Host-pathogen interactions and pathogen evolution are underpinned by protein-protein interactions between viral and host proteins. An understanding of how viral variants affect protein-protein binding is important for predicting viral-host interactions, such as the emergence of new pathogenic SARS-CoV-2 variants. Here we propose an artificial intelligence-based framework called UniBind, in which proteins are represented as a graph at the residue and atom levels. UniBind integrates protein three-dimensional structure and binding affinity and is capable of multi-task learning for heterogeneous biological data integration. In systematic tests on benchmark datasets and further experimental validation, UniBind effectively and scalably predicted the effects of SARS-CoV-2 spike protein variants on their binding affinities to the human ACE2 receptor, as well as to SARS-CoV-2 neutralizing monoclonal antibodies. Furthermore, in a cross-species analysis, UniBind could be applied to predict host susceptibility to SARS-CoV-2 variants and to predict future viral variant evolutionary trends. This in silico approach has the potential to serve as an early warning system for problematic emerging SARS-CoV-2 variants, as well as to facilitate research on protein-protein interactions in general.

Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis.

Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility.

COVID-19 in early 2021: current status and looking forward.

Since the first description of a coronavirus-related pneumonia outbreak in December 2019, the virus SARS-CoV-2 that causes the infection/disease (COVID-19) has evolved into a pandemic, and as of today, >100 million people globally in over 210 countries have been confirmed to have been infected and two million people have died of COVID-19. This brief review summarized what we have hitherto learned in the following areas: epidemiology, virology, and pathogenesis, diagnosis, use of artificial intelligence in assisting diagnosis, treatment, and vaccine development. As there are a number of parallel developments in each of these areas and some of the development and deployment were at unprecedented speed, we also provided some specific dates for certain development and milestones so that the readers can appreciate the timing of some of these critical events. Of note is the fact that there are diagnostics, antiviral drugs, and vaccines developed and approved by a regulatory within 1 year after the virus was discovered. As a number of developments were conducted in parallel, we also provided the specific dates of a number of critical events so that readers can appreciate the evolution of these research data and our understanding. The world is working together to combat this pandemic. This review also highlights the research and development directions in these areas that will evolve rapidly in the near future.

COVID-19 Delta variants-Current status and implications as of August 2021.

The SARS-CoV-2 Delta variant has evolved as the dominant strain of the current pandemic. Studies have shown that this variant has increased infectivity/viral load, and reduced neutralization by the host antibodies from convalescent patients/vaccinees. Clinically, Delta variant infection has been observed/documented in convalescent patients/vaccinees, although with less incidence of severe diseases, but can serve as reservoir to spread the infection to the unvaccinated. The current understanding (as of 18 August 2021) on the virologic aspect (including the amino acid substitutions), clinical implications, and public health implications will be discussed in this mini review, and recommendations to health authorities will be provided.

Significant reduction of humoral response to SARS-CoV-2 4 months after the diagnosis of COVID-19.

A commentary on "Humoral immune response to SARS-CoV-2 in Iceland".

Rational design, engineer, and characterization of a novel pegylated single isomer human arginase for arginine depriving anti-cancer treatment.

AIMS: Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. MAIN METHODS: Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20 kDa linear as A20L, 20 kDa branched as A20Y, and 40 kDa branched as A40Y) by cell-based and animal studies. KEY FINDINGS: Arginase conjugates showed comparable systemic half-lives, about 20 h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72 h after drug administration. Arginase modified with a linear 20 kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. SIGNIFICANCE: These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism.

The SARS-CoV-2 spike L452R-E484Q variant in the Indian B.1.617 strain showed significant reduction in the neutralization activity of immune sera.

To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q variant), pseudotyped virus was constructed (with the D614G background). The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay. Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/new vaccine development.

A deep-learning pipeline for the diagnosis and discrimination of viral, non-viral and COVID-19 pneumonia from chest X-ray images.

Common lung diseases are first diagnosed using chest X-rays. Here, we show that a fully automated deep-learning pipeline for the standardization of chest X-ray images, for the visualization of lesions and for disease diagnosis can identify viral pneumonia caused by coronavirus disease 2019 (COVID-19) and assess its severity, and can also discriminate between viral pneumonia caused by COVID-19 and other types of pneumonia. The deep-learning system was developed using a heterogeneous multicentre dataset of 145,202 images, and tested retrospectively and prospectively with thousands of additional images across four patient cohorts and multiple countries. The system generalized across settings, discriminating between viral pneumonia, other types of pneumonia and the absence of disease with areas under the receiver operating characteristic curve (AUCs) of 0.94-0.98; between severe and non-severe COVID-19 with an AUC of 0.87; and between COVID-19 pneumonia and other viral or non-viral pneumonia with AUCs of 0.87-0.97. In an independent set of 440 chest X-rays, the system performed comparably to senior radiologists and improved the performance of junior radiologists. Automated deep-learning systems for the assessment of pneumonia could facilitate early intervention and provide support for clinical decision-making.

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies.

Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the beta rather than the alpha isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2beta(+) than in skin-specific top2beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2beta-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2alpha-dependent. These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.

Estimated prevalence and viral transmissibility in subjects with asymptomatic SARS-CoV-2 infections in Wuhan, China.

The role of subjects with asymptomatic SARS-CoV-2 infection in the current pandemic is not well-defined. Based on two different approaches to estimate the culminative attack rate (seroprevalence of antibodies against SARS-CoV-2, and a four compartment mathematical model) and the reported number of patients with COVID-19, the ratio of asymptomatic versus symptomatic SARS-CoV-2 infection was estimated to be 7 (95% CI: 2.8-12.4) in Wuhan, Hubei, China, the first epicenter of this pandemic, which has settled with no new cases. Together with detailed recording of the contact sources in a cohort of patients, and applying the estimations to an established mathematical model, the viral transmissibility of the subjects with asymptomatic SARS-CoV-2 infection is around 10% of that of the symptomatic patients (95% CI: 7.6%-12.3%). Public health measures/policies should address this important pool of infectious source in combat against this viral pandemic.

A four-compartment model for the COVID-19 infection-implications on infection kinetics, control measures, and lockdown exit strategies.

Objective: To analyse the impact and repercussions of the surge in healthcare demand in response to the COVID-19 pandemic, assess the potential effectiveness of various infection/disease control measures, and make projections on the best approach to exit from the current lockdown. Design: A four-compartment model was constructed for SARS-CoV-2 infection based on the Wuhan data and validated with data collected in Italy, the UK, and the US. The model captures the effectiveness of various disease suppression measures in three modifiable factors: (a) the per capita contact rate (ß) that can be lowered by means of social distancing, (b) infection probability upon contacting infectious individuals that can be lowered by wearing facemasks, personal hygiene, etc., and (c) the population of infectious individuals in contact with the susceptible population, which can be lowered by quarantine. The model was used to make projections on the best approach to exit from the current lockdown. Results: The model was applied to evaluate the epidemiological data and hospital burden in Italy, the UK, and the US. The control measures were identified as the key drivers for the observed epidemiological data through sensitivity analyses. Analysing the different lockdown exit strategies showed that a lockdown exit strategy with a combination of social separation/general facemask use may work, but this needs to be supported by intense monitoring which would allow re-introduction/tightening of the control measures if the number of new infected subjects increases again. Conclusions and relevance: Governments should act early in a swift and decisive manner for containment policies. Any lockdown exit will need to be monitored closely, with regards to the potential of lockdown reimplementation. This mathematical model provides a framework for major pandemics in the future.

A novel scoliosis instrumentation using special superelastic nickel-titanium shape memory rods: a biomechanical analysis using a calibrated computer model and data from a clinical trial.

STUDY DESIGN: Biomechanical analysis of scoliosis instrumentation using superelastic Nickel-titanium shape memory (SNT) rods. OBJECTIVE: To compare SNT with conventional Titanium (Ti) and Cobalt-chrome (Co-Cr) rods. A clinical trial has documented comparable efficacy between two adolescent idiopathic scoliosis (AIS) cohorts instrumented using SNT versus conventional Ti rods. The shape memory and superelasticity of the SNT rod are thought to allow easy rod insertion, progressive curve correction, and correction from spinal tissue relaxation, but study is yet to be done to assess the effects of the shape memory and superelasticity. METHODS: Instrumentations of AIS patients from the clinical trial were computationally simulated using SNT, Ti and Co-Cr rods (5.5 or 6 mm; 30°, 50° or 60° sagittal contouring angles; 0°, 25° or 50° coronal over-contouring angles). Curve correction, its improvement from stress relaxation in the spine, and loads in the instrumentation constructs were computed and compared. RESULTS: The simulated main thoracic Cobb angles (MT) and thoracic kyphosis with the SNT rods were 4°-7° higher and 1°-2° lower than the Ti and Co-Cr rods, respectively. Bone-implant forces with Ti and Co-Cr rods were higher than the SNT rods by 84% and 130% at 18 °C and 35% and 65% at 37 °C, respectively (p < 0.001). Further corrections of the MT from the simulated stress relaxation in the spine were 4°-8° with the SNT rods versus 2°-5° with the Ti and Co-Cr rods (p < 0.001). CONCLUSION: This study concurs with clinical observation that the SNT rods are easier to insert and can result in similar correction to the conventional rods. The SNT rods allow significantly lower bone-implant forces and have the ability to take advantage of post-instrumentation correction as the tissues relax.

Personnel protection strategy for healthcare workers in Wuhan during the COVID-19 epidemic.

Objective: To identify the effectiveness of a personnel protection strategy in protection of healthcare workers from SARS-CoV-2 infection. Design: During the COVID-19 pandemic, 943 healthcare staff sent from Guangzhou to Wuhan to care for patients with suspected/confirmed COVID-19 received infection precaution training before their mission and were equipped with Level 2/3 personal protective equipment (PPE), in accordance with guidelines from the National Health Commission of China. We conducted a serological survey on the cumulative attack rate of SARS-CoV-2 among the healthcare workers sent to Wuhan and compared the seropositive rate to that in local healthcare workers from Wuhan and Jingzhou. Results: Serial tests for SARS-CoV-2 RNA and tests for SARS-CoV-2 immunoglobulin M and G after the 6-8 week mission revealed a zero cumulative attack rate. Among the local healthcare workers in Wuhan and Jingzhou of Hubei Province, 2.5% (113 out of 4495) and 0.32% (10 out of 3091) had RT-PCR confirmed COVID-19, respectively. The seropositivity for SARS-CoV-2 antibodies (IgG, IgM, or both IgG/IgM positive) was 3.4% (53 out of 1571) in local healthcare workers from Wuhan with Level 2/3 PPE working in isolation areas and 5.4% (126 out of 2336) in healthcare staff with Level 1 PPE working in non-isolation medical areas, respectively. Conclusions and relevance: Our study confirmed that adequate training/PPE can protect medical personnel against SARS-CoV-2.

COVID-19: Special Precautions in Ophthalmic Practice and FAQs on Personal Protection and Mask Selection.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory coronavirus-2, was first reported in December 2019. The World Health Organization declared COVID-19 a pandemic on March 11, 2020 and as of April 17, 2020, 210 countries are affected with >2,000,000 infected and 140,000 deaths. The estimated case fatality rate is around 6.7%. We need to step up our infection control measures immediately or else it may be too late to contain or control the spread of COVID-19. In case of local outbreaks, the risk of infection to healthcare workers and patients is high. Ophthalmic practice carries some unique risks and therefore high vigilance and special precautions are needed. We share our protocols and experiences in the prevention of infection in the current COVID-19 outbreak and the previous severe acute respiratory syndrome epidemic in Hong Kong. We also endeavor to answer the key frequently asked questions in areas of the coronaviruses, COVID-19, disease transmission, personal protection, mask selection, and special measures in ophthalmic practices. COVID-19 is highly infectious and could be life-threatening. Using our protocol and measures, we have achieved zero infection in our ophthalmic practices in Hong Kong and China. Preventing spread of COVID-19 is possible and achievable.

Author Correction: Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.