Referee ReportThe manuscript at hand reports an overview of the computational alchemy approach to evaluate catalysts and provides a standard procedure to perform such computations for specific applications. The paper does not present any new research, but rather outlines the computational alchemy method and provides an open-source and user-friendly tool to the community for them to efficiently perform their own catalyst search. Computational alchemy is an approximate method that allows us to obtain large data from a single DFT calculation, thus allowing us to perform large-scale screening of catalysts. This method was initially described by Straatsma and McCammon in 1992 and has been recently shown to hold great promise in accelerating catalyst search with less computational effort. The current work gives a detailed review of this approach and describes all the approximations that go into the methodThe manuscript provides two examples of implementation of the method, which include prediction of binding energies for OH adsorption on Pt(111) surface and predictions of reaction barriers of CH4* dehydrogenation on Pt(111) surface. These two examples serve as benchmarks of the method for binding energy estimation and reaction barrier estimation, respectively. Additionally, the authors have developed a web interface, using Jupyter Notebooks, for an easy understanding of the implementation of the method.  In conclusion, the manuscript is predominantly well written, presents a clear description of the methodology, benchmarks the methods using two examples, and provides clear and user-friendly software. I believe the tools provided will be of significant use to the materials design community and aid in the design of new catalyst materials. My recommendation, therefore, is to accept the manuscript to be published in the International Journal of Quantum Chemistry.I identified a few typos in the manuscript, which I mentioned as comments on the Authorea platform. 

Pollutants can have severe detrimental effects on insects, even at sublethal doses. Agrochemicals have been identified as important causes of pollinator declines, but the impacts of other anthropogenic compounds, such as metallic trace elements contaminating soils and waters, have received considerably less attention. Here, we exposed honey bee colonies to chronic field-realistic concentrations of lead in food and demonstrate that consumption of this single trace element impaired bee cognition and morphological development. Honey bees exposed to the highest lead concentration had reduced olfactory learning performances and developed smaller heads, which may have constrained their cognitive functions. Our results show that lead pollutants can have dramatic effects on honey bee health and may contribute to the widespread decline of pollinators.

1. The role of interspecific interactions in structuring low-diversity helminth communities is a controversial topic in parasite ecology research. Most parasitic communities of fish are species poor; thus, interspecific interactions are believed to be unimportant in structuring these communities. 2. We explored the factors that might contribute to the richness and coexistence of helminth parasites of a poecilid fish in a neotropical river. 3. Repeatability of community structure was examined in parasitic communities among 11 populations of Pseudoxiphophorus bimaculatus in the La Antigua River Basin, Veracruz, Mexico. We examined the species saturation of parasitic communities and explored the patterns of species co-occurrence. We also quantified the associations between parasitic species pairs and analysed the correlations between helminth species abundance to look for repeated patterns among the study populations. 4. Our results suggested that interspecific competition could occur in species-poor communities, aggregation played a role in determining local richness, and intraspecific aggregation allowed the coexistence of species by reducing the overall intensity of interspecific competition.

Background: Early extubation after cardiac surgery results in better postoperative outcomes but the optimal time for extubation remains unclear. Premature extubation may lead to unplanned reintubation that may result in adverse outcomes. The present study was undertaken to compare preoperative and operative risks and outcomes of patients with prolonged intubation >48 hours and reintubation after cardiac surgery. Aims: This is a retrospective chart review of 1259 patients who had cardiac surgery at a community hospital. After excluding patients with either operating room death, extubation <48 hours without reintubation or extubation >48 hours with reintubation, the final sample included 83 patients (6.6%) requiring reintubation after extubation in <48 hours and 100 (8.0%) with prolonged intubation without requiring reintubation. Results: Bivariate analyses revealed few statistically different preoperative and operative risks between patients with reintubation and prolonged intubation. Reintubation patients were older (p = .033) and had lower body mass index (p = .000), higher preoperative hematocrit (p = .021), and more chronic kidney disease stages >2 (p = .046) but lower odds for intra-aortic balloon pump (p = .006) and emergency surgery (p = .005). Reintubation led to worse postoperative outcomes than prolonged intubation: more acute kidney injury stage 1-3 (p = .014), coma/encephalopathy (p = .004), postoperative transfusion (p = .003), increased intensive care unit length of stay (p = .001) and hospital mortality (p = .007). Based on binary and ordinal logistic regression analyses, the differences in preoperative and operative risks were either inconsistent or trivial contributors and reintubation appears to make the largest independent contribution to poor postoperative outcomes. Conclusion: While early extubation remains the goal, patients with marginal weaning readiness may benefit from more recovery time before extubation. This study suggests that premature extubation may increase unplanned reintubation that could adversely affect postoperative outcomes after cardiac surgery.

Influence grain miss-orientations have on mechanical behaviour of Ni-based DS superalloys was investigated using crystal plasticity finite element modelling, in this review. Loading axes aligned with solidification direction, in both low-cycle-fatigue (LCF) and fatigue-crack-growth (FCG) behaviour, were considered. Influences of grain miss-orientations were investigated based on FE-modelling using actual microstructures measured with EBSD. Since the FE-modelling was able to simulate full history of fatigue stress-strain responses, under LCF loading, it was employed to explain heterogeneous deformation and localised high-stresses (dependent on grain-sizes and miss-orientations) linked to shorter LCF-life in test data that validated the FE-model. The model was then used to study FCG behaviour by considering crack-tip deformation under fatigue loading. Since FCG was exclusively due to mechanical deformation, it was sufficient to use accumulated plastic strain as a damage criterion, in XFEM. Results revealed a high dependency on grain-orientation.

Several classes of exact analytic solutions for the time-fractional (2+1)-dimensional Ito equation are derived with the aid of Mathematica package. The Kudryashov simple equation method and its modified version are implemented to tackle the mentioned equation analytically. The obtained soliton solutions have been expressed by Logarithmic, Logarithmic-exponential, Logarithmic-periodic, and Logarithmic-hyperbolic functions with a set of free parameters. Graphical illustrations for some obtained solutions with special choices of free constants and various fractional orders are included. The two used methods provide the effectiveness, applicability, and convenient handling of the solution process for nonlinear evolution equations that appear in the various real life problems.

Acquisition of new prophages that are able to increase the bacterial fitness by lysogenic conversion is believed to be important strategy of bacterial adaptation to changing environment. However, in contrast to the factors determining the range of bacteriophage lytic activity, little is known about the factors that define the lysogenization host range. Bacteriophage phi24B is the paradigmal model of stx-converting phages, encoding the toxins of the Shiga-toxigenic E. coli (STEC). This virus has been shown to lysogenize the wide range of E. coli strains that is much broader than the range of the strains supporting its lytic growth. Therefore, phages produced by the STEC population colonizing the small intestine are potentially able to lysogenize symbiotic E. coli in the hindgut, and these secondary lysogens may contribute to the overall patient toxic load and to lead to the emergence of new pathogenic STEC strains. We demonstrate, however, that O antigen effectively limit the lysogenization of the wild E. coli strains by phi24B phage. The lysogens are formed from the spontaneous rough mutants and therefore have increased sensitivity to other bacteriophages and to the bactericidal activity of the serum if compared to their respective parental strains.

The current Covid-19 pandemic is a significant global health threat. The outbreak has profoundly affected all healthcare professionals, including heart surgeons. To adapt to these exceptional circumstances, cardiac surgeons had to change their practice significantly. We herein discuss the challenges and broad implications of the Covid-19 pandemic from the perspective of the heart surgeons.

Objective: Increased adrenergic tone can be a trigger of orthostatic stress of vasovagal syncope (VVS). This study aimed to explore the diagnostic value of treadmill exercise test (TET) combined with head up tilt test (HUTT) for VVS. Methods: A total of 73 patients with unexplained syncope or presyncope were enrolled. VVS was diagnosed in 57 patients according to the Calgary Score (≥-2). Initially, all patients were subjected to the first HUTT. Then, patients with negative response in HUTT would further received TET on the next day. At last, patients who remained getting negative response in TET would be subjected to the second HUTT within 10min after TET. The symptoms of syncope, heart rate and blood pressure were recorded during the tests. Results: Syncope or presyncope occurred in 34 patients in the first HUTT. The sensitivity and specificity of HUTT for Calgary score-based VVS were 56.1% and 87.5%, respectively. Then, another 14 patients in TET and 9 patients in the second HUTT experienced syncope or presyncope during the tests. The sensitivity of TET combined with HUTT for VVS significantly increased to 94.7%, with the specificity only slightly decreasing to 81.3%. No patients required anticholinergics injection to restore vital signs during the tests. Conclusion: The combination of TET with HUTT is an effective and safe diagnostic strategy for VVS.

Background: Atrial conduction velocity may represent atrial fibrillation (AF) substrate after pulmonary vein isolation (PVI). To elucidate the association between whole left atrial conduction velocity (LACV) and AF recurrence after PVI. Methods and Results: This observational study enrolled 279 patients who underwent PVI alone as an initial AF ablation procedure. After PVI, the left atrium was mapped with a 20-pole multielectrode in conjunction with the CARTO3 system during 100-ppm right atrial pacing. Left atrial conduction distance and conduction time were calculated from the start to the end of the propagation wave front in the left atrium. LACVs on the anterior and posterior routes were calculated as conduction distance divided by conduction time. Anterior and posterior LACVs were slower in patients with AF recurrence than in those without (anterior, 0.79 [0.71, 0.86] vs. 0.96 [0.90, 1.06], p < 0.001; posterior, 0.99 [0.89, 1.14] vs. 1.10 [1.00, 1.29], p < 0.001). AF recurrence was best predicted by anterior LACV with a cut-off value of 0.87 m/s (sensitivity 87%, specificity 81%, and predictive accuracy 84%). Multivariate analysis demonstrated that a slow anterior LACV < 0.87 m/s was an independent predictor of AF recurrence with an adjusted hazard ratio of 11.8 (6.36 – 22.0). Patients with anterior low-voltage areas demonstrated slower anterior LACV than those without low-voltage areas (0.89 [0.71, 1.00] vs. 0.94 [0.87, 1.05], p < 0.001). Conclusion: A slow LACV in the entire left atrium was an excellent predictor of AF recurrence after PVI, suggesting the necessity of additional ablations.

Introduction: The isolation of superior vena cava (SVCI) and pulmonary vein isolation (PVI) improve the success rate of atrial fibrillation (AF) ablation. Limited information is available on the quantitative assessment of the narrowing of SVC after ablation. Methods: Ninety-one AF patients with SVC potentials were enrolled in this study. After PVI, SVCI was performed circumferentially at the level of the lower border of the right pulmonary artery. Radiofrequency (RF) pulses were delivered on a point-by-point basis for 30s at each point with an irrigated catheter in a temperature-controlled mode with the maximum temperature set at 42℃ and the maximum power at 25W. Follow up contrast-enhanced computed tomography was performed at four months after the ablation procedure. SVC narrowing was followed up in time (mean ± standard deviation = 20 ± 4.2 months). Results: All SVCIs were successfully achieved without severe complications. The pre-ablation SVC dimension at the level of the isolation line was 2.50 ± 0.94 cm2, and the post-ablation SVC dimension was 2.19 ± 0.82 cm2 (p = 0.016). Severe stenosis (reductions of SVC dimension > 75%) was not observed in this study. Moreover, the relationship between the SVC narrowing and the RF application time was not significant in this study. In the eight SVC cases with SVC narrowing, the mean SVC area recovered as a function time from 1.56 ± 0.42 cm2 to 1.80 ± 0.57cm2. Conclusion: The SVCI caused minor reductions in the SVC dimensions, but did not cause severe stenosis with life-threatening symptoms.

Objective: The clinical symptoms, audiological and imaging features of unilateral cochlear nerve canal stenosis were reported. Method: The clinical data of 12 patients with unilateral cochlear nerve canal stenosis diagnosed in Beijing Friendship Hospital from January 2018 to December 2019 were analyzed retrospectively, including age of onset, clinical symptoms, signs, audiology, HRCT and MRI of temporal bone and so on. Results: Twelve patients (6 males and 6 females) were identified with unilateral cochlear nerve canal stenosis. All patients presented with hearing loss and no other complaints. Among them, 2 patients were accompanied with accessory ears and the rest had no positive signs. 11 patients had severe sensorineural hearing loss, 1 patient had normal low-frequency hearing and high-frequency hearing loss. Imaging showed that 9 patients were suspected atresia of the cochlear nerve canal, 3 patients were narrow. Conclusion: For patients with unilateral stenosis of cochlear canal, early diagnosis and intervention should be carried out as early as possible, and the healthy ears should be protected.

Continuous monitoring and analysis of the evolution, recombination and epidemic of avian influenza virus will help to prevent and control the emergence of new avian influenza virus. The genes of 153 H5N6 avian influenza viruses selected from our long-term surveillance data and the GISAID for the 2016-2019 period were dissected in detail. Our analysis shows that the genes of H5N6 AIVs have been divided into more lineages, and that mutations leading to amino acid replacement of hemagglutinin and neuraminidase occurred mainly between 2017 and 2018. All H5N6 viruses are differentiated into at least 20 distinct genotypes derived from different evolutionary pathways. G1 genotype has replaced other genotypes to become dominant genotype of AIV. The results of animal experiments show that H5N6 of different genotypes has high virulence to mice. which indicates that H5N6 AIVs, especially the reassortment strains, are a potential threat to public health.

Objectives: Utilization of clinician-performed head and neck ultrasound among diagnostic radiologists, otolaryngologists, endocrinologists, and general surgeons, using Medicare Provider Utilization and Payment Data available through CMS.gov. Estimation of the potential impact clinician-performed ultrasounds may have on the traditional model of radiology-based ultrasound exams. Design: From 2012-2015, the files were filtered to include 4 provider types: Diagnostic Radiology (DR), Endocrinology (ENDO), General Surgery (GS), and Otolaryngology (OTO). Billable procedures are listed by HCPCS code and a filter was applied to include the following codes: 76536 Ultrasound, soft tissues of the head and neck, diagnostic; 76942 Ultrasonic guidance for needle placement; 10022 Fine needle aspiration, with imaging guidance. Setting: The Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File, available through the Centers for Medicare & Medicaid Services. Participants: Diagnostic Radiology (DR), Endocrinology (ENDO), General Surgery (GS), and Otolaryngology (OTO). Main outcome measures: Charges submitted, facility vs. non-facility, reimbursements, and superusers. Results and Conclusions: In 2015, OTOs submitted charges for 2.1% of all head and neck diagnostic ultrasounds (76536) performed on Medicare beneficiaries. DRs submitted more 76536 charges from 2012-2015, ENDOs to a lesser degree, and OTO and GS remained flat in charges. 10.5% of OTOs in the PUF submitted more than 100 charges apiece during 2015, as compared to a smaller proportion of radiologists (4.5%) who did so. Among surgeons in 2015, OTOs performed more diagnostic HNUS than GSs, and the percentage of OTOs performing US compared to their specialty peers was 3.5 times higher than GSs.

The paper deals with boundedness problems to integral operators in weighted grand Bochner-Lebesgue spaces. We will treat both cases: when a weight function appears as a multiplier in the definition of the norm, or when it defines the absolute continuous measure of integration. Together with the diagonal case we deal with the off-diagonal case. To get the appropriate result for the Hardy-Littlewood maximal operator we rely on the reasonable bound of the sharp constant in the Buckley type theorem which is also determined here.

Vitamin D insufficiency is closely related to various kinds of metabolic diseases. Acted as a marker of vitamin D status, 25-HydroxyvitaminD3 detection possesses important practical significance. In this study, highly sensitive fluorescent detection of 25-HydroxyvitaminD3 using truncated affinity-improved aptamers were developed, based on fluorescence intensity changes of PicoGreen (PG) generated upon binding to double-stranded DNA (dsDNA) formed through hybridization of aptamer and corresponding complementary strand. Four truncated aptamers were obtained by intercepting the small hairpin loop as the functional domain and retaining double helix structural domains of different lengths that exist in the selected original 25-HydroxyvitaminD3 aptamer. Under the optimized PG concentration, we conducted comparison experiments for affinity and specificity of these four truncated aptamers. Among them, the shortest aptamer with only 21 bp, D3-4, was found to show the highest affinity and specificity to 25-HydroxyvitaminD3, with the limit of detection of 0.04μg/mL, which solved the problem that original long aptamer could not applied for this fluorescent detection of 25-HydroxyvitaminD3. The truncated 25-HydroxyvitaminD3-specific aptamer with highly enhanced affinity performs promising application in sensitive detection of 25-HydroxyvitaminD3.

Background Porcine aortic roots (PAR) have been reported in the literature with acceptable short and long-term outcomes for the treatment of aortic root aneurysms. However, their efficacy in type A aortic dissection (TAAD) is yet to be defined. Methods Using data from a locally collated aortic dissection registry, we compared the outcomes in patients undergoing aortic root replacement for TAAD using either of two surgical options: i) PAR or ii) composite valve grafts (CVG). A retrospective analysis was conducted for all procedures in the period 2005-2018. Results A total of 252 patients underwent procedures for TAAD in the time period. Sixty-five patients had aortic root replacements (PAR n=30, CVG n=35). Between group comparisons identified a younger CVG group (50.5 vs 64.5, p<0.05) although all other covariates were comparable. Operative parameters were comparable between the two groups. The use of PAR did not significantly impact operative mortality (OR 0.93, 95% CI 0.22-3.61, p=0.992), stroke (OR 2.91, 0.25 – 34.09, p=0.395), re-operation (OR 0.91, 95% CI 0.22 – 3.62, p=0.882) or length of stay (coef 2.33, -8.23 – 12.90, p=0.659) compared to CVG. Five-year survival was similar between both groups (PAR 59% vs CVG 69%, p=0.153) and re-operation was negligible. Echocardiography revealed significantly lower aortic valve gradients in the PAR group (8.69 vs 15.45 mmHg, p<0.0001), and smaller left ventricular dimensions both at 6 weeks and 1 year follow up (p<0.05). Conclusions This study highlights the comparable short and mid-term outcomes of PAR in cases of TAAD, in comparison to established therapy.

There are several routes of African swine fever (ASF) introduction into a country. Among the possible routes of entry, quarantine policies determine the possibility of introduction by legal import of live pigs and pig products. This study aimed at assessing the probability of ASF introduction through legal import of live pigs and pig products during the high risk period (HRP) using a quantitative stochastic approach during 2009-2018. The result indicates that the mean annual probability of ASF introduction by legal import of live pig was 1.58×10-7 (1.52~1.67×10-7 95% CI). The mean annual probability by legal import of pig products was 1.59×10-10 (1.55~1.64×10-10 95% CI), of which Poland assumed 87.9% of the mean annual risk. The current import quarantine policy of Korean government may be enough to block the release of the virus via legal import of live pigs and pig products, and it should be continually enforced. This result can help to elucidate source of infection and minimize the catastrophic consequences of the potential ASF reintroduction into South Korea by designing risk mitigation strategies such as risk-based selection of routes to be assessed and prevented and decreased exposure possibility by increased control of food waste and swill feeding practices.

Outbreak AlertsNovel coronavirus, also known as SARS-CoV-2 linked pandemic, started from Wuhan China during December 2019 (Guo et al., 2020 ). Transmission from the original place took place long before the World Health Organization (WHO) declared it a public emergency on 30th January 2020. As of 12th April, WHO has confirmed 1,614,951 live infected cases and 99,887 deaths in around 200 countries. In India, the first coronavirus positive case was reported from Kerala on 30th January 2020 (Ministry of Health and Family Welfare, 2020d ). Later, the positive cases in India came from Delhi dweller who returned from Italy and a man from Telangana who returned from Dubai. After that, some positive cases were detected within Italian tourists and their tour guide in Rajasthan. Overall, the virus spread in the country has primarily occurred due to foreign travelers or Indian travelers coming from abroad.Currently, India is standing up in the initial stage of community transmission. As per 30th March 2020 Ministry of Health and Family Welfare, Government of India has announced 1224 COVID-19 cases from all over the 27 states and union territories with maximum from Maharashtra (192 cases) and Kerala (202 cases) (Ministry of Health and Family Welfare, 2020a ). The trend of COVID-19 in India has marked slow increase with the primary reproduction number R0 value 1.5 as compared to China (R0 value 2.3), Italy (R0 value 2.34) and Iran (R0 value 2.73) during their 3rd week from the onset of initial SARS CoV-2 positive cases (Cereda et al., 2020; Mandal et al., 2020; Zhao et al., 2020 ). On average, each patient transmits the infection to an additional 2.2 individuals. Based on data from the first cases in Wuhan and investigations by the China CDC, the incubation time can be from 3 to 7 days and up to 2 weeks as the longest time (95% CI, 9.2 to 18) (Singhal, 2020 ). As per the WHO 70th situation report, most of the European regions like Italy, Spain, France are dealing with up to 11%, 7.8%, 6.2%, of case-fatality rate, even more than China (4%)(Onder, Rezza, & Brusaferro, 2020; World Health Organization, 2020 ). Globally, the case-fatality rate is around 2-3% however, severely affected patients may die due to excessive alveolar damage, which leads to progressive respiratory failure as evident from many countries, including Italy and China. SARS-CoV-2 is the seventh coronavirus known to infect humans. Along with SARS-CoV, MERS-CoV, and SARS-CoV-2 severe symptoms causing epidemics whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms (Li et al., 2020; Yang et al., 2020 ).For now, more than 500 whole-genome sequences of different strains of SARS-CoV are reported. Out of these, around 160 isolates have been reported in recent outbreaks mostly from China, Italy, Iran, the USA, Japan, Australia, France, and two from India as well. Two known Indian isolates SARS-CoV-2/166/human/2020/IND (GeneBank: MT050493.1) of 29,851 bp and SARS-CoV-2/29/human/2020/IND (GenBank: MT012098.1) of 29,854 bp are deposited by National Institute of Virology, Pune, Maharashtra. Although both strains are isolated from swabs of infected patients from Kerala, the sequencing of more isolates should be carried out regional wise across major infected areas. Further, systematic gene-level mutational analysis of local strains will enable researchers to identify several unique features of the SARS-CoV-2 genome and the development of more efficient therapeutics and vaccines.Several properties of SARS-CoV-2 make its prevention difficult, namely, non-specific features of the disease, the infectivity even before the onset of symptoms, transmission from asymptomatic people, and long incubation period. Hence, the Indian Government has projected proactive measures to inhibit the spread of SARS-CoV-2 from initial careers coming from abroad to the local community. Implementation of 21 days lockdown all over the country has greatly helped to flatten the logarithm spread within the community (Government of India, 2020) . Meanwhile, to meet the requirement of personal protection equipment, masks and ventilators, and other essential items, the government is allowing domestic companies and manufacturers clearing quality tests to come-up with more supplies. The supply of N95 masks has been ramped up to 1,00,000/day by local manufactures mostly and DRDO (Ministry of Health and Family Welfare, 2020b ).Moreover, total government laboratories approved and supported by Indian Council of Medical Research (ICMR) to provide diagnostic kit for SARS-CoV-2 testing has been increased to 123 all over the country(Indian Council of Medical Research, 2020b) . The government-led awareness programs based on WHO, CDC, and FAO recommendation on COVID-19 has been enforced to all the states (Ministry of Health and Family Welfare, 2020c ). Besides, the state government issued instructions on the closing of all schools and colleges, malls, and any form of the public gathering. As per reports, a widely-used drug Chloroquine, has recently been reported as a potential broad-spectrum antiviral drug. It blocks the virus infection by increasing endosomal pH required for virus/cell fusion, as well as to interfere with the glycosylation of cellular receptors of SARS-CoV (Savarino, Di Trani, Donatelli, Cauda, & Cassone, 2006; Wang et al., 2020; Yan et al., 2013) . Indian government has allowed restricted use of Chloroquine among doctors and other staff members coming in direct contact with severe patients to avoid transmission (Indian Council of Medical Research, 2020a ). Besides, the Central Drugs Standard Control Organization approved constricted public health use of lopinavir/ritonavir combination amongst symptomatic COVID-19 patients(Bhatnagar et al., 2020 ).

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical entity associated with significant morbidity and mortality. Common comorbidities including hypertension, coronary artery disease, diabetes, chronic kidney disease, obesity, and increasing age predispose to preclinical diastolic dysfunction that often progresses to frank HFpEF. That said, clinical HFpEF is typically associated with some degree of diastolic dysfunction or can occur in the absence of many conventional diastolic dysfunction indices. The exact biologic links between risk factors, structural changes, and clinical manifestations are not clearly apparent. Innovative approaches including deformation imaging have enabled deeper understanding of HFpEF cardiac mechanics beyond conventional metrics. Furthermore, predictive analytics through data driven platforms have allowed for a deeper understanding of HFpEF phenotypes. This review focuses on the changes in cardiac mechanics that occur through preclinical myocardial dysfunction to clinically apparent HFpEF.

Angiotensin converting enzyme-2 (ACE2) is the receptor for the coronavirus SARS-CoV-2, which causes COVID-19. We propose the following hypothesis: Imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing Angiotensin-II (ANG II) signaling, a primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of ANG II to ANG peptides that counteract pathophysiological effects of ACE1-generated ANGII. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: 1) ANG II receptor blockers (ARBs); 2) ACE1 inhibitors (ACEIs); 3) Agonists of receptors activated by ACE2-derived peptides [e.g., ANG (1-7), which activates MAS1]; 4) Recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved ARBs and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19.

The emergence of coronavirus disease 2019 (COVID-19) is caused by the 2019 novel coronavirus (2019-nCoV). The 2019-nCoV first broke out in Wuhan and subsequently spread worldwide owing to its extreme transmission efficiency. The fact that the COVID-19 cases and mortalities are reported in globally and the WHO has declared this outbreak as the pandemic. The international health authorities have focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the disease severity. Due to the lack of a known efficient therapy and public health emergency, repurposing drugs chloroquine (CQ) analogues appear to be the best tool against 2019-nCoV infection. These analogues have shown potential efficacy to inhibit 2019-nCoV in vitro that leads to focus in several new trials. This review discusses the possible effective roles and mechanisms of CQ analogues for interfering with the 2019-nCoV replication cycle and infection.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targetting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed; an agenda for drug re-purposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methodologies aimed at discovering novel chemical and biological means targetting a short-list of host and viral entities should extend the arsenal of anti-SARS-CoV-2 agents. This longer-term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide.

The emergence in December 2019 of SARS-CoV-2, and its infectious disease COVID-19, has resulted in a worldwide pandemic. Despite the realization that humanity is under a constant threat from respiratory viruses with pandemic potential, such as coronaviruses and influenza viruses, the discovery of a safe and effective prophylactic drug against such infections has remained elusive. The benefits of such a drug for the prevention, containment, or mitigation of emerging and endemic viral threats would be significant. As research on the mechanisms of viral infection has advanced, the repositioning and repurposing of existing drugs and therapeutics has played a significant role in our attempts to find efficacious treatments. This is especially true for COVID-19, though numerous existing drugs were previously studied for their usefulness in treating both SARS-CoV and MERS-CoV infections. Ambroxol, a semi-synthetic derivative of the alkaloid vasicine, has been researched and marketed for more than half a century. Ambroxol was originally marketed as a respiratory mucolytic, mucokinetic, expectorant, and secretolytic. Decades of research have shown it to possess multiple effects, with minimal side effects and a favorable safety profile. Among the mechanisms of action and molecular targets that have been shown for Ambroxol, some of these are potentially of benefit for the prevention and treatment of viral infections caused by influenza viruses, rhinoviruses, and coronaviruses. If proven to be safe and effective, the repurposing of Ambroxol as a phylactic and treatment for these viral infections would be a major advancement in public health, by lowering the morbidity and mortality caused by these viruses.