Lopinavir combined with ritonavir were reported to benefit the patients with SARS by reducing the viral loads. However, in the latest clinical trials, no benefit was observed with lopinavir-ritonavir treatment beyond standard care in patients with COVID-19. We comment here that this disappointed result of clinical trial might result from the low volume of the lung distribution of lopinavir. The major reasons were listed below: 1) The binding affinity of ACE2 with SARS-CoV-2 spike protein is ~10- to 20-fold higher than the binding affinity of ACE2 with SARS-CoV spike protein, indicating that SARS-CoV-2 can enter AT2 cells in lung much easier than SARS-CoV. Therefore, the viral loads of SARS-CoV-2 might be much higher than viral loads of SARS-CoV in the lung tissue. 2) The concentration of lopinavir in the lung tissue was 1.18 μg equiv/ml in rats. The low volume of the lung distribution of lopinavir might not be enough to inhibit the coronavirus replication due to the high viral loads in the lung tissue. 3) In contrast, the concentration of chloroquine in the lung tissue was much higher (30.76 ± 0.85 μg equiv/ml) in rats, which might lead to its clinical and virologic benefits in the treatment of COVID-19 patients. Together, we proposed here that anti-SARS-CoV-2 drug repurposing studies should pay more attentions to the lung tissue distribution of antiviral drugs. The efficacy of antiviral drugs might depend on their lung tissue distributions
COVID-19 is a disease which is sweeping the globe, often with devastating consequences. The more we understand, the more it appears that infection has a very wide clinical spectrum from totally asymptomatic to life threatening. Without widespread community testing it is impossible to ascertain true infection rates and develop strategies which reduce or prevent transmission without the need for on-going draconian measures such as complete national lockdown. These measures are mandatory at the time of writing, however widespread adoption of face masks has been shown to help prevent transmission of other respiratory pathogens, and also infections acquired by healthcare staff. Combining mass testing with a combination of social distancing and face mask use might offer a way forward until a mass COVID-19 vaccination programme can be established.
The aim of the study is to investigate the impairment of diastolic function of the left ventricle (LV) and the right ventricle (RV) in arterial hypertension outpatients. Materials and methods. Arterial hypertension patients (n=299) and practically healthy people (n=62) were examined on an outpatient basis. Echocardiographically, diastolic dysfunctions of both ventricles were evaluated. Results. All the arterial hypertension patients had a pattern of diastolic dysfunction (DD) of the RV of different grades (grade I RVDD and grade II RVDD), regardless of the presence or absence of pulmonary arterial hypertension. Patterns of grade I LVDD and grade I RVDD were detected in 84 patients. Patterns of grade I LVDD and grade II RVDD were detected in 77 patients. Patterns of grade II LVDD and grade II RVDD were detected in 41 patients. A pattern of grade II RVDD with normal left ventricular diastolic function was detected in 97 patients with a short duration of disease (3.92±0.48 years) versus the other groups with more than 15 years of hypertension. 175 arterial hypertension patients had grade I or II LVDD only in 18.3% of cases according to the recommendations of the American and European societies of echocardiographers (2016). Conclusion. The patients with a short period of hypertensive disease have only the pseudonormal pattern of RVDD, which can be an early diagnostic marker of heart failure. Echocardiographic diagnosis of diastolic function made according to various criteria can both increase the number of chronic heart failure patients and significantly decrease it.
Controversy surrounds the cause of the pressure gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Left ventricular cavity obliteration (LVCO) was first described as the cause of the gradient but subsequently systolic anterior motion (SAM) of the mitral valve has been established as the cause. Nevertheless, the two gradients, though different in origin and significance, share similar characteristics. They both have a similar “dagger” profile, are obtained from the cardiac apex, are associated with a hyperdynamic left ventricle, and the gradients are worsened by Valsalva. The distinction has clinical relevance, because treating the intra cavitary gradient (ICG) of LVCO as if it were a SAM associated gradient associated with HOCM would be inappropriate and possibly harmful. To clarify the cause and characteristics of the ICG in patients with LVCO in patients without HOCM we assessed the extent and duration of cavity obliteration and for differentiation we compared the spectral profiles with patients with HOCM and severe aortic stenosis (AS). Higher ICG is associated with greater extent and more prolonged apposition of LV walls. The spectral profile of patients with AS, HOCM and LVCO are differentiated by the peak/mean gradient ratios of 2 or less, 2-3, and 3 or greater, respectively in > 90% of patients. Most patients with LVCO without HOCM or severe LVH have an ICG < 36 mmHg. The magnitude of ICG is quantitatively associated with extent and duration of LVCO. Spectral profiles of severe AS, HOCM, and LVCO can be differentiated by the peak/mean gradient ratio.
Here we present a young asymptomatic male incidentally diagnosed to have aortic regurgitation (AR). The patient had a history of a blunt trauma to the thorax two years back but did never have any symptoms. Transthoracic echocardiography showed a moderately dilated left ventricle with normal systolic function and severe AR with normal nondilated aortic root and tri-leaflet aortic valve. To diagnose the etiology of the AR a trans-esophageal echocardiogram (TEE) was done, which revealed a perforation in the non-adjacent leaflet (NAL) and confirmed severe AR with two AR jets being clearly visualised, one through the point of incomplete coaptation and other one through the perforated area in the NAL. The patient was treated with aortic valve replacement and was doing well on follow-up.
The leopard coral grouper, Plectropomus leopardus, belonging to genus Plectropomus, family Epinephelinae, is a carnivorous coral reef fish widely distributing in the tropical and subtropical water of Indo-Pacific Oceans. Due to its appealing body appearance and delicious taste, P. leopardus has become a popular commercial fish for aquaculture in many countries. However, the lack of genomic and molecular resources for P. leopardus hinders its biological studies and genomic breeding programs. Here we report the de novo sequencing and assembly of P. leopardus genome using 10× Genomics and high-throughput chromosome conformation capture (Hi-C) technologies. Using 127.36 Gb 10× Genomics we generated a 902.90 Mb genome assembly with a contig and scaffold N50 of 31.8 Kb and 33.47 Mb, respectively. The scaffolds were clustered and oriented into 24 pseudo-chromosomes with 13.39 Gb valid Hi-C data. BUSCO analysis showed that 95.3% of the conserved single-copy genes were retrieved, indicating a good entirety of the assembly. We predicted 23,234 protein-coding genes, among which 96.5% were functional annotated. The P. leopardus genome provides a valuable genomic resource for genetics, evolutionary and biological studies of this species. Particularly, it is expected to benefit the development of genomic breeding programs in the farming industry.
Mini-commentary on BJOG-19-1802.R1 & BJOG-19-1803.R1Title: To be decodedZarko Alfirevic,Department of Women’s and Children’s Health, University of LiverpoolSimon GatesCancer Research UK Clinical Trials Unit, University of BirminghamEmail contact: Zarko Alfirevic, Zarko@liverpool.ac.ukRandomised trials remain gold standard for evaluation of effectiveness of medical interventions. However, they are expensive, time consuming and demand huge efforts from participants, researchers and clinical services that facilitate them. Even when trials are successfully completed, peer reviewers often find them wanting. One of the most common criticisms is a ‘lack of power’ to tackle clinically important outcomes. Why is this happening time and again?When an important clinical question creates an equipoise, trialists are faced with difficult choices. If they design a trial to tackle the most important (often rare) outcomes aiming to detect modest, but plausible, risk reductions from a proposed intervention, such studies are rarely feasible and very expensive forcing most funders to simply walk away. Common ‘remedies’ are to change the outcome to something more common and less important (often composite), or to propose an unrealistic risk reduction, sometimes in excess of 50%. Trials of magnesium sulphate for neuroprotection included in the seminal Cochrane review (Doyle LW et al. DOI: 10.1002/14651858.CD004661.pub3) that triggered changes in numerous guidelines world-wide were not an exception (Table 1).Cerebral palsy is a rare, but devastating complication of prematurity and even a very modest reduction would, surely, be worth detecting. The problem is that even in the most ‘at risk’ groups, the incidence of cerebral palsy will not exceed 10%. A conventional sample size calculation estimates that to detect a ‘massive’ 25% risk reduction in cerebral palsy, in excess of 5,000 women would have to be randomised.Interestingly, such a priori sample size calculations are not a feature of most published meta-analyses. Step forward Trial Sequential Analysis (TSA). The TSA is a deceptively simple concept; meta-analysis sample size needs to be increased to allow not only for the heterogeneity of included studies, but also for repeated testing when meta-analyses are being updated and therefore subjected to repeated significance testing. Interested readers can find out more from the Copenhagen Trial Unit’s website - vocal proponents of this methodology (www.ctu.dk/tsa).In their two sister papers, Wolf et al have, quite ingeniously, used TSA to determine the size of their randomised trial and, by doing so, avoided the risk of their randomised trial and updated meta analysis being criticised as ‘underpowered’ (Wolf H et al. BJOG 2020 xxxx (RCT); Wolf H et al. (BJOG 2020 xxxx (SR & MA). Could this concept be a methodological ‘game changer’ in perinatal trials?The concept of TSA has been widely criticised, and a Cochrane Collaboration expert panel recommended against its use (https://methods.cochrane.org/sites/default/files/public/uploads/tsa_expert_panel_guidance_and_recommendation_final.pdf). Key criticisms are, first, that decision-makers require a summary of the currently available evidence and this should not depend on past and future updates. Second, TSA focuses only on statistical significance. Interpretation of meta-analysis should be based on the estimates of the treatment effect and its uncertainty, rather than whether an arbitrary significance threshold is passed. Third, the ways that evidence accumulates in systematic reviews and individual trials are fundamentally different. Review updates are not equivalent to trial interim analyses; updates are not pre-planned and their number cannot be determined in advance. Furthermore, reviews address multiple clinically-relevant effects on several outcomes or subgroup analyses, which need to be integrated into an overall conclusion. The Cochrane expert panel concluded: “Any sequential adjustment procedure is necessarily based on a particular instance of the evolution of evidence that applies to a limited context and cannot satisfy the requirements of all decision makers.”Table 1. Key features of randomised trials of MgSO4given to pregnant women for prevention of cerebral palsy in infants born preterm
Abstract This study describes the response of Arthrospira platensis to a variety of temperature conditions as reflected in variations of photosynthetic parameters, pigmentation, and biomass productivity in indoor photobioreactor (PBR) cultivations. These experiments are designed to better understand the impact of temperature, seasonal variations, and acclimation effects on outdoor biomass production. The irradiance level and temperature range (20 – 39°C) are chosen to enable modeling of semi-continuous operation of large-scale outdoor PBR deployments. Overall, the cultivations were quite stable with some pigment-related instabilities after prolonged high temperature exposure. Changes in productivity with temperature, as reflected in measured photosynthetic parameters, are immediate and mainly attributable to the temperature dependence of the photosaturation parameter, a secondary factor being variation in pigment content on a longer time scale corresponding to turnover of the culture population. Though pigment changes have minimum impact on productivity, prolonged exposure at 35°C and above yields a clear degradation in performance. Productivities in a semi-continuous operation are quantitatively reproduced with a productivity model incorporating photosynthetic parameters measured herein. This study confirms the importance of temperature for biomass and pigment production in Arthrospira cultivations and provides a basis for risk assessments related to temperature mitigation for large-scale outdoor cultivations. Keywords: Arthrospira Platensis, photosynthetic parameters, pigment production, productivity modeling, photobioreactors
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.
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.
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.
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.
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.
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.
Theoretical elucidation of the turn-off mechanism of the luminescence of a chemosensor based on a metal-organic framework (MOF) [Zn2(OBA)4(BYP)2] (BYP: 4,4’-bipyridine; H2OBA: 4,4’-oxybis(benzoic acid)), selective to nitrobenzene via quantum chemical computations is presented. The electronic structure and optical properties of Zn-MOF were investigated through the combination of density functional theory (DFT) and time-dependent-DFT methods. Our results indicate that the fluorescence emission is governed by a linker (BPY) to linker (OBA) charge transfer (LLCT) involving orbitals π-type. Next, interaction with the analyte was analyzed, where very interesting results were obtained, i.e. the LUMO is now composed by orbitals from nitrobenzene, which changes the emissive state of the Zn-MOF. This fact suggests that the LLCT process is blocked, inducing then the fluorescence quenching. Otherwise, the Morokuma-Ziegler energy decomposition and NOCV (Natural Orbitals for Chemical Valence) on the Zn-MOF-nitrobenzene interactions were studied in detail, which illustrate the possible channels of charge transfer between Zn-MOF and nitrobenzene. Finally, we believe that this proposed methodology can be applied to different chemosensor-analyte systems to evidence the molecular and electronic factors that govern the sensing mechanisms.