Accurate assessment of aetiology of mitral regurgitation (MR) is one of the key steps in the decision-making process and further clinical management of patients with severe MR. Our clinical case illustrates the added value of three-dimensional echocardiography (3DE) in assessment of mitral valve morphology and identification of an unexpected mechanism of MR which was not previously diagnosed using conventional echocardiography. 3DE helped to choose appropriate management strategy in this patient. We believe our observations may have an important clinical impact, encouraging a wider use of 3DE in patients with complex mechanisms of MR

Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.

Despite their therapeutic potential, many protein drugs remain inaccessible to patients since they are difficult to secrete. Each recombinant protein has unique physicochemical properties and requires different machinery for proper folding, assembly, and post-translational modifications (PTMs). Here we aimed to identify the machinery supporting recombinant protein secretion by measuring the protein-protein interaction (PPI) networks of four different recombinant proteins (SERPINA1, SERPINC1, SERPING1 and SeAP) with various PTMs and structural motifs using the proximity-dependent biotin identification (BioID) method. We identified PPIs associated with specific features of the secreted proteins using a Bayesian statistical model, and found proteins involved in protein folding, disulfide bond formation and N-glycosylation were positively correlated with the corresponding features of the four model proteins. Among others, oxidative folding enzymes showed the strongest association with disulfide bond formation, supporting their critical roles in proper folding and maintaining the ER stability. Knock down of ERP44, a measured interactor with the highest fold change, led to the decreased secretion of SERPINC1, which relies on its extensive disulfide bonds. Proximity-dependent labeling successfully identified the transient interactions supporting synthesis of secreted recombinant proteins and refined our understanding of key molecular mechanisms of the secretory pathway during recombinant protein production.

Hemodialysis requires repeated, reliable access to the systemic circulation; therefore, a well-functioning vascular access (VA) procedure is crucial for stable hemodialysis. VA infections (VAIs) constitute the most challenging complication and cause considerable morbidity, loss of access, and even death. In this study, we investigated the molecular profiles of different bacterial isolates retrieved from various types of VA grafts. We collected clinical isolates from hemodialysis patients with VAIs in our institution for the period between 2013 and 2018. We identified the bacterial isolates using standard biochemical procedures; we used a polymerase chain reaction for coagulase-negative staphylococcus (CoNS) and Burkholderia cepacia complex (BCC) species identification. The antibiotic resistance and molecular profile were analyzed using the disk diffusion method and multilocus sequence typing, respectively. We studied 150 isolates retrieved from patients with VAI and observed that Staphylococcus aureus was the predominant bacterial species, followed by S. argenteus, BCC, and CoNS. According to multilocus sequence typing data, we identified a wide variety of sequence types (STs) in S. aureus isolates, with ST59, ST45, and ST239 being the predominant types. Burkholderia cepacia with two new ST types, namely ST1723 and ST1724, accounted for most of the BCC infections, along with ST102 B. contaminans, which were mainly isolated from infected tunneled-cuffed catheters. In summary, the increased incidence of S. argenteus and BCC infections provides insights into their potential clinical effects in VAIs. The various STs identified in different bacterial species indicate the high genetic diversity of bacterial species isolated from VAIs in our institution.

In exact analyses of bodies in the elastic-plastic area, the behaviour of the material above critical stress values plays a key role. In addition, under cyclic stress, important phenomena to be taken into account are the various types (modifications) of strengthening and design (adaptation) of the material or structure. In this process, it is important to define several groups of characteristics. These include for instance initial area of plasticity or load which defines the interface between elastic and plastic deformation area. The characteristics also include the relevant law of plastic deformation which specifies the velocity direction of plastic deformation during plastic deformation. The strengthening condition is also important to determine position, size and shape of the subsequent loading area. The practical part of this article is dedicated to the comparison of results obtained in the analysis of stresses and deformations of particular structural elements in the elastic-plastic area by FEM using models of different types of deformation strengthening.

The present investigation is concerned with high-cycle axial fatigue testing of a 2 mm AA6060-T6 HYB butt weld produced in the solid state using AA6082 filler metal addition. The results complement the three-point bend testing and the tensile testing done in two previous studies. In this study, optical microscope and scanning electron microscope examinations have been carried out to reveal the joint macro/microstructure and document possible surface and root defects deemed to affect fatigue life. In the as-welded condition, the HYB weld suffers from surface irregularities at the weld face and “kissing” bond formation in the root region. Despite of this, the subsequent testing shows that the fatigue properties exceed those reported for comparable AA6082-T6 gas metal arc butt welds and matching those reported for corresponding high-strength laser beam and friction stir weldments.

Extreme drought impacts ecosystem function and processes dramatically. However, a comprehensive understanding of how extreme drought affects root biomass at regional scales remains elusive. Here, we investigated the effects across six grasslands with extreme drought treatment replicated across a precipitation gradient in Inner Mongolia, China. We found the root biomass and belowground net primary productivity (BNPP) were significantly positively correlated with precipitation at the reginal scale. Extreme drought decreased the slope of this correlation in 0-10 cm and increased in 10-20 cm. Root biomass and BNPP increased by extreme drought in the four relatively arid sites and decreased in the two relatively mesic sites in 0-10 cm, and the reverse pattern showed in 10-20 cm. These shifts were driven by the response of soil moisture. Our findings suggest that including vertical responses of belowground primary productivity to extreme drought should improve models predictions of plant roots to future climate change.

A document by Francesco Zanon. Click on the document to view its contents.

Cardiac pacing is the only effective therapy for patients with symptomatic brady-arrhythmia. Traditional right ventricular apical pacing causes electrical and mechanical dyssynchrony resulting in left ventricular dysfunction, recurrent heart failure and atrial arrhythmias. Physiological pacing activates the normal cardiac conduction thereby providing synchronized contraction of ventricles. Though His bundle pacing (HBP) acts as an ideal physiological pacing modality, it is technically challenging and associated with troubleshooting issues during follow up. Left bundle branch pacing (LBBP) has been suggested as an effective alternative to overcome the limitations of HBP as it provides low and stable pacing threshold, lead stability and correction of distal conduction system disease. This paper will focus on the implantation technique, troubleshooting, clinical implications and a review of published literature of LBBP

Multiple functional and hard-to-quantify sensorial product attributes that can be satisfied by a large number of cosmetic ingredients are required in the design of cosmetics. To overcome this challenge, a new optimization-based approach for expediting cosmetic formulation is presented. It exploits the use of a hierarchy of models in an iterative manner to refine the search for creating the highest-quality cosmetic product. First, a systematic procedure is proposed for optimization problem formulation, where the cosmetic formulation problem is defined, design variables are specified, and a set of models for sensorial perception and desired product properties are identified. Then, a solution strategy that involves iterative model adoption and two numerical techniques (i.e., generalized disjunctive programming reformulation and model substitution) is applied to improve the efficiency of solving the optimization problem and to find better solutions. The applicability of the proposed procedure and solution strategy is illustrated with a perfume formulation example.

Objectives: This study investigated whether perioperative treatment with glucocorticoids (GC) and disease-modifying anti-rheumatic drugs (DMARDs) can improve clinical outcomes and reduce long-term complications for patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA). Methods: Patients were allocated into three groups based on perioperative drug therapy: A. control group (no GC or DMARDs), B. DMARD group (DMARDs given without GC) and C. co-therapy group (DMARDs plus GC). The patients were followed and received questionnaires at the latest follow-up. Baseline characteristics, pre- and post-operative HSS knee score, laboratory parameters, and surgical complications were collected and analyzed. Results: 56 RA patients undergoing 91 TKAs were included in this study. The average follow-up duration was 11.4 years. Patients who received perioperative GC with DMARDs (group C) achieved better HSS score (C:84.04 vs A:78.96 vs B:76.50, p=.008), pain relief (VAS: C: 1.12 vs B: 1.73, p=0.02), higher functional assessment (C:16.17 vs B:13.23, p=0.03) and range of motion (C:132.15 vs A:112.57 vs B:112.51, p<0.001) compared the other treatment groups at time of latest follow-up. Aside from greater post-operative hemoglobin seen in group A compared to group B (P=0.04), no other differences were noted in laboratory tests, blood loss and transfusion, short-term or long-term complications between treatment groups. Conclusions: Perioperative treatment with GC combined DMARDs for RA patients is associated with improved HSS score, better function and range of motion, and reduced postoperative pain in the long term when compared to treatment with DMARDs alone or management without anti-rheumatic medication.

Aims How plant-plant interactions vary with the changes of biotic and abiotic factors has debated for a long time among ecologists. The aim of this study was to explore how different neighbors influenced the responses of the intensity and importance of competition on Stipa grandis and S. krylovii to the change of soil nutrition condition. Methods The seedlings of the target species, S. grandis and S. krylovii, were grow alone and in two-species mixtures with different neighbors under two soil nutrition treatments. For each target species, we measured the biomass, root: shoot ratio, intensity and importance of competition and nutrition-addition effect. Important Findings We founded that the competition responses were mediated by the identities of neighbors and target species. (1) When in mixture with Leymus chinensis, both intensity and importance of competition negatively increased with the increase of soil nutrition. The competition importance was significantly negative on S. grandis under both soil nutrition treatments and on S. krylovii under the high soil nutrition treatment, supporting Grime’s theory. (2) When in S. grandis – S. krylovii mixture system, the competition inhibition decreased while competition importance showed no significant effects on both target species with the increase of soil nutrition, indicating competitive reduction. (3) When in mixture with Agropyron cristatum, the competition intensity significantly influenced by the interaction between target species and soil nutrition, suggesting competitive change along the soil nutrition gradient. The competition importance was significantly negative on S. grandis under the low soil nutrition treatment and on S. krylovii under the high soil nutrition treatment. Ultimately, our results demonstrate that the identities of both target and neighbor species influenced the responses of intensity and importance of competition to the change of soil nutrition condition. Several mechanisms potentially contributed to these different competition effects on different target species.

Inherent in climate change experiments is the assumption that researchers seek to understand the impacts of contemporary climate change and not the impacts of changes in the abiotic environment that are not predicted to occur. In general, climate warming is expected to be asymmetrical, with a mean increase in temperature that is driven more by warming at night rather than during the day. However, climate warming experiments tend to disproportionately increase daytime temperatures. If day and night warming have different effects on ecosystems, the mismatch in timing may produce misleading inference about the effects of climate change. To better understand how the timing of warming affects species and their interactions, we examined a food chain of lady beetles, aphids and host plants within environmental chambers programmed to simulate four w treatments (ambient, constant warming, day warming, and night warming). Our results show that the timing of warming influences predators and their interactions with prey in several ways. In plant-only treatments, all warming treatments increased plant above-ground biomass. When aphids were added, the positive direct effect of warming on plants disappeared, and night-warming indirectly reduced plant biomass more than the day- and constant-warming treatments. Although our feeding trial experiments found that lady beetles in day-warming treatments consumed the most aphids in a 24 hour period, predators generated a trophic cascade in only the night warming treatment. Our results contributes to mounting evidence predators can mediate the effects of climate warming and that these predators are affected by day and night warming differently.

1 | INTRODUCTIONLeishmaniasis is a vector-borne protozoan disease transmitted to humans by the bite of blood-feeding female phlebotomine sand flies. Although it is often not fatal, it poses a major public health problem worldwide (Yaghoobi-Ershadi, 2016). Leishmaniasis remains a neglected vector‐borne disease. It is estimated that about 1.3 million people are diagnosed with cutaneous leishmaniasis annually in the world (Piroozi et al., 2019). The presence of this vector‐borne disease has been reported in 102 countries worldwide, including Iran, and an estimated one billion people are at risk of contracting the disease (Alvar et al., 2012; Razavinasab et al., 2019; WHO, 2018). According to the WHO report in 2018, most of the cases of cutaneous leishmaniasis were reported from 48 countries in the world (WHO, 2018).Cutaneous leishmaniasis is more difficult to control in endemic areas than other infectious diseases, which has been attributed to the complexity of the epidemiological and biological aspects of the disease (Yaghoobi-Ershadi, 2016). Despite many efforts to control the disease, it is still present in many parts of the world, and it is endemic in countries such as Syria, Afghanistan, Brazil, Iraq, Iran, Pakistan, Colombia, and Algeria (WHO, 2018).There are two epidemiological forms of the vector-borne protozoan disease in Iran; Anthroponotic Cutaneous Leishmaniasis (A.C.L) and Zoonotic Cutaneous Leishmaniasis (Z.C.L) caused by Leishmania tropica and Leishmania major, respectively (M. R. Aflatoonian et al., 2019). Also, two sand fly species have been identified as the main vectors of the two forms of Cutaneous Leishmaniasis in Iran. ACL is mainly transmitted by Phlebotomus sergenti and ZCL by Ph. Papatasi (M. R. Aflatoonian et al., 2019). The annual incidence of cutaneous leishmaniasis in Iran is very high, and the country ranks among the first six countries in the world in terms of the incidence of the disease (Piroozi et al., 2019). A.C.L is widely distributed in several provinces in Iran, including Tehran, Kerman, Mashhad, Yazd and Shiraz (Afshar et al., 2017). Kerman province is one of the endemic focus of A.C.L in Iran, and several cases have been reported in different cities of the province, including Kerman, Bam, Rafsanjan, Baft, Shahrbabak and Sirjan (M. Aflatoonian & Sharifi, 2014).The distribution of A.C.L is affected by various factors, including epidemiological factors, environmental factors, migration, urbanization, and natural disasters (Desjeux, 2001). Some of the most effective ways of controlling A.C.L include prevention through the use of personal protective equipment and environmental interventions aimed at eliminating the vectors and the reservoirs of the disease (Nilforoushzadeh, Bidabadi, Hosseini, Nobari, & Jaffary, 2014). Another effective way of controlling the disease and reduce its spread is to increase the awareness of the residents living in the endemic areas.In general, health behaviors and hygiene practices can be influenced by gender, age, education and knowledge (Kirunda et al., 2015). Understanding the level of knowledge, attitudes, and practices (KAP) of residents living in endemic areas is necessary in designing health promotion interventions and reducing the risk of exposure. Also, identifying the risk factors associated with the disease in the endemic areas can help reduce the incidence of the disease. In recent years, many studies have been conducted on the KAP towards leishmaniasis in Asia and Africa (Akram, Khan, Qadir, & Sabir, 2015a; Amin et al., 2012; Awosan et al., 2013; Doe, Egyir-Yawson, & Kwakye-Nuako; Kebede et al., 2016; Khbou, Najahi, Zribi, Aoun, & Gharbi, 2019; Nandha, Srinivasan, & Jambulingam, 2014; Sarkari, Qasem, & Shafaf, 2014). In Iran, KAP studies on leishmaniasis have been conducted in Fars (Sarkari et al., 2014), Ilam (Vahabi et al., 2013a), and Isfahan provinces (Saberi et al., 2012) in the past years.Kerman, a city in the southwest of Iran, is one of the endemic foci of A.C.L. Therefore, there is a need to understand the KAP of residents living these areas and the risk factors associated with the disease. In this study, we aimed to assess and compare the levels of KAP towards A.C.L among residents in three endemic areas in the suburb of Kerman city. The present study also aimed to identify the risk factors associated with A.C.L in these areas. To the best of our knowledge, the present survey is the first KAP study on A.C.L and associated risk-related factors among residents in three endemic areas (Allahabad, Shahrak Sanati and Sarasiab) in the suburb of Kerman city.

This study explored the nature, dynamics and role of collective-affirmation in attracting mass cooperation and support to check further spreading and to motivate people to observe preventive measures to reduce the casualties of COVID-19. A Narrative Thematic Analysis Design was employed in which a heterogeneous sample (N= 32, Age range = 36-61 years) was chosen through a purposive sampling method. The participants were interviewed about their experiences of lockdown. The novelty, suddenness and incurability of COVID-19 caused a set of perceived psychological distress and danger to individual and collective life. The Janata (public) curfew was perceived as a curfew of the people, by the people and for the people. The lockdown denoted a strong faith of the Indian government in the positive virtues of Indian People and vice versa. The mass support and adherence to the suggested preventive government measures were facilitated by collective-affirmation in the well-known positive Bhartiya (Indian) cultural and moral values. Collective-affirmation inherent in the Bhartiya collective cultural values catalyzed mass behaviours change in the form of adherence to the essential restrictions and recommendations. Collective-affirmation may have occurred due to the faith of the government in the virtues of the Indians and their perceived administrative capability of the government. A culture-specific collective-affirmation seems to emerge which initiated mass behavioural changes. The findings may have implications for changing people to face difficult situations, to accept social policies aimed at eradicating poverty, illiteracy, corruption and violence, and to adopt a healthy lifestyle to enhance their well-being.KeywordsBhartiya cultural heritage; Collective-affirmation; COVID-19; lockdown; mass behaviour change.

The lifetime risk for prolapse surgery is nearly 20%, and worldwide vaginal hysterectomy is the most commonly performed surgical procedure for uterine prolapse. Uterine-sparing procedures are attractive options in women without contraindications for these surgeries. The majority of these procedures involve mesh-based approaches; however, patients and surgeons are increasingly worried about the use of meshes. For a meshless urogynecological perspective, we aim to introduce a novel surgical technique in which the critical organ cervix, serving as a roof in terms of pelvic-support, is isolated, after which the prolapse of the remaining uterus is removed, and all pelvic compartments are revised.

“Atrial Fibrillation and Premature Ventricular Complexes” – is there a unifying diagnosis?

Introduction: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing, MPP) has been shown to improve CRT response, although MPP response using automated pacing vector programming has not been demonstrated in the Middle East. Objective: Compare the impact of MPP to conventional biventricular pacing (BiV) using echocardiographic and clinical changes at 6 months post-implant. Methods: This prospective, randomized study was conducted at 13 Middle Eastern centers. After de novo CRT-D implant (Abbott Unify Quadra MP™ or Quadra Assura MP™) with quadripolar LV lead (Abbott Quartet™), patients were randomized to either BiV or MPP therapy. In BiV patients, the LV pacing vector was selected per standard practice; in MPP patients, the two LV pacing vectors were selected automatically using VectSelect. CRT response was defined at 6 months post-implant by a reduction in LV end-systolic volume (ESV) ≥15%. Results: One-hundred and forty-two patients (61 years old, 68% male, NYHA class II/III/IV 19%/75%/6%, 33% ischemic, 57% hypertension, 52% diabetes, 158 ms QRS, 25.8% ejection fraction [EF]) were randomized to either BiV (N=69) or MPP (N=73). After 6 months, MPP vs. BiV patients experienced greater ESV reduction (25.0% vs. 15.3%, P=0.08), greater EF elevation (11.9% vs. 8.6%, P=0.36), significantly greater ESV response rate (68.5% vs. 50.7%, P=0.04), and significantly greater NYHA class improvement rate (80.8% vs. 60.3%, P=0.01). Conclusions: With MPP and automatic LV vector selection, more CRT patients in the Middle East experienced reverse remodeling and clinical improvement relative to conventional BiV pacing.

Low-field nuclear magnetic resonance (NMR) relaxometry is an attractive approach for point-of-care testing medical diagnosis, industrial food science, and in situ oil-gas exploration. However, one of the problems is the inherently long relaxation time of the (liquid) sample (and hence low signal-to-noise ratio) which causes unnecessarily long repetition time. In this work, a new methodology is presented for a rapid and accurate object classification using NMR relaxometry with the aid of machine learning techniques. It is demonstrated that the sensitivity and specificity of the classification are substantially improved with a higher order of (pseudo)-dimensionality (e.g., 2D or multidimensional). This new methodology (the so-called Clustering NMR) may be extremely useful for rapid and accurate object classification (in less than a minute) using the low-field NMR.

Background: Whether there is also a correlation between viral shedding duration and the clinical course of illness in COVID-19 has not yet been determined. Methods: In this retrospective study, we included 239 adult inpatients (all ≥18 years old) with laboratory-confirmed COVID-19 from the Wuhan Tongji Hospital (Wuhan, China). Results: Of the subset of 239 patients included in this study, 33 patients died due to COVID-19 and 45 patients demonstrated clinical progression to critical illness. Patients with a long duration of viral RNA shedding as compared to short duration of viral RNA shedding also had significantly lower mortality rates ((9.5% vs. 18.6%, P= 0.04) and a lower rate of progression to critical illness (16.7% vs. 21.2%, P= 0.37). Viral RNA shedding is an independent risk factor for mortality within 28 days of observation (OR 0.94, 95% CI: 0.88-0.99, P= 0.025, by multivariable regression analyses) and increased duration of viral shedding is correlated with a significant survival advantage (P =0.047) and lower risk of progression to critical illness (P =0.029, by Kaplan-Meier analyses). Conclusions: Prolonged viral RNA shedding duration is associated with improved patient prognosis and reduces the risk of progression to critical illness in this subset of COVID-19 patients. Further clinical studies are necessary to determine if a longer duration of viral RNA shedding with COVID-19 is predictive of an overall better patient prognosis and outcome.

West Dongting Lake (WD) receives water from local rivers, the Yuan and Lishui Rivers, within the lake basin and is recharged by the Yangtze River outside the basin through three outfalls. Thus, water pollution control is more complicated in WD than in lakes disconnected from the Yangtze River. Here, major ion tracing which was a method rarely applied in the river-lake system was used to characterize the contribution of water and total nitrogen (TN) from the inflow rivers to WD, and 9 sampling sites in WD and its inflow rivers were investigated in December 2016 (the dry season, DS), April 2017 (the normal season, NS) and August 2017 (the wet season, WS). Na+ and Cl－ were suitable tracer ions used in the ion tracing model to estimate the water and TN contributions from inflow rivers to WD. Results showed that the water and TN in WD who presented river and lacustrine phases were mainly contributed by local rivers rather than the three outfalls, in which the contribution of Yuan River was larger than that of Lishui River. However, the contribution rates of water and TN of the three outfalls to WD during WS reached above 20% and 30% respectively, indicating that the contribution of the three outfalls could not be ignored, in which the contributions of water and TN from Songzi outfall were higher than those from Taiping and Ouchi outfalls. Therefore, we suggest that the relevant departments should identify key river management targets during different water periods, implement refined management over water pollution in WD, and prioritize the pollutant input of Yuran River and Songzi outfall (especially during WS).

We present, by using previous results on extended Petri Nets, the relations of various hydrological dynamical systems ($\mathtt{HDSys}$) derived from the water budget ($\mathtt{DynWB}$). Once $\mathtt{DynWB}$ has been implemented, there exist a consistent way to get the equations for backward travel time distributions ($\mathtt{DynTT}$), for the forward response time distribution ($\mathtt{DynRTD}$) and for the concentration for a solute or a tracer ($\mathtt{DynC}$). We show that the $\mathtt{DynWB}$ has a correspondence one to many with the $\mathtt{DynTT}$. In fact to any one of the $\mathtt{DynWB}$ equation correspond as many equation as the input precipitation events times. The $\mathtt{DynTT}$ is related to $\mathtt{DynRTD}$ by the Niemi’s relationship and, in presence of multiple, $n$ outputs, by the specification of $n-1$ partition functions, which determine which fraction of water volume, injected in the control volume at a specific time $t_{in}$, goes asymptotically into a specific output. The $\mathtt{DynC}$, given $\mathtt{DynTT}$, depends further on the solute/tracer concentration in inputs. The paper clarifies the complicate set of relations above by using an example from literature. Upon the introduction of the appropriate information, it is also shown how these ($\mathtt{HDSys}$) can be solved simultaneously without duplicating calculations. It is also shown that these systems can be solved exactly, under the hypothesis of uniform mixing of water ages inside each reservoir within the system.

We should be considering age, comorbidities and health-care system performance to relax Covid-19 related social distancing measuresDear Editor,Aiming to avoid a health system collapses due to the COVID-19 pandemic; social distancing measures are taken broadly.1 The very high or high-risk population is of specific concern, once expected to have an increase rate of admission.2 Besides criticised, the strategy seems to be working properly and now brings the discussion about when the measures will be relaxed with safety.Comparisons with other pandemics are not entirely appropriate, but it seems reasonable to look back at the past and consider valuable lessons learned. The direct association between death and age as well as for comorbidities or clinical risk is observed in other viral infections similarly to the current outbreak.3-13 Age is also a known as an independent survival factor. On the other hand, it should be highlighted that young children are the exception once have an immature immune system, main reasons why we generally see a “J-like” curve shape as schematically represented by the Figure 1. Although, age-mortality rate seems to be similar amongst world regions, the poor healthcare and quality index is associate with increase death rate.14Unfortunately, we were relying on certainties that are fragile for the moment. There is no solid evidence about herd immunity in patients with asymptomatic disease. Moreover, we all expect that the patients that recovered from the infection are hopefully immune or at least have a mild disease in case of re-infection but the knowledge about the immune response and anti-bodies nature is currently imature15, 16. There is also scare evidence about mass use disposable barrier methods, such as face masks or gloves, will diminish the viral transmission.17 Although community use of personal protection equipment might give a sensation of safety in some cultures, the misuse or re-use could be dangerous and there is no evidence assuring the benefit provided by community manufactured masks.18,19Therefore, once the evidence is being gathered and a vaccine, probably the most reliable scientific based way out of this crisis, will take at least some months to be available, we should consider relax social distancing measures based on age adjusted by comorbidities as a first step whilst continuing with hand washing associated with high standards of self-hygiene when possible.Bruno H R de Paula1*, Renan G A Carraretto2, Nathalia M P B Barreto31 Department of Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust,Cambridge CB2 0QQ, UK2 Universidad Privada del Este, Ciudad Presidente Franco - Paraguay3 Division of Cardiology, Hospital Pró-Cardiaco, Rio de Janeiro, Brazil* Correspondent authorCompeting InterestsThe authors declare that they have no competing interestsReferences:1. Lewnard, Joseph A., and Nathan C. Lo. ”Scientific and ethical basis for social-distancing interventions against COVID-19.” The Lancet. Infectious diseases (2020).2. nhs.uk. 2020. Who’s At Higher Risk From Coronavirus - Coronavirus (COVID-19) . [online] Available at: <https://www.nhs.uk/conditions/coronavirus-covid-19/people-at-higher-risk-from-coronavirus/whos-at-higherrisk-from-coronavirus/> [Accessed 4 May 2020].3. Ramiro, Diego, et al. ”Age-specific excess mortality patterns and transmissibility during the 1889–1890 influenza pandemic in Madrid, Spain.” Annals of epidemiology 28.5 (2018): 267-272.4. Cilek, Laura, Gerardo Chowell, and Diego Ramiro Fariñas. ”Age-specific excess mortality patterns during the 1918–1920 influenza pandemic in Madrid, Spain.” American journal of epidemiology187.12 (2018): 2511-2523.5. Viboud, Cécile, et al. ”Global mortality impact of the 1957–1959 influenza pandemic.” The Journal of infectious diseases 213.5 (2016): 738-745.6. Ma, Junling, Jonathan Dushoff, and David JD Earn. ”Age-specific mortality risk from pandemic influenza.” Journal of theoretical biology 288 (2011): 29-34.7. Donaldson, Liam J., et al. ”Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study.” Bmj 339 (2009): b5213.8. Chan‐Yeung, Moira, and Rui‐Heng Xu. ”SARS: epidemiology.” Respirology 8 (2003): S9-S14.9. Verity, Robert, et al. ”Estimates of the severity of coronavirus disease 2019: a model-based analysis.” The Lancet Infectious Diseases (2020).10. Glynn, Judith R. ”Protecting workers aged 60–69 years from COVID-19.” The Lancet Infectious Diseases (2020).11. Onder, Graziano, Giovanni Rezza, and Silvio Brusaferro. ”Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.” Jama (2020).12. www1.nyc.gov. 2020. COVID-19: Data - NYC Health. [online] Available at:<https://www1.nyc.gov/site/doh/covid/covid-19-data.page> [Accessed 4 May 2020].13. Cromer, Deborah, et al. ”The burden of influenza in England by age and clinical risk group: a statistical analysis to inform vaccine policy.” Journal of Infection 68.4 (2014): 363-371.14. Global - Paget, John, et al. ”Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project.” Journal of global health 9.2 (2019).15. Wu, Fan, et al. ”Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications.” (2020).16. Altmann, Daniel M., Daniel C. Douek, and Rosemary J. Boyton. ”What policy makers need to know about COVID-19 protective immunity.”The Lancet (2020).17. Cheng, Kar Keung, Tai Hing Lam, and Chi Chiu Leung. ”Wearing face masks in the community during the COVID-19 pandemic: altruism and solidarity.” The Lancet (2020).18. Leung, Chi Chiu, Tai Hing Lam, and Kar Keung Cheng. ”Mass masking in the COVID-19 epidemic: people need guidance.” Lancet 395.10228 (2020): 945.19. Liu, Xiaopeng; Zhang, Sisen. COVID-19: face masks and human-to-human transmission.  Influenza And Other Respiratory Viruses,[s.l.], p. 1-2, 5 abr. 2020. Wiley. http://dx.doi.org/10.1111/irv.12740.

COVID-19 has undergone rapid spread worldwide, with the number of infected patients and death events being increased at exponential rates, and thus considered an epidemic disaster. However, SARS-CoV-2 has reduced case-fatality rate and enhanced transmission capacity that favor its propagation and make it evolutionarily more advanced than the other coronaviruses. Further, SARS-CoV-2 preserves virulence to certain patients while keeping some patients symptom-free. It is hypothesized here that SARS-CoV-2 functions as a natural selection pressure for human evolution. That is, COVID-19 is an epidemic disaster at the individual level but may be evolutionarily beneficial for the human at the population level, and survived individuals from SARS-CoV-2 infection may be more tolerable to redox pressure and not suffer anymore from diseases such as hypertension if without external intervention.