Electron Beam Melting (EBM) is one of a few additive manufacturing technologies capable of making full-density functional metallic parts realized from raw materials in the form of powders. The ability of direct fabrications of metallic parts can accelerate product designs and developments in a wide range of metallic-part applications, especially for complex components, which are difficult to make by conventional manufacturing means. To capitalize on these benefits, it must be shown that the mechanical performances of parts produced by EBM can meet design requirements. In this research an intensive mechanical characterization aimed at determining static and fatigue performance of the alloy Ti6Al4V processed by EBM has been performed. The effect of both postprocessing treatments (HIP and surface finish) on the mechanical behavior was evaluated by mechanical testing, microstructural study, computed tomography analysis and fracture surface investigation.
Birds have been observed to have dietary preferences for unsaturated fatty acids (FAs) during migration. Polyunsaturated fatty acids (PUFAs) increase the exercise performance of migrant birds; however, PUFAs are also peroxidation prone and might therefore incur increased costs in terms of enhanced oxidative stress in migratory individuals. To shed light on this potential constraint, we analysed plasma FA composition and estimated the susceptibility to peroxidation of migrants and residents of the partially migratory common blackbird (Turdus merula) at a stop-over site during autumn migration. As predicted, migrant birds had higher relative and absolute levels of PUFAs compared to resident birds. This included the strictly dietary ω-3 PUFA α-linoleic acid, suggesting a dietary preference for these fatty acids in migrants. Interestingly, the FA unsaturation index, which is an index of lipid peroxidation susceptibility, did not differ between migrants and residents. These findings suggest a mechanism where birds alter their levels of metabolic substrate to increase exercise performance without simultaneously increasing the risk of lipid peroxidation and oxidative stress. In summary, our results are in line with the hypothesis of increased exercise performance being constrained by oxidative stress during migration, which is manifested in changes in the composition of key FAs to retain the unsaturation index constant despite the increased levels of peroxidizable PUFAs.
Coronavirus disease 2019 (COVID-19) is a remarkably challenging health issue that provoked all the health-care providers to contemplate some measures about the situation. All the health-care workers frontline (esp. emergency service, pulmonologists, infection disease specialist and anesthesiologist) have produced recommendations on prevention and taking care of COVID-19 patient (1,2). Whereas, at the second line another important issue is the ongoing healthcare for the continual disease situations.There are two main critical issues on cardiovascular surgery in this pandemic. Firstly, to delay the elective surgeries is essential to sustain the health-care service. Elective case triage is trickier for cardiovascular procedures which are relatively progressive conditions. Definitive decision to defer a procedure should be made regarding firstly to the capacity of health-care system, and then availability of surgical/anesthesia staff, intensive care unit beds, need for isolation beds, ventilators, cardiopulmonary bypass machine, extracorporeal membrane oxygenator, supplies such as sutures, grafts, valves and blood and blood product availability. The patient status should be taken into account to defer or to perform the procedure, as well. Therefore, we developed “Level of Priority” (LoP) statement for cardiovascular procedures (3). Elective cases are defined as LoP I that may be postponed as much as possible. LoP II to IV cases should be reconsidered by individual basis by “Heart Team”. The situations that can be managed by percutaneous coronary intervention, endovascular procedures and etc. may be handled by non-operative manners.The second one is the personal protection equipment and infection measures while dealing with a suspected / confirmed COVID-19 patient. It is obvious that a suspected / confirmed COVID-19 patient ought to be assessed with specific measures for any medical or surgical intervention. Personal protection equipment (PPE) is the most crucial measure during the pandemic. It is recognized that many centers are facing PPE shortages and there are recommendations to re-sterile the masks to be effective for reuse.(4) More measures should be taken into consideration for sterile environment such as surgical procedures. Some added measures such as face shield may be recommended for surgical procedures. The surgical team who scrubbed in, must wear extra equipment such as surgical coat and double gloves. It may be recommended to fix the long-sleeve gloves to the surgical coat by adhesive drapes (3). It is obvious that this kind of working environment with all this equipment is challenging, sometimes irritating and disquieting. One other big problem is the fraught feeling of health-care providers to be diseased or to be contagious for their family. Therefore, health-care providers may need enormous support for burnouts during the pandemic.The other measures such as preparation of the operating room (OR), anesthesiologic management, transportation of patients and disinfection of OR were discussed in the referring article (3).In conclusion, it is important to assess the “Level of Priority” for surgical procedures to support the service of health-care facility. More than that, whole surgical team should be protected by adequate PPE and should take the time to get full protected.
Objective. To externally validate the M6 risk model and the two-step triage strategy (2ST) to triage pregnancies of unknown location (PUL), and compare performance with the M4 model and beta human chorionic gonadotropin (BhCG) ratio cut-offs. Design. Model validation study. Setting. Eight UK hospitals with early pregnancy assessment units. Population. Women presenting with a PUL and BhCG >25 IU/L. Methods. Women were managed using the 2ST protocol: step 1 classifies PUL as low risk of ectopic pregnancy (EP) if presenting progesterone ≤2 nmol/L, M6 is used as step 2 in the remaining cases. We validated 2ST and M6 alone (with and without progesterone as a predictor: M6P and M6NP). M6 and M4 require the BhCG ratio over two days. Based on these models, we classified PUL as high risk for EP when the risk was ≥5%. We meta-analysed centre-specific results. Main outcome measures. Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP. Results. Of 2899 eligible women, the main analysis excluded 297 (10%) women that were lost to follow-up. 16% (95% confidence interval 12-20) of women had presenting progesterone ≤2 nmol/L. The area under the ROC curve for EP was 0.88 (0.86-0.90) for 2ST and 0.89 (0.86-0.91) for M6P. Sensitivity for EP was 94% (89%-97%) for 2ST and 96% (91%-98%) for M6P. Both approaches had good overall calibration, with modest variability between centres. M4 and BhCG ratio cut-offs had inferior performance and lower clinical utility. Conclusions. The 2ST and M6P alone are the best approaches to triage PUL.
The incidence of mechanical complications of acute coronary syndromes (ACS) needing cardiac surgery has reduced significantly in the last years due to early diagnosis and treatments. Covid-19 pandemic, however, would generate in the patients a sense of fear regarding access to the ERs so they probably underestimate symptoms such as chest pain or angina equivalents until situation does not became critical. In this way, this behaviour could create a vast pool of patients who will enter the hospital in much more critical situations and with mechanical complications of an evolving ACS needing cardiac surgery treatment.
A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74,000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS-CoV-2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID-19 infection and its treatment, due to consequences of myocarditis and the use of QT-prolonging drugs. Most crucially, the surge in COVID-19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID-19 pandemic, including performance of only urgent/emergent procedures, afterhours/7-day per week laboratory operation, single attending-only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow-up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients in order to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.
NK cells are an important arm of the innate immune system, and they constitutively express the NKp30 receptor. NKp30-mediated responses are triggered by the binding of specific ligands, such as tumour cell-derived B7-H6, and involve the secretion of cytotoxic mediators TNF-α, IFN-γ, perforins and granzymes. The latter two constitute a target cell-directed response that is critical in the process of immunosurveillance. The structure of NKp30 is presented, focusing on the ligand-binding site, on the ligand-induced structural changes, and on the experimental data available correlating structure and binding affinity. The translation of NKp30 structural changes to disease progression is also reviewed. NKp30 role in immunotherapy has been explored in chimeric antigen receptor T-cell (CAR-T) therapy. However, antibodies or small ligands targeting NKp30 have not yet been developed. The data reviewed unveils the key structural aspects that must be considered for drug design in order to develop novel immunotherapy approaches.
The manuscript describes a computational study that provides molecular-level insight into shale gas adsorption and transport in shale rocks, which are composed of organic and inorganic matter. Atomistic simulations were used to generate realistic models of the organic matter structures with both micro- and mesoporosity, and correspond to mature and overmature type-II kerogens. These porous material models are unique to most other previous kerogen models since they contain other components (asphaltene/resin, hydrocarbons and carbon dioxide/water fractions) that are typically not modeled. The inclusion of these additional components significantly influences the resulting porous structure characteristics. The adsorption and diffusion behavior of methane (as a shale gas proxy) and methane/carbon dioxide mixtures were simulated in the model structures. Several key industrial-relevant findings are described in the manuscript.
Environmental variability can lead to dispersal: why stay put if it is better elsewhere? Without clues about local conditions, the optimal strategy is often to disperse a set fraction of offspring. Many habitats contain environmentally differing sub-habitats. Is it adaptive for individuals to sense in which sub-habitat they find themselves, using environmental clues, and respond plastically by altering the dispersal rates? This appears to be done by some plants which produce dimorphic seeds with differential dispersal properties in response to ambient temperature. Here we develop a mathematical model to show, that in highly variable environments, not only does sensing promote plasticity of dispersal morph ratio, but individuals who can sense their sub-habitat and respond in this way have an adaptive advantage over those who cannot. With a rise in environmental variability due to climate change, our understanding of how natural populations persist and respond to changes has become crucially important.
Scimitar syndrome is rare malformation defined as partial or total anomalous pulmonary venous return of the right lung veins to the inferior vena cava just above or below the diaphragm. Severe forms of the disease are diagnosed in infancy and childhood . However, because of the mild form of the syndrome in adult patients, they remain asymptomatic and few cases are reported in the literature. We report an unusual presentation of this syndrome mimicking unstable angina in one of the two described cases.
Peroxiredoxins (PRXs) are intracellular antioxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5, and PRX6) in the CSF and serum of 16 patients with MS, 16 patients with NMOSD, and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (p < 0.05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood–brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.
As Dr. Thomson eloquently notes in his valuable letter , underlying respiratory diseases appear to be less of a risk factor for poor outcome in COVID-19 patients than either underlying cardiovascular disease or diabetes. This intriguing finding emerged from several studies that examined underlying medical conditions in COVID-19 patients.In a single-center retrospective analysis of critically ill adults admitted to the intensive care unit of a hospital from China between late December 2019 and January 26, 2020, 22% of the non-survivors had cerebrovascular disease, 22% had diabetes, and 6% had chronic respiratory disease . The analysis of data from patients with laboratory-confirmed COVID-19 from hospitals in China through January 29, 2020 found that 16.2% of those with serious disease had diabetes, 23.7% had hypertension, and 3.5% had chronic obstructive pulmonary disease . A study of electronical medical records of COVID-19 patients admitted between January 16 and February 3, 2020 to a hospital from Wuhan found that hypertension and diabetes mellitus, the most common comorbidities, were present in 37.9%, 13.8%, of the patients with severe disease, respectively, but only in 3.4% of the patients with chronic obstructive pulmonary disease . Finally, an analysis of all COVID-19 cases reported through February 11, 2020, extracted from the Infectious Disease Information System in China, found that case fatality rates in individuals with cardiovascular disease, chronic respiratory disease, and diabetes were 10.5%, 6.3%, and 7.3% respectively, as compared to 0.9% among patients with no comorbidities . In a case series of COVID-19 patients hospitalized in Wuhan, China, ICU patients were more likely to have underlying diabetes than patients that did not receive ICU care (22.2% vs 5.9%) .The studies mentioned above did not stratify patients by therapies they were receiving. However, one commonality between cardiovascular disease and diabetes is that they are often treated with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-I receptor blockers (ARBs), widely used to inhibit the formation and action of angiotensin II.ACE shares 42% amino acid identity with ACE2 , a membrane-bound aminopeptidase  extensively expressed on type II human alveolar cells . The genes encoding these two proteins are thought to have emerged by duplication . ACE2 is distributed on many tissues and shows highest expression levels in the heart, kidney, lung, small intestine, and testis . On the apical surface of polarized respiratory epithelial cells, ACE2 is a crucial and primary receptor for the cellular entry of SARS-CoV, the virus that caused the 2002-2003 SARS outbreak [12-16]. SARS-CoV binding to ACE2 mediates entry into human or animal cells . ACE2 is also the receptor for SARS-CoV-2, the etiologic agent of COVID-19 . Structural analyses indicate that SARS-CoV-2 binds the ACE2 receptor with a 10-20-fold higher affinity than SARS-CoV [19, 20].The entry of SARS-CoV and SARS-CoV-2 into their target cells is mediated by the viral spike (S) glycoprotein, which is located on the outer envelope of the virion . The S glycoprotein has two functional subunits, S1, which binds the cellular receptor, and S2, which contains domains required for the fusion between viral and cellular membranes [22, 23]. Viral binding and membrane fusion represent the initial and critical steps during the infection cycle of the coronavirus  and the first step in establishing the infection [25, 26]. Binding is followed by internalization of ACE2 and down‐regulation of its activity on the cell surface [27-29].SARS-CoV binds ACE2 through a region of the viral S1 subunit called the minimal receptor-binding domain (RBD) . RBD is the most important determinant of the SARS-CoV host range, and studies about the “species jump” during the 2002-2003 SARS outbreak revealed that changes of only one or two amino acids in this region were sufficient to make the virus “jump” to a new host [26, 30, 31].ACE and ACE2 are two members of the renin angiotensin system that negatively regulate each other [32, 33] and are distinct in their substrate specificity and function . ACE converts angiotensin I to angiotensin II and mediates aldosterone release, vasoconstriction, sodium retention, cell proliferation, and organ hypertrophy . ACE2 cleaves a single residue from angiotensin I to form angiotensin-(1-9), and a single residue from angiotensin II to form angiotensin-(1-7). In humans, ACE2 has a 400-fold higher catalytic efficiency when it uses angiotensin II as a substrate as compared to when it uses angiotensin I . ACE2 and angiotensin-(1-7), through the Mas receptors, oppose ACE and mediate vasodilation and anti-proliferative, anti-hypertrophic, cardioprotective, and reno-protective effects [8, 35, 37]. ACE2 has physiological and pathological importance  and its dysregulation was implicated in heart disease, hypertension, and diabetes [36, 38-40]. ACE2 is not inhibited by ACE inhibitors  and several studies indicate that the ACE2/Angiotensin-(1-7)/Mas axis has anti-inflammatory effects [41, 42].It was recently hypothesized that treatment with ACE inhibitors and/or ARBs may lead to ACE2 overexpression and this could increase the risk of severe COVID-19 , possibly by increasing the internalization of SARS-CoV-2. Several lines of evidence indicate that pharmacological manipulation of the renin-angiotensin-aldosterone pathway could affect ACE2 receptor levels. In animal studies, the selective blockade of angiotensin II synthesis or activity increased cardiac Ace2 gene expression and activity [44, 45], and treatment with ARBs increased the levels of cardiovascular ACE2 receptors [46-49]. While this link is thought-provoking as a possibility, there isn’t currently sufficient evidence to contemplate changing patients’ existing therapeutic regimens in order to minimize their risk of COVID-19 complications. The first clinical evidence exploring this link indicated that the use of ACEI and ARBs appear to improve the clinical outcome of COVID-19 patients with hypertension . We will only learn about any possible associations, along with their magnitude and direction, from carefully conducted and adequately powered clinical trials.It is also important to consider that an increase in ACE2 levels does not necessarily entail a negative impact for the course of COVID-19. ACE2, by forming angiotensin-(1-7) from angiotensin II, could diminish the deleterious effects of angiotensin II and, consequently, it is also possible that ACE inhibitors or ARBs could, in fact, lower the risk of complications . However, increased ACE2 and the formation of angiotensin-(1-7), by inhibiting COX-2, could exert anti-inflammatory effects [52, 53], underscoring the multitude of possible effects and the need to conduct studies to interrogate these connections. Finally, it is not known whether an increase in the expression of ACE2 would also lead to an increased shedding and increased levels of soluble ACE2, which could act as a decoy receptor and lower viral entry into cells . In support of this, recombinant human ACE2 ameliorated the lung injury induced by the avian influenza H5N1 virus in mice . It is also important to consider that from the relatively limited amount of human data, plasma ACE2 activity does not appear to be statistically different between individuals taking ACE inhibitors or ARBs and those not taking these medications, but these results do not reflect the levels of cellular receptors . Structural analyses indicate that the binding of the SARS-CoV spike protein to ACE2 does not occlude the catalytically active site of the receptor [26, 57], and it was hypothesized that angiotensin II binding to ACE2 could induce a conformational change in the receptor, which will no longer be favorable for SARS-CoV-2 binding . The mining of existing datasets, preclinical studies, and clinical trials will help shed light on these complex and sometimes conflicting scenarios.A decrease in the number of ACE2 receptors appears to be involved in acute lung injury and cardiovascular pathology [58, 59], and may be detrimental during coronavirus infection. A mouse Ace2 knockout developed severe cardiac contractility defects and increased angiotensin II levels, and the additional deletion of Ace rescued this phenotype . In acute lung injury models, the loss of Ace2precipitated severe acute lung failure, and this was attenuated by the exogenous recombinant human ACE2 in both Ace2 knock-out and in wild-type mice . Attenuation of the Ace2 catalytic function perturbed the pulmonary renin-angiotensin-aldosterone system and increased inflammation and vascular permeability , and Ace2 overexpression decreased lung inflammation in an animal model of acute lung injury . In vitro and in experimental animals, SARS-CoV and the SARS-CoV spike protein downregulated ACE2 expression [12, 28]. In mice with lung injury, injection of the SARS-CoV spike protein worsened the acute lung failure and caused lung edema, increased vascular permeability, and decreased lung function, and this pathology was attenuated by blocking the renin-angiotensin-aldosterone pathway . Thus, animals infected with SARS-CoV or treated with the spike protein resemble Ace2 knockout animals . It is relevant that a pilot study of patients with acute respiratory distress syndrome reported the accumulation of angiotensin I and the decrease of angiotensin-(1-9), indicating decreased ACE2 activity, among non-survivors . Thus, SARS-CoV and SARS-CoV-2 might contribute to severe respiratory symptomatology partly because the viruses, by binding the ACE2 receptors, also deregulate protective pathways in the lungs.Thus, either increased or decreased numbers of pulmonary ACE2 receptors may be detrimental during SARS-CoV or SARS-CoV-2 infection, most likely for distinct reasons. An increased number of ACE2 receptors may lead to a higher viral load and more severe clinical disease. Diabetes increases ACE2 expression, as shown in several experimental models, and the resulting increased viral load might explain the more severe course of COVID-19 in diabetic patients [64, 65]. Interestingly, in a rodent model of diabetes, ibuprofen inhibited the ACE/angiotensin II/angiotensin type 1 receptor axis and enhanced the ACE2/angiotensin-(1-7)/Mas receptor axis . Too few functional ACE2 receptors, which decrease even more as a result of high viral loads and enhanced receptor internalization , might exacerbate acute lung injury, increase angiotensin II levels, and alter the balance between pro- and anti-inflammatory responses. It is relevant that in a study on twelve COVID-19 patients from China, plasma angiotensin II levels were markedly elevated as compared to healthy control individuals, and linearly associated with the viral load and with the lung injury . The animal studies that documented an age-dependent decrease in ACE2 expression in the lung and the aortic might also explain, at least in part, the age-dependent increase in the risk of serious COVID-19 complications [69, 70].SARS-CoV can also bind cells through alternative receptors that include the C-type lectins DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) and/or L-SIGN (liver/lymph node-SIGN) [14, 71-73]. It will be critical to understand the potential involvement of the same, or alternative receptors in the pathogenesis of COVID-19.It has been less clear why SARS-CoV and SARS-CoV-2 lead to severe lung disease , in contrast to other, previously known coronaviruses, which usually result in mild upper respiratory infections and cause pneumonia only rarely, mostly in newborn, the elderly, and immunocompromised individuals [74-77]. One of the possibilities advanced for SARS is that the burden of viral replication and the immune status of the host may both shape the severity of the infection [57, 78, 79]. The same might be true for COVID-19, and further exploring the link between viral burden, chronic medical conditions, long-term medication usage, and the severity of the infection will be critical.An important lesson from SARS and MERS is the association between the incubation period and disease severity. For any infectious disease, the incubation period varies among individuals, even for the same outbreak, and depends on the initial infective dose, the speed of pathogen replication within a host, and host defense mechanisms . During the 2002-2003 SARS outbreak, a study in Hong Kong revealed that patients with shorter incubation times developed more severe disease . The same was found in MERS patients from South Korea, where longer incubation times were associated with a lower risk of death . Interestingly, during the SARS outbreak in Hong Kong, healthcare workers, who have a higher infecting dose, had 34% shorter median incubation times than non-healthcare workers . It will be interesting to examine whether the same is true for SARS-CoV-2, and whether the incubation period is different in COVID-19 patients when they are stratified by age, coexisting morbidities, and therapies they receive for chronic diseases. While the association between the incubation period and mortality might simply indicate that the disease was confirmed earlier in patients with longer incubations, and reflect earlier treatment opportunities , it is also plausible that high viral loads might mediate the link between the two.Two factors decisive for the successful control of outbreaks are the ability to isolate asymptomatic individuals and the ability to trace and quarantine their contacts [84, 85]. Several studies reported asymptomatic shedding of SARS-CoV-2, indicating that asymptomatic carriers, or individuals with very mild symptoms, may sustain transmission [86-89]. For example, nearly 18% of the passengers who tested positive for SARS-CoV-2 on the Diamond Princess cruise ship were asymptomatic . Another valuable finding that emerged from the COVID-19 outbreak analysis in Singapore, and has a strong impact on infection control, is that after becoming asymptomatic, some patients continued to shed the virus for up to several days. In one instance, a patient continued to have detectable respiratory shedding, as shown by PCR, for eight consecutive days after becoming asymptomatic . Another study revealed that several children with COVID-19 persistently tested positive for viral RNA on fecal swabs after their nasopharyngeal cultures became negative. Even though replication-competent virus was not detected in the fecal swabs, this finding leaves open the possibility of SARS-CoV-2 fecal-oral transmission . These findings illustrate the challenges in understanding SARS-CoV-2 transmission and in identifying infected individuals, tracing their contacts, and implementing preparedness plans. One of the absolute requirements, to clarify these questions and overcome these obstacles, is ensuring the prompt and large-scale testing of symptomatic individuals and of their asymptomatic contacts. This, together with the social distancing measures, are currently our only available assets in facing a pandemic that, even though it was preceded by multiple warnings in recent years, is unlike any other infectious disease that we experienced in modern history.
Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield across global regions is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control and pollination services in adjacent crops using a global dataset of 529 sites. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimize floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future.
Specific therapies in pregnant women are discussedThe health crisis caused by the novel SARS-cov-2 (2019-nCoV) related pandemic requires urgent and necessary therapeutic response. Pregnant women are just as exposed as the general population and should not be excluded, because of their status, from discussions on effective and well tolerated candidate treatments. While in countries that have opted for national containment, daily non-emergency medical and surgical activities are suspended, obstetric services continue to operate relentlessly and are experiencing a surge in so-called ”at-risk” pregnancies. Some countries have now recommended routine screening of all pregnant women 1 but the low availability and performance of the current tests limits their use. Management of an infected pregnant women is essentially conditioned by maternal symptomatology. Women with little or no symptoms do not require routine treatment or in-patient care and simply need to be monitored for up to 15 days for evidence of respiratory deterioration. In the absence of validated specific treatment, the primary approach to therapy is mainly symptomatic and delivery is considered in the event of critical respiratory distress in order to maximize oxygenation and lung capacity2–4 . However, it has been reported that women with respiratory signs may be given antiviral treatment to improve their clinical condition 2,4To date, there is no proven effective strategy, although many teams are working tirelessly to identify an effective treatment. Four molecules are leading in this race:1) Remdesivir is a novel nucleotide analogue prodrug which incorporates into nascent viral RNA chains and results in pre-mature termination. Its effectiveness has been already demonstrated against others coronaviruses such as SARS-Cov and MERS-Cov5, and it has proven to be highly effective on in vitro 2019-nCoV infection6. Compassionate use in human were also reported 7 and phase 3 studies are currently underway.2) (Hydroxy)chloroquine has been known for years because of its effectiveness in the treatment of inflammatory diseases and against malaria. Recent studies have shown antiviral effects of chloroquine and in vitro studies concluded that it was highly effective in the control of 2019-nCoV 6,8. Elevation of endosomal pH and interference with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2 conduct to block virus infection. (Hydroxy)chloroquine has been used in 2019-nCoV infected humans with highly controversial restuls9,10 and well-designed randomized studies should be available soon.3) Lopinavir, a viral protease inhibitor, with its pharmacological booster Ritonavir (LPV/R) are commonly used in HIV positive patients. It has already been used for SARS-Cov. Some countries such as China and India approved its use in symptomatic infected patients although a first randomized, controlled, open-label trial showed no benefit of LPV/R over standard care in patients with severe 2019-nCoV disease11.4) Ribavirin, is a guanosine analog that interferes with the replication of RNA and DNA viruses. It has been used for years in the treatment of chronic hepatitis C. Based on its direct anti‐viral activity against 2019‐nCoV in vitro and some evidence for its potential efficacity during the prior SARS-Cov and MERS-Cov outbreaks, it has been suggested as a potential candidate for the treatment of 2019-nCoV diease12. 2019-nCoV infected patients treated with Ribavirin have been reported by Chinese studies4,13but its exact benefit remains to be demonstrated in well designed randomized studies as well.To date, all four drugs are being independently tested in Phase 3 studies, mostly national, to investigate their efficacy and safety in the management of 2019-nCoV disease. Several European countries have also set up, as a result of joint efforts since mid-March, a randomized, multicentre, open-label trial to evaluate and compare the efficacy and toxicity of the first three treatments mentioned above.14With regard to the possibility of treating pregnant patients with these molecules, few data are available for Remdesivir. Only one study reports its use in six pregnant women in a randomized trial during Ebola epidemics. The authors reported no adverse effect15.Many more pharmacological studies on maternal-fetal tolerance of Hydroxy(chloroquine), Lopinavir and Ribavirin are available. The historical use of (hydroxy)chloroquine in antimalarial treatment, but also in connective tissue diseases, has resulted in a well-documented safety and tolerance profile in pregnant women16. Animal studies, undertaken during the Zika virus epidemic, have also suggested that chloroquine may also reduce the risk of viral transplacental transmission to the fetus17. The optimal dosage to be used in pregnant women will have to be specified, but it appears that there is no pharmacokinetic difference between chloroquine and its major metabolite between pregnant and non-pregnant women18. With respect to the use of protease inhibitors during pregnancy, such as Lopinavir, some teams have reported an increased risk of preterm delivery. However, a specific analysis of more than 4,000 pregnant women found a similar incidence and rate of adverse pregnancy outcomes than in controls at all three trimesters of pregnancy, including preterm birth, low birth weight and birth defects19. Significant teratogenic effects have been demonstrated in all animal species exposed to Ribavirin, it is therefore currently contraindicated in pregnant women and in their male sexual partners, although the ribavirin pregnancy registry did not bring evidence of teratogenicity in humans20.The use of antiviral therapy in infected pregnant patients should follow the same indication as in the general population, but some obstetric specificities should be emphasized.1) The main goal should be to slow down and at best stop the clinical progression of the disease, i.e to remain asymptomatic and to avoid progression to acute respiratory distress syndrome in symptomatic cases. In the latter, the obstetrician is often called on to perform an emergency delivery and thus to induce extreme prematurity. Expert consensus provided obstetric guidance, but the management of cases at between 25 and 32 weeks’ remains challenging in the absence of effective antiviral treatment1.2) The second objective would be to rapidly decrease viral load and duration of contagiousness in infected pregnant women. The majority of them are doing well, but the infection can disrupt their obstetrical calendar. Some procedures need to be performed at a specific age, such as first trimester serum markers, ultrasound examinations, chorionic villi sampling (CVS). The same applies to access to termination of pregnancy. All such procedures may indeed be delayed, either to limit contagion, to limit the burden on the health care team (due to reinforced barrier measures…) or in the particular case of CVS/amniocentesis, to limit the theoretical risk of fetal transmission.3) Finally, the third advantage could be to introduce preventive treatment in case of maternal contact with an infected person, similar to what is done for seasonal influenza and oseltamivir21.The use of immunotherapy such as Tocilizumab, plasma of recovered coronavirus patient, Interferons, were not discussed here as they are currently understudy only for critically ill COVID-19 patients. No place for these treatments in a patient who is still pregnant should be considered for the time being, since if the pregnant woman presents a very severe form, the birth will be considered as a priority.The results of the Phase 3 therapeutic studies should be available soon. However, it is unfortunate that infected pregnant women are not included in any appropriate research protocols. Consequently, in this period of pandemic, mutual exchanges of experience between all countries’ maternity hospitals must be carried out in order to ensure the best possible management of infected pregnant women.