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A continent-wide high genetic load in African buffalo revealed by a cline in the freq...
Pim van Hooft
Wayne Getz

Pim van Hooft

and 4 more

May 08, 2020
Recent microsatellite studies of two African buffalo (Syncerus caffer) populations in South Africa indicated a high genetic load due to genome-wide high-frequency occurrence of deleterious alleles. These alleles have a negative effect on two male traits: body condition and bovine tuberculosis resistance. Here, we study the occurrence of these male-deleterious alleles throughout most of the buffalo’s range using previously published microsatellite data (2-17 microsatellite loci genotyped on 1676 animals from 34 localities). We uncovered a continent-wide frequency cline of microsatellite alleles associated with male-deleterious traits, with frequencies decreasing from 25 °S to 5 °N (adjusted R2 = 0.87). Further, there was a continent-wide presence of linkage disequilibrium (LD) between male-deleterious-trait-associated alleles at five linked locus pairs (interlocus distance: 0.5-28 Megabase). The fraction of positive interlocus associations among these locus pairs was 0.65 (95% CI: 0.52-0.77; expected fraction with free recombination: 0.5), indicating that many male-deleterious alleles co-occur in haplotypes. We argue that the allele-frequency cline and LD likely result from genome-wide balancing selection of male-deleterious alleles with equilibrium allele and haplotype frequencies determined by the activity of a sex-chromosomal gene-drive system, the latter which was indicated in earlier studies and seemingly originated in southern Africa. The selection pressures involved must be high to prevent destruction of the allele-frequency cline and haplotypes by LD decay. Since most buffalo populations are stable, our results indicate that natural mammal populations can withstand a high genetic load. Nevertheless, we expect that a high genetic load makes many buffalo populations relatively sensitive to environmental stresses.
Structural and functional contributions of conducting tissues to genotypic and enviro...
Jeanne Simon
Maïda Cardoso

Jeanne Simon

and 9 more

May 08, 2020
Conductive tissues are main routes of resource transport, that are crucial for the growth of fleshy fruit. Yet, very few quantitative data of xylem and phloem areas are available and their variabilities are unknown. This study aimed at better understanding and quantifying the structural and functional properties of the conductive tissues in tomato pedicel. 11 contrasting genotypes were described and the impact of water deficit was studied depending on stress intensity and stage of application. In parallel, MRI was used to assess the proportion and size of active xylem vessels in the stem. Results were implemented in a Virtual Fruit model to assess the potential contribution of pedicel conductive tissues in the variability of fruit fresh and dry masses. On their whole, results suggested that variations in the properties of conducting tissues are involved in the genotypic and environmental variations of fruit mass. The study also highlights the interest to combine methods and to integrate knowledge to better understand plant functioning, and finally to improve plant models. Flow-MRI was shown to be an easy non-destructive method to measure the functional properties of conducting tissues such as the proportion of active vessels and their diameter.
Considerations in Head  and Neck Oncologic Reconstructions and Microsurgery During CO...
Vinay Kant Shankhdhar

Dr. Suvashis Dash, AIIMS, New Delhi, India

and 1 more

May 08, 2020
COVID outbreak has incapacitated the healthcare system around the world. Existing resources and manpower are being redirected to take care of the COVID-19 disease patients. People with head and neck cancers with the need of post ablative reconstruction are in difficult situation owing to multiple factors like poor general condition, disease progression and potential chance of getting an infection of COVID -19 in a health care facility as well as doubt regarding treatment completion i.e. adjuvant treatment. Appropriate reconstruction following ablative surgery, especially in advanced disease, facilitates functional recovery and thus adding to the quality of life of the patients.The reconstructive procedures are resource-intensive, requiring long hours of surgery, trained manpower, and multiple team members. However, if adequate surgical excision demands the reconstructive procedure, then it should not be a hindrance for the standard treatment.  We need to review our approach in the face of the devastating COVID-19 pandemic. We are presently working in resource constraints like limited availability of staff and limited availability of personal protective equipment especially in plastic surgery procedures which requires the use of loupes and microscope. Thus, the challenge is to ensure proper reconstruction with limited available resources and maintaining safety standards for the staff in the operation theatre. This work is based on our experience and evidence from the literature.
Basal cuspal tear of a porcine bioprosthetic mitral valve causing massive mitral regu...
Muhammed  Tamim
CHRISTOS ALEXIOU

Muhammed Tamim

and 4 more

May 08, 2020
Although porcine mitral bioprostheses provide predictably good long-term outcomes, unexpected leaflet tears leading to abrupt haemodynamic changes may occur. We report on a patient who presented with acute dyspnea due to cuspal tear of a porcine bioprosthetic mitral valve causing severe mitral regurgitation, her condition was subsequently complicated by systemic infection, probably pneumonia, and was successfully managed with urgent redo-mitral valve replacement.
Specific technical refinements of tracheotomy in Covid-19 patients. A report of four...
Daniela Pasero
davide rizzo

Daniela Pasero

and 7 more

May 08, 2020
Key points:Covid-19 patients are often intubated for a long time, with indication to tracheotomy, at high risk for transmitting the disease.Open surgical sub-isthmic tracheotomy above the ETT cuff should always be performed on fully paralyzed patients, to minimize the airflow and aerosolisation from alveolar space.Other technical refinements described in the paper are finalized to reduce the “no seal” time from ETT cuff deflation and cannula cuff inflation, which can become shorter than 2 seconds.Risks connected to tracheotomy in Covid-19, a conceptually extremely hazardous procedure, can be significantly reduced by rational measures and teamwork.Dear Editor,Tracheotomy, more than any other procedure, increases the risk of transmission from Covid-19 patients to operators because of aerosolisation1: a cough with an opened trachea and no seal from a cuff is the worst exposure situation.We describe our experience with tracheotomy in Covid-19, analyzing steps at risk and describing technical refinements to minimize such risk.
Cloning capacity helps tropical seeds counter animal predation
Zhenyu Wang
Lin Cao

Zhenyu Wang

and 5 more

May 08, 2020
Seed predators have the potential to act as agents of natural selection that influence seed traits. Accordingly, plants deploy a variety of mechanisms (e.g. resistance and tolerance strategy) to lessen the impact of predation on seed crop or on an individual seed. In this study, we found a novel mechanism (i.e. cloning strategy) in a tropical plant species in countering animal predation. We found both rodent damaged and human artificially damaged seed fragments of a large-seeded tree Garcinia xanthochymus in the Xishuangbanna tropical forest of China could develop into seedlings in both field and laboratory conditions. G. xanthochymus seed has no endosperm in seeds, and its seed tissue own strong capacity of differentiation and cloning. Seed damage would negatively affect seedling growth and germination, but the seed germination rate was remarkably high. Our study suggests that, as a novel strategy countering animal predation, seed cloning would play a significant role in stabilizing the mutualism between plant and animals.
Theoretic quantum Information entropies for the generalized hyperbolic potential
Akpan Ikot
Gaotsiwe Joel Rampho

Akpan Ikot

and 5 more

May 08, 2020
The Shannon entropy (S) and the Fisher Information (I) entropies are investigated for a generalized hyperbolic potential in position and momentum spaces. Firstly, the Schrodinger equation is solved exactly using the Nikiforov-Uvarov-Functional Analysis (NUFA) method to obtain the energy spectra and the corresponding wave function. By Fourier transforming the position space wave function, the corresponding momentum wave function was obtained for the low lying states corresponding to the ground and first excited state. The positions and momentum Shannon entropy and Fisher Information entropies were calculated numerically. Finally, the Bialynicki-Birula and Mycielski (BBM) and the Stam-Cramer-Rao inequalities for the Shannon entropy and Fisher Information entropies respectively were tested and was found to be satisfied for all cases considered
Residency education in Coronavirus Disease 2019 (COVID-19) times: Experience of a Chi...
Matias Alvarez
Antonia Lagos

Matias Alvarez

and 4 more

May 08, 2020
KEY POINTSThe COVID-19 pandemic has presented the Otolaryngology community with new challenges.Exposure to outpatient attention, endoscopic procedures and surgeries has been significantly reduced for residents worldwide.Our Otolaryngology residency program has implemented different measures to reduce residents’ exposure to high-risk infection situations.Concomitant measures have been taken to increase simulation training, and up-to-date seminars and courses for residents.Adaptation and flexibility of regular training curricula are required in order to diminish the negative impact in residents ’ education.Keywords : COVID-19, SARS-CoV-2, residents, residency education, otolaryngology.
Outcome in patients with partial and full-thickness cheek defects following free flap...
Stefan Janik
Stefan Grasl

Stefan Janik

and 8 more

May 08, 2020
Objectives: To evaluate whether the extent of tumor resection and free flap reconstruction influences functional outcome and complications in patients with solid malignancies of the cheek. Design and Participants: We retrospectively assessed recipient site complications and functional outcomes in 47 patients with solid malignancies of the cheek who underwent either partial (n=30; 63.8%) or full-thickness (n=17; 36.2%) cheek resection with free flap reconstruction. Setting: Retrospective, multicentric analysis Results: Full thickness resections with creation of through-and-through defects were not associated with significantly higher complication rates (70.6% vs. 46.7%; p=0.138) compared to partial defects. Recipient site complications occurred in 55.3% of patients and were noticed most likely after reconstruction of suborbital defects (69.2%; p=0.268) of which occurrence of salivary fistulae was the most common (46.2%; p=0.035). Similarly, functional outcomes including oral incompetence, ectropion, and trismus were not affected by the extent of resection (p=0.766). However, oral incompetence was higher in patients with tumors originating from oral cavity (p=0.020) and after the performance of mandibulectomy (p=0.003). Conclusions: There was no difference in functional outcome or recipient site morbidity between tumor resections resulting in full-thickness and partial defects.
Neurological complications in benign parapharyngeal space tumors -- Systematic review...
Muhammad Faisal
Rudolf  Seemann

Muhammad Faisal

and 8 more

May 08, 2020
Background: Parapharyngeal space tumors with complex anatomy and diverse histology and have remained a challenging phenomenon for treating physicians. Objective: Assess the factors for selection of surgical approach and association of neurological complications with tissue of origin in parapharyngeal space tumors. Type of review: Systematic review and meta-analysis of retrospective studies in accordance with PRISMA guidelines Methods: We have conducted a comprehensive web search on Pubmed, Web of Science, EMBASE, Cochrane Library, Biomedical Literature Database (CBM) and Clinicaltrials.gov. Two researches reviewed all identified articles independently with a third reviewer for adjudication. Patient demographics and other clinicopathological characteristics were explored. Main outcome measures: Primary outcomes assessed were post-operative complications i.e. neurological and salivary, surgical approaches used and the factors used for the selection of surgical approaches. Results: The systematic review has identified 631 patients of benign parapharyngeal space tumors with neurogenic and salivary tissue histology in 13 studies with a mean age of 42.9 ± 7.76 years and a median follow-up of 40.98 ± 19.1 months. Salivary gland (50.8%) and neurogenic (49.1%) tumors were the most common histological entities. Tumor size, location, histology, deep parotid lobe involvement and proximity to great vessels or skull base were the deciding factors in selecting the surgical approach. Factors considered to select surgical approach do not seem to have a correlation with the outcome in terms of neurological sequalae (p=0.106). Neurological deficit was observed in 48% of patients with neurogenic histology (148/310) while only 13% patients with salivary tumor developed neurological deficit. The pooled RR was 2.41 (95% CI 1.80 – 3.23, p=0.001). Conclusion: Neurologic complications are significantly associated with neurogenic benign tumors rather than surgical approach.
Acute Complicated Type B Aortic Dissection during the New York City COVID-19 Surge.
Shinichiro Ikeda
Michael Shih

Shinichiro Ikeda

and 3 more

May 08, 2020
The impact of the COVID-19 pandemic in New York City (NYC) is dramatic. COVID-19 cases surged, hospitals expanded to meet capacity, and NYC remains the global epicenter of this pandemic. During this unprecedented time, a young woman with known Marfan syndrome presented with an acute complicated type B aortic dissection to our Aortic Center. Using the Provisional Extension to Induce Complete Attachment technique, we treated this patient and quickly discharged her the next day to decrease the risk of COVID-19 infection. Her progress was monitored using frequent phone calls and one office visit at two weeks.
Minimally invasive congenital cardiac surgery with unsnared inferior vena cava
Alvise Guariento
Claudia Cattapan

Alvise Guariento

and 3 more

May 08, 2020
Here we report two cases of residual atrial septal defect (ASD) with inferior extension towards the inferior vena cava (inferior sinus venosus type). In both cases, patients underwent surgical repair of their ASD in childhood. However, signs of persistent hemodynamic right ventricular overload were detected at the last follow-up and a residual ASD was demonstrated. Both underwent successful minimally invasive surgical closure of the ASD by combining a right postero-lateral mini-thoracotomy (sub-axillary approach) and total peripheral cardiopulmonary bypass, avoiding snaring of the inferior vena cava. This allowed an optimal visualization of the residual intra-cardiac shunt and its subsequent closure.
Peripheral femoral venoarterial extracorporeal membrane oxygenation as bridge to hear...
Erik Orozco-Hernandez
Brett Melnikoff

Erik Orozco-Hernandez

and 4 more

May 08, 2020
Heart-Lung transplant (HLT) is a widely accepted modality for certain patients with advanced and refractory cardiopulmonary disease. Some of these patients are critically ill on the transplant waiting list, and venoarterial extracorporeal membrane oxygenation (VA-ECMO) can be used as a bridge to transplantation. Although the experience with ECMO as a bridge to lung transplant is promising, there is limited evidence to use ECMO as a bridge to HLT. Femoral cannulation remains a concern for ambulation given the risk of bleeding and cannula complications despite studies reporting its safety. We present a case of a 56-year-old male with interstitial lung disease (ILD) and severe secondary pulmonary hypertension, who was successfully bridged to HLT with ambulatory femoral VA-ECMO.
Breaking through permeability-selectivity trade-off of thin-film composite membranes...
Liang Shen
Ming Yi

Liang Shen

and 5 more

May 07, 2020
In this study, we deployed a modified interfacial polymerization process to incorporate multifunctional crown ethers (CEs) into thin-film composite (TFC) polyamide membranes. These CE additives acted as both the phase-transfer catalyst and co-solvent to facilitate the diffusion of amine monomers into the organic phase and also enhanced the free volume content of the selective layer, facilitating water transport and inhibiting the diffusion of draw solutes. Various characterization techniques were employed to elucidate the modification mechanism as a function of CE chemical and physical properties on the microstructure of resultant TFC membranes and consequently separation performances. Compared to TFC membranes produced from traditional interfacial polymerization method, CE-modified membranes exhibited a 146% water flux enhancement and 59% lower reverse salt fluxes with a suitable draw solution. CE-modified membranes also exhibited improved antifouling performance with a lower flux drop (34% decline) and a higher flux recovery ratio (38% improvement).
Experimental and Numerical Investigations of the Shear Behavior of Binary Particle Bl...
Jiecheng Yang
Poom Bunchatheeravate

Jiecheng Yang

and 4 more

May 07, 2020
In this study, a Schulze Ring Shear Tester and the Discrete Element Method (DEM) are employed to investigate the effect of polydispersity on the binary shear flows. Both experimental results and DEM simulations show that the pre-shear stresses are greater for binary blends than for monodispersed particles. The flowability of these mixtures is strongly affected by the solid fraction, with minimal flow function values correlating to maximum packing fraction. However, minimum flow function values are not observed at the same packing fractions where the maximum pre-shear stress occurs. The powder friction has a slightly higher contribution to powder strength than powder adhesion, and the frictional component follows the same trend as shear stress with mixture composition. Using DEM, it is demonstrated that the addition of small adhesive particles reduces the averaged angular velocity of the larger particles, which makes a contribution to the larger shear stress for binary blends.
Simple inheritance, complex regulation: supergene-mediated fire ant queen polymorphis...
Samuel Arsenault
Joanie King

Samuel Arsenault

and 5 more

May 07, 2020
The fire ant Solenopsis invicta exists in two alternate social forms: monogyne nests contain a single reproductive queen and polygyne nests contain multiple reproductive queens. This colony-level social polymorphism corresponds with individual differences in queen physiology, queen dispersal patterns, and worker discrimination behaviors, all evidently regulated by an inversion-based supergene that spans more than 13Mb of a “social chromosome,” contains over 400 protein-coding genes, and rarely undergoes recombination. The specific mechanisms by which this supergene influences expression of the many distinctive features that characterize the alternate forms remain almost wholly unknown. To advance our understanding of these mechanisms, we explore effects of social chromosome genotype and natal colony social form on gene expression in virgin queens sampled as they embarked on nuptial flights, using RNA-sequencing of two important tissues. We observe relatively minor effects of natal social form, that is, of the social/developmental environment, on gene expression profiles, but substantial effects of genotype, including i) supergene-associated gene upregulation, ii) allele-specific expression, and iii) pronounced extra-supergene trans-regulatory effects. These findings, along with observed spatial variation in differential and allele-specific expression within the supergene region, highlight the complex gene regulatory landscape that emerged following evolutionary divergence of the inversion-mediated Sb haplotype from its homolog that largely retained the ancestral gene order. The distinctive social chromosome-linked gene expression trajectories we document at the onset of a queen’s reproductive life expand the known record of relevant molecular correlates of a complex social polymorphism and point to putative genetic underpinnings of the alternate social syndromes.
Insights into the roles of surface oxygen species of manganese oxides for the ozone e...
Lei Zhang
sheng wang

Lei Zhang

and 5 more

May 07, 2020
Manganese oxides with varied Mn valance states but identical morphology were synthesized. Their behaviors of ozone decomposition were investigated following the order of Mn3O4 < Mn2O3 < MnO2 < MnO2-H-200. It was deduced that the superior O3 decomposition capacity for MnO2-H-200 was strongly associated with abundant oxygen vacancies. Among Mn3O4, Mn2O3 and MnO2, the difference on O3 decomposition efficiency was dependent on divergent nature of oxygen vacancy. DFT calculation revealed that Mn3O4 and MnO2 possessed lower formation energy of oxygen vacancy, while MnO2 had the minimum desorption energy of peroxide species (O2*), suggesting that the promotion of the O3 decomposition capability was attributed to the easier O2* desorption. The insights on the deactivation mechanism for MnO2-H-200 further validated the assumptions. As the reaction proceeded, adsorbed oxygen species accumulated on the catalyst surface, and a portion of them were transformed to lattice oxygen.
Applying machine learning algorithms in spatial piping erosion susceptibility in Zara...
Saeid Janizadeh
Kourosh Ahmadi

Saeid Janizadeh

and 5 more

May 07, 2020
Soil erosion is threatening land sustainability. Piping erosion is one of the land degradation processes that lead to significant landscape and environmental changes, and request a proper mapping survey. The purpose of this study is to survey piping erosion susceptibility maps in Zarandeieh watershed of Markazi province using Random Forest (RF), Support Vector Machine (SVM), and Bayesian Generalized Linear Models (Bayesian GLM) machine learning methods. For this purpose, due to the influence of different physiographic, environmental and soil conditions on the development and formation of piping, 18 variables were considered for modeling the piping erosion sensitivity in Zarandieh watershed. Based on field surveys and aerial photographs, 152 points of piping erosion were identified in the studied area, 70% of which was used for modeling, and 30% for model validation. The area under curve (AUC) was used to evaluate the performance of the models used. The results of the pipping erosion susceptibility showed that all three RF, SVM and Bayesian GLM models, have a good performance in the validation stage such as the AUC shown with values of 0.9 for RF, 0.88 for SVM, and 0.87 for Bayesian GLM. Altitude, PH and Bulk density are the variables that had the most impact on the pipping erosion sensitivity in the study area. This result shows that topographical and soil chemical factors are responsible for the piping distribution in the Zarandieh watershed.
Tracheotomy in the SARS-CoV-2 Pandemic
Head and Neck Editor

William R. Carroll, MD

May 07, 2020
Hunter Skoog MD1, Kirk Withrow MD1, Harishanker Jeyarajan MD1, Benjamin Greene MD1, Hitesh Batra MD2, Daniel Cox MD3, Albert Pierce MD4, Jessica W. Grayson MD1, William Carroll MD1
An Overview of COVID-19 Testing and Implications for Otolaryngologists
Head and Neck Editor

Xiao Zhao, MD, PhD

May 07, 2020
Background : Testing for SARS-CoV-2 is important for decision making prior to surgery in otolaryngology. An understanding of current and developing testing methods is important for interpreting test results.Methods : We performed a literature review of current evidence surrounding SARS-CoV-2 diagnostic testing highlighting its utility, limitations, and implications for otolaryngologists.Results : The currently accepted RT-PCR test for SARS-CoV-2 has varying sensitivity according to which subsite of the aerodigestive tract is sampled. Nasal swab sensitivities appear to be about 70%. Chest CT imaging for screening purposes is not currently recommended.Conclusion : Due to the current sensitivity of RT-PCR based testing for SARS-CoV-2, a negative test cannot rule out COVID-19.  Full PPE should be worn during high risk procedures such as aerosol generating procedures even if testing is negative. Patients who test positive during screening should have their surgeries postponed if possible until asymptomatic and have tested negative for SARS-CoV-2.
Separation of C2-C4 Hydrocarbons from Methane by Zeolite MFI Hollow Fiber Membranes F...
Byunghyun Min
Akshay Korde

Byunghyun Min

and 5 more

May 07, 2020
Separation of higher hydrocarbons from methane is an important and energy-intensive operation in natural gas processing. We present a detailed investigation of thin and oriented MFI zeolite membranes fabricated from 2D MFI nanosheets on inexpensive α-alumina hollow fiber supports, particularly for separation of n-butane, propane, and ethane (“natural gas liquids”) from methane. The present MFI membranes display high permeances and selectivities for C2-C4 hydrocarbons over methane, driven primarily by stronger adsorption of C2-C4 hydrocarbons. We study the separation characteristics under unary, binary, ternary and quaternary mixture conditions, including the pressure dependence. The membranes are highly effective in quaternary mixture separation at elevated feed pressures, for example allowing n-butane/methane separation factors of 170–280 and n-butane permeances of 710–2700 GPU in the 1-9 bar feed pressure range. Furthermore, we parametrize and apply multicomponent Maxwell-Stefan transport equations to predict the main trends in separation behavior over a range of operating conditions.
Objective Olfactory Evaluation of Self-reported Loss of Smell in a Case Series of 86...
Head and Neck Editor

Jerome R. Lechien, MD, PhD, MS

May 07, 2020
Objective : To investigate olfactory dysfunction (OD) in patients with mild COVID-19 through patient-reported outcome questionnaires and objective psychophysical testing.Methods : COVID-19 patients with self-reported sudden-onset OD were recruited. Epidemiological and clinical data were collected. Nasal complaints were evaluated with the sino-nasal outcome-22 (SNOT-22). Subjective olfactory and gustatory status was evaluated with the National Health and Nutrition Examination Survey (NHNES). Objective OD was evaluated using psychophysical tests.Results : Eighty-six patients completed the study. The most common symptoms were fatigue (72.9%), headache (60.0%), nasal obstruction (58.6%) and postnasal drip (48.6%). Total loss of smell was self-reported by 61.4% of patients. Objective olfactory testings identified 41 anosmic (47.7%), 12 hyposmic (14.0%), and 33 normosmic (38.3%) patients. There was no correlation between the objective test results and subjective reports of nasal obstruction or postnasal drip.Conclusion : A significant proportion of COVID-19 patients reporting OD do not have OD on objective testing.
Tracheotomy in COVID-19 patients:  Optimizing patient selection and  identifying prog...
Head and Neck Editor

Thomas James Stubington, MD

May 07, 2020
BackgroundTracheotomy, through its ability to wean patients off ventilation, can shorten ICU length of stay and in doing so increase ICU bed capacity, crucial for saving lives during the COVID-19 pandemic. To date, there is a paucity of patient selection criteria and prognosticators to facilitate decision-making and enhance precious ICU capacity.MethodsProspective study of COVID-19 patients undergoing tracheotomy (n=12) over a 4-week period (March-April 2020). Association between pre- and post- operative ventilation requirements and outcomes (ICU stay, time to decannulation, and death) were examined.ResultsPatients who sustained FiO2≤50% and PEEP≤8cm H2O in the 24h pre-tracheotomy exhibited a favourable outcome. Those whose requirements remained below these thresholds post-tracheotomy could be safely stepped down after 48h.ConclusionSustained FiO2≤50% and PEEP≤8cm H2O in the 48h post-tracheotomy are strong predictive factors for a good outcome, raising the potential for these patients to be stepped down early, thus increasing ICU capacity.
A shift to avoid Covid-19 risk and safeguard health governance
Francesco Ferrara
Antonio Vitiello

Francesco Ferrara

and 1 more

May 07, 2020
Immunosuppressive therapies, such as multiple sclerosis, are a risk for people with this condition because they can expose them to a greater risk of Sars-CoV-2 infection. For these reasons, recommendations from agencies, patient associations and scientific societies follow one another quickly so that therapy is guaranteed with good efficacy and without risk, choosing from the many drugs available in multiple formulations.
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