Clinicians, patients, administrators and researchers have become increasingly frustrated by the lack of indication (i.e. problem) information included in prescriptions, despite the obvious benefit this would provide to patients and other healthcare providers [1]. Medication indications are not routinely documented by prescribers, both in inpatient and outpatient settings.[2, 3] Calls have been made to introduce a sixth ‘right’ into the medication management process, whereby the right patient is given the right drug and dose at the right time via the right route for the right indication [4]. Indications-based prescribing has recently gained traction as a potential way forward to facilitate indication documentation [4, 5]. Indications-based prescribing, not currently supported by most electronic prescribing systems (EPSs), describes the scenario where prescribers initially select an indication, not a medication, and the EPS presents the user with suggested medications for addressing the problem. There are clear advantages with this approach, including those associated with guided prescribing (e.g. more appropriate drug selections) and with indication documentation (e.g. improved communication between providers), prompting work to begin on developing EPS functionality in the US to support indications-based prescribing. In a recent usability evaluation of a prototype of this functionality, indications-based prescribing was more efficient to use, resulted in fewer medication errors and in higher usability scores than the traditional EPS functionality [6].

Hydrogen peroxide (H2O2), as clean oxidant, has long suffered from low efficiency and selectivity for the oxidation of olefins. In the present paper, the redox important ferrate anion (FeO42-) has been anchored into a silanol-decorated polyoxometalates (POM) to form single–site supported Fe-POM catalyst. And possible reaction mechanism for the epoxidation of propylene with hydrogen peroxide (H2O2) catalyzed by the Fe-POM catalyst have been investigated based on density functional theory with M06L functional. The study of molecular geometry, electronic structure, and bonding feature shows that the Fe-POM complex can be viewed as a high-valent Fe-oxo (Fe=O) species. The propylene molecule was activated by the Fe-POM catalyst via an effective electron transfer from propylene to the Fe-POM catalyst to form a cation propylene radical. Due to the high reactivity of radical species, the calculated activation energy barrier is only 4.50 kcal mol-1 for epoxidation of propylene to epoxypropane catalyzed by the Fe-POM catalyst. Subsequently, the calculated free energy profiles show that H2O2 was decomposed into a H2O molecule and a surface O species over the Fe-POM catalyst, and the remaining O atom attaches to the exposed the Fe center, resulting in the replenishing of Fe-POM catalyst via a two-state reaction pathway. The calculated activation energy barrier for this process is 23.42 kcal mol–1, and thus decomposition of H2O2 is the rate-determining step for the whole reaction. The Fe center serves as an electron acceptor, accepting electrons from the binding propylene molecule to form radical species in the first half of the reaction, and acts as the role of electron donor in the rest reaction steps to eliminate the radical feature, reduce the reactivity, and stop the reaction at the stage of the desired epoxypropane product.

The mechanisms of rhodium-catalyzed coupling reaction of ketoxime and 1,3-enynes were investigated by employing the density functional theory (DFT) calculations. Different 1,3-enynes would lead to different annulation products. Reaction A undergoes five sequential steps (C-H activation, 1,3-enyne migratory insertion, 1,4-Rh migration, cyclization, and deprotonation) to lead to [4 + 1] annulation product. Whereas, due to the electronic effect, the process generating [4 + 2] product in reaction A is restricted. In contrast, the electron-withdrawing group of N(Me)2 group in 1,3-enyne would bring about the [4 + 2] annulation product in reaction B. Our calculated results indicate that no [4 + 1] annulation product could be obtained in reaction C, in agreement with the experimental observation that the cis-allyl hydrogen in 1,3-enyne is crucial for the [4 + 1] annulation reaction.

Gene therapy medicinal products have the potential to provide curative treatment to many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency, but the risks, and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms. This article provides an overview of basic requirements across the EU, an overview of the new streamlined process and discusses available guidance for developers. All these initiatives are aimed to remove hurdles for ATMP developers and facilitate faster access to patients.

Background: The relationship between socioeconomic status (SES) and the prognosis of HF with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction remains unsettled. Objective: To analyze the relationship between SES and the prognosis of patients with incident HFrEF and HFpEF. Methods: Prospective study over 15 years (2003-2017) on 9658 patients diagnosed with HF. Main outcomes were mortality and hospitalizations for HF. The independent relationship between SES and the prognosis, stratifying patients for cardiovascular co-morbidity after propensity score-matching was analyzed. Results: After matching 7116 patients, during a median follow-up of 8.11 years, 5616 patients died (78.9%) and 5549 patients were hospitalized (78.0%). High income level was associated with a lower all-cause mortality (RR for HF patients [95% CI]: 0.86 [0.80-0.92], RR for HFrEF: 0.88 [0.82-0.95] and RR for HFpEF: 0.82 [0.75-0.90], P <0.001 in all cases), and cardiovascular mortality (RR for HF: 0.84 [0.76-0.92], RR for HFrEF: 0.87 [0.81-0.93] and RR for HFpEF: 0.88 [0.77-0.88], P <0.001 in all cases), less hospitalizations (RR for HF: 0.70 [0.65-0.78], RR for HFrEF: 0.78 [0.68-0.88] and RR for HFpEF: 0.61 [0.55-0.68], P <0.001 in all cases), and less 30-day readmissions (RR for HF: 0.67 [0.59-0.75], RR for HFrEF: 0.71 [0.63-0.79] and RR for HFpEF: 0.61 [0.55-0.69], P <0.001 in all cases), after adjustment for comorbidities, and other potential confounders. Analyses of recurrent hospitalizations gave larger SES benefits than time-to-first-event analyses. Conclusions: In this propensity-matched study, a high net annual household income is associated with an improved prognosis of patients with incident HFrEF and HFpEF.

Background and Purpose L-DOPA induced dyskinesia is a debilitating side effect of treating Parkinson’s disease with L-DOPA. There is a need to discover a treatment that has the same benefits as L-DOPA treatment without the associated side effects. Here, we demonstrate the anti-dyskinetic potential of doxycycline and the analog compound COL-3 (without antimicrobial activity) in hemiparkinsonian rats presenting L-DOPA-induced dyskinesia. Experimental Approach Wistar adult male rats received a unilateral medial forebrain bundle injection of 6-hydroxydopamine and were then orally administered L-DOPA once a day for 14 days. This resulted in dyskinetic-like behavior. Key Results A single injection of doxycycline (intraperitoneal) or COL-3 (intracerebroventricular) together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of the L-DOPA benefits. Doxycycline treatment was associated with decreased expression of FosB, cyclooxygenase-2, astrocytes, and microglia, which had previously been found to be elevated in the basal ganglia of rats exhibiting dyskinesia. In addition, metalloproteinase-2/-9 activity, metalloproteinase-3 expression, and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant positive correlation with the intensity of dyskinesia, which was decreased with the doxycycline treatment. Conclusion and Implications Given the long-established and safe use of doxycycline and the similar effect of COL-3 (without antimicrobial activity), this study indicates that both drugs should undergo testing for their ability to reduce signs of dyskinesia induced by L-DOPA in patients with Parkinson’s disease.

Massive amounts of gas hydrates occur naturally in the pores of sediments or fractures in permafrost regions and beneath the oceans. For hydrate formation in confinement, the equilibrium condition can shift to harsher conditions, lowering the water activity, and subsequently depressing the hydrate freezing temperature at a given pressure. Conversely, the nucleation and rate of hydrate formation, as well as hydrate conversion can be increased in confinement. Therefore, reliable assessment of the hydrate distribution in nature requires accurate thermodynamic and kinetic models of hydrate formation; however, these models tend to be based upon the properties of bulk hydrates. Hydrate formation and growth promotion in confinement are potentially interesting for hydrate technological applications, such as gas separation, energy storage, and flow assurance. This paper reviews the thermodynamic and kinetic properties and their interrelations of gas hydrates in confined spaces.

Landscape anthropization has been identified as one of the main drivers of pathogen emergence worldwide, facilitating pathogen spillover between domestic species and wildlife. The present study investigated Carnivore protoparvovirus-1 (CPPV) infection using molecular methods in 98 free-ranging wild guignas (Leopardus guigna) and 262 co-occurring owned, free-roaming rural domestic cats. We also assessed landscape anthropization variables as potential drivers of infection. CPPV DNA was detected in guignas across their entire distribution range, with observed prevalence of 13.3% (real-time PCR) and 9% (conventional PCR) in guignas, and 6.1% (conventional PCR) in cats. Prevalence in guigna did not vary depending on age, sex, study area or landscape variables. Prevalence was higher in juvenile cats (16.7%) than in adults (4.4%). Molecular characterization of the virus by amplification and sequencing of almost the entire vp2 gene (1746 bp) from one guigna and five domestic cats was achieved, showing genetic similarities to canine parvovirus 2c (CPV-2c) (one guigna and one cat), feline panleukopenia virus (FPV) (one cat), CPV-2 (no subtype identified) (two cats), CPV-2a (one cat). The CVP-2c-like sequence found in a guigna clustered together with domestic cat and dog CPV-2c sequences from South America, suggesting possible spillover from a domestic to a wild species as the origin of infection in guigna. No clinical signs of disease were found in PCR-positive animals except for the CPV-2c-infected guigna, which had hemorrhagic diarrhea and died a few days after arrival at a wildlife rescue center. Our findings reveal widespread presence of Carnivore protoparvovirus-1 across the guigna distribution in Chile and suggest that virus transmission potentially occurs from domestic to wild carnivores, causing severe disease and death in susceptible wild guignas.

The low concentration methyl iodides (CH3I) adsorption process on reduced silver-functionalized silica aerogel (Ag0-Aerogel) was studied. The kinetic data were acquired using a continuous flow adsorption system. Because the corresponding physical process was observed, the shrinking core model (SCM) was modified and applied. An average CH3I pore diffusivity was calculated, the CH3I-Ag0-Aerogel reaction was identified as a 1.37 order reaction instead of first order reaction, and the nth order reaction rate constant was determined. This modified SCM significantly increases the accuracy of adsorption behavior prediction at low adsorbate concentration. Modeling results indicate that the overall adsorption process is controlled by the pore diffusion. However, at low adsorbate concentration (<100 ppbv), the CH3I adsorption is limited to the surface reaction due to the low uptake rate in a predictable time period.

A group of drugs used in Intra-Arterial Chemotherapy (IAC) have intrinsic ionic properties, which can be used for filtering excessive drugs from blood in order to reduce systemic toxicity. The ion-exchange mechanism is utilized in an endovascular Chemofilter device which can be deployed during the IAC for capturing ionic drugs after they have had their effect on the tumor. In this study, the concentrated solution theory is used to account for the effect of electrochemical forces on the drug transport and adsorption by introducing an effective diffusion coefficient in the advection-diffusion-reaction equation. Consequently, a multi-physics model coupling hemodynamic and electrochemical forces is developed and applied to simulations of the transport and binding of Doxorubicin in the Chemofilter device. A comparison of drug adsorption predicted by the computations to that measured in animal studies demonstrated the benefits of using concentrated solution theory over the Nernst-Plank relations for modeling drug binding.

We describe two cases of favorable and unexpected recovery in positive patients with COVID-19, suffering from multiorgan comorbidity and already assisted with the left ventricular assist device. We have observed that, although in the presence of more comorbidities, when the maintenance of a valid support of the cardiovascular function is guaranteed, the possibility of successfully overcoming the SARS-CoV-2 infection is still alive.

The current coronavirus (COVID-19) pandemic is associated with severe pulmonary and cardiovascular complications. This report describes a young patient with COVID-19 without any comorbidity presenting with severe cardiovascular complications, manifesting with pulmonary embolism, embolic stroke, and right heart failure. Management with short-term mechanical circulatory support, including different cannulation strategies, resulted in a successful outcome despite his critical cardiovascular status.

Background The Carpentier-Edwards Perimount valves have a proven track record in aortic valve replacement: good durability, hemodynamic performance, rates of survival, and infrequent valve-related complications and PPM. The St. Jude Medical Trifecta is a newer valve that has shown comparable early and midterm outcomes. Studies show reoperation rates of Trifecta are comparable to Perimount valves, with a few recent studies bringing into focus early SVD, and increased midterm SVD in younger patients. Given that midterm data for Trifecta is still sparse, we wanted to confirm the early low reoperation rates of Trifecta persist over time compared to Perimount. Methods The Maritime Heart Centre Database was searched for isolated AVR or AVR+CABG between January 2011 and December 2016. Primary end point of the study was all-cause reoperation rate. Results 711 Perimount and 453 Trifecta implantations were included. The reoperation hazards were determined for age: 0.96 (0.92-0.99, p=0.02), female (vs male): 0.35 (0.08-1.53, p=0.16), smoker (vs non-smoker): 2.44 (0.85-7.02, p=0.1), and Trifecta (vs Perimount): 2.68 (0.97-7.39, p=0.06). Kaplan-Meier survival analysis in subgroups—age < 60, age ≥ 60, male, female, smoker, and non-smoker—showed Perimount having lower reoperation rates than Trifecta in patient younger than 60 (p=0.02) and those with smoking history (p<0.01). Conclusions The rates of reoperation of Perimount and Trifecta were comparable, with Trifecta showing higher rates in patients younger than 60 years, and current smokers. Continued diligence and further independent reporting of midterm reoperation and SVD rates of the Trifecta, including detailed echocardiographic follow up, are needed to confirm these findings.

Coronavirus (CoV) pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, severe acute respiratory syndrome CoV (SARS-CoV) caused SARS pandemic in 2003 and SARS-CoV-2 caused the ongoing COVID-19 pandemic. Both viruses have been reported to originate from bats. Thus, direct or indirect interspecies transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the interspecies transmission. Angiotensin converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Especially, SARS-CoV-2 tended not to use murine or non-mammal ACE2s. Meanwhile, pangolin CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acids that may determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin CoV. Our studies promote the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.

Aims In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. Methods We carried out a systematic review and meta-analysis of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. Results In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44140 patients were included. Five of the studies were in patients with pneumonia, two in patients with Influenza, and one in patients with acute bronchitis. There was uncertainty as to the effects on mortality (RR 0.87 [0.63, 1.18]), but pleuro-pulmonary complications were more common with NSAID use (RR 2.62 [1.96, 3.50]). However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. Conclusion Short-term NSAID use during acute lower respiratory tract infections was associated with more pleuro-pulmonary complications although this may be due to confounding by indication. There remains significant uncertainty on the effects on mortality. Such results should be interpreted cautiously given the very low quality of evidence. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.

Background and aim. Classical and paradoxical low-flow, low-gradient aortic stenosis (LFLGAS) are the most challenging aortic stenosis (AS) subtypes. The current therapeutic options are aortic valve replacement (AVR) and conservative management. The matter is controversial because AVR promotes long-term survival, but it is invasive, while no aortic valve replacement (noAVR) in non-invasive, but it is associated with poor prognosis. This meta-analysis aims to investigate the survival rate in patients with LFLGAS undergoing AVR versus noAVR interventions. Methods. A meta-analysis was conducted comparing the outcomes of AVR and noAVR in terms of survival. A meta-regression was carried out to investigate the impact of preserved and reduced left ventricular ejection fraction (LVEF) on survival in both the AVR and noAVR group. Results. The log IRR of survival between AVR group and noAVR group was 0.58 [0.28, 0.87] (p-value = 0.0001), suggesting that survival is significantly better in the AVR group compared to the noAVR group. The meta-regression revealed that low LVEF is related to higher survival rates in the AVR group (p-value = 0.04) when compared to preserved LVEF. LVEF has no impact on survival in the noAVR group (p-value = 0.18). Conclusions. Patients with LFLGAS have better survival in the AVR group rather than in the noAVR group. Reduced LVEF was related to better survival than preserved LVEF in the AVR, and no difference between low and preserved LVEF was found in the noAVR group.

The “coronavirus disease 2019 (COVID-19)” outbreak was first reported in December 2019 (China). Since then, this disease has rapidly spread across the globe and in March 2020 the World Health Organization (WHO) declared the COVID-19 pandemic.1 Since the outbreak was first announced, our journal has extensively focused on the clinical features, outcomes, diagnosis, immunology, and pathogenesis of COVID-19 and its infectious agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We published our first COVID-19 article on 19 February, focusing for the first time on the clinical characteristics of 140 cases of human-to-human coronavirus transmission without any links to the Huanan Wet Market.2 Hypertension and diabetes were mentioned as risk factors and there was no increased prevalence in allergic patients. This early study reported that the main symptoms at hospital admission were fever (91.7%), cough (75.0%), fatigue (75.0%), gastrointestinal symptoms (39.6%), and dyspnea (36.7%). Lymphopenia and eosinopenia were also reported as important signs and biomarkers for monitoring and severity of the patients.2 The prevalent eosinopenia in COVID-19 patients and the possible anti-viral role of eosinophils were further discussed in several following publications inAllergy .3,4 Our second COVID-19 paper brought attention to the wide range of clinical manifestations of this disease, from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia as well as with only diarrhea.5Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with pre-existing chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were severe. Another article, timely appearing in our journal, alerted the scientific community that even in experienced hands there was a 14.1% false negative polymerase chain reaction (PCR) diagnosis in COVID-19 cases and were later diagnosed positive after repeated tests.6 A pediatric article was also published extensively analyzing 182 cases and it was reported that children with COVID-19 showed a mild clinical course.7 Patients with pneumonia had a higher proportion of fever and cough and increased inflammatory biomarkers compared to those without pneumonia. There were 43 allergic patients in this series and there was no significant difference between allergic and non-allergic COVID-19 children in disease incidence, clinical features, laboratory, and immunological findings. Allergy was not a risk factor for disease and severity of SARS-CoV-2 infection and did not significantly influence the disease course of COVID-19 in children.7The immunology of COVID-19 was extensively reviewed in two articles from leading experts with a comprehensive discussion of the tip of the iceberg in COVID-19 epidemiology, anti-viral response, antibody response to SARS-CoV-2, acute phase reactants, cytokine storm, and pathogenesis of tissue injury and severity. 8,9Two studies timely reported the role of possible trained immunity in countries with a Bacillus Calmette-Guérin (BCG) vaccination programme and a relatively low COVID-19 prevalence and mortality rate.10,11 In an extensive RNA sequencing analyses of SARS-CoV-2 receptor and their molecular partners revealed that ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells.12Allergists, respiratory physicians, pediatricians, and other health care providers treating patients with allergic diseases are frequently in contact with patients potentially infected with SARS-CoV-2. Practical considerations and recommendations given by experts in the field of allergic diseases can provide useful recommendations for clinical daily work. Since the beginning of this current pandemic, our journal has disseminated clinical reports, 2,3,5,6,13 statements on the urgent need for accuracy in designing and reporting clinical trials in COVID-19,14 preventive measures,10,11,15 and Position Statements elaborated by experts in the field in close collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and its task force “Allergy and Its Impact on Asthma (ARIA) ”.16-28 (keynote information in table 1). A compendium answering 150 frequently encountered questions regarding COVID-19 and allergic diseases has been recently published by experts in their respective area.29 In addition, readers can put further questions regarding this “living ” compendium electronically to the authors and their answers will be available through a new category in the journal’s webpage.30Besides, EAACI in collaboration with ARIA, has provided recommendations on operational plans and practical procedures for ensuring optimal standards in the daily clinical care of patients with allergic diseases, whilst ensuring the safety of patients and healthcare workers.23Table 1: Examples of recently published recommendations, statements and Position Papers of the EAACI

Dear Editor,we read with great interest the article recently published by Morishima L et al. (1 ). The Authors report an high incidence of Anisakis-specific IgE antiboides in patients with anaphylaxis in two towns in Japan.Worlwide the incidence of Anisakis patients is related to the ingestion of raw fish in seaside places. Herein we present the case of a child who has experienced an anaphylaxis with acute respiratory symptoms and a strange scrotal mass, in Calabria, a region completely surrounded by the sea in Southern Italy.An 8-year-old child italian child referred to our Emergency Department with a clinical complaint characterized by acute respiratory distress and right testicular pain since almost 24 hours, that worsened during the day. The respiratory picture resolved almost immediately with the use of corticosteroids via i.v. The clinical examination showed the presence of a painful testicle-independent swelling of about 1 cm in diameter, between the perineal plane and the scrotum, in the absence of signs of inflammation.The doppler ultrasonography demonstrated the presence of phlogistic area at the level of the right epididymis. We decide for home observation and medical therapy (betamethasone and amoxy-clavulanic acid) with mild improvement in symptoms in the following 3 days.After 4 days the child came back to our attention with an important scrotal lymphadenitis consensual to the previous epididymitis, with erythematous and warm scrotal skin. The intense scrotal pain, as in a clinical picture of acute scrotum, did not allow to visit the boy correctly.A second US showed an independent mass from the testicle of about 1 cm.The laboratory findings were completely negative, including testicular markers for tumour.The formula was; white blood cells 5.800, Neutrophiles 48.9%, Lymphocytes 41.8%, Eosinophils 0.8%. At surgical exploration the testicle was normal and a paratesticular granulomatous mass of about 2 cm in diameter was removed.The section of the anatomical specimen in the operatory room left us speechless.Inside the operating specimen we found … Worms! The histological examination confirmed a case of extra-gastrointestinal anisakiasis.