Corid-19 and religions freedom in Portugal. The failure of a state of law stress test

Under the pretext of covid-19. the collective dimension of the freedom of worship was suspended in Portugal, through a declaration of state of emergency, between March 19 and May 2 2020. This was a gross violation of art.19. paragraph 6. of the Constitution, according to which the state of emergency cannot affect the freedom of religion. The very declarations and renewals of the state of emergency were not based on the legally required scientific advise, as the National Public Health Council (the Government's advisory body on public health matters) was silenced. In fact, lockdowns had several exceptions, but none contemplated religious activities, which was a subversion of the constitutional hierarchy of fundamental rights. When there was no state of emergency, the Government continued to limit fundamental rights through administrative regulations, invoking impertinent legal rules. The reaction of the public authorities to the covid-19 situation constituted a social paradigm shift, without previous scientific support, against the rale of law and with increasingly tragic effects. It was a trend with totalitarian tones-and, as it is well known, hostility to the free exercise of religion is typical of totalitarianism. © 2022 Iuris Universal Ediciones. All rights reserved.

Development of an air purifier with UVC radiation and HEPA filter in the context of COVID-19

The transmission of respiratory infections has an important role on human health, especially in the current context of the COVID-19 pandemic. In this work, we present the assessment of an air purifier that uses ultraviolet-C (UVC) radiation and a "High Efficiency Particulate Air” (HEPA) filter as mechanisms to decontaminate indoor environments with low air circulation. To assess the physicochemical and microbicidal characteristics of the equipment, the irradiance produced by the lamp, the flow rate at the entrance and exit of the device, possible changes in the ozone concentration and the equipment's decontamination potential for Staphylococcus aureus, Escherichia coli and Candida albicans. The total dose of UVC radiation that the air receives when passing through the equipment was 801.4 μJ cm-2, which would represent an inactivation of up to 80% of SARS-CoV-2 in the air. Furthermore, the filtration efficiency dropped with smaller particle diameter, and reduced to around 60% for particles with less than 1 μm and remained above 90% for PM2.5 and PM10 . In microbiological tests, there was a reduction of 99.4%, 99.9% and 99.5% for S aureus, E. coli and C. albicans, respectively, in 11 minutes. © 2022 Associação Brasileira de Engenharia Sanitária e Ambiental Este é um artigo de acesso aberto distribuído nos termos de licença Creative Commons.

Influenza and schizophrenia: Howcan we shed a light in the new virus from an old association?

Introduction: COVID-19 raises serious concerns regarding its unknown consequences for health, including psychiatric long term outcomes. Historically, influenza virus has been responsible for pandemics associated with schizophrenia. Epidemiological studies showed increased risk for schizophrenia in children of mothers exposed to the 1957 influenza A2 pandemic. Controversy remains concerning the mechanisms of pathogenesis underlying this risk. Objective(s): We aim to review the evidence for the association between influenza infection and schizophrenia risk, the possible pathogenic mechanisms underlying and correlate these findings with the schizophrenia hypothesis of neurodevelopment. Method(s): We reviewed literature regarding evidence from epidemiological, translational animal models and serological studies using medline database. Result(s): The biological mechanisms likely to be relevant account to the effects of infection-induced maternal immune activation, microglial activation, infection-induced neuronal autoimmunity, molecular mimicry of the influenza virus, neuronal surface autoantibodies and psychosis with potential infectious antecedents. Influenza infection may fit into the theory of the neurodevelopment of schizophrenia as a factor that alters the normal maturation processes of the brain (possible second or third hit). Conclusion(s): Influenza infection has multiple pathogenic pathways in both pre and post natal processes that might increase the risk of schizophrenia or psychosis. The existing evidence regarding the relationship between influenza virus and psychosis might help us draw similar long-term concerns of COVID-19.

Stress Predictors in Nursing Students during the COVID-19 Pandemic Confinement

Background: The COVID-19 pandemic has largely impacted nursing education. Owing to the element of confinement, emergency education fostered conflicts between problems and their solutions, leading to higher stress among students. Objective: The aim of the study was to identify the determinants of perceived stress in nursing students during confinement due to the COVID-19 pandemic. Methods: This multicentric, quantitative, and cross-sectional study employed the multiple linear regression model. The study was conducted at seven nursing graduate schools in the Iberian Peninsula, with 1,058 nursing graduate students in confinement. An online questionnaire was administered to nursing students between April 23rd and May 02nd, 2020. According to socio-demographic data, COVID-19 experience, satisfaction with learning strategies, and coping strategies ( Brief COPE scale ) of the nursing students, the model was developed with the Perceived Stress Scale as the explained variable. Results: Stress is predictable in the form of greater coping-avoidance (b = 2.415;p < .001) when a family member is infected (b =-2.354;p = .005) and in younger students (b =-.104;p = .002). It tends to be lower with higher coping-reflective (b =-2.365;p < .001) and when the students have a more favourable self-perceived life (b =-1.206;p < .001). Furthermore, the stress has been found to be higher in Portuguese students (b =-1.532;p < .001) and women (b = 2.276;p < .001) than their Spain and male counterparts, respectively. Among variables related to academics, perceived stress is higher when the students are dissatisfied with the time spent on the computer (b = 1.938) and with the evaluation methods (b = 1.448). Conclusion: Personal factors and the ease of mobilisation of the proposed training strategies affect the students’ ability to deal with stress. Emergency education should consider stress predictors so that the students can adapt to training better. © 2022 Lourenço et al.

Impact of COVID-19 on colorectal cancer management: Single-center experience

Background: Colorectal cancer (CCR) is the third most common and the second most deadly cancer with 1.9 million new diagnoses worldwide in 2020. COVID-19 pandemic placed an unprecedented burden on health systems worldwide, directly impacting cancer patients’ management. Health-care systems reorganization led to a decrease on all non-urgent surgical and medical procedures, delaying cancer screening protocols. This study aims to access the impact of COVID-19 on Colorectal Cancer management in a Portuguese Oncology Department. Methods: A retrospective cohort study comparing the new colorectal cancer diagnosis between March/2019 and March/2022. New diagnosis between March/2019 and March/2020 were assigned to Cohort 1 “Before COVID-19 Pandemic” and new diagnosis between March/2020 and March/2022 assigned to Cohort 2 “During COVID-19 Pandemic”. Data was collected from digital medical records and statistical analysis performed using SPSS V.25 IBM®. Results: Between March/19 and March/22 were diagnosed 313 new colorectal cancers, 116 (37%) assigned to Cohort 1 “Before COVID-19 Pandemic” and 197 (63%) to Cohort 2 “During COVID-19 Pandemic”. Analysing the new diagnosis in Cohort 2, 105 (34%) occurred between March/20-21 and 92 (29%) between March/21-22. Mean age at diagnosis of 69 (30-96) years for Cohort 1 and 68 (32-94) years for Cohort 2. 42% (n=49) females and 58% (n=68) males in Cohort 1 compared to 38% (n=77) females and 62% (n=123) males in Cohort 2. Colorectal cancer screening diagnosed 36% (n=42) patients in Cohort 1 and 35% (n=69) in Cohort 2. Clinical presentation with bowel obstruction was seen in 25% (n=29) in Cohort 1 and 37% (n=74) in Cohort 2 (p=0.02). Metastatic disease at diagnosis in 13% (n=14) for Cohort 1 and 26% (n=52) for Cohort 2 (p=0.07). Regarding management, 39% (n=46) underwent adjuvant systemic treatment in Cohort 1 compared to 28% (n=55) in Cohort 2 (p=0.03). Palliative systemic treatment was agreed for 7% (n=10) in Cohort 1 and 17% (n=36) in Cohort 2 (p=0.02). At diagnosis, best supportive care was decided for 2% (n=2) in the first Cohort and 15% (n=30) (p=0.03). Overall survival of 25 (1-36) months for Cohort 1 and 10 (1-23) months for Cohort 2. Conclusions: Comparison between pre-pandemic and in-pandemic periods revealed a numeric reduction on new cases of colorectal cancer in each 12 months period. Despite similar rate of diagnosis by colorectal cancer screening, statistical significance was found when comparing clinical presentation with bowel obstruction or metastatic disease. Despite that, less patients underwent adjuvant systemic treatment in cohort 2 and more were evaluated for best supportive care at diagnosis. These findings may be explained by more advanced disease in more fragile patients in the Cohort 2 population. The results of our study contribute to the evidence on the impact of COVID-19 pandemics on colorectal cancer with fewer diagnosis, more advanced disease, and lack of re-establishment of pre-pandemic rate of new diagnosis. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosures: All authors have declared no conflicts of interest.

LUNGCOVID: SARS-CoV-2 Infection in Patients With Thoracic Tumors - Multicenter Observational Study in Portugal

Introduction: Since the beginning of the COVID-19 pandemic, health care system was readjusted and thoracic cancer patients with COVID-19 were studied in international registries. In patients with malignant thoracic neoplasms the differential diagnosis is complex, due to the location of the disease and symptoms related to cancer. Age, smoking status, comorbidities, previous corticotherapy treatment, performance status and stage of thoracic malignancies have been described as prognostic factors. Some registries and series of COVID-19 in thoracic malignancy patients reported mortality rates of 26% (CCC-19), 32% (TERAVOLT), 39% (UKCCMP) and even 47% (Dutch Oncology COVID-19 Consortium). A national survey on the impact of COVID-19 in lung cancer patients' treatment has been presented by the Portuguese Lung Cancer Study Group. However, a national study of COVID-19 patients with thoracic malignancies has not been done. Objectives: To access the frequency and severity of COVID-19 in Portuguese patients with thoracic malignancies, and to study clinical manifestations, intensive care admission and factors associated with a worst outcome. Methods: LUNGCOVID is a multicenter national observational study. Patients with primary thoracic malignancy, age 18-years-old and SARS-CoV-2 infection diagnosed by reverse-transcriptase polymerase chain reaction or antigenic test since March 2020, will be eligible. Clinicopathological characteristics will be accessed by reviewing medical records. The variables to be studied are: age, sex, performance status, smoking habits, presence of comorbidities, previous corticotherapy treatment, factors related to the underlying cancer disease (stage of the disease, histological type), treatments, previous chest radiotherapy, oncologic systemic treatment, COVID-19 symptoms, need of intensive care admission and survival. Results: Section not applicable Conclusion: Section not applicable. Keywords: SARS-CoV-2, thoracic tumors, Outcome

The oasis (opicapone in sleep disorder) study in Parkinson's disease: Design and rationale of an open-label, single-arm, pilot trial

Background and aims: Opicapone (OPC) proved to be effective in the treatment of end-of-dose motor fluctuations in Parkinson's disease (PD) patients. Non-motor symptoms have a substantial impact on health-related quality of life and are reported in approximately 90% of idiopathic PD patients. End-of-dose motor fluctuations and associated sleep disorders are commonly observed in PD patients who receive treatment with levodopa (L-dopa)/DOPA decarboxylase inhibitors (DDCI). This study aims to evaluate the effects of OPC treatment on sleep disorders in PD patients with ‘wearing-off’. Methods: Approximately 30 patients (aged ≥30 years) with idiopathic PD, treated with 3–8 daily doses of L-dopa/DDCI, with ‘wearing-off’ and sleep disorders will receive OPC 50 mg once daily during a 6-week evaluation period. L-dopa/DDCI daily dose, but not number of intakes, may be adjusted according to the patients' response in the first 2 weeks, and is kept unchanged afterwards (Fig. 1). As a pilot study, no formal sample size calculation was performed. [Formula presented] Results: The primary endpoint is change from baseline in total score of Parkinson's Disease Sleep Scale-2. Secondary endpoints include tolerability, functional motor and non-motor assessments (Movement Disorder Society-Non-Motor Symptoms Scale, Parkinson's Disease Questionnaire-8, Parkinson's Fatigue Scale, ON/OFF home diary), and Clinical and Patient Global Impression of Change scales. Study sites are in Germany and Portugal. First-patient-in is expected for early 2021 and last-patient-out for late 2021. Timelines might be impacted by the COVID-19 situation. Conclusions: This pilot study will provide preliminary data on the potential effect of OPC 50 mg once daily as adjunctive therapy to L-dopa/DDCI on PD-associated sleep disorders.

Adoption (early levodopa with opicapone in Parkinson's patients with motor fluctuations) study in Parkinson's disease: Design and rationale of a randomized prospective, open-label exploratory trial

Background and aims: Opicapone (OPC) proved to be effective in the treatment of end-of-dose motor fluctuations in Parkinson's disease (PD) patients. About 80–100% of PD patients show some degree of wearing-off within 10 years of levodopa (L-dopa) therapy. Approaches to optimize the L-dopa regimen include increasing the dose or ‘fractionating’ the total daily dose. This study aims to explore the potential of adjunctive OPC versus an additional dose of L-dopa/dopa decarboxylase inhibitor (DDCi) to optimize the L-dopa/DDCi regimen as first-line approach to treat wearing-off. Methods: Approximately 100 patients (aged ≥30 years) with idiopathic PD, treated with 3–4 daily oral L-dopa doses up to 600 mg, and signs of wearing-off (<2 years) will be equally randomized to receive OPC 50 mg once daily or an additional dose of 100 mg/25 mg L-dopa/DDCI during a 4-week open-label evaluation period (Fig. 1). [Formula presented] Results: Primary endpoint is the change from baseline in OFF-time. Secondary endpoints include tolerability, functional motor and non-motor assessments (Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale, MDS-Non-Motor Symptoms, Parkinson's Disease Questionnaire-8), and global impression of change scales (Clinical Global Impression of Change, Patient Global Impression of Change). As this is a descriptive/exploratory study, no formal sample size calculation was performed. Study sites are in Germany, Italy, Portugal, Spain, and the UK. First-patient-in is expected for 2021 and last-patient-out for late 2022. Timelines might be impacted by the COVID-19 situation. Conclusions: This study will evaluate the potential of adjunctive OPC versus an additional dose of L-dopa/DDCi as first-line approach to treat wearing-off in PD patients.

COVID-19 Portal: Machine Learning Techniques Applied to the Analysis of Judicial Processes Related to the Pandemic

The COVID-19 pandemic created new demands, not only for health services, but also for services in other domains such as the judicial system. New tools that assist in the analysis of the judicial process may help in this problem. In particular, artificial intelligence (AI) techniques may be applied to provide a qualitative analysis of legal documents. Although there exist a number of works that apply AI in the judicial domain, few target the pandemic or publicly provide the information extracted from the texts. Following the suggestions and needs of a legal expert, we have developed the COVID-19 Portal. It extracts documents from the Supreme Federal Court in Brazil, and applies AI technologies to obtain fine-grained quantitative and qualitative information on words used in the texts. This information is made available on a website and can help lawyers identify trends and develop arguments for judicial processes related to the pandemic. © 2021, Springer Nature Switzerland AG.

Impact of COVID-19 pandemia on the diagnosis of breast cancer in one region of north of Portugal: One year experience

Background: The onset of COVID-19 pandemic forced lockdown and halted breast cancer screening programs. We aimed to investigate the impact of COVID-19 on the new diagnosis and staging of breast cancer. Methods: In this cohort study, we included all patient with new diagnosis of breast cancer who were admitted to our Hospital (Hospital Pedro Hispano, Matosinhos, Portugal), between March 2019 and March 2021. We collected data on baseline clinical conditions such as age, stage at diagnosis and treatment. We created two different groups were created: 1st group- before COVID-19 pandemia (March 1, 2019 to March 16, 2020);2nd group - COVID-19 pandemia (March 17, 2020 to March 31, 2021). A comparative assessment between groups was carried out. Results: Were included 483 patients;n=289 in the 1st group and n= 194 in the 2nd group. The median age was 60 years old in the 1st group and 59 years old in the 2nd group. In the 1st group, 13% patients were diagnosis with ductal in situ carcinoma (DCIS), 51% in stage I, 24% in stage II, 9.5% in stage III and 3% in stage IV. In 2nd group, 9% had DCIS, 30% were in stage I, 40% in stage II, 11% in stage III and 10% in stage IV. Stage at diagnosis was significantly higher in the 2nd group (p< 0.001) This situation was mainly due to tumour size (T). In the 1st group, most patients (n=91;38%) had tumour size between 10 e 20mm (T1c in TNM classification). One the other hand, 40% (n=78) of patients included in the 2nd group had tumour size between 20 e 50mm (T2), with significant differences between them (p=0.004). No difference was found between groups in nodular involvement (p=0.189), with the majority of patients (∼50% in both groups) presenting without nodular involvement (N0 in TMN classification). 10% of patients in 2nd group and 3% in 1st group had metastatic disease at diagnosis, with differences between them (p=0.006). 49% (n=119) of patients in 1st group and 52% (n=100) in the 2nd group were treated with chemotherapy, without differences between those groups. Conclusions: Our results show that during one year after COVID-19 pandemia the incidence of breast cancer decreased, and patients were diagnosis in more advanced stages. This situation could have been related to patient referral to non COVID-19 Hospitals or correspond to a true sub-diagnosis. Legal entity responsible for the study: M. Vilaça. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Opicapone OCEAN study in Parkinson's: Design of a randomized double-blind placebo-controlled trial

Background and aims: Opicapone (OPC) proved to be effective in the treatment of end-of-dose motor fluctuations in Parkinson's Disease (PD) patients [1,2]. End-of-dose motor fluctuations and associated pain are commonly observed in PD patients on L-dopa/DOPA decarboxylase inhibitors (DDCI). They have a detrimental impact on the quality-of-life [3] and are in part mediated via dopaminergic pathways. [4]. Therefore, an a-priori presumption was made that OPC will overcome end-of-dose fluctuation related pain and consequently improve patients' well-being. Methods: Patients (30 years old) with idiopathic PD, treated with three to eight daily oral doses of L-dopa/DDCI and with 'wearing-off' (end-of-dose deterioration) phenomenology, and experiencing PD associated pain will be randomised (1:1) to OPC 50mg once-daily or placebo during a 24-week evaluation-period (Figure 1). To detect a minimum clinically relevant magnitude of effect between arms, 70 subjects per group is necessary. Results: The primary endpoint is change from baseline in Domain 3 (fluctuation-related pain) of King's-Parkinson's- Disease-Pain-Scale (KPPS). Secondary endpoints include tolerability, functional motor and non-motor assessments (KPSS, MDS-NMS, PDQ-8, Hauser's home diary), and Global Impression of Change (CGI-C, PGI-C). Study sites are in Germany, Italy, Portugal, Spain and UK. First-patient-in is expected for 2021 and Last-patient-out to late 2022. Timelines might be impacted by COVID-19 pandemic situation. Conclusion: This study will further evaluate the impact of 50mg opicapone once daily as adjunctive therapy to L-dopa/ DDCI on fluctuation-associated pain. (Figure Presented).

Opicapone ADOPTION study in Parkinson's: Design of a randomized prospective, open-label exploratory trial

Background and aims: Opicapone (OPC) proved to be effective in the treatment of end-of-dose motor fluctuations in Parkinson's Disease (PD) patients [1,2]. About 50% of PD patients within 2-5 years, and 80-100% patients within 10 years of L-dopa therapy, show some degree of motor complications [3,4]. Subsequently, the standard approach is to alter the L-dopa dosing regimen, either by increasing the dose or by 'fractionating' its total daily dose [5]. This study aims to explore the potential of OPC to optimize L-dopa/ DDCi as first line approach to treat wearing-off. Methods: Approximately 100 patients (aged 30 years) with idiopathic PD, treated with 3-4 daily oral L-dopa doses up to 600mg, and signs of wearing-off (<2 years) will be equally randomised to receive OPC 50mg once-daily or 100mg L-dopa/DDCI during a 4-week open-label evaluation-period (Figure 1). Results: Primary endpoint is the change from baseline in OFF-time. Secondary endpoints include tolerability, functional motor and non-motor assessments (MDSUPDRS, MDS-NMS, PDQ-8, Hauser's home diary) and Global Impression of Change (CGI-C, PGI-C). As this is an descriptive/exploratory study, no formal sample size calculation was performed. Study sites are in Germany, Italy, Portugal, Spain and UK. First-patient-in is expected for 2021 and Last-patient-out to late 2022. Timelines might be impacted by COVID-19 pandemic situation. Conclusion: This study will evaluate the potential of OPC to optimize L-dopa/DDCi as first line approach to treat wearing-off.

Opicapone OASIS study in Parkinson's: Design of an open-label, single-arm, pilot trial

Background and aims: Opicapone proved to be effective in the treatment of end-of-dose motor fluctuations in Parkinson's Disease (PD) patients [1,2]. Non-motor symptoms have a substantial impact on health-related quality-of-life and are reported in about 90% of idiopathic PD patients [3]. End-of-dose motor fluctuations and associated sleep disorders are commonly observed in PD patients under treatment with L-dopa/DOPA decarboxylase inhibitors (DDCI). Therefore, there is the expectation that opicapone might improve such symptoms. Methods: Approximately 30 patients (aged 30 years) with idiopathic PD, treated with 3-8 daily oral doses of L-dopa/ DDCI, with 'wearing-off' and experiencing sleep disorders will receive OPC 50mg once-daily during a 6-week evaluationperiod. L-dopa/DDCI daily dose, but not number of intakes, may be adjusted according to subject response in the first 2 weeks, and kept unchanged afterwards (Figure 1). As a pilot study, no formal sample size calculation was performed. Results: The primary endpoint is change from baseline in total score of Parkinson's Disease Sleep Scale (PDSS-2). Secondary endpoints include tolerability, functional motor and non-motor assessments [MDS-NMS, PDQ-8, Fatigue Scale (PFS-16), ON/OFF home diary] and Global Impression of Change (CGI-C, PGI-C). Study sites are in Germany and Portugal. First-patient-in is expected for 2021 and Last-patient-out to late 2021. Timelines might be impacted by COVID-19 pandemic situation. Conclusion: This study will further evaluate the potential impact of OPC 50mg once-daily as adjunctive therapy to L-dopa/DDCI on PD-associated sleep disorders. (Figure Presented).

Deep Learning in Image Analysis for COVID-19 Diagnosis: a Survey

COVID-19 achieved the highest concentration of confirmed cases in the Americas with a significant impact in Latin America and the Caribbean region, where access to water and sanitation is restricted. In this scenario, we surveyed deep learning techniques applied to extract information from images to detect pneumonia caused by SARS-COV-2, directly assisting health professionals through an automatic case screening. We identify the main public and private image datasets and deep network architectures. Thereby, we identified challenges and research directions. Thus, our goal is to provide a theoretical basis to contribute to the development of computational systems to aid the diagnosis of COVID-19.

Impact assessment of SARS-CoV-2 testing on cancer patients undergoing immunosuppressive treatment

Background: On March 11, 2020, COVID-19 was declared a global pandemic. Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this infection may remain asymptomatic. The European Society of Medical Oncology and the Portuguese Health Authority recommended both a symptomatic survey and laboratory testing in all cancer patients (pts) undergoing immunosuppressive treatment (IT). The impact of this measure is still unknown. We report our experience in a Portuguese center. Methods: Since March 2020, a symptomatic survey has been performed at our institution before each hospital visit. From April 6 through May 8, 2020, reverse-transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 testing was added on cancer pts before undergoing IT. The impact of this intervention was evaluated comparing the hospitalization rate of cancer pts due to COVID-19, before and after the introduction of RT-PCR testing. Retrospective analysis of clinical data was performed. Results: 444 tests were carried out on 244 pts and laboratory SARS-CoV-2 infection was confirmed in 11 (5%);5 were male, with a median age of 65 years [34-76]. Breast and colorectal cancer were prevalent;2 pts had lung cancer;6 advanced disease. Ongoing IT in these pts was temporarily suspended: 9 pts under chemotherapy, 1 atezolizumab and 1 rituximab. Only 1 patient was symptomatic (9%) and previously hospitalized. No admission due to COVID-19 was registered in this group. Since March 7, 179 pts were admitted due to COVID-19 at our center: 12 were active cancer pts (6.7%) of which 4 were under IT. 6 of the oncological pts passed away, all of them had advanced diseases, 1 was under IT. Of the dead pts, lung and breast tumors were prevalent. Among all COVID-19 hospitalizations, the prevalence of pts under IT was similar before and after the implementation of the RT-PCR testing (2.2% vs. 2.4%). Conclusions: We found a significant percentage of active cancer pts diagnosed with asymptomatic COVID-19. Due to the small sample size of COVID-19 pts under IT, it is difficult to evaluate the impact of RT-PCR testing. However, on a long-term analysis, this intervention may reduce the risk of severe complications related to COVID-19 in cancer pts. Health education and dynamic organization are also important measures. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.