De novo human angiotensin-converting enzyme 2 decoy NL-CVX1 protects mice from severe disease after severe acute respiratory syndrome Coronavirus 2 infection

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements number 852985.info:eu-repo/semantics/publishedVersio

De novo human angiotensin - converting enzyme 2 Decoy NL-CVX1 protects mice from severe disease after severe acute respiratory syndrome coronavirus 2 infection

The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.info:eu-repo/semantics/publishedVersio

Current and novel therapeutic opportunities for systemic therapy in biliary cancer

Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Effects of chronological age, relative age, and maturation status on accumulated training load and perceived exertion in young sub-elite football players

The aims of this study were 1) to analyze the influence of chronological age, relative age, and biological maturation on accumulated training load and perceived exertion in young sub-elite football players and 2) to understand the interaction effects amongst age grouping,maturation status, and birth quartiles on accumulated training load and perceived exertion in this target population. A 6-week period (18 training sessions and 324 observation cases) concerning 60 young male sub-elite football players grouped into relative age (Q1 to Q4), age group (U15, U17, and U19), and maturation status (Pre-peak height velocity (PHV), Mid-PHV, and Post- PHV) was established. External training load data were collected using 18 Hz global positioning system technology (GPS), heart-rate measures by a 1 Hz short-range telemetry system, and perceived exertion with total quality recovery (TQR) and rating of perceived exertion (RPE). U17 players and U15 players were 2.35 (95% CI: 1.25–4.51) and 1.60 (95% CI: 0.19–4.33) times more likely to pertain to Q1 and Q3, respectively. A negative magnitude for odds ratio was found in all four quartile comparisons within maturation status (95% CI: 6.72–0.64), except for Mid-PHV on Q2 (95% CI: 0.19–4.33). Between- and within-subject analysis reported significant differences in all variables on age group comparison measures (F = 0.439 to 26.636, p = 0.000 to 0.019, η2 = 0.003–0.037), except for dynamic stress load (DSL). Between-subject analysis onmaturity status comparison demonstrated significant differences for all training load measures (F = 6.593 to 14.424, p = 0.000 to 0.037, η2 = 0.020–0.092). Interaction effects were found for age group xmaturity band x relative age (Λ Pillai’s = 0.391, Λ Wilk’s = 0.609, F = 11.385, p = 0.000, η2 = 0.391) and maturity band x relative age (Λ Pillai’s = 0.252, Λ Wilk’s = 0.769,F=0.955, p = 0.004, η2 = 0.112). Current research has confirmed the effects of chronological age, relative age, and biological maturation on accumulated training load. Perceived exertion does not seem to show any differences concerning age group or maturity status. Evidence should be helpful for professionals to optimize the training process and young football players’ performance.This work is supported by national funds (FCT—Portuguese Foundation for Science and Technology) under the project UIBD/DTP/04045/2020info:eu-repo/semantics/publishedVersio

Current policies are insufficient to protect or restore Brazil’s cost-effective conservation priority zones

In Brazil, conservation priority zones, in spite of their key role in preserving natural vegetation and its environmental resources are frequently located outside the country’s public network of protected areas (PAs). Here we present the first study on land-use impacts inside Brazil’s unprotected (i.e. outside PAs) Cost-Effective conservation priority Zones (CEZs), for the period 2020–2050. CEZs are conservation priority zones that had experienced low levels of human impact in 2020. In this study, we consider various governance scenarios, including different deforestation control and native vegetation restoration policies. To this end, a land-use change model is combined with a downscaling method to generate natural vegetation cover projections at a 0.01 ${^\circ}$ resolution. Results, which include the effects of climate change on the expansion of the Brazilian agriculture, project native vegetation losses (through deforestation) or gains (through restoration) inside unprotected CEZs. If the current pattern of disregard for the environment persists, our results indicate that a large share of the native vegetation inside Brazil’s CEZs is likely to disappear, with negative impacts on biodiversity preservation, green-house gas emissions and ecosystem services in general. Moreover, even if fully implemented and enforced, Brazil’s current Forest Code is insufficient to adequately protect CEZs from anthropization, especially in the Cerrado biome. We expect that this study can help improving the conservation and restoration of CEZs in Brazil

Mortality predictors in patients with takotsubo cardiomyopathy

Takotsubo cardiomyopathy (TC) is characterized by transient left ventricular dysfunction in the absence of artery coronary disease. The prognosis is generally favorable but there are cases of death. TC is a rare disease with a low number of events and because of that, there are few studies that describe mortality predictors