Key Entry Research Articles

PB1820: CD47-BLOCKER TTI-622 COMBINED WITH AZACITIDINE IN PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA (AML) AND WITH AZACITIDINE + VENETOCLAX IN ELDERLY OR UNFIT PATIENTS WITH TP53-WILDTYPE AML

Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a “don’t eat me” signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Increased expression of CD47 is an adverse prognostic factor in acute myeloid leukemia (AML) due to its association with reduced event-free and overall survival, and blockade of CD47 has shown pre-clinical and clinical activity in AML. In vitro, both azacitidine and venetoclax significantly enhanced the pro-phagocytic effect of TTI-622 on macrophages. Aims: To characterize the safety and preliminary efficacy profile of TTI-622 in combination with azacitidine in newly diagnosed TP53-mutated AML and in combination with azacitidine + venetoclax in elderly or unfit, newly diagnosed TP53-wildtype AML. Pharmacokinetics and immunogenicity of TTI-622 combined with azacitidine ± venetoclax will also be investigated. Primary endpoints include dose-limiting toxicities, incidence of adverse events (AEs) and complete response (CR). Minimal residual disease status will also be evaluated. Methods: As part of an ongoing dose-escalation and expansion trial of TTI-622 (NCT03530683), patients with AML meeting the below key entry criterion are enrolled. Cohort A includes patients with newly diagnosed TP53-mutated AML. Cohort B includes patients with newly diagnosed TP53-wildtype AML who are either elderly (375 years) or unfit. Unfit patients include those < 75 years with one or more of the following comorbidities: Eastern Cooperative Oncology Group (ECOG) performance status of 2, clinically significant heart or lung comorbidities, contraindication to anthracycline therapy, or other comorbidity the investigator regards as incompatible with intensive remission induction chemotherapy. All patients from both cohorts must have documented bone marrow or peripheral blast counts 3 20% and must have received no prior systemic therapy for AML nor hypomethylating agents for any antecedent hematologic disorders prior to transformation to AML. Patients must have no extramedullary disease or leukocytosis >25,000/mL. Renal function must be 330 mL/minute based on Cockcroft-Gault estimate. There are no restrictions based on neutrophil or platelet counts, or hemoglobin level. Patients with AML secondary to antecedent hematologic disorders or therapy induced will not comprise more than 50% of either Cohort. Up to 30 patients will be enrolled into each cohort. In 28-day cycles, patients in both Cohorts will receive TTI-622 8 mg/kg intravenous (IV) infusions weekly combined with azacitidine 75 mg/m2 administered either IV or subcutaneously for 7 consecutive days, repeated approximately every 4 weeks. Patients in Cohort B will also receive venetoclax 100 mg and 200 mg orally on Days 1 and 2, respectively, followed by 400 mg (or equivalent adjusted for azoles) daily thereafter. Safety monitoring includes clinical laboratories and assessments of AEs based on CTCAE v 4.03. Response assessments of both bone marrow and peripheral blood are performed at the end of Cycles 1, 2 and 4; and then every 3 cycles thereafter. Response assessment is per the ELN2017 criteria. Results: Results N/A (trial-in-progress) Summary/Conclusion: Conclusion N/A (trial-in-progress)

IMPAIRED ACE2 GLYCOSYLATION AND PROTEASE ACTIVITY LOWERS SUSCEPTIBILITY TO SARS-COV-2 INFECTION IN GITELMAN/BARTTER SYNDROMES

Objective: ACE2, part of the counterregulatory arm of the ennin-angiotensin system, serves both as protective toward oxidative stress and cardiovascular enninling and as key entry for SARS-CoV-2. ACE2 has two isoforms, non-glycosylated and glycosylated, being this latter accountable for the binding with SARS-CoV-2. After the binding, viruses use proteases as cathepsin-L (Cat-L) to entry the cells. Both ACE2 glycosylation and Cat-L activity are pH-dependent. Gitelman and Bartter syndromes (GS/BS), rare genetic tubulopathies, are characterized by electrolytic alterations, activation of the ennin-angiotensin system, yet normo-hypotension, increased levels of ACE2 and metabolic alkalosis with likely increased intracellular pH. We reported that during the first wave of COVID-19 in early 2020 none of our cohort of 128 GS/BS patients from the major hotspots in Northern Italy had been infected or suffered any major COVID-19 symptoms and in a second survey on the same cohort in 2021 we reported only 8 positives, 4 asymptomatic and 4 with very light symptoms This study aims to investigate potential mechanisms as ACE2 glycosylation and Cat-L activity related to patients’ metabolic alkalosis and viral entry/infection. Design and method: Mononuclear cells ACE2 glycosylation (Western blot) and blood Cat-L activity (ELISA) from 20 GS/BS patients have been compared to those from 15 heathy subjects. Results: Non-glycosylated ACE2 was higher in GS/BS (0.82 ± 0.19 d.u. vs 0.67 ± 0.13 p = 0.01); glycosylated ACE2 was not different (0.85 ± 0.28 in GS/BS vs 0.73 ± 0.23 p = 0.19). Cat-L activity was lower in GS/BS (3.90 ± 1.13 r.f.u. vs 5.31 ± 0.8 p &lt; 0.001) and inversely correlated with blood bicarbonate (HCO3-), while a negative correlation between glycosylated ACE2 and HCO3- approaches statistical significance (p = 0.08). Conclusions: GS/BS's metabolic alkalosis, likely by increasing intracellular pH, influences the glycosylation of ACE2 and the activity of Cat-L, providing a mechanistic explanation for the near complete absence of COVID-19 or its symptoms reported in our cohort. These findings provide a rationale for pursuing the identification and/or synthesis of new drugs that specifically target ACE2 glycosylation and/or proteases involved in SARS-CoV-2 infection.

MO041: Impaired ACE2 glycosylation and protease activity lowers susceptibility to SARS-COV-2 infection in Gitelman/Bartter syndromes

BACKGROUND AND AIMSACE2, part of the counter-regulatory arm of the renin–angiotensin system, serves both as protective toward oxidative stress and cardiovascular remodeling and as a key entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 has two isoforms, non-glycosylated and glycosylated, the latter being accountable for the binding with SARS-CoV-2. After the binding, viruses use proteases as cathepsin-L (Cat-L) to entry the cells. Both ACE2 glycosylation and Cat-L activity are pH-dependent. Gitelman and Bartter syndromes (GS/BS), rare genetic tubulopathies, are characterized by electrolytic alterations, activation of the renin–angiotensin system, yet normo-hypotension, increased levels of ACE2 and metabolic alkalosis with likely increased intracellular pH. We reported that during the first wave of COVID-19 in early 2020 none of our cohort of 128 GS/BS patients from the major hotspots in Northern Italy had been infected or suffered any major COVID-19 symptoms and in a second survey on the same cohort in 2021, we reported only eight positives, four asymptomatic and four with very light symptoms This study aims to investigate potential mechanisms as ACE2 glycosylation and Cat-L activity related to patients’ metabolic alkalosis and viral entry/infection.METHODMononuclear cells ACE2 glycosylation (Western blot) and blood Cat-L activity (ELISA) from 20 GS/BS patients have been compared with those from 15 healthy subjects.RESULTSNon-glycosylated ACE2 was higher in GS/BS (0.82 ± 0.19 d.u. versus 0.67 ± 0.13, P = 0.01); glycosylated ACE2 was not different (0.85 ± 0.28 in GS/BS versus 0.73 ± 0.23, P = 0.19). Cat-L activity was lower in GS/BS (3.90 ± 1.13 r.f.u. versus 5.31 ± 0.8, P <0 0.001) and inversely correlated with blood bicarbonate (HCO3−), while a negative correlation between glycosylated ACE2 and HCO3− approaches statistical significance (P = 0.08).CONCLUSIONGS/BS's metabolic alkalosis, likely by increasing intracellular pH, influences the glycosylation of ACE2 and the activity of Cat-L, providing a mechanistic explanation for the near-complete absence of COVID-19 or its symptoms reported in our cohort. These findings provide a rationale for pursuing the identification and/or synthesis of new drugs that specifically target ACE2 glycosylation and/or proteases involved in SARS-CoV-2 infection.

Bioanalytical approaches for the detection, characterization, and risk assessment of micro/nanoplastics in agriculture and food systems.

This review discusses the most recent literature (mostly since 2019) on the presence and impact of microplastics (MPs, particle size of 1μm to 5mm) and nanoplastics (NPs, particle size of 1 to 1000nm) throughout the agricultural and food supply chain, focusing on the methods and technologies for the detection and characterization of these materials at key entry points. Methods for the detection of M/NPs include electron and atomic force microscopy, vibrational spectroscopy (FTIR and Raman), hyperspectral (bright field and dark field) and fluorescence imaging, and pyrolysis-gas chromatography coupled to mass spectrometry. Microfluidic biosensors and risk assessment assays of MP/NP for in vitro, in vivo, and in silico models have also been used. Advantages and limitations of each method or approach in specific application scenarios are discussed to highlight the scientific and technological obstacles to be overcome in future research. Although progress in recent years has increased our understanding of the mechanisms and the extent to which MP/NP affects health and the environment, many challenges remain largely due to the lack of standardized and reliable detection and characterization methods. Most of the methods available today are low-throughput, which limits their practical application to food and agricultural samples. Development of rapid and high-throughput field-deployable methods for onsite screening of MP/NPs is therefore a high priority. Based on the current literature, we conclude that detecting the presence and understanding the impact of MP/NP throughout the agricultural and food supply chain require the development of novel deployable analytical methods and sensors, the combination of high-precision lab analysis with rapid onsite screening, and a data hub(s) that hosts and curates data for future analysis.

Carbon footprint and carbon neutrality pathway of green tea in China

With the rising popularity of the concept of “carbon neutralization”, low-carbon products are likely to gain more advantages. Related to this, green tea— an important beverage that is widely consumed in China—along with emissions from planting, processing, and use phase should be given attention. Meanwhile, quantifying the carbon footprint (CF) of green tea is an essential task in developing the pathway to carbon neutrality. In this study, we quantified the CF and mitigation potential of green tea through life cycle assessment, after which we investigated the pathway toward carbon neutrality in 16 major tea-producing regions (except Hainan and Taiwan) in China. The system boundary was divided into six subsystems from cradle to grave: cultivation, processing, transport, packaging, consumption, and disposal. The results showed that the total carbon emissions of green tea reached 44.13 Mt CO2eq in 2019, of which 43% came from consumption and 28% from cultivation. There were 18.78 Mt CO2eq emissions from fertilizer production and application, while there was a 7.71 Mt CO2eq carbon sink of tea trees. The average carbon intensity was 24.30 kg CO2eq kg−1 tea, while Shandong and Guizhou ranked as the top two provinces. Sichuan, Hubei, and Yunnan Provinces had the largest amounts of carbon emissions at 6.79, 6.14, and 5.96 Mt CO2eq, respectively. By 2030, 2050 and 2060, total carbon emissions would be reduced by 46%, 63%, and 86%, respectively, under carbon neutrality assumption. A small amount of 6.14 Mt CO2eq carbon emissions was retained to be offset by carbon trading or zero-carbon cultivation. Finally, the results indicate that adopting low-carbon fertilizers and clean energies will be a key entry point for carbon-neutral green tea.

Alternative LIM homeodomain splice variants are dynamically regulated at key developmental steps in vertebrates.

BackgroundAlternative splicing provides a broad strategy to amplify the genome. Yet how alternative splicing influences neurodevelopment or indeed which variants are translated at developmental choice points remains poorly explored. Here we focused on a gene important for neurodevelopment, the Lim homeodomain transcription factor, Lhx9. Lhx9 has two noncanonical splice variants, Lhx9a and Lhx9b which compared with the canonical variant Lhx9c have a truncated homeodomain and an alternative C‐terminal sequence, suggesting that, if translated, these variants could differently impact on cellular function.ResultsWe created a unique antibody tool designed to selectively detect noncanonical Lhx9 variants (Lhx9ab) and used this to examine the protein expression dynamics in embryos. Lhx9ab variants were translated and dynamically expressed similarly between mouse and chicken at key developmental choice points in the spinal cord, limbs and urogenital ridge. Within the spinal cord, enrichment of Lhx9c vs Lhx9ab expression was observed during key migration and axonal projection choice points.ConclusionsThese data support the notion that the expression dynamics between canonical and noncanonical Lhx9 variants could play an important role in spinal neuron maturation. More broadly, determining the temporal dynamics of alternative protein variants is a key entry point to understand how splicing influences developmental processes.

Smart Vehicle Monitoring and Accident Prevention System using Arm

Abstract: After drunken driving, mobile phone usage is the leading cause of accidents around the world. Also, at sudden stoppages on cross roads or due to sudden obstructions on road, natural or otherwise the driver cannot anticipate back bumper and side collision. Also, low height railing or pavements in blind spots while parking may damage the vehicle. Costly mobile phone jammers while effective render emergency communication impossible. As alcohol detection and vehicle tracking system are successfully implemented we are proposing an essential vehicle safety kit which is absent in majority of the vehicles on Indian roads. Furthermore, this can be an addition to the developing cognitive driver assistance system. The proposed system provides vehicle with safety features like SMS alert facility, blind spot detection and tail gating detector. The vehicle is equipped with angle sensors and a GSM modem interfaced with NXP ARM 2148 processor. The driver has access to a user interface consisting of LCD and switching ports. The driver may aware two modes of angle sensing with sensors located on centre of the Vehicle. A braking system can be actuated in the parking mode if the distance measured from the sensors crosses the defined threshold. In case of an emergency the driver can send a text or call from the stored numbers in the memory using the keypad. To save time and to maintain the driver’s focus on the road a default text can be sent to a default number by a single key pad entry. Call service from the system eliminates the need of using the phone and prevents driver’s loss of focus. Further the freedom to choose the number and the corresponding message to be sent is available when the vehicle is at rest. The system thus prevents accidental damage to the vehicle and its driver while eliminating the use of phone by the driver. Keywords: PIC Microcontroller, LPC2148, LCD 16*2, GSM Module, ADXL335, GPS Module

Review on Smart Vehicle Monitoring and Accident Prevention System Using Arm

Abstract: After drunken driving, mobile phone usage is the leading cause of accidents around the world. Also, at sudden stoppages on cross roads or due to sudden obstructions on road, natural or otherwise the driver cannot anticipate back bumper and side collision. Also, low height railing or pavements in blind spots while parking may damage the vehicle. Costly mobile phone jammers while effective render emergency communication impossible. As alcohol detection and vehicle tracking system are successfully implemented we are proposing an essential vehicle safety kit which is absent in majority of the vehicles on Indian roads. Furthermore, this can be an addition to the developing cognitive driver assistance system. The proposed system provides vehicle with safety features like SMS alert facility, blind spot detection and tail gating detector. The vehicle is equipped with angle sensors and a GSM modem interfaced with NXP ARM 2148 processor. The driver has access to a user interface consisting of LCD and switching ports. The driver may aware two modes of angle sensing with sensors located on centre of the Vehicle. A braking system can be actuated in the parking mode if the distance measured from the sensors crosses the defined threshold. In case of an emergency the driver can send a text or call from the stored numbers in the memory using the keypad. To save time and to maintain the driver’s focus on the road a default text can be sent to a default number by a single key pad entry. Call service from the system eliminates the need of using the phone and prevents driver’s loss of focus. Further the freedom to choose the number and the corresponding message to be sent is available when the vehicle is at rest. The system thus prevents accidental damage to the vehicle and its driver while eliminating the use of phone by the driver. Keywords: PIC Microcontroller, LPC2148, LCD 16*2, GSM Module, ADXL335, GPS Module

Adipose tissue in COVID-19: detection of SARS-CoV-2 in adipocytes and activation of the interferon-alpha response

ObjectiveObesity is a recognized risk factor for the progression to severe forms of COVID-19, yet the mechanisms of the association are unclear.MethodsSubcutaneous abdominal adipose tissue specimens of subjects deceased from COVID-19 (n = 23) were compared to those of controls dying abruptly from causes other than infectious (accidental trauma, sudden cardiac death). Alterations of lung parenchyma consistent with moderate to severe disease were detected in all COVID-19 cases, not in controls. Investigations included: histopathologic features, detection of virus antigens and genome, characterization of infiltrating leukocytes, transcription levels of immune-related genes.ResultsBy RT-PCR, the SARS-CoV-2 genome was detected in the adipose tissue of 13/23 (56%) cases of the COVID-19 cohort. The virus nucleocapsid antigen was detected in the cytoplasm of 1–5% adipocytes in 12/12 COVID-19 cases that were virus-positive by PCR in the adipose tissue (one case could not be assessed due insufficient tissue). The adipose tissue of COVID-19 cases showed leukocyte infiltrates and upregulation of the interferon-alpha pathway. After adjusting for age and sex, the activation score of IFN-alpha was directly related with transcription levels of the ACE2 gene, a key entry factor of SARS-CoV-2.ConclusionsIn lethal COVID-19 cases, the SARS-CoV-2 nucleocapsid antigen has been detected in a sizeable proportion of adipocytes, showing that the virus may directly infect the parenchymal cells of subcutaneous fat. Infection appears to activate the IFN alpha pathway and to attract infiltrating leukocytes. Due to the huge numbers of adipocytes in adults, the adipose tissue represents a significant reservoir for SARS-CoV-2 and an important source of inflammatory mediators.

Tissue-resident memory T cells in the urogenital tract.

Our understanding of T cell memory responses changed drastically with the discovery that specialized T cell memory populations reside within peripheral tissues at key pathogen entry sites. These tissue-resident memory T (TRM) cells can respond promptly to an infection without the need for migration, proliferation or differentiation. This rapid and local deployment of effector functions maximizes the ability of TRM cells to eliminate pathogens. TRM cells do not circulate through peripheral tissues but instead form isolated populations in the skin, gut, liver, kidneys, the reproductive tract and other organs. This long-term retention in the periphery might allow TRM cells to fully adapt to the local conditions of their environment and mount customized responses to counter infection and tumour growth in a tissue-specific manner. In the urogenital tract, TRM cells must adapt to a unique microenvironment to confer protection against potential threats, including cancer and infection, while preventing the onset of auto-inflammatory disease. In this Review, we discuss insights into the diversification of TRM cells from other memory T cell lineages, the adaptations of TRM cells to their local environment, and their enhanced capacity to counter infection and tumour growth compared with other memory T cell populations, especially in the urogenital tract.

Cryosphere Services to Support SDGs in High Mountains

The cryosphere is able to provide a variety of services for the benefit of human well-being and underpins regional sustainable development. The cryosphere deterioration induced by climate change is impacting the services and will subsequently impede the efforts to meet sustainable development goals (SDGs) in high mountain societies. Here, we detail the context of cryosphere services and establish a dataset for its linkage to SDGs. This allows us to uncover its roles in supporting SDGs, directly by a causal connection and indirectly through either cascading effects or interconnection among SDGs. We find that the SDGs in association with the basic needs of high mountain societies are mostly affected by the cryosphere services. The different types of services pitch in with distinctions to be embraced by various SDGs, whilst some play a prominent role in the contribution to a broad range of SDGs. We further investigate how the services behave in their contributions to SDGs, by taking a view via the lens of a network that deciphers the relationship between the services and SDG targets as well as the interconnections among SDG targets. With an insight into the centrality and modularity of services in the network, we then delineate the inherent criticality of services to SDG targets as a whole, and reveal the specificity of services that co-contribute to a cluster of SDG targets in each network community. We take out the services from the network and maintain their interlinks to the targets of each underlying SDG system represented in six key entry points, so that the services critical to the transformation pathways in the entry points for SDGs in high mountains can be identified. Finally, we discuss the trade-offs that can occur in high mountains, which is unique for the cryosphere services. It creates more complexity in the assessment of overall benefits that the cryosphere services may provide to SDGs, and urges the balance that has to be maintained in attaining those services for the transformation.

Association Between Virtual Care Use and Same-Day Primary Care Access in VA Primary Care-Mental Health Integration.

Introduction:Same-day referrals from primary care to mental health increase subsequent mental health treatment engagement. VA Primary Care-Mental Health Integration (PC-MHI) clinics offer integrated mental health services embedded in primary care clinics, providing a key entry point to mental health care. Although telehealth use expanded rapidly after the onset of COVID-19, the impact of telehealth on same-day primary care access among new PC-MHI mental health patients is unknown. To address this knowledge gap, we examined associations between telehealth use and same-day primary care access in VA PC-MHI.Methods:We examined electronic health record data to identify same-day primary care appointments among PC-MHI patients who initiated care during 3/1/2018 to 10/29/2021. We used logistic regression analyses to evaluate the effect of telehealth on same-day primary care access. Time, demographic characteristics, mental health diagnoses (PTSD and depression), and substance use disorder diagnosis were evaluated as covariates.Results:New PC-MHI patients who were seen via telehealth were less likely to receive same-day primary care access than patients seen in person (OR: 0.54; 95% CI: 0.41-0.71; P < .001).Conclusions:Despite the potential advantages of using telehealth to increase access, VA patients with an initial PC-MHI visit via telehealth were less likely than patients seen in person to be referred from primary care. Telehealth may adversely affect primary care referrals to mental health services, an outcome that could ultimately reduce specialty mental health care continuity. There is an urgent need to identify strategies to facilitate PC-MHI care coordination in the telehealth context.

Research on the Relationship between Entrepreneurial Self-Efficacy and Entrepreneurial Intention

Entrepreneurship is a key concept to understand the rapid development of China’s economy since the reform and opening-up. It is related to the revitalization of the Chinese nation. Formulating effective entrepreneurial policies and measures, carrying out entrepreneurship education, and promoting entrepreneurial actions are important issues that government agencies, educational institutions, and the society at all levels are paying attention to. The key lies in the insight into the psychological cognitive mechanism and motivation source of entrepreneurs in starting a business. Upon reviewing previous studies, this article believes that entrepreneurial self-efficacy and entrepreneurial intentions are the key concepts and entry points connecting entrepreneurial characteristics, entrepreneurial behavior, and cognitive research. This study explores the relationship between entrepreneurial self-efficacy and entrepreneurial intention from five dimensions: entrepreneurial planning efficacy, entrepreneurial resource acquisition, relationship coordination efficacy, risk-taking efficacy, as well as innovation and reform efficacy. Suggestions and strategies have been proposed in this article to integrate the entrepreneurial ecology of universities, society and the government, reform the entrepreneurial education model, as well as improve the entrepreneurial willingness of college students.

Patterns of post-partum HIV care engagement.

The antenatal care setting is a key entry point for HIV testing and initiation of lifetime antiretroviral therapy (ART) for women with HIV. In contrast to pregnancy, when HIV care engagement and participation in programmes to prevent mother-to-child transmission are typically high, the post-partum period can present unique barriers and added complexities, which compromise engagement after delivery.1–4 Not enough is known about patterns of post-partum care engagement for different populations of women with HIV.

Participatory mapping reveals biocultural and nature values in the shared landscape of a Nordic UNESCO Biosphere Reserve

Abstract Making the right decisions for sustainable development requires sound knowledge of the values and spatial distribution of the services co‐produced by ecosystems and people. UNESCO's Man and the Biosphere programme and associated Biosphere Reserves (BRs) are key learning sites or model regions for sustainable development providing key entry points for transdisciplinary work on sustainable development. However, there is limited research exploring spatial distribution of socio‐cultural Ecosystem Service (ES) values in BRs and how those values vary according to the BR zonation. We used a transdisciplinary approach to design and implement a public participation geographical information systems (PPGIS) survey in a recently designated BR to (a) asses the spatial distribution of ES values in the different zones, (b) identify hotspots of ES values, (c) identify spatial bundles of ES values and (d) assess the social‐ecological characteristics that determine the distribution of those values. We found that stakeholders identify high biocultural ES values, mapping predominantly places for outdoor recreation, biodiversity, agricultural products and cultural heritage. Buffer zones had high agricultural and cultural heritage values while extractive values were largely absent from cores zones. We identified five spatial ES‐value bundles highlighting distinct places important for ES values related to ‘multifunctional landscapes’ located close to settlements, ‘cultural landscapes’ associated with agricultural land, ‘wild animal resources’ along the coastlines, ‘outdoor recreation and biodiversity’ and ‘passive cultural values’ widely distributed in high and moderately populated areas. We found that accessibility was important for ES values and that people value nature close to where they live. We show the importance of biocultural values in the region, and agricultural landscapes were highly valued for multiple ES values beyond agricultural products alone. We show that BRs have become places that link cultural heritage, agricultural and biodiversity values in multifunctional landscapes. We put our findings into the local context and suggest how they can inform land‐use planning and management through policies aimed at maintaining key agricultural landscapes that provide social‐ecological resilience. Additionally, we discuss the value of our study for the wider BR network and how similar work can contribute to monitoring of BR implementation. A free Plain Language Summary can be found within the Supporting Information of this article.

Age-Related Susceptibility of Ferrets to SARS-CoV-2 Infection.

ABSTRACTSusceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the outcome of coronavirus disease 2019 (COVID-19) have been linked to underlying health conditions and the age of affected individuals. Here, we assessed the effect of age on SARS-CoV-2 infection using a ferret model. For this, young (6-month-old) and aged (18- to 39-month-old) ferrets were inoculated intranasally with various doses of SARS-CoV-2. By using infectious virus shedding in respiratory secretions and seroconversion, we estimated that the infectious dose of SARS-CoV-2 in aged animals is ∼32 PFU per animal, while in young animals it was estimated to be ∼100 PFU. We showed that viral replication in the upper respiratory tract and shedding in respiratory secretions is enhanced in aged ferrets compared to young animals. Similar to observations in humans, this was associated with higher transcription levels of two key viral entry factors, ACE2 and TMPRSS2, in the upper respiratory tract of aged ferrets.IMPORTANCE In humans, ACE2 and TMPRSS2 are expressed in various cells and tissues, and differential expression has been described in young and old people, with a higher level of expressing cells being detected in the nasal brushing of older people than young individuals. We described the same pattern occurring in ferrets, and we demonstrated that age affects susceptibility of ferrets to SARS-CoV-2. Aged animals were more likely to get infected when exposed to lower infectious dose of the virus than young animals, and the viral replication in the upper respiratory tract and shedding are enhanced in aged ferrets. Together, these results suggest that the higher infectivity and enhanced ability of SARS-CoV-2 to replicate in aged individuals is associated, at least in part, with transcription levels of ACE2 and TMPRSS2 at the sites of virus entry. The young and aged ferret model developed here may represent a great platform to assess age-related differences in SARS-CoV-2 infection dynamics and replication.

Quit smoking: a personalized cessation program required

With 13 million smokers in France in 2019, smoking remains a major health issue. The LAST (Lieux d'accompagnement à la santé sans tabac [Locations for Health Support without Tobacco]) project set up in New-Aquitaine aims to encourage smokers to get help to quit smoking. In order to identify the barriers and levers to be mobilized to encourage smokers to seek help and then build with them the ideal cessation program, an individual qualitative study based on semi-structured interviews was conducted in May 2019 with 19 smokers at the contemplation or preparation step (transtheo-retical model). Smokers interviewed were unfamiliar with the cessation aids available and use them infrequently. Reasons include lack of information about their effectiveness, perceived cost, and fear of developing another form of addiction. Regarding the ideal program for them, using a health professional was cited by the majority, followed by physical activity (to avoid weight gain), nicotine replacement therapy and other drug treatments. The need to combine aids and to personalize the withdrawal offer is a strong demand. The development of the "ideal", personalized cessation aid program seems to be an opportunity for each smoker to choose the aids that are most in line with his or her needs and values. First-line professionals, because of their proximity, appear to be a key entry point to accompany cessation attempts.

Role of Peptides in Antiviral (COVID-19) Therapy

Trends in the developing era to discover and design peptide-based treatments throughout an epidemic infection scenario such as COVID-19 could progress into a more efficient and low-cost therapeutic environment. However, the weakening of proteolysis is one downside of natural peptide drugs. But, peptidomimetics may help resolve this issue. In this review, peptide and peptide-based drug discovery were summarized to target one key entry mechanism of severe coronavirus pulmonary emboli syndrome (SARS-CoV-2), which encompasses the association of the host angiotensin-converting enzyme-2 (ACE2) receptor and viral spike (S) protein. Furthermore, the benefits of proteins, peptides and other possible actions that have been studied for COVID-19 through new peptide-based treatments are discussed in the review. Lastly, an overview of the peptide-based drug therapy environment is comprised of an evolutionary viewpoint, structural properties, operational thresholds, and an explanation of the therapeutic area.

How the Euripid collaboration contributes to price transparency of pharmaceuticals

Abstract Background Spending on pharmaceuticals is growing continuously with a forecast of reaching over one trillion Euro in the next five years. Also, the average price of newly launched medicines is steeply raising, thus putting pressure on public payers. With several new advanced therapies in the pipeline, there are concerns in terms of both affordability and access for all patients who may need these treatments. To manage high launch prices, public payers in Europe more and more rely on private law contractual arrangements with pharmaceutical companies, requiring significant price discounts and other types of managed-entry agreements (MEAs). Methods In spring 2021 we analysed the EURIPID database (www.euripid.eu) for occurrence and frequency of MEA in the 28 countries (AT, BE, BG, CH, CY, CZ, DK, EE, EL, ES, FI, FR, HR, HU, IE, IL, IS, IT, LV, LT, NL, NO, PT, RO, SE, SI, SK, and UK) that are covered. Euripid is a voluntary, non-profit collaboration between mainly European countries on building up and maintaining a database with information on national prices of medicinal products. Results 24 out 28 countries acknowledge the existence of MEA in their country. The highest number was identified in Italy with 1,317 agreements, followed by Latvia with 555 and Austria with 235. Seven countries use MEA as more or less standard instrument to manage their public pharmaceutical budget, whereas other countries just use it on case-by-case basis. Analysis shows that products above 100.0 Euro per unit (i.e. per shot or tablet) are much more likely to have a MEA than products with lower prices. Still, we found MEA in place also for products with a sales price per unit with &amp;lt;1.0 Euro. When looking into therapeutic areas, Antineoplastic and immunomodulating agents (ATC group L) including cancer medicines and immunosuppressants and medicines for the nervous system (ATC group N) dominated. Also, for some companies the likelihood of a MEA is higher than for others. Key messages Managed Entry Agreements (MEA) have become a standard tool for many public payers to manage high launch prices of pharmaceuticals. The scope of use varies widely: in some countries almost all newly launched pharmaceuticals are subject to such an agreement.

Market entry for wind energy: Strategic approaches for the original equipment manufacturer

AbstractWind energy is a valuable resource, but many developing and emerging economies (DEEs) are not utilizing the tremendous wind capacity available to them. This means there is a potential for wind turbine original equipment manufacturers (OEMs) to penetrate new markets to increase profits, and to contribute to Sustainable Development Goals. This article explores the potential triggers for wind energy diffusion and provides the basis for inclusive market entry strategies for wind power OEMs. Indications are that early wind energy path creation is driven by climate adaptation, vested interests in fossil fuels and hydropower, and the business case potential. A negative business case potential in many DEEs formed a substantial barrier. A shift to increased local value creation, collaboration with traditional power producers, and promoting wind for climate adaptation are key novel inclusive market entry strategies to open and develop new markets.