Value for money of medicine sampling and quality testing: evidence from Indonesia.

BACKGROUND: Substandard and falsified medicines (SFMs) are a public health concern of global importance. Postmarket surveillance in the form of medicine sampling and quality testing can prevent and detect SFM, however, there is remarkably scarce evidence about the cost and value for money of these activities: how much do they cost and how effective are they in detecting SFM? METHODS: Between February and October 2022, Systematic Tracking of At Risk Medicines (STARmeds) collected and analysed for quality 1274 samples of 5 medicines from physical and online retail outlets in 7 Indonesian districts. We collated data on the resources consumed by STARmeds, related to all stages of medicines sampling and quality testing including design, fieldwork and laboratory analysis. We used activity-based costing principles to calculate the financial and economic cost of medicine quality surveillance from the perspective of a hypothetical medicines' regulator. We calculated the cost per day and per week of fieldwork, per sample collected and per substandard sample. We used bootstrapping to capture uncertainty in the number of samples collected, by seller location type (urban, rural and online). RESULTS: The total cost of sampling and testing medicines from the market was US$712 964 (current 2022 values). Laboratory costs represented the largest share (70%), followed by other direct costs (12%) and indirect costs (7%). On average, it costs STARmeds US$479 (95% CI US$462 to US$516) to collect one medicine sample and US$5990 (95% CI US$5601 to US$6258) to identify one substandard sample. CONCLUSION: Our findings bring urgently needed and novel information on the cost and value for money of medicine quality surveillance. These may support planning and budgeting of the Indonesian pharmaceutical regulator, but also of regulators and researchers elsewhere, particularly in low-income and middle-income settings, as well as international organisations with health regulation and quality of care remits.

Retrieving biodiversity data from multiple sources: making secondary data standardised and accessible.

Biodiversity data, particularly species occurrence and abundance, are indispensable for testing empirical hypothesis in natural sciences. However, datasets built for research programmes do not often meet FAIR (findable, accessible, interoperable and reusable) principles, which raises questions about data quality, accuracy and availability. The 21st century has markedly been a new era for data science and analytics and every effort to aggregate, standardise, filter and share biodiversity data from multiple sources have become increasingly necessary. In this study, we propose a framework for refining and conforming secondary biodiversity data to FAIR standards to make them available for use such as macroecological modelling and other studies. We relied on a Darwin Core base model to standardise and further facilitate the curation and validation of data related including the occurrence and abundance of multiple taxa of a region that encompasses estuarine ecosystems in an ecotonal area bordering the easternmost Amazonia. We further discuss the significance of feeding standardised public data repositories to advance scientific progress and highlight their role in contributing to the biodiversity management and conservation.

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

BACKGROUND: Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. METHODS: We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. RESULTS: Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3ß/ß-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. CONCLUSIONS: We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

Influence of Lemongrass Essential Oil (Cymbopogon flexuosus) Supplementation on Diabetes in Rat Model.

(1) Background: Species of the genus Cymbopogon and its essential oil are known for their antioxidant and hypoglycemic effects. This study aimed to investigate the impact of the essential oil of Cymbopogon flexuosus (EOCF), and its major component, citral, on glycemic, lipid, antioxidant parameters, and oxidative stress in a type 1 diabetes (DM1) rat model. (2) Methods: Initially, EOCF was analyzed by Gas chromatography-mass spectrometry (GC-MS) and the antioxidant activity of EOCF and citral was evaluated. Next, male Wistar rats (3 months old, 200-250 g) induced with DM1 using Streptozotocin (STZ) were divided into four groups: negative control supplemented with an 80% Tween solution, two groups of animals supplemented with EOCF (32 mg/kg and 64 mg/kg) and with citral (32 mg/kg), and treated for 14 days. Measurements of blood glucose levels and body weight were taken; after euthanasia, biochemical markers, including lipid profile, uric acid, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were evaluated. (3) Results: The predominant compounds in EOCF were α-citral (53.21%) and neral (19.42%), constituting 72.63% citral. EOCF showed good antioxidant activity, significantly greater than citral. EOCF supplementation demonstrated a mitigating effect on glycemic, lipid, and hepatic abnormalities induced by DM1. (4) Conclusions: EOCF emerges as a promising therapeutic option for the management of DM1.

Effects of ActiGraph's filter, epoch length and non-wearing time algorithm on step counts in people with COPD.

The influence of the ActiGraph® processing criteria on estimating step counts in chronic obstructive pulmonary disease (COPD) remains uncertain. This study aimed to assess the influence of filters, epoch lengths and non-wearing time (NWT) algorithms on steps/day in people with COPD. ActiGraph GT3X+ was worn on the waist for seven days. Steps were detected using different filters (normal and low-frequency extension [LFE]), epoch lengths (15s and 60s), and NWT algorithms (Choi and Troiano). Linear mixed-effects model was applied to assess the effects of filter, epoch length, NWT algorithm on steps/day. Lin's concordance correlation and Bland-Altman were used to measure agreement. A total of 136 people with COPD (107 male; 69 ± 8 years; FEV1 51 ± 17% predicted) were included. Significant differences were found between filters (p < 0.001), but not between epoch lengths or NWT algorithms. The LFE increased, on average, approximately 7500 steps/day compared to the normal filter (p < 0.001). Agreement was poor (<0.3) and proportional bias was significant when comparing steps/day computed with different filters, regardless of the epoch length and NWT algorithm. Filter choice but not epoch lengths or NWT algorithms seem to impact measurement of steps/day. Future studies are needed to recommend the most accurate technique for measuring steps/day in people with COPD.

Politics and confidence toward the COVID-19 vaccination: A Brazilian cross-sectional study.

This study has the aim of assessing the Brazilian perceptions, influencing factors and political positioning on the confidence concerning COVID-19 vaccination. To achieve the objective, the methods rely on a cross-sectional survey of Brazilian citizens, distributed through different social networks. The sample is composed of 1,670 valid responses, collected from almost all Brazilian states and state capitals. To analyze the data and give a clear view of the variables' relationship, the study used bivariate and comparative graphs. Results show a higher level of confidence in vaccines from Pfizer and AstraZeneca, while the lower level of confidence is associated with vaccines from Sinopharm and Sputinik5. Vaccine efficacy is the most significant influencing factor that helps in the decision to get vaccinated. Also, individuals are less willing to get vaccinated if their political preferences are related to the right-wing. The results led to three main health and social implications: i) the vaccination strategy campaigns should take in count vaccine efficacy and political aspects; ii) the vaccination process should be adapted to regions with different political positions; and iii) a reinforcement in the educational policies of the vaccine's importance to the public health, to avoid the politization of a health issue.

Serum butyrylcholinesterase activity in healthy dogs with and without exposure to diazinon.

BACKGROUND: Cholinesterase is a biomarker for poisonings by anticholinesterase agents, but its reference values are scarce, and possible interaction with collars containing parasiticides has not been studied. OBJECTIVES: We aimed to evaluate the serum cholinesterase activity of healthy dogs without a history of contact with anticholinesterase agents and healthy animals exposed to commercial collars containing organophosphate. METHODS: Ninety-nine dogs were used and included healthy animals without recent exposure to anticholinesterase agents and healthy animals previously exposed to diazinon collars. Serum quantification of the enzyme butyrylcholinesterase (BuchE) through spectrophotometry was conducted on all samples. In experiment 1, BuchE activity was quantified at time 0 and 7 days after, a time when the samples were kept at -18°C. In experiment 2, sampling times were 0, 7, 14, 21, 28, and 56 days. RESULTS: Time 0 values were 4622.38 ± 1311.53 U/L. After 7 days, a significant decay was observed, with a mean of 3934.45 ± 1430.45 U/L. Spearman's test was performed, finding a weak correlation between ALT, creatinine, total plasma proteins, age, weight, red blood cells, platelets, leukocytes, and BuchE activities. In experiment 2, the mean at time 0 was 4753 ± 454.8 U/L. With exposure to the collar, there was a decay of up to 93% after 14 days. CONCLUSIONS: Normality values of serum BuchE in healthy dogs without a history of exposure to anticholinesterase agents were 4360.8-4883.96 U/L. Freezing serum caused a decrease in BuchE activity. Exposure to commercial collars containing diazinon also reduced BuchE activity without clinical signs, indicating that previously exposed animals should be evaluated carefully.

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling.

BACKGROUND: Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. METHODS: We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. RESULTS: We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. CONCLUSIONS: Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

Predictors of poor neurodevelopmental outcomes of very preterm and very low birth weight infants.

BACKGROUND: Despite recent improvements, premature infants remain at high risk for long-term morbidity and poorer neurodevelopment, particularly very preterm (VP) and very low birth weight (VLBW). The aim of this study was to describe neurodevelopmental outcomes at two years and identify potential predictors of worse performance. METHODS: In a retrospective cohort, a two-years' neurodevelopmental evaluation was analyzed. Multivariable regressions were used to study the association of perinatal history with neurodevelopmental outcomes. Subjects included VP and/or VLBW born at a Portuguese III-level perinatal center between 2011-2017. Milestones outcomes were assessed using the Griffiths' Mental Development Scales. RESULTS: One hundred seventy-seven infants were included. Two-years milestones were not achieved in 18.6% in language domain and 7.3% in motor function, 4.5% wore glasses and 1.1% auditory prosthesis/cochlear implant. Almost 30% needed intervention, 18.6% occupational therapy, 16.4% physiotherapy and 13.6% speech therapy. Griffiths' Mental Development Scales was performed in 139, with a mean global quotient of 98.3 and hearing/speech as the least quoted scale. Global development delay (GDD) was present in 14.8% and cerebral palsy in 2.8%. Multivariate analysis by logistic regression adjusted to gestational age, birth weight and confounding variables, revealed a statistically significant association between GDD and hydrocephalus with shunt/reservoir (OR:19.01), retinopathy of prematurity stage ≥2 (OR:7.86) and neonatal sepsis (OR:3.34). CONCLUSIONS: Consistent with recent studies, preterm are at increased risk of neurodevelopmental impairment, mainly due to GDD and language delay, rather than cerebral palsy. In this population, hydrocephalus, retinopathy of prematurity and neonatal sepsis were strongly associated with poorer outcomes. Insight into these factors is essential to refer patients for specific early intervention programs.

Detecting Enteric Pathogens in Low-Risk Drinking Water in Dhaka, Bangladesh: An Assessment of the WHO Water Safety Categories.

The microbiological quality of water is usually assessed by fecal coliform bacteria, and the presence of E. coli as an indicator of fecal contamination is widely recommended by international guidelines. This study aimed to assess the prevalence of diarrheagenic pathogens, in both public and personal domain water sources and examine the reliance on the WHO drinking water risk assessment guidelines. This study was conducted in a low-income urban community in Dhaka, Bangladesh between September 2014 and October 2015. Polymerase chain reaction (PCR) was used to detect the marker and virulence genes of Escherichia coli, Vibrio cholerae, Salmonella species, and Campylobacter species, and the culture method was employed for the quantitative assessment of E. coli. According to the WHO guidelines, 48% of the public domain source water and 21% of the personal domain point-of-drinking water were classified in the low-risk group, i.e., 0 CFU of E. coli/100 mL. However, when using PCR, we detected pathogens in 39% (14/36) of the point-of-drinking water samples and 65% (74/114) of the public domain water source samples classified in the low-risk group. Our study showed that relying solely on E. coli detection as a measure of water quality may overlook the presence of other pathogens in the drinking water. In addition to the culture-based method, the detection of virulence genes by PCR should also be considered to add more scrutiny to the detection of diverse types of pathogens.

Health, Economic, and Social Impacts of Substandard and Falsified Medicines in Low- and Middle-Income Countries: A Systematic Review of Methodological Approaches.

Little is known about the adverse health, economic, and social impacts of substandard and falsified medicines (SFMs). This systematic review aimed to identify the methods used in studies to measure the impact of SFMs in low- and middle-income countries (LMICs), summarize their findings, and identify gaps in the reviewed literature. A search of eight databases for published papers, and a manual search of references in the relevant literature were conducted using synonyms of SFMs and LMICs. Studies in the English language that estimated the health, social, or economic impacts of SFMs in LMICs published before June 17, 2022 were considered eligible. Search results generated 1,078 articles, and 11 studies were included after screening and quality assessment. All included studies focused on countries in sub-Saharan Africa. Six studies used the Substandard and Falsified Antimalarials Research Impact model to estimate the impact of SFMs. This model is an important contribution. However, it is technically challenging and data demanding, which poses challenges to its adoption by national academics and policymakers alike. The included studies estimate that substandard and falsified antimalarial medicines can account from 10% to ∼40% of total annual malaria costs, and SFMs affect rural and poor populations disproportionately. Evidence on the impact of SFMs is limited in general and nonexistent regarding social outcomes. Further research needs to focus on practical methods that can serve local authorities without major investments in terms of technical capacity and data collection.

Introduction of the Personal Domain in Water Sanitation and Hygiene (WASH), a New Approach to Identify Missing Health Impacts.

The water sanitation and hygiene (WASH) sector has provided beneficiaries in low and middle-income countries with latrines and clean water for decades. However, we still need good evidence documenting the expected health impact. This paper investigates why we lack this evidence and ways to move forward. Using mTEC agar, we monitored E. coli contamination on selected "hotspot" surfaces within the kitchen environments of 32 low-income households in Dhaka, Bangladesh, every six weeks for two years. Despite being washed, the highest average contamination was found on food plates, at 253 cfu/10 cm2, followed by cutting knives, with 240 cfu/10 cm2. The drinking vessel surfaces and the latrine doorknobs had the lowest contaminations, with E. coli means of 167 and 73 cfu/10 cm2, respectively. These findings imply a need to measure an individual's pathogen exposure as close to the mouth as possible to estimate the true pathogen exposure. The paper proposes introducing the new "personal domain"-the point of consumption-as the physical sphere in which WASH interventions should be assessed. With this approach, we can observe and quantify the different pathogen exposure routes and, with this, further improve WASH interventions.

Perceptions of institutional performance and compliance to non-pharmaceutical interventions: How performance perceptions and policy compliance affect public health in a decentralized health system.

Trust in institutions is a key driver to shape population attitudes and behavior, such as compliance of non-pharmaceutical interventions (NPI). During the COVID-19 pandemic, this was fundamental and its compliance was supported by governmental and non-governmental institutions. Nevertheless, the situation of political polarization in some countries with decentralized health systems increased the difficulty of such interventions. This study analyzes the association between non-pharmaceutical interventions' compliance and individual perception regarding institutions' performance during the COVID-19 pandemic in Brazil. A web survey was conducted in Brazil between November 2020 and February 2021. Bivariate analysis and ordered logit regressions were performed to assess the association between NPIs compliance and perceived institutions' performance. Results suggest a negative association between NPIs' compliance and Federal Government and Ministry of health perceived performance, which may reflect the political positioning of the respondents. Moreover, we find a positive association between NPI compliance and the perceived performance of the remaining institutions (state government, federal supreme court, national congress, WHO, media and SUS). Our contribution goes beyond the study of a relationship between non-pharmaceutical interventions' compliance and institutions' performance, by pointing out the importance of subnational and local governmental spheres in a decentralized health system, as well as highlighting the importance of social communication based on health organizations' information and scientific institutions.

Lifestyle integrated functional exercise for people with interstitial lung disease (iLiFE): A mixed-methods feasibility study.

BACKGROUND: People with interstitial lung disease (ILD) present low levels of physical activity (PA) and spend most of their time at home, especially in advanced stages of the disease. The Lifestyle Integrated Functional Exercise for people with ILD (iLiFE) embedding PA in patients' daily routines was developed and implemented. OBJECTIVES: This study aimed to explore the feasibility of iLiFE. METHODS: A pre/post mixed-methods feasibility study was conducted. Feasibility of iLiFE was determined by participant recruitment/retention, adherence, feasibility of outcome measures and adverse events. Measures of PA, sedentary behaviour, balance, muscle strength, functional performance/capacity, exercise capacity, impact of the disease, symptoms (i.e., dyspnoea, anxiety, depression, fatigue and cough) and health-related quality of life were collected at baseline and post-intervention (12-weeks). Semi-structured interviews with participants were conducted in-person immediately after iLiFE. Interviews were audio-recorded, transcribed and analysed by deductive thematic analysis. RESULTS: Ten participants (5♀, 77±3y; FVCpp 77.1 ± 4.4, DLCOpp 42.4 ± 6.6) were included, but only nine completed the study. Recruitment was challenging (30%) and retention high (90%). iLiFE was feasible, with excellent adherence (84.4%) and no adverse events. Missing data were associated with one dropout and non-compliance with the accelerometer (n = 1). Participants reported that iLiFE contributed to (re)gain control in their daily life, namely through improving their well-being, functional status and motivation. Weather, symptoms, physical impairments and lack of motivation were identified as threats to keep an active lifestyle. CONCLUSIONS: iLiFE seems to be feasible, safe and meaningful for people with ILD. A randomised controlled trial is needed to strengthen these promising findings.

Influence of Seasonal Hazards on Water, Sanitation, and Hygiene-Related Behavior and Implications for Cholera Transmission in Bangladesh.

Most cholera outbreaks in Bangladesh are seasonal, peaking in the dry and post-monsoon periods. Therefore, we investigated whether changes in water, sanitation, and hygiene (WASH) behavior in three populations in Bangladesh during the year could help explain why these two periods are particular to cholera transmission. The study used a mixed-method design, including a repeated cross-sectional study, focus group discussions, and key informant interviews. Through a repeated cross-sectional study, WASH-related variables were assessed during the dry, monsoon, and control seasons in 600 households from coastal Satkhira, inland Sirajganj, and the Dhaka slums. Seasonal behavioral changes were observed in all study areas. Dhaka and Satkhira had an increased mean distance to water sources during the dry and monsoon seasons (Dhaka: control season, 12 m [95% CI, 11-13]; dry season, 36 m [95% CI, 18-55]; and monsoon season, 180 m [95% CI, 118-243]; Satkhira: control season, 334 m [95% CI, 258-411]; dry season, 669 m [95% CI, 515-822]; and monsoon season, 2,437 m [95% CI, 1,665-3,209]). The participants attributed this to pollution of the usual water source. Perceived water quantity was lowest during the dry season in Dhaka and Sirajganj, and during the monsoon season in Satkhira. Handwashing with soap declined in all areas during the dry and monsoon seasons. Open defecation was frequent among children younger than 5 years, increasing during seasonal climate hazards. Results show that WASH-related behavior changed seasonally, increasing the risk of cholera transmission through multiple hygiene-related transmission pathways. Future research would benefit by ensuring that the length of studies covers all seasons throughout the year and also by looking in more detail at people's behavior and hygiene practices.

Factors associated with non-pharmaceutical interventions compliance during COVID-19 pandemic: a Portuguese cross-sectional survey.

BACKGROUND: The use of non-pharmaceutical interventions (NPI) is one of the main tools used in the coronavirus disease 2019 (COVID-19) pandemic response, including physical distancing, frequent hand washing, face mask use, respiratory hygiene and use of contact tracing apps. Literature on compliance with NPI during the COVID-19 pandemic is limited. METHODS: We studied this compliance and associated factors in Portugal, between 28th October 2020 and 11th January 2021 (Portuguese second and third waves of the pandemic), using logistic regressions. Data were collected through a web-based survey and included questions regarding NPI compliance, COVID-19-related concerns, perception of institutions' performance, agreement with the measures implemented and socio-demographic characteristics. RESULTS: From the 1263 eligible responses, we found high levels of compliance among all COVID-19 related NPI, except for the contact tracing app. Females and older participants showed the highest compliance levels, whereas the opposite was observed for previously infected participants. There was heterogeneity of COVID-19 NPI compliance across Portuguese regions and a clear gradient between concern, government performance's perception or agreement and compliance. CONCLUSIONS: Results suggested areas for further study with important implications for pandemic management and communication, for future preparedness, highlighting other factors to be accounted for when recommending policy measures during public health threats.

Trade-offs during the COVID-19 pandemic: A discrete choice experiment about policy preferences in Portugal.

The need to control the sanitary situation during the COVID-19 pandemic has led governments to implement several restrictions with substantial social and economic impacts. We explored people's trade-offs in terms of their income, life restrictions, education, and poverty in the society, compared to their willingness to avoid deaths. We applied a web-based discrete choice experiment to elicit preferences of the Portuguese citizens for these attributes and computed the marginal rate of substitution in terms of avoided deaths. We recorded 2,191 responses that faced the possibility of having 250 COVID-19 related deaths per day as the worst possible outcome from the choice levels presented. Estimates suggested that individuals would be willing to sacrifice 30% instead of 10% of their income to avoid approximately 47 deaths per day during the first six months of 2021. For the same period, they would also accept 30% of the students' population to become educationally impaired, instead of 10%, to avoid approximately 25 deaths; a strict lockdown, instead of mild life restrictions, to avoid approximately 24 deaths; and 45% of the population to be in risk of poverty, instead of 25%, to avoid approximately 101 deaths. Our paper shows that avoiding deaths was strongly preferred to the remaining societal impacts; and that being a female, as well as working on site, led individuals to be more averse to such health hazards. Furthermore, we show how a DCE can be used to assess the societal support to decision-making during times of crisis.

Osteosarcoma-Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis.

Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma-related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)-based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma-derived EXs as natural nanocarriers of the positron-emitter copper-64 (64 Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with 64 Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole-body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of 64 Cu-NODAGA-EXs in metastatic lesions as small as 2-3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)-labeled EXs and D-luciferin-loaded EXs. These findings show that tumor-derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.

Can Intersectoral Interventions Reduce Substance Use in Adolescence? Evidence From a Multicentre Randomized Controlled Study.

Objectives: We measure the impacts of an intersectoral intervention tackling adolescent substance use implemented between 2017 and 2019 in a tri-border region of Brazil, Paraguay, and Argentina. Methods: The intervention involved 23 institutions from different sectors and 880 adolescents, equally split between randomly selected treatment and control classes across institutions. Treatment group students were involved in the co-development of activities to tackle substance use within their institutions. Both treatment and control group students benefited from the activities developed and implemented from the second year of the intervention. We use difference-in-differences models to measure the impacts of participation in the co-development of the activities on alcohol, tobacco, and cannabis consumption. Results: Adolescents involved in the co-development of activities are 8 pp less likely to consume tobacco and cannabis, and 13 pp less likely to consume alcohol (p < 0.01), compared to those who only participate in the activities. Among cannabis users, frequent consumption is also reduced by the intervention. Peer frequency of consumption is strongly associated with individual consumption. Conclusion: Co-development of activities by the subjects themselves can be key to decreasing substance use in this very crucial stage of life, especially if the institutions and the implementers are familiar with the area and subjects of the intervention.