The 'Covid-Trigger': New Light on Urban Agriculture and Systemic Approach to Urbanism to Co-Create a Sustainable Lisbon.

In 2018, Lisbon won the title of Green capital of Europe 2020. It was described by the Expert Panel as an inspirational city which had started its journey towards sustainability during a period of economic crisis. A year later, Covid-19 had become a global pandemic. Imposed confinements highlighted the extent to which globalisation has spread the virus, as well as the particular fragility of places like cities where people, living together, were asked to not physically interact anymore. Exploring further that very particular global crisis can help to identify the faults in our economic systems and to ask why Lisbon was neither resilient nor sustainable in the face of that adversity. In addition to highlighting how weak our health is, Covid-19 has exacerbated vulnerabilities in Lisbon such as job losses (especially in the touristic sector), food supply (Portugal imports 70% of its food) and food waste. This paper explores how the activity which, 'par excellence', meets the most basic of our needs (food), through the example of Urban Agriculture (UA), could contribute to discussions on what makes a city sustainable. A literature review on UA in Lisbon highlights its various benefits, complemented by a broader literature review which converges to showing how UA can help to address the vulnerabilities generated or exacerbated by Covid. Having shown its potential contribution to addressing crises, this article then suggests to examine how systems approaches could help to incorporate UA further in a new type of more participatory urbanism aimed at creating sustainable cities.

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling.

Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HµREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HµREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. For in vitro to in vivo extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the in vivo situation in these long-term culture models.

Identification of six cell surface proteins for specific liver targeting.

PURPOSE: Cell surface proteins are the primary means for a cell to sense and interact with its environment and their dysregulation has been linked to numerous diseases. In particular, the identification of proteins specific to a single tissue type or to a given disease phenotype may enable the characterization of novel therapeutic targets. We tested here the feasibility of a cell surface proteomics approach to identify pertinent markers directly in a clinically relevant tissue. EXPERIMENTAL DESIGN: We analyzed the cell surface proteome of freshly isolated primary heptatocytes using a glycocapture-specific approach combined with a robust bioinformatics filtering. RESULTS: Using primary lung epithelial cell cultures as negative controls, we identified 32 hepatocyte-specific cell surface proteins candidates. We used mRNA expression to select six markers that may provide adequate specificity for targeting therapeutics to the liver. CONCLUSIONS AND CLINICAL RELEVANCE: We demonstrate the feasibility and the importance of conducting such studies directly in a clinically relevant tissue. In particular, the cell surface proteome of freshly isolated hepatocytes differed substantially from cultured cell lines.

In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP.

Abstract 1. The metabolism and drug-drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs. 2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1. 3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency.

Quality of life instruments used in mental health research: properties and utilization.

Quality of life (QoL) assessment is increasingly used in mental health. Multiple instruments exist, but the conditions for choosing one instrument over another for purposes of a specific study are not clear. We performed a systematic review to identify the QoL instruments used in mental health. The instruments were systematically described regarding their intrinsic properties (e.g., generic v. disease-specific) and their characteristics of utilization in studies (e.g., study objectives). Using cluster analyses, we investigated the existence of similar instruments with respect to each of these sets of characteristics and studied potential links between instruments' intrinsic properties and their characteristics of utilization. We included 149 studies in which 56 distinct instruments were used. Similarities were found among instruments in terms of their intrinsic properties as well as their characteristics of utilization, leading to the construction of four clusters of instruments in each case. However, no relevant links were identified between instruments' intrinsic properties and their characteristics of utilization, suggesting that the choice of QoL instruments did not depend on their properties. A consensus about common QoL instruments must be reached to facilitate the choice of instruments, the comparison of results and thus to have an impact on clinical and policy decision-making.

An integrated approach of community health worker support for HIV/AIDS and TB care in Angónia district, Mozambique.

BACKGROUND: The need to scale up treatment for HIV/AIDS has led to a revival in community health workers to help alleviate the health human resource crisis in sub-Saharan Africa. Community health workers have been employed in Mozambique since the 1970s, performing disparate and fragmented activities, with mixed results. METHODS: A participant-observer description of the evolution of community health worker support to the health services in Angónia district, Mozambique. RESULTS: An integrated community health team approach, established jointly by the Ministry of Health and Médecins Sans Frontières in 2007, has improved accountability, relevance, and geographical access for basic health services. CONCLUSION: The community health team has several advantages over 'disease-specific' community health worker approaches in terms of accountability, acceptability, and expanded access to care.

Comparison of multiplex PCR assays and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness.

The performances of four multiplex PCR (m-PCR) were compared to direct immunofluorescence assay (DFA) and HuH7 cell culture for the detection of viruses in 263 children admitted to hospital with an acute respiratory illness. One hundred fifty (57.6%) nasal aspirates were found DFA-positive; 188 (72.3%) were found positive by both DFA and HuH7 cell culture, and 242 (92%) were PCR-positive. The m-PCR detected 124 viruses which were not found by conventional methods: 68 rhinovirus, 17 human metapneumovirus, 15 respiratory syncytial virus (RSV), 8 parainfluenza virus (PIV), 5 coronavirus 229E, 3 OC43 and 3 NL63, 4 enterovirus, 2 influenza virus B and C virus. The m-PCR were more sensitive, had the advantages of a shorter delay in specific diagnosis, and a lower cost than DFA and culture. Using these m-PCR, the prevalence of each virus was compared between in-patient and out-patient groups of children attending the emergency unit of the hospital. Nasal aspirates from 411 (91.5%) children were found positive by the PCRs. RSV, rhinovirus, and influenza virus were the most frequent viruses detected in this population, representing 43.6%, 31.8%, and 8.8% of the virus found, respectively, followed by human metapneumovirus (4.4%), coronavirus (3.4%), parainfluenza virus (3.2%), adenovirus (2.3%), and enterovirus (2.1%). RSVs were detected more significantly in the in-patient group than in the out-patient group, and influenza viruses were detected more frequently in the out-patient group than in the in-patient group. Moreover, the use of m-PCR pointed out the frequency of rhinovirus and mixed viral detections in these patients. In conclusion, according to the requirements of speed and low cost of the methods, and to achieve the highest rate of detection of respiratory viruses, the combined use of DFA and m-PCR is today likely to be the best way to improve diagnosis of respiratory illnesses in children.