The participatory value-sensitive design (VSD) of a mHealth app targeting citizens with dementia in a Danish municipality.

The Sammen Om Demens (together for dementia), a citizen science project developing and implementing an AI-based smartphone app targeting citizens with dementia, is presented as an illustrative case of ethical, applied AI entailing interdisciplinary collaborations and inclusive and participative scientific practices engaging citizens, end users, and potential recipients of technological-digital innovation. Accordingly, the participatory Value-Sensitive Design of the smartphone app (a tracking device) is explored and explained across all of its phases (conceptual, empirical, and technical). Namely, from value construction and value elicitation to the delivery, after various iterations engaging both expert and non-expert stakeholders, of an embodied prototype built on and tailored to their values. The emphasis is on how moral dilemmas and value conflicts, often resulting from diverse people's needs or vested interests, have been resolved in practice to deliver a unique digital artifact with moral imagination that fulfills vital ethical-social desiderata without undermining technical efficiency. The result is an AI-based tool for the management and care of dementia that can be considered more ethical and democratic, since it meaningfully reflects diverse citizens' values and expectations on the app. In the conclusion, we suggest that the co-design methodology outlined in this study is suitable to generate more explainable and trustworthy AI, and also, it helps to advance towards technical-digital innovation holding a human face.

Mechanisms of Action of Ozone Therapy in Emerging Viral Diseases: Immunomodulatory Effects and Therapeutic Advantages With Reference to SARS-CoV-2.

Medical oxygen-ozone (O2-O3) is a successful therapeutic approach accounting on the assessed beneficial action of ozone in the range 30-45 µg/ml (expanded range 10-80 µg/ml according to different protocols), as in this dosage range ozone is able to trigger a cellular hormetic response via the modulating activity of reactive oxygen species (ROS), as signaling molecules. The ozone-dependent ROS-mediated fatty acid oxidation leads to the formation of lipid ozonization products (LOPs), which act as signal transducers by triggering ROS signaling and therefore mitohormetic processes. These processes ultimately activate survival mechanisms at a cellular level, such as the Nrf2/Keap1/ARE system activation, the AMPK/FOXO/mTOR/Sir1 pathway and the Nrf2/NF-kB cross talk. Furthermore, indirectly, via these pathways, LOPs trigger the HIF-1α pathway, the HO-1 signaling and the NO/iNOS biochemical machinery. Ozone-driven shift of cytokine activation pathways, from pro-inflammatory to anti-inflammatory immediately afterwards, also exert direct immunoregulatory effects on regulatory T lymphocytes as well as on the intestinal microbiota, which in turn can affect immune response thus influencing the progression of the disease. In this review, we will describe the biological and biochemical mechanisms of action of ozone therapy with the aim of evaluating both positive and critical aspects of ozone use as a therapeutic adjuvant in the light of emerging viral infections, such as SARS-CoV-2 and microbiome-associated disorders related to SARS-CoV-2.

Refining Value Sensitive Design: A (Capability-Based) Procedural Ethics Approach to Technological Design for Well-Being.

Fundamental questions in value sensitive design include whether and how high-tech products/artefacts could embody values and ethical ideals, and how plural and incommensurable values of ethical and social importance could be chosen rationally and objectively at a collective level. By using a humanitarian cargo drone study as a starting point, this paper tackles the challenges that VSD's lack of commitment to a specific ethical theory generates in practical applications. Besides, it highlights how mainstream ethical approaches usually related to VSD are incapable of solving main ethical dilemmas raised by technological design for well-being in democratic settings. Accordingly, it is argued that VSD's ethical-democratic import would substantially be enhanced by the espousal of a procedural ethics stance and the deliberative approach to value and welfare entailed by Amartya Sen's capability approach. Differently from rival ethical-political theories, its normative and meta-ethical foundations better handle human diversity, value-goal pluralism, conflicting vested interests as well as the epistemic-moral disagreements typical of contemporary complex democracies. Particularly, Sen's capability approach procedural-deliberative tenets result in an "objective-impartial" choice procedure selecting a "hierarchy" of plural incommensurable values and rational goals thus, suitable to validate an applied science such as welfare-oriented technological design in concrete social environments. Conclusions suggest that refining VSD with a capability-based procedural approach to ethics fosters the concern for democracy and social justice while preserving vital scientific-technical standards. Major advantages are at an applied level to delivering ethically and socially justified, but yet highly functional technologies and high-tech products/artefacts.

High HIV-1 diversity in immigrants resident in Italy (2008-2017).

The proportion of new diagnoses of HIV infection in immigrants residing in Italy raised from 11% in 1992 to 29.7% in 2018. To investigate the HIV clades circulating in this community a retrospective study was performed in 557 HIV-infected immigrants living in 12 Italian cities. Immigrants originated from East-Europe and Central-Asia (11.7%), North Africa and Middle East (7.3%), South and South-East Asia (7.2%), Latin America and the Caribbean (14.4%), and sub-Saharan Africa (59.4%). More than 87% of immigrants were on antiretroviral therapy (ART), although 26.6% of them were viremic. A 22.0% of immigrants had hepatitis (HBV and/or HCV) and/or tuberculosis. HIV phylogenetic analysis on sequences from 192 immigrants showed the presence of clades B (23.4%), G (16.1%), C (10.4%), A1 (9.4%), F1 (5.2%), D (1.6%) and Circulating Recombinant Forms (CRFs) (33.9%). CRF02_AG represented 72.3% of the total CRFs. Clusters between immigrants and Italian natives were also present. Drug resistance mutations to NRTI, NNRTI, and PI drug classes occurred in 29.1% of ART-treated and in 12.9% of ART-naïve individuals. These data highlight the need for tailored public health interventions in immigrants to avoid spreading in Italy of HIV genetic forms and ART-resistant variants, as well as HIV co-morbidities.

No metagenomic evidence of tumorigenic viruses in cancers from a selected cohort of immunosuppressed subjects.

The possible existence of yet undiscovered human tumorigenic viruses is still under scrutiny. The development of large-scale sequencing technologies, coupled with bioinformatics techniques for the characterization of metagenomic sequences, have provided an invaluable tool for the detection of unknown, infectious, tumorigenic agents, as demonstrated by several recent studies. However, discoveries of novel viruses possibly associated with tumorigenesis are scarce at best. Here, we apply a rigorous bioinformatics workflow to investigate in depth tumor metagenomes from a small but carefully selected cohort of immunosuppressed patients. While a variegated bacterial microbiome was associated with each tumor, no evidence of the presence of putative oncoviruses was found. These results are consistent with the major findings of several recent papers and suggest that new human tumorigenic viruses are not common even in immunosuppressed populations.

Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Oldest Adults: Predictors of In-Hospital Mortality and Need for Post-acute Care.

OBJECTIVES: Older age is associated with higher risk of death during acute exacerbations of chronic obstructive pulmonary disease (AE-COPD). Older patients hospitalized for AE-COPD often require post-acute care after acute phase. The aim of this study was to evaluate components of a comprehensive geriatric assessment and clinical/laboratory parameters, in order to find predictors of in-hospital mortality and need for post-acute care in patients aged 80 and older hospitalized for AE-COPD. DESIGN: Prospective observational study. SETTING: Hospital assessment. PARTICIPANTS: 121 patients consecutively admitted to an internal medicine and geriatrics department for AE-COPD. MEASURES: Activities of Daily Living (ADL) Hierarchy scale, Geriatric Index of Comorbidity, cognitive impairment, and clinical and laboratory parameters were collected. RESULTS: Mean age: 87.0 ± 4.9 years; male: 54.5%. In-hospital mortality (18.2% of patients) was significantly associated with functional disability, high comorbidity, cognitive impairment, anemia, older age, lower albumin, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and white blood cell levels, oral corticosteroids taken before admission, and no angiotensin-converting enzyme inhibitors or angiotensin receptor blockers taken before admission. In a stepwise logistic regression, functional dependence (P = .006), cognitive impairment (P = .038), and oral corticosteroids therapy before hospitalization (P = .035) were independently associated with a higher risk of in-hospital mortality. Among laboratory parameters, only NT-proBNP remained significantly associated with in-hospital mortality (P = .026). The need for post-acute care (18.2% of survivors) was associated with older age, higher admission Pco2, greater comorbidity, and cognitive impairment. In a stepwise logistic regression, only cognitive impairment (P = .016) and ln_Pco2 (P = .056) confirmed their association with the need for post-acute care. CONCLUSIONS/IMPLICATIONS: Preadmission functional dependence, cognitive impairment, and corticosteroid use, plus elevated NT-proBNP at admission are risk factors for mortality during an AE-COPD in the oldest old. Therefore, medical providers should consider these, as well as the patient's advance directives, in planning hospital care. Furthermore, providers should arrange especially careful posthospitalization monitoring and frequent follow-up of individuals with cognitive impairment and baseline hypercapnia.

Correlates of infection and molecular characterization of blood-borne HIV, HCV, and HBV infections in HIV-1 infected inmates in Italy: An observational cross-sectional study.

Coinfection of blood-borne hepatitis B and hepatitis C viruses (HBV and HCV, respectively) in human immunodeficiency virus type 1 (HIV-1)-positive individuals frequently occurs in inmate population and peculiar viral strains and patterns of virological markers may be observed.Plasma from 69 HIV-1-positive inmates was obtained from 7 clinical centers connected with correctional centers in different towns in Italy. HIV, HBV, and HCV markers were tested by commercial assays. Virus genotyping was carried out by sequencing the protease and reverse transcriptase-encoding region (PR-RT region) for HIV and a region encompassing the NS5B gene for HCV and subsequent phylogenetic analysis.Twelve over 14 HIV-subtyped inmates were infected with HIV-1 subtype B strains. The 2 non-B strains belonged to subtype G and CRF02_AG, in an Italian and a Gambian patient, respectively. Variants carrying the K103N and Y181C resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were found in 2 out of 9 patients naive for combined antiretroviral therapy (cART) (22.2%). Most HIV-positive patients (92.8%) showed evidence of past or present HBV and/or HCV infection. Prevalence of HBV and HCV was 81.2% for both viruses, whereas prevalence of HBV/HCV coinfection was 69.6%. A significantly higher presence of HCV infection was found in Italians [odds ratio (OR) 11.0; interval 1.7-80.9] and in drug users (OR 27.8; interval 4.9-186.0). HCV subtypes were determined in 42 HCV or HBV/HCV-coinfected individuals. HCV subtypes 1a, 3a, 4d, and 1b were found in 42.9%, 40.5%, 14.3%, and 2.4% of inmates, respectively. Low titers of HBV DNA in HBV DNA positive subjects precluded HBV subtyping.The high prevalence of HBV and HCV coinfections in HIV-infected inmates, as well as the heterogeneity of HIV and HCV subtypes suggest the need to adopt systematic controls in prisons to monitor both the burden and the genetic forms of blood-borne viral infections, in order to apply targeted therapeutic interventions.

Molecular characterization of HIV-1 subtype C gp-120 regions potentially involved in virus adaptive mechanisms.

The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are target of the immune response, are modulated during the disease course. We found an increase of "shifting" putative N-glycosylation sites (PNGSs) in the α2 helix (in C3) and in C4 and an increase of sites under positive selection pressure in the α2 helix during the chronic stage of disease. These sites are close to CD4 and to co-receptor binding sites. We also found a negative correlation between electric charges of C3 and V4 during the late stage of disease counteracted by a positive correlation of electric charges of α2 helix and V5 during the same stage. These data allow us to hypothesize possible mechanisms of virus escape involving constant and variable regions of gp120. In particular, new mutations, including new PNGSs occurring near the CD4 and CCR5 binding sites could potentially affect receptor binding affinity and shield the virus from the immune response.

Temporal characterization of drug resistance associated mutations in HIV-1 protease and reverse transcriptase in patients failing antiretroviral therapy.

The aim of this study was to evaluate the prevalence of genotypic resistance for each drug-class, and of single resistance-mutations in 1075 HIV-1 infected multi-treated patients undergoing their first genotypic resistance-test (GRT) after virological failure, over the years 1999-2003. First GRT was requested in 2003 for patients at earlier stages of failure, with less advanced disease, higher CD4-cell-count, lower HIV-RNA, and lower drug-experience with respect to 1999. Prevalence of resistance to all three drug-classes decreased from 33.3% in 1999 to 14.8% in 2003 (p < 0.001). Patients with protease-inhibitor (PI) resistant viruses decreased from 68.1% in 1999 to 34.1% in 2003 (p < 0.001); patients with nucleoside reverse transcriptase-inhibitor (NRTI) resistant viruses remained unchanged (85.4% in 1999; 86.4% in 2003); patients with non-NRTI (NNRTI) resistant viruses increased from 36.1% in 1999 to 52.3% in 2003 (p = 0.005) (corresponding to an increased NNRTI-use and decreased PI-use). From 1999 to 2003, resistance-mutations to drugs with high genetic-barrier significantly decreased (L90M/V82A/M46I/I54V/G73S/I84V/G48V for PIs; M41L/D67N/L210W/V1181 for NRTIs, p < 0.05), while mutations to drugs with low genetic-barrier increased (D30N in protease, M184V/K103N/V108I in reverse transcriptase, p < 0.05). Taken together, earlier recruitment to first GRT in patients with less severe disease, and with lower prevalence of drug-resistant viruses may further improve therapeutic strategies aimed at longer and greater control of HIV-related disease progression.

Limited development and progression of resistance of HIV-1 to the nucleoside analogue reverse transcriptase inhibitor lamivudine in human primary macrophages.

OBJECTIVES: The aim of this study was to investigate the development and progression of phenotypic resistance to the HIV-1-reverse transcriptase (RT) inhibitor lamivudine, and genotypic variations of HIV-1-RT occurring under lamivudine treatment in HIV-1-infected human primary monocytes-macrophages (M/M). METHODS: Cellular passages in the presence of lamivudine were performed every 2 weeks by transferring supernatants of infected M/M to fresh M/M. A fitness assay using wild-type virus and a lamivudine-resistant HIV-1 virus (harbouring the M184V RT mutation) was performed in peripheral blood mononuclear cells. Culture supernatants were tested for p24 antigen production and RT activity. The M184V RT mutant virus was obtained by site-directed mutagenesis on a CCR5-using HIV-1 backbone. RESULTS: The mutagenized M184V RT virus showed full resistance to lamivudine in M/M. However, no detectable phenotypic and genotypic resistance (neither virus breakthrough, nor RT resistance-related mutations) developed in M/M infected by HIV-1 and cultured for up to seven passages in vitro (i.e. 105 days). This inefficiency of M/M to develop M184V RT mutated virus is tightly related to the low 2'-deoxynucleotide (dNTP) pool in such cells, which in turn decreases the kinetics of HIV-1-RT. Despite this, the M184V RT mutant virus replicates in M/M, although with a 30% decreased efficiency compared with the wild-type. CONCLUSIONS: Our results show that the chances of development of resistance are far lower in M/M than in lymphocytes. This underlines the importance and the peculiar role of M/M as reservoirs of either wild-type or resistant strains in human organs.

HIV fitness and resistance as covariates associated with the appearance of mutations under antiretroviral treatment.

The ability of human immunodeficiency virus (HIV) strains to replicate in human target cells represents a major driving force of the progression of the disease. Despite antiretroviral treatment, HIV overcomes drug pressure by adding new (compensatory) mutations, appearing in a specific and sequential order, that modulate its replication capacity and favour viral escape. In the case of M184V (a mutation involving the catalytic site of HIV reverse transcriptase), no pathways of viral escape have been defined so far; it is thus conceivable that the mutated virus maintains a relatively low replicative capacity. At the time of interruption of specific viral pressure (lamivudine in the case of M184V), wild-type virus easily overgrows mutated strains. A deep molecular analysis (90 clones) conducted on proviral DNA of lymphocytes demonstrates that M184V strains are no longer detected in plasma and proviral DNA shortly after interruption of therapeutic regimens including lamivudine (even if a new therapeutic regimen has been started). This supports the concept that the low fitness of M184V strains is not easily compensated by additional mutations. Taken together, the results suggest that the assessment of viral fitness, either direct (through biological methods) or indirect (through the identification of specific mutations that affect the replicative capacity), may provide substantial advancements in the definition of the long-term efficacy of antiretroviral therapy.