High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients

Funding Information: This work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, Aga Khan Development Network (AKDN)–Portugal Collaborative Research Network in Portuguese-speaking countries in Africa (project 332821690). CQC is supported by FCT through projects UIDB/00313/2020 and UIDP/QUI/00313/2020, co-funded by COMPETE2020-UE. iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Portugal, is supported by FCT through projects UIDB/04138/2020 and UIDP/04138/2020. Inês Bártolo is supported by FCT through Norma Transitória–DL57/2016/CP1376/CT0012. Ana Rita Diniz (SFRH/BD/89140/2012), Francisco Martin (SFRH/BD/87488/2012), Inês Moranguinho (SFRH/BD/131062/2017), and Américo Alves (SFRH/BD/128910/2017) were supported by Ph.D. grants from FCT, Portugal. Publisher Copyright: © 2022 by the authors.Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.publishersversionpublishe

Evolución del comportamiento físico químico de los pozos en Termas de Rio Hondo como aporte al diagnóstico de situación actual

En la Provincia de Santiago del Estero, la Ciudad de Termas de Rio Hondo constituye un importante ce ntro urbano turístico invernal. Posee en el subsuelo, aguas termales usadas en balneoterapia con propiedades termomedicinales. La extracción excesiva en época de temporada invernal asociadas al turismo, genera un desfasaje entre las demandas potenciales y la disponibilidad del recurso, alterando el sistema. La geoquímica, provee información sobre la distribución de los elementos químicos y su evolución espacial y temporal en el sistema hídrico, caracterizando el agua de los acuíferos y definiendo problemas ambientales. La metodología, se basó en la selección de resultados de análisis físico-químicos existentes y actuales comparados, respecto a TSD. Las anomalías observadas en la concentración de los iones, respecto a las profundidades de explotación están asociadas a la presión antrópica del sistema.In the province of Santiago del Estero, the City of Termas de Rio Hondo is a major urban center winter resort. It has in the subsurface thermal properties used in balneotherapy termomedicinales. Excessive extraction in times of winter season associated with tourism, generates a potential mismatch between the demands and resource availability, altering the system. The geochemistry, provides information on the distribution of chemical elements and their spatial and temporal evolution in the water system, characterizing water aquifers and defining environmental problems. The methodology was based on the selection of results of physicochemical analysis of existing and current compared with respect to TSD. The anomalies observed in the concentration of ions, with respect to depths of operation are associated with human pressure system.Universidad Nacional de La Plat

Psychometric properties of the measure of achieved capabilities in homeless services

Background Purposeful participation in personally meaningful life tasks, enjoyment of positive reciprocal relationships, and opportunities to realize one’s potential are growth-related aspects of a meaningful life that should be considered important dimensions of recovery from homelessness. The extent to which homeless services support individuals to achieve the capabilities they need to become who they want to be and do what they want to do is, in turn, an important indicator of their efectiveness. In this study, we developed a measure of achieved capabilities (MACHS) for use in homeless services settings, and assessed its construct and concurrent validity. Methods We analysed data collected from homeless services users at two time points in eight European countries to assess the factor structure and psychometric properties of the new measure. Participants were adults engaged with either Housing First (n=245) or treatment as usual (n=320). Results Exploratory and confrmatory factor analyses yielded a four-factor structure of the capabilities measure: community integration, optimism, safety, and self-determination. We obtained evidence for construct validity through observed correlations between achieved capabilities and recovery, working alliance and satisfaction with services. Moreover, we obtained evidence of the measure’s concurrent validity from its positive association between HF and personal recovery, which was fully mediated by achieved capabilities. Conclusions Findings demonstrate that the MACHS is a valid and reliable measure that may be used to assess the extent to which homeless services support their clients to develop capabilities needed for growth-related recovery. Implications for practice and future research directions are discussed.info:eu-repo/semantics/publishedVersio

Artificial intelligence for diagnosis and Gleason grading of prostate cancer: The PANDA challenge

Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology. Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted kappa, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.KWF Kankerbestrijding ; Netherlands Organization for Scientific Research (NWO) ; Swedish Research Council European Commission ; Swedish Cancer Society ; Swedish eScience Research Center ; Ake Wiberg Foundation ; Prostatacancerforbundet ; Academy of Finland ; Cancer Foundation Finland ; Google Incorporated ; MICCAI board challenge working group ; Verily Life Sciences ; EIT Health ; Karolinska Institutet ; MICCAI 2020 satellite event team ; ERAPerMe

Preclinical electrogastrography in experimental pigs

Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology

Narcissism and the strategic pursuit of short-term mating : universal links across 11 world regions of the International Sexuality Description Project-2.

Previous studies have documented links between sub-clinical narcissism and the active pursuit of short-term mating strategies (e.g., unrestricted sociosexuality, marital infidelity, mate poaching). Nearly all of these investigations have relied solely on samples from Western cultures. In the current study, responses from a cross-cultural survey of 30,470 people across 53 nations spanning 11 world regions (North America, Central/South America, Northern Europe, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, Southeast Asia, and East Asia) were used to evaluate whether narcissism (as measured by the Narcissistic Personality Inventory; NPI) was universally associated with short-term mating. Results revealed narcissism scores (including two broad factors and seven traditional facets as measured by the NPI) were functionally equivalent across cultures, reliably associating with key sexual outcomes (e.g., more active pursuit of short-term mating, intimate partner violence, and sexual aggression) and sex-related personality traits (e.g., higher extraversion and openness to experience). Whereas some features of personality (e.g., subjective well-being) were universally associated with socially adaptive facets of Narcissism (e.g., self-sufficiency), most indicators of short-term mating (e.g., unrestricted sociosexuality and marital infidelity) were universally associated with the socially maladaptive facets of narcissism (e.g., exploitativeness). Discussion addresses limitations of these cross-culturally universal findings and presents suggestions for future research into revealing the precise psychological features of narcissism that facilitate the strategic pursuit of short-term mating