HIV Disease Progression Among Antiretroviral Therapy Patients in Zimbabwe: A Multistate Markov Model.

Background: Antiretroviral therapy (ART) impact has prolonged survival of people living with HIV. We evaluated HIV disease progression among ART patients using routinely collected patient-level data between 2004 and 2017 in Zimbabwe. Methods: We partitioned HIV disease progression into four transient CD4 cell counts states: state 1 (CD4 ≥ 500 cells/μl), state 2 (350 cells/μl ≤ CD4 < 500 cells/μl), state 3 (200 cells/μl ≤ CD4 < 350 cells/μl), state 4 (CD4 < 200 cells/μl), and the absorbing state death (state 5). We proposed a semiparametric time-homogenous multistate Markov model to estimate bidirectional transition rates. Covariate effects (age, gender, ART initiation period, and health facility level) on the transition rates were assessed. Results: We analyzed 204,289 clinic visits by 63,422 patients. There were 24,325 (38.4%) patients in state 4 (CD4 < 200) at ART initiation, and 7,995 (12.6%) deaths occurred by December 2017. The overall mortality rate was 3.9 per 100 person-years. The highest mortality rate of 5.7 per 100 person-years (4,541 deaths) was from state 4 (CD4 < 200) compared to other states. Mortality rates decreased with increase in time since ART initiation. Health facility type was the strongest predictor for immune recovery. Provincial or central hospital patients showed a diminishing dose-response effect on immune recovery by state from a hazard ratio (HR) of 8.30 [95% confidence interval (95% CI), 6.64-10.36] (state 4 to 3) to HR of 3.12 (95% CI, 2.54-4.36) (state 2 to 1) compared to primary healthcare facilities. Immune system for male patients was more likely to deteriorate, and they had a 32% increased mortality risk (HR, 1.32; 95% CI, 1.23-1.42) compared to female patients. Elderly patients (45+ years) were more likely to immune deteriorate compared to 25-34 years age group: HR, 1.35; 95% CI, 1.18-1.54; HR, 1.56; 95% CI, 1.34-1.81 and HR, 1.53; 95% CI, 1.32-1.79 for states 1 to 2, state 2 to 3, and states 3 to 4, respectively. Conclusion: Immune recovery was pronounced among provincial or central hospitals. Male patients with lower CD4 cell counts were at a higher risk of immune deterioration and mortality, while elderly patients were more likely to immune deteriorate. Early therapeutic interventions when the immune system is relatively stable across gender and age may contain mortality and increase survival outcomes. Interventions which strengthen ART services in primary healthcare facilities are essential

Synergistic sequential emission of fractional 10.600 and 1540 nm lasers for skin resurfacing. an ex vivo histological evaluation

Background: Fractional ablative and non-ablative lasers are useful treatments for skin rejuvenation. A procedure that provides the sequential application of fractional ablative followed by non-ablative laser treatment may reduce patients’ downtime and deliver better cosmetic results than with either laser alone. Objective: The purpose of the current study was to demonstrate the ameliorative and therapeutic effects in skin remodeling of the synergistic use of the two laser wavelengths (fractional ablative CO2 and non-ablative 1540 nm) with three different types of pulse shapes, S-Pulse (SP), D-Pulse (DP) and H-Pulse (HP), through which the CO2 laser can emit, performing an ex vivo histological evaluation. Methods: In this prospective study, ex vivo sheep inner thigh skin was chosen due to its similarity to human skin tissue, and a histological evaluation was performed. Three irradiation conditions, using all of the three CO2 pulse shapes (alone or averaged), were investigated: (1) 10.600 nm alone, the sequential irradiation of the two wavelengths in the same perfectly controlled energy pulses (DOT) for the entire scan area; ((2) 10.600 nm followed immediately by 1540 nm; and (3) 1540 nm followed immediately by 10.600 nm). Results: When comparing ablative to sequential irradiations, the synergy of the two wavelengths did not alter the typical ablative pulse shape of the 10.600 nm laser alone. With the same CO2 pulse shape, the lesion depth did not vary with the synergy of the two wavelengths, while thermal lesion width increased compared to CO2 alone. The ablation rate was achieved, while the total thermal lesion coverage in the scanning area of CO2 − 1540 lasers was greater than when using CO2 alone and then the other sequential irradiation. Conclusions: This study provides important preclinical data for new and early uses of the novel 10.600/1540 nm dual-wavelength non-ablative fractional laser. The synergy of the two wavelengths enhanced all the benefits already available when using CO2 laser systems both in terms of tone strengthening, thanks to a greater shrinking effect, and in terms of stimulation and collagen remodeling thanks to a greater volumetric thermal effect

Markov modelling of viral load adjusting for CD4 orthogonal variable and multivariate conditional autoregressive mapping of the HIV immunological outcomes among ART patients in Zimbabwe

BACKGROUND: This study aimed to jointly model HIV disease progression patterns based on viral load (VL) among adult ART patients adjusting for the time-varying "incremental transients states" variable, and the CD4 cell counts orthogonal variable in a single 5-stage time-homogenous multistate Markov model. We further jointly mapped the relative risks of HIV disease progression outcomes (detectable VL (VL ≥ 50copies/uL) and immune deterioration (CD4 < 350cells/uL) at the last observed visit) conditional not to have died or become loss to follow-up (LTFU). METHODS: Secondary data analysis of individual-level patients on ART was performed. Adjusted transition intensities, hazard ratios (HR) and regression coefficients were estimated from the joint multistate model of VL and CD4 cell counts. The mortality and LTFU transition rates defined the extent of patients' retention in care. Joint mapping of HIV disease progression outcomes after ART initiation was done using the Bayesian intrinsic Multivariate Conditional Autoregressive prior model. RESULTS: The viral rebound from the undetectable state was 1.78times more likely compared to viral suppression among patients with VL ranging from 50-1000copies/uL. Patients with CD4 cell counts lower than expected had a higher risk of viral increase above 1000copies/uL and death if their VL was above 1000copies/uL (state 2 to 3 (λ23): HR = 1.83 and (λ34): HR = 1.42 respectively). Regarding the time-varying effects of CD4 cell counts on the VL transition rates, as the VL increased, (λ12 and λ23) the transition rates increased with a decrease in the CD4 cell counts over time. Regardless of the individual's VL, the transition rates to become LTFU decreased with a decrease in CD4 cell counts. We observed a strong shared geographical pattern of 66% spatial correlation between the relative risks of detectable VL and immune deterioration after ART initiation, mainly in Matabeleland North. CONCLUSION: With high rates of viral rebound, interventions which encourage ART adherence and continual educational support on the barriers to ART uptake are crucial to achieve and sustain viral suppression to undetectable levels. Area-specific interventions which focus on early ART screening through self-testing, behavioural change campaigns and social support strategies should be strengthened in heavily burdened regions to sustain the undetectable VL. Sustaining undetectable VL lowers HIV transmission in the general population and this is a step towards achieving zero HIV incidences by 2030

A review of multistate modelling approaches in monitoring disease progression: Bayesian estimation using the Kolmogorov-Chapman forward equations.

There are numerous fields of science in which multistate models are used, including biomedical research and health economics. In biomedical studies, these stochastic continuous-time models are used to describe the time-to-event life history of an individual through a flexible framework for longitudinal data. The multistate framework can describe more than one possible time-to-event outcome for a single individual. The standard estimation quantities in multistate models are transition probabilities and transition rates which can be mapped through the Kolmogorov-Chapman forward equations from the Bayesian estimation perspective. Most multistate models assume the Markov property and time homogeneity; however, if these assumptions are violated, an extension to non-Markovian and time-varying transition rates is possible. This manuscript extends reviews in various types of multistate models, assumptions, methods of estimation and data features compatible with fitting multistate models. We highlight the contrast between the frequentist (maximum likelihood estimation) and the Bayesian estimation approaches in the multistate modeling framework and point out where the latter is advantageous. A partially observed and aggregated dataset from the Zimbabwe national ART program was used to illustrate the use of Kolmogorov-Chapman forward equations. The transition rates from a three-stage reversible multistate model based on viral load measurements in WinBUGS were reported

The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells

In this paper we report on the cloning and characterization of mouse CCR8. Like its human homologue, it is predominantly expressed in the thymus. In the periphery, murine CCR8 mRNA was found most abundantly expressed in activated Th2-polarized cells and in NK1.1+ CD4+ T cells. Human CCR8 is also preferentially expressed in human Th2-polarized cells and clones. This pattern of expression suggests that CCR8 is part of a Th2-specific gene expression program. The CCR8 ligands I-309 and its mouse homologue T cell activation gene 3 (TCA-3) are potent chemoattractants for Th2-polarized cells. Taken together, these observations strongly suggest that CCR8 plays a role in the control of Th2 responses, and may represent a potential target for treatment of allergic diseases

Revista de libros

Se reseñan los siguientes libros: - Max Marchand: Hygiéne affective de l,éducateur, d'aprés la notion de “couple de l'éducateur et de l'eléve consideres dans leurs relations concretes". Essai sur une éducation á base existentielle. Prefacio de Louis Bourgey. Presses Universitaires de Flanee, París 1956. Volumen en rústica de 135 págs - La Educación Superior en los Estados Unidos: Frangís Millet Rogers. Editorial Nova, Buenos Aires 1958. Volumen en rústica de 127 págs. - Francisco Ayala: La Crisis Actual de la Enseñanza. Editorial Nova. Compendio N° 18, Buenos Aires 1958. Volumen en rústica de 75 pags. - Ricardo Nassif: Pedagogía General. Editorial Kapelusz. Buenos Aires 1958. Volumen en tela, 304 págs. - Pedro Salinas: Ensayos de literatura hispánica. (Del Cantar de Mío Cid a García Loica). Editorial Aguilar, Madrid, 1958. Vol rústica, 404 págs - Martín Heidfgger: ¿Qué significa pensar? (Trad. de Haraldo Kahnemann). Ed. Nova, Buenos Aires, 1958. Vol. rústica, 236 págs - Gillo Dorfles: Constantes técnicas de las artes. Editorial Nueva Visión, Buenos Aires. 1958. Vol. rústica, 211 páginas.Universidad Nacional de La Plat

Revista de libros

Se reseñan los siguientes libros: - Max Marchand: Hygiéne affective de l,éducateur, d'aprés la notion de “couple de l'éducateur et de l'eléve consideres dans leurs relations concretes". Essai sur une éducation á base existentielle. Prefacio de Louis Bourgey. Presses Universitaires de Flanee, París 1956. Volumen en rústica de 135 págs - La Educación Superior en los Estados Unidos: Frangís Millet Rogers. Editorial Nova, Buenos Aires 1958. Volumen en rústica de 127 págs. - Francisco Ayala: La Crisis Actual de la Enseñanza. Editorial Nova. Compendio N° 18, Buenos Aires 1958. Volumen en rústica de 75 pags. - Ricardo Nassif: Pedagogía General. Editorial Kapelusz. Buenos Aires 1958. Volumen en tela, 304 págs. - Pedro Salinas: Ensayos de literatura hispánica. (Del Cantar de Mío Cid a García Loica). Editorial Aguilar, Madrid, 1958. Vol rústica, 404 págs - Martín Heidfgger: ¿Qué significa pensar? (Trad. de Haraldo Kahnemann). Ed. Nova, Buenos Aires, 1958. Vol. rústica, 236 págs - Gillo Dorfles: Constantes técnicas de las artes. Editorial Nueva Visión, Buenos Aires. 1958. Vol. rústica, 211 páginas.Universidad Nacional de La Plat

Revista de libros

Se reseñan los siguientes libros: - Max Marchand: Hygiéne affective de l,éducateur, d'aprés la notion de “couple de l'éducateur et de l'eléve consideres dans leurs relations concretes". Essai sur une éducation á base existentielle. Prefacio de Louis Bourgey. Presses Universitaires de Flanee, París 1956. Volumen en rústica de 135 págs - La Educación Superior en los Estados Unidos: Frangís Millet Rogers. Editorial Nova, Buenos Aires 1958. Volumen en rústica de 127 págs. - Francisco Ayala: La Crisis Actual de la Enseñanza. Editorial Nova. Compendio N° 18, Buenos Aires 1958. Volumen en rústica de 75 pags. - Ricardo Nassif: Pedagogía General. Editorial Kapelusz. Buenos Aires 1958. Volumen en tela, 304 págs. - Pedro Salinas: Ensayos de literatura hispánica. (Del Cantar de Mío Cid a García Loica). Editorial Aguilar, Madrid, 1958. Vol rústica, 404 págs - Martín Heidfgger: ¿Qué significa pensar? (Trad. de Haraldo Kahnemann). Ed. Nova, Buenos Aires, 1958. Vol. rústica, 236 págs - Gillo Dorfles: Constantes técnicas de las artes. Editorial Nueva Visión, Buenos Aires. 1958. Vol. rústica, 211 páginas.Universidad Nacional de La Plat

Samhd1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities

Coreceptor Usage by HIV-1 and HIV-2 Primary Isolates: The Relevance of CCR8 Chemokine Receptor as an Alternative Coreceptor

The human immunodeficiency virus replication cycle begins by sequential interactions between viral envelope glycoproteins with CD4 molecule and a member of the seven-transmembrane, G-protein-coupled, receptors' family (coreceptor). In this report we focused on the contribution of CCR8 as alternative coreceptor for HIV-1 and HIV-2 isolates. We found that this coreceptor was efficiently used not only by HIV-2 but particularly by HIV-1 isolates. We demonstrate that CXCR4 usage, either alone or together with CCR5 and/or CCR8, was more frequently observed in HIV-1 than in HIV-2 isolates. Directly related to this is the finding that the non-usage of CXCR4 is significantly more common in HIV-2 isolates; both features could be associated with the slower disease progression generally observed in HIV-2 infected patients. The ability of some viral isolates to use alternative coreceptors besides CCR5 and CXCR4 could further impact on the efficacy of entry inhibitor therapy and possibly also in HIV pathogenesis