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Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.

In Brazil, ~35% of people living with HIV (PLHIV) have poor adherence to antiretroviral therapy (ART). HIV-related stigma is associated with worst continuum of care outcomes, however evidence from Brazil is scarce. We explored pathways between HIV-related stigma dimensions and ART adherence among Brazilian cisgender gay, bisexual and other men who have sex with men (MSM) living with HIV. A sample of MSM ≥18 years was recruited online between February/March 2020 through advertisements on Hornet, a location-based dating app. Validated scales were used to assess ART adherence and HIV-related stigma. Indirect and direct pathways between HIV-related stigma dimensions and ART adherence were estimated using structural equation models while considering socio-demographic and substance use related variables. Models were estimated using mean- and variance-adjusted weighted least squares, and goodness of fit indices were calculated. Among 1,719 MSM living with HIV who reported starting ART, 70% were adherent. There was evidence of indirect effects of concerns about public attitudes (standardized coefficient (SC) = -0.095, 95% confidence interval (95%CI) = -0.172 - -0.017) and personalized HIV-stigma (SC = -0.022, 95%CI = -0.043 - -0.001) on ART adherence mediated through negative self-image. Personalized HIV stigma and concerns about public attitudes were both positively associated with negative self-image (SC = 0.129, 95%CI = 0.066-0.193; SC = 0.549, 95%CI = 0.494-0.603), and concerns about public attitudes was associated with HIV disclosure concerns (SC = 0.522, 95%CI = 0.463-0.581). However, the direct paths from personalized HIV stigma and concerns about public attitudes to ART adherence were not significant. Our research underscores the critical need for multifaceted interventions to eliminate HIV-related stigma at both individual and societal levels. At the individual level, psychotherapeutic interventions to improve self-image might helpful. Additionally, public policy should aim to dismantle structural stigma with awareness campaigns on various media channels, integration of anti-stigma curriculum into schools, and training for professionals.

Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders.

In this study, the modulation of enzymatic biocatalysts were developed by the use of lipase B from Candida antarctica covalently immobilized on an eco-friendly support, cashew apple bagasse, activated with 10% glycidol–ethylenediamine–glutaraldehyde (GEG) under different immobilization strategies (5 mM or 100 mM ionic strength and in absence or presence of 0.5% (v/v) Triton X-100). The biocatalysts were characterized for thermal and organic solvents stabilities and compared with the soluble enzyme. The biocatalysts were then applied to the hydrolysis of the rac-indanyl acetate (2:1 ratio enzyme/substrate) at pH 7.0 and 30 °C for 24 h. For all the strategies evaluated, GEG promoted kinetic resolution of rac-indanyl acetate with maximum conversion (50%) and led to (R)-indanol with excellent enantiomeric excess (97%), maintaining the maximum conversion for five consecutive cycles of hydrolysis. Therefore, the use of cashew apple bagasse has proved to be a promising eco-friendly support for enzyme immobilization, since it resulted in stable biocatalysts for enzymatic kinetic resolution.Graphic abstract

Background Epidemiologic studies have highlighted the association of environmental factors with the development and progression of autoimmune and chronic inflammatory diseases. Among the environmental factors, smoking has been associated with increased susceptibility and poor prognosis in rheumatoid arthritis (RA). However, the immune and molecular mechanism of smoking-induced arthritis aggravation remains unclear. The transcription factor aryl hydrocarbon receptor (AHR) regulates the generation of Th17 cells, CD4 T cells linked the development of autoimmune diseases. AHR is activated by organic compounds including polycyclic aromatic hydrocarbons (PAHs), which are environmental pollutants that are also present in cigarette smoke. In this study, we investigated the role of AHR activation in the aggravation of experiment arthritis induced by exposure to cigarette smoke. Methods Mice were exposed to cigarette smoke during the developmental phase of antigen-induced arthritis and collagen-induced arthritis to evaluate the effects of smoking on disease development. Aggravation of articular inflammation was assessed by measuring neutrophil migration to the joints, increase in articular hyperalgesia and changes in the frequencies of Th17 cells. In vitro studies were performed to evaluate the direct effects of cigarette smoke and PAH on Th17 differentiation. We also used mice genetically deficient for AHR ( Ahr KO) and IL-17Ra ( Il17ra KO) to determine the in vivo mechanism of smoking-induced arthritis aggravation. Results We found that smoking induces arthritis aggravation and increase in the frequencies of Th17 cells. The absence of IL-17 signaling ( Il17ra KO) conferred protection to smoking-induced arthritis aggravation. Moreover, in vitro experiments showed that cigarette smoke can directly increase Th17 differentiation of T cells by inducing AHR activation. Indeed, Ahr KO mice were protected from cigarette smoke-induced arthritis aggravation and did not display increase in TH17 frequencies, suggesting that AHR activation is an important mechanism for cigarette smoke effects on arthritis. Finally, we demonstrate that PAHs are also able to induce arthritis aggravation. Conclusions Our data demonstrate that the disease-exacerbating effects of cigarette smoking are AHR dependent and environmental pollutants with AHR agonist activity can induce arthritis aggravation by directly enhancing Th17 cell development.

Efficacy of daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) for PrEP is strongly dependent on the adherence. We examined the concordance between indirect adherence measures and protective drug levels among participants retained through 48 weeks in the PrEP Brasil Study. PrEP Brasil was a prospective, multicenter, open-label demonstration project evaluating PrEP provision for men who have sex with men (MSM) and transgender women (TGW) at higher risk for HIV infection within the setting of Brazilian Public Health System. Three indirect adherence measures were obtained at week 48: medication possession ratio (MPR), pill count and self-report (30-days recall). Tenofovir diphosphate (TFV-DP) concentration in Dried Blood Spot (DBS) was measured at week 48. Areas under (AUC) the receiver operating characteristics (ROC) curve were used to evaluate the concordance between achieving protective drug levels (TFV-DP≥700fmol/punch) and the indirect adherence measures. Youden's index and distance to corner were used to determine the optimal cutoff points for each indirect adherence measure. We calculated sensitivity, specificity, negative (NPV) and positive (PPV) predictive values for the found cutoff points. Finally, Delong test was used to compare AUCs. From April, 2014 to July, 2016, 450 participants initiated PrEP, 375(83.3%) were retained through 48 weeks. Of these, 74% (277/375) had TFV-DP ≥700fmol/punch. All adherence measures discriminated between participants with and without protective drug levels (AUC>0.5). High indirect adherence measure was predictive of protective drug levels (PPV>0.8) while low indirect adherence measure was not predictive of lack of protective drug levels (NPV<0.5). No significant differences were found between the adherence methods (p = 0.44). Low-burden measurements such as MPR and self-report can be used to predict PrEP adherence in a public health context in Brazil for MSM and TGW retained through 48 weeks. Clinical Trial Number: NCT01989611.

Habitat size and climate are known to affect the trophic structure and dynamics of communities, but their interactive effects are poorly understood. Organisms from different trophic levels vary in terms of metabolic requirements and heat dissipation. Indeed, larger species such as keystone predators require more stable climatic conditions than their prey. Likewise, habitat size disproportionally affects large-sized predators, which require larger home ranges and are thus restricted to larger habitats. Therefore, food web structure in patchy ecosystems is expected to be shaped by habitat size and climate variations. Here we investigate this prediction using natural aquatic microcosm (bromeliad phytotelmata) food webs composed of litter resources (mainly detritus), detritivores, mesopredators, and top predators (damselflies). We surveyed 240 bromeliads of varying sizes (water retention capacity) across 12 open restingas in SE Brazil spread across a wide range of tropical latitudes (-12.6° to -27.6°, ca. 2,000 km) and climates (△ mean annual temperature = 5.3°C). We found a strong increase in predator-to-detritivore mass ratio with habitat size, which was representative of a typical inverted trophic pyramid in larger ecosystems. However, this relationship was contingent among the restingas; slopes of linear models were steeper in more stable and favorable climates, leading to inverted trophic pyramids (and top-down control) being more pronounced in environments with more favorable climatic conditions. By contrast, detritivore-resource and mesopredator-detritivore mass ratios were not affected by habitat size or climate variations across latitudes. Our results highlight that the combined effects of habitat size, climate and predator composition are pivotal to understanding the impacts of multiple environmental factors on food web structure and dynamics.

PurposeHigh cardiac vagal control in endurance athletes has been generally associated with adequate recovery from training and readiness to cope high-intensity training. A method that improves cardiac vagal control in endurance athletes could therefore be advantageous. Accordingly, we sought to test whether ischemic preconditioning (IPC) could enhance cardiac vagal control in endurance runners.MethodsFifteen subjects underwent IPC, sham ultrasound (SHAM) or control (CT), in random order. Subjects were informed both IPC and SHAM would be beneficial vs. CT (i.e., similar placebo induction), and IPC would be harmless despite ischemia sensations (i.e., nocebo avoidance). Resting cardiac vagal control was assessed via respiratory sinus arrhythmia (RSA) and heart rate variability (HRV) indexes. Post-exercise cardiac vagal control was assessed via heart rate recovery [HR time constant decay (T30) and absolute HR decay (HRR30s)] during 30-s breaks of a discontinuous incremental test. Capillary blood samples were collected for lactate threshold identification.ResultsRSA and HRV were similar among interventions at pre- and post-intervention assessments. Lactate threshold occurred at 85 ± 4% of maximal effort. T30 was similar among interventions, but IPC increased HRR30s at 70% and 75% of maximal effort vs. SHAM and CT (70%: IPC = 31 ± 2 vs. SHAM = 26 ± 3 vs. CT = 26 ± 2 bpm, mean ± SEM, P < 0.01; 75%: IPC = 29 ± 2 vs. SHAM = 25 ± 2 vs. CT = 24 ± 2 bpm, P < 0.01).ConclusionIPC did not change resting cardiac vagal control, but boosted fast post-exercise cardiac vagal reactivation at exercise intensities below lactate threshold in endurance runners.

Our goal was to investigate the cortical thickness and subcortical volume in subjects with craniocervical dystonia and its subgroups. We studied 49 subjects, 17 with cervical dystonia, 18 with blepharospasm or oromandibular dystonia, and 79 healthy controls. We performed a whole group analysis, followed by a subgroup analysis. We used Freesurfer software to measure cortical thickness, subcortical volume and to perform a primary exploratory analysis in the craniocervical dystonia group, complemented by a region of interest analysis. We also performed a secondary analysis, with data generated from Freesurfer for subgroups, corrected by false discovery rate. We then performed an exploratory generalized linear model with significant areas for the previous steps using clinical features as independent variables. The primary exploratory analysis demonstrated atrophy in visual processing regions in craniocervical dystonia. The secondary analysis demonstrated atrophy in motor, sensory, and visual regions in blepharospasm or oromandibular dystonia, as well as in limbic regions in cervical dystonia. Cervical dystonia patients also had greater cortical thickness than blepharospasm or oromandibular dystonia patients in frontal pole and medial orbitofrontal regions. Finally, we observed an association between precuneus, age of onset of dystonia and age at the MRI exam, in craniocervical dystonia; between motor and limbic regions and age at the exam, clinical score and time on botulinum toxin in cervical dystonia and sensory regions and age of onset and time on botulinum toxin in blepharospasm or oromandibular dystonia. We detected involvement of visual processing regions in craniocervical dystonia, and a pattern of involvement in cervical dystonia and blepharospasm or oromandibular dystonia, including motor, sensory and limbic areas. We also showed an association of cortical thickness atrophy and younger onset age, older age at the MRI exam, higher clinical score and an uncertain association with longer time on botulinum toxin.

The facile preparation of oxygen-generating microparticles (M) consisting of Polycaprolactone (PCL), Pluronic F-127, and calcium peroxide (CPO) (PCL-F-CPO-M) fabricated through an electrospraying process is disclosed. The biological study confirmed the positive impact from the oxygen-generating microparticles on the cell growth with high viability. The presented technology could work as a prominent tool for various tissue engineering and biomedical applications. The oxygen-generated microparticles fabricated through electrospraying processes were thoroughly characterization through various methods such as X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) analysis, and scanning electron microscopy (SEM)/SEM-Energy Dispersive Spectroscopy (EDS) analysis. The analyses confirmed the presence of the various components and the porous structure of the microparticles. Spherical shape with spongy characteristic microparticles were obtained with negative charge surface (ζ = -16.9) and a size of 17.00 ± 0.34 μm. Furthermore, the biological study performed on rat chondrocytes demonstrated good cell viability and the positive impact of increasing the amount of CPO in the PCL-F-CPO-M. This technological platform could work as an important tool for tissue engineering due to the ability of the microparticles to release oxygen in a sustained manner for up to 7 days with high cell viability.