A Mathematical Model for Fibrous Dysplasia: The Role of the Flow of Mutant Cells.

Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model.

Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

RNA-based bone histomorphometry: method and its application to explaining postpubertal bone gain in a G610C mouse model of osteogenesis imperfecta.

Bone histomorphometry is a well-established approach to assessing skeletal pathology, providing a standard evaluation of the cellular components, architecture, mineralization, and growth of bone tissue. However, it depends in part on the subjective interpretation of cellular morphology by an expert, which introduces bias. In addition, diseases like osteogenesis imperfecta (OI) and fibrous dysplasia are accompanied by changes in the morphology and function of skeletal tissue and cells, hindering consistent evaluation of some morphometric parameters and interpretation of the results. For instance, traditional histomorphometry combined with collagen turnover markers suggested that reduced bone formation in classical OI is accompanied by increased bone resorption. In contrast, the well-documented postpubertal reduction in fractures would be easier to explain by reduced bone resorption after puberty, highlighting the need for less ambiguous measurements. Here we propose an approach to histomorphometry based on in situ mRNA hybridization, which uses Col1a1 as osteoblast and Ctsk as osteoclast markers. This approach can be fully automated and eliminates subjective identification of bone surface cells. We validate these markers based on the expression of Bglap, Ibsp, and Acp5. Comparison with traditional histological and tartrate-resistant acid phosphatase staining of the same sections suggests that mRNA-based analysis is more reliable. Unlike inconclusive traditional histomorphometry of mice with α2(I)-Gly610 to Cys substitution in the collagen triple helix, mRNA-based measurements reveal reduced osteoclastogenesis in 11-wk-old animals consistent with the postpubertal catch-up osteogenesis observed by microCT. We optimize the technique for cryosections of mineralized bone and sections of paraffin-embedded decalcified tissue, simplifying and broadening its applications. We illustrate the application of the mRNA-based approach to human samples using the example of a McCune-Albright syndrome patient. By eliminating confounding effects of altered cellular morphology and the need for subjective morphological evaluation, this approach may provide a more reproducible and accessible evaluation of bone pathology.

Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition.

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system.

Pyridinic-N Coordination Effect on the Adsorption and Activation of CO2 by Single Vacancy Iron-Doped Graphene.

Graphene doped with different transition metals has been recently proposed to adsorb CO2 and help reduce the greenhouse effect. Iron-doped graphene is one of the most promising candidates for this task, but there is still a lack of full understanding of the adsorption mechanism. In this work, we analyze the electronic structure, geometry, and charge redistribution during adsorption of CO2 molecules by single vacancy iron-doped graphene by DFT calculations using the general gradient approximation of Perdew, Burke, and Ernzernhof functional (PBE) and the van der Waals density functional (vdW). To understand the impact of the pyridinic-N coordination of the iron atom, we gradually replaced the neighboring carbon atoms by nitrogen atoms. The analysis indicates that chemisorption and physisorption occur when the molecule is adsorbed in the side-on and end-on orientation, respectively. Adsorption is stronger when pyridinic-N coordination increases, and the vdW functional describes the chemical interactions and adsorption energy differently in relation to PBE without significant structural changes. The development of the chemical interactions with the change of coordination in the system is further investigated in this work with crystal overlap Hamilton population (COHP) analysis.

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.

La reproducibilidad de la alineación dental en medidas digitales y manuales / Reproducibility of dental alignment in digital and manual measurements taken on dental casts

Introducción: La incorporación de modelos digitales ofrece al ortodoncista una alternativa a los modelos de estudio de yeso que se utilizan habitualmente. Estos son un componente estándar de los registros de ortodoncia y son fundamentales para el diagnóstico y la planificación del tratamiento. No obstante, es importante indagar sobre la confiabilidad de las nuevas tecnologías. Objetivo: Evaluar la reproducibilidad de las medidas digitales y manuales de alineación dental en modelos iniciales de pacientes de ortodoncia. Métodos: Se realizó un estudio de evaluación de tecnología diagnóstica, con 80 modelos de yeso, que fueron digitalizados con el escáner Ineos X5. Una vez obtenidos los modelos en yeso y sus imágenes digitales, el investigador que obtuvo el mejor resultado en la calibración inter e intra examinador realizó la medición de la alineación dental. Las medidas manuales se tomaron con un calibrador digital, y las digitales fueron tomadas en el software Nemocast. El análisis incluyó el cálculo del coeficiente de correlación intraclase (CCI) y los límites de acuerdo de Bland y Altman. Un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: Los valores de CCI oscilaron entre 0,643 y 0,874. Más de la mitad de las mediciones obtuvieron valores de CCI superiores a 0,81, lo que se consideró una reproducibilidad "casi perfecta", según la interpretación sugerida por Landis y Koch. Se obtuvo un promedio de las diferencias entre -0,2 a -0,4, con límites de acuerdo estrechos. Conclusiones: Se encontró una reproducibilidad "casi perfecta" y un promedio de las diferencias cercano a cero entre las medidas manuales y digitales(AU)

Introduction: The incorporation of digital models offers the orthodontist an alternative to the plaster study models that are commonly used. These are a standard component of orthodontic records and are critical to diagnosis and treatment planning. It is important to inquire about the reliability of new technologies. Objective: To evaluate the reproducibility of digital and manual measurements of dental alignment in initial models of orthodontic patients. Methods: A diagnostic technology evaluation study was carried out with 80 plaster models that were digitized with the Ineos X5 Scanner. Once the plaster models and digital images of them were obtained, the researcher who obtained the best result in the inter and intra examiner calibration performed the dental alignment measurement. Manual measurements were taken with a digital caliper, and digital ones were taken in the Nemocast software. The analysis included the calculation of the Intraclass Correlation Coefficient (ICC) and the Bland and Altman limits of agreement. A value of p <0.05 was considered statistically significant. Results: ICC values ​​ranged between 0.643 and 0.874, more than half of the measurements obtained ICC values ​​higher than 0.81, which was considered "almost perfect" reproducibility according to the interpretation suggested by Landis and Koch. Differences between -0.2 to -0.4 were averaged with narrow limits of agreement. Conclusions: An "almost perfect" reproducibility was found and an average of the differences close to zero between manual and digital measurements.

Contributing factors for self-reported HIV in male Peruvian inmates: results of the 2016 prison census.

Introduction: Worldwide, prisons are high-risk settings for the transmission of infectious diseases such as HIV. There is a need to understand the health conditions of prisoners to improve and implement timely strategies for HIV diagnosis and control. Hence, we aimed to identify factors associated with self-reported HIV (srHIV) among Peruvian inmates. Methods: This study is a secondary data analysis of the First Peruvian Prison Census conducted in 2016. We estimated the prevalence of srHIV in prisoners who were male at birth and the association of srHIV with other social conditions, criminal records, and prevalent health conditions. Nested models identified a multivariable parsimonious model for factors associated with srHIV and yielding prevalence ratios adjusted by the included parameters. Results: The census surveyed 71,087 male inmates of whom 0.4% reported srHIV (n = 305), and 82% of whom were receiving antiretroviral treatment (n = 220). In our final multivariable model, srHIV was independently associated with age between 36 and 55 years old vs. >55 years old [parsimonious prevalence ratio (pPR) = 1.98, 95% CI, 0.96-4.08], having a stable partner out of prison (pPR = 1.64, 95% CI, 1.24-2.19), being homosexual (pPR = 4.16, 95% CI, 2.50-6.90), self-report of prevalent tuberculosis co-infection (pPR = 2.55, 95% CI, 1.82-3.58), self-report of prevalent sexually transmitted infections (pPR = 34.49, 95% CI, 24.94-47.70), and self-report of prevalent illicit drug use 30 days before the survey (pPR = 1.91, 95% CI, 1.43-2.56). Conclusion: Self-reported HIV is associated with multiple social, health and prison risks among Peruvian inmates. Deeply understanding these factors would help to design HIV prevention and control strategies in Peruvian prisons.

A Bayesian approach for mixed effects state-space models under skewness and heavy tails.

Human immunodeficiency virus (HIV) dynamics have been the focus of epidemiological and biostatistical research during the past decades to understand the progression of acquired immunodeficiency syndrome (AIDS) in the population. Although there are several approaches for modeling HIV dynamics, one of the most popular is based on Gaussian mixed-effects models because of its simplicity from the implementation and interpretation viewpoints. However, in some situations, Gaussian mixed-effects models cannot (a) capture serial correlation existing in longitudinal data, (b) deal with missing observations properly, and (c) accommodate skewness and heavy tails frequently presented in patients' profiles. For those cases, mixed-effects state-space models (MESSM) become a powerful tool for modeling correlated observations, including HIV dynamics, because of their flexibility in modeling the unobserved states and the observations in a simple way. Consequently, our proposal considers an MESSM where the observations' error distribution is a skew-t. This new approach is more flexible and can accommodate data sets exhibiting skewness and heavy tails. Under the Bayesian paradigm, an efficient Markov chain Monte Carlo algorithm is implemented. To evaluate the properties of the proposed models, we carried out some exciting simulation studies, including missing data in the generated data sets. Finally, we illustrate our approach with an application in the AIDS Clinical Trial Group Study 315 (ACTG-315) clinical trial data set.

Cancer vaccine strategies for the treatment of diffusely infiltrating gliomas.

Diffusely infiltrating gliomas - including glioblastoma (GBM), isocitrate dehydrogenase (IDH) mutant gliomas, and histone 3 (H3) altered gliomas - are primary brain tumors with an invariably fatal outcome. Despite advances in the understanding of their biology, standard, targeted and immune checkpoint inhibitor immunotherapies have proven ineffective in arresting their inexorable progression and associated morbidity and mortality. Recognizing the unique aspects of the immunogenicity of cancer cells, the last decade has seen the development and evaluation of vaccine-based therapies for the treatment of solid tumors, including gliomas. Here we review the current vaccine strategies for the treatment of GBM, IDH-mutant gliomas and diffuse midline glioma H3 K27M-altered. We discuss potential benefits and challenges of vaccine therapies in these specific patient populations.

Effects of home confinement on physical activity, nutrition, and sleep quality during the COVID-19 outbreak in amateur and elite athletes.

Introduction: Despite the progress in the management of the pandemic caused by COVID-19, it is necessary to continue exploring and explaining how this situation affected the athlete population around the world to improve their circumstances and reduce the negative impact of changes in their lifestyle conditions that were necessitated due to the pandemic. The aim of this study was to analyze the moderating influence of physical activity (PA) and dietary habits on the impact of the COVID-19 pandemic experience on sleep quality in elite and amateur athletes. Materials and methods: A total of 1,420 elite (40.1%) and amateur (59.9%) athletes (41% women; 59% men) from 14 different countries participated in a cross-sectional design study. Data were collected using a battery of questionnaires that identified sociodemographic data, sleep quality index, PA levels, dietary habits, and the athletes' perception of their experience during the COVID-19 pandemic. Means and standard deviations were calculated for each variable. The analysis of variances and the correlation between variables were carried out with non-parametric statistics. A simple moderation effect was calculated to analyze the interaction between PA or dietary habits on the perception of the COVID-19 experience effect on sleep quality in elite and amateur athletes. Results: The PA level of elite athletes was higher than amateur athletes during COVID-19 (p < 0.001). However, the PA level of both categories of athletes was lower during COVID-19 than pre-COVID-19 (p < 0.01). In addition, amateurs had a higher diet quality than elite athletes during the pandemic (p = 0.014). The perception of the COVID-19 experience as controllable was significantly higher (p = 0.020) among elite athletes. In addition, two moderating effects had significant interactions. For amateur athletes, the PA level moderated the effect of controllable COVID-19 experience on sleep quality [F (3,777) = 3.05; p = 0.028], while for elite athletes, the same effect was moderated by dietary habits [F (3,506) = 4.47, p = 0.004]. Conclusion: Elite athletes had different lifestyle behaviors compared to amateurs during the COVID-19 lockdown. Furthermore, the relevance of maintaining high levels of PA for amateurs and good quality dietary habits by elite athletes was noted by the moderating effect that both variables had on the influence of the controllable experience during the COVID-19 pandemic on sleep quality.

Impact of gastrointestinal digestion simulation on brewer's spent grain green extracts and their prebiotic activity.

Brewer's spent grain (BSG) is a by-product of the beer industry and a potential source of bioactive compounds. In this study, two methods of extracting bioactive compounds from brewer's spent grain were used - solid-to-liquid conventional extraction (SLE) and solid-to-liquid ohmic heating extraction (OHE) coupled with two ratio combinations of solvents: 60 % and 80 % ethanol:water (v/v). The bioactive potential of the BSG extracts was assessed during the gastrointestinal tract digestion (GID) and the differences in their antioxidant activity, total phenolic content and characterization of the polyphenol profile was measured. The SLE extraction using 60 % ethanol:water (v/v) was the extraction method with higher antioxidant activity (33.88 mg ascorbic acid/g BSG - initial; 16.61 mg ascorbic acid/g BSG - mouth; 15.58 mg ascorbic acid/g BSG - stomach; 17.26 mg ascorbic acid/g BSG - duodenum) and higher content in total phenolics (13.26 mg gallic acid/g BSG - initial; 4.80 mg gallic acid/g BSG - mouth; 4.88 mg gallic acid/g BSG - stomach; 5.00 mg gallic acid/g BSG - duodenum). However, the OHE extraction using 80 % ethanol:water (v/v), had a higher bioaccessibility index (99.77 % for ferulic acid, 72.68 % for 4-hydroxybenzoic acid, 65.37 % for vanillin, 28.99 % for p-coumaric, 22.54 % for catechin) values of polyphenols. All the extracts enhanced (except for SLE for 60 % ethanol:water (v/v) at 2 and 1.5 %, and for 80 % ethanol:water (v/v) at 2 % with Bifidobacterium animalis spp. lactis BB12, where no growth was observed) the growth of the probiotic microorganisms tested (Bifidobacterium animalis B0 - O.D.'s between 0.8240 and 1.7727; Bifidobacterium animalis spp. lactis BB12 - O.D.'s between 0.7219 and 0.8798; Lacticaseibacillus casei 01 - O.D.'s between 0.9121 and 1.0249; and Lactobacillus acidophilus LA-5 - O.D.'s between 0.8595 and 0.9677), demonstrating a potential prebiotic activity of BSG extracts.

Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation-bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis.

Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. As fusion begins, La reappears as a low molecular weight species at the osteoclast surface, where it promotes fusion. La's role in promoting osteoclast fusion is independent of canonical La-RNA interactions and involves direct interactions between La and Annexin A5, which anchors La to transiently exposed phosphatidylserine at the surface of fusing osteoclasts. Disappearance of cell-surface La, and the return of full length La to the nuclei of mature, multinucleated osteoclasts, acts as an off switch of their fusion activity. Targeting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La's potential as a therapeutic target.

Clinical characteristics and outcomes of hospital-manifested COVID-19 among Brazilians.

OBJECTIVES: To analyze the clinical characteristics and outcomes of admitted patients with the hospital- versus community-manifested COVID-19 and to evaluate the risk factors related to mortality in the first population. METHODS: This retrospective cohort included consecutive adult patients with COVID-19, hospitalized between March and September 2020. The demographic data, clinical characteristics, and outcomes were extracted from medical records. Patients with hospital-manifested COVID-19 (study group) and those with community-manifested COVID-19 (control group) were matched by the propensity score model. Logistic regression models were used to verify the risk factors for mortality in the study group. RESULTS: Among 7,710 hospitalized patients who had COVID-19, 7.2% developed symptoms while admitted for other reasons. Patients with hospital-manifested COVID-19 had a higher prevalence of cancer (19.2% vs 10.8%) and alcoholism (8.8% vs 2.8%) than patients with community-manifested COVID-19 and also had a higher rate of intensive care unit requirement (45.1% vs 35.2%), sepsis (23.8% vs 14.5%), and death (35.8% vs 22.5%) (P <0.05 for all). The factors independently associated with increased mortality in the study group were increasing age, male sex, number of comorbidities, and cancer. CONCLUSION: Hospital-manifested COVID-19 was associated with increased mortality. Increasing age, male sex, number of comorbidities, and cancer were independent predictors of mortality among those with hospital-manifested COVID-19 disease.

Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

COVID-19 outcomes in people living with HIV: Peering through the waves

Abstract Objective To evaluate clinical characteristics and outcomes of COVID-19 patients infected with HIV, and to compare with a paired sample without HIV infection. Methods This is a substudy of a Brazilian multicentric cohort that comprised two periods (2020 and 2021). Data was obtained through the retrospective review of medical records. Primary outcomes were admission to the intensive care unit, invasive mechanical ventilation, and death. Patients with HIV and controls were matched for age, sex, number of comorbidities, and hospital of origin using the technique of propensity score matching (up to 4:1). They were compared using the Chi-Square or Fisher's Exact tests for categorical variables and the Wilcoxon for numerical variables. Results Throughout the study, 17,101 COVID-19 patients were hospitalized, and 130 (0.76%) of those were infected with HIV. The median age was 54 (IQR: 43.0;64.0) years in 2020 and 53 (IQR: 46.0;63.5) years in 2021, with a predominance of females in both periods. People Living with HIV (PLHIV) and their controls showed similar prevalence for admission to the ICU and invasive mechanical ventilation requirement in the two periods, with no significant differences. In 2020, in-hospital mortality was higher in the PLHIV compared to the controls (27.9% vs. 17.7%; p = 0.049), but there was no difference in mortality between groups in 2021 (25.0% vs. 25.1%; p > 0.999). Conclusions Our results reiterate that PLHIV were at higher risk of COVID-19 mortality in the early stages of the pandemic, however, this finding did not sustain in 2021, when the mortality rate is similar to the control group.

Lesão Miocárdica e Prognóstico em Pacientes Hospitalizados com COVID-19 no Brasil: Resultados do Registro Nacional de COVID-19 / Myocardial Injury and Prognosis in Hospitalized COVID-19 Patients in Brazil: Results From The Brazilian COVID-19 Registry

Resumo Fundamento As complicações cardiovasculares da COVID-19 são aspectos importantes da patogênese e do prognóstico da doença. Evidências do papel prognóstico da troponina e da lesão miocárdica em pacientes hospitalizados com COVID-19 na América Latina são ainda escassos. Objetivos Avaliar a lesão miocárdica como preditor independente de mortalidade hospitalar e suporte ventilatório mecânico em pacientes hospitalizados, do registro brasileiro de COVID-19. Métodos Este estudo coorte é um subestudo do registro brasileiro de COVID-19, conduzido em 31 hospitais brasileiros de 17 cidades, de março a setembro de 2020. Os desfechos primários incluíram mortalidade hospitalar e suporte ventilatório mecânico invasivo. Os modelos para os desfechos primários foram estimados por regressão de Poisson com variância robusta, com significância estatística de p<0,05. Resultados Dos 2925 pacientes [idade mediana de 60 anos (48-71), 57,1%], 27,3% apresentaram lesão miocárdica. A proporção de pacientes com comorbidades foi maior nos pacientes com lesão miocárdica [mediana 2 (1-2) vs. 1 (0-20)]. Os pacientes com lesão miocárdica apresentaram maiores valores medianos de peptídeo natriurético cerebral, lactato desidrogenase, creatina fosfoquinase, N-terminal do pró-peptídeo natriurético tipo B e proteína C reativa em comparação a pacientes sem lesão miocárdica. Como fatores independentes, proteína C reativa e contagem de plaquetas foram relacionados com o risco de morte, e neutrófilos e contagem de plaquetas foram relacionados ao risco de suporte ventilatório mecânico invasivo. Os pacientes com níveis elevados de troponina apresentaram um maior risco de morte (RR 2,03, IC95% 1,60-2,58) e suporte ventilatório mecânico (RR 1,87;IC95% 1,57-2,23), em comparação àqueles com níveis de troponina normais. Conclusão Lesão cardíaca foi um preditor independente de mortalidade hospitalar e necessidade de suporte ventilatório mecânico em pacientes hospitalizados com COVID-19.

Abstract Background Cardiovascular complications of COVID-19 are important aspects of the disease's pathogenesis and prognosis. Evidence on the prognostic role of troponin and myocardial injury in Latin American hospitalized COVID-19 patients is still scarce. Objectives To evaluate myocardial injury as independent predictor of in-hospital mortality and invasive mechanical ventilation support in hospitalized patients, from the Brazilian COVID-19 Registry. Methods This cohort study is a substudy of the Brazilian COVID-19 Registry, conducted in 31 Brazilian hospitals of 17 cities, March-September 2020. Primary outcomes included in-hospital mortality and invasive mechanical ventilation support. Models for the primary outcomes were estimated by Poisson regression with robust variance, with statistical significance of p<0.05. Results Of 2,925 patients (median age of 60 years [48-71], 57.1% men), 27.3% presented myocardial injury. The proportion of patients with comorbidities was higher among patients with cardiac injury (median 2 [1-2] vs. 1 [0-2]). Patients with myocardial injury had higher median levels of brain natriuretic peptide, lactate dehydrogenase, creatine phosphokinase, N-terminal pro-brain natriuretic peptide, and C-reactive protein than patients without myocardial injury. As independent predictors, C-reactive protein and platelet counts were related to the risk of death, and neutrophils and platelet counts were related to the risk of invasive mechanical ventilation support. Patients with high troponin levels presented a higher risk of death (RR 2.03, 95% CI 1.60-2.58) and invasive mechanical ventilation support (RR 1.87, 95% CI 1.57-2.23), when compared to those with normal troponin levels. Conclusion Cardiac injury was an independent predictor of in-hospital mortality and the need for invasive mechanical ventilation support in hospitalized COVID-19 patients.