Resistance to thrombomodulin correlates with liver stiffness in chronic liver disease a prospective single-center cohort study.

INTRODUCTION Chronic liver disease (CLD) is characterized by changes in haemostasis, embracing both hypo- and hypercoagulability. Global hemostatic tests such as thrombin generation assays evaluate the hemostatic balance, to better assess bleeding and thrombotic risks. In addition, procoagulant state in patients with CLD has been demonstrated using modified thrombin generation assays with thrombomodulin, a cofactor for protein C activation. In this study, we prospectively determined thrombin generation and thrombomodulin resistance in patients with CLD staged with liver stiffness measurement (LSM), using both the fully automated analyzer ST Genesia® Thrombin Generation System (STG) and the calibrated automated thrombogram assay (CAT). MATERIALS AND METHODS Demographic, clinical and laboratory characteristics, and blood samples were collected from 65 patients with CLD. Liver stiffness was measured by transient elastography, and thrombin generation and thrombomodulin resistance, by STG and CAT. RESULTS Patients were separated based on LSM of <21 and ≥21 kilopascals (kPa). The propagation rate of thrombin generation was higher in patients with LSM ≥21 kPa and the thrombin generation rate increased as LSM increased. In addition, thrombomodulin resistance assessed by STG and CAT was higher in patients with LSM ≥21 kPa. However, ETP inhibition by activated protein C was comparable in patients with LSM <21 and ≥21 kPa. Finally, LSM correlated with most thrombin generation parameters. CONCLUSION The STG automated system may have value in the assessment of patients with chronic liver disease in the routine coagulation laboratory. LSM ≥21 kPa identify a procoagulant phenotype in these patients, including thrombomodulin resistance

Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice

Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity

Female Genital Mutilation/Cutting in the Swiss HIV Cohort Study: A Cross-Sectional Study.

FGM/C is a harmful practice that involves injury of the external female genitalia without medical purpose. It is mainly practiced in Africa, Asia, and the Middle East. However, with the migratory flows, women and girls with FGM/C and its consequences live all over the world. The lack of knowledge on how to care for women and girls living with FGM/C extends among all categories of health professionals involved in women's health, including infectious disease specialists. This is a national, exploratory descriptive cross-sectional study aimed to generate descriptive statistics about FGM/C among HIV-infected migrant women included in the Swiss HIV Cohort Study (SHCS). Among the 387 women interviewed about FGM/C and who provided an answer, 80 (20.7%) reported to have undergone FGM/C. Fifty-six of the 80 women (70.0%) who reported having undergone FGM/C, also reported that they had never discussed their cutting with a health professional before. Our study demonstrates how common female genital mutilation is in women living with HIV and who have migrated to Switzerland and suggest how care and prevention could be improved significantly

Female Genital Mutilation/Cutting in the Swiss HIV Cohort Study: A Cross-Sectional Study

FGM/C is a harmful practice that involves injury of the external female genitalia without medical purpose. It is mainly practiced in Africa, Asia, and the Middle East. However, with the migratory flows, women and girls with FGM/C and its consequences live all over the world. The lack of knowledge on how to care for women and girls living with FGM/C extends among all categories of health professionals involved in women's health, including infectious disease specialists. This is a national, exploratory descriptive cross-sectional study aimed to generate descriptive statistics about FGM/C among HIV-infected migrant women included in the Swiss HIV Cohort Study (SHCS). Among the 387 women interviewed about FGM/C and who provided an answer, 80 (20.7%) reported to have undergone FGM/C. Fifty-six of the 80 women (70.0%) who reported having undergone FGM/C, also reported that they had never discussed their cutting with a health professional before. Our study demonstrates how common female genital mutilation is in women living with HIV and who have migrated to Switzerland and suggest how care and prevention could be improved significantly

Characterization of Human Immunodeficiency Virus Type 1 (HIV-1) Diversity and Tropism in 145 Patients With Primary HIV-1 Infection

Viral diversity during primary HIV-1 infection (PHI) relating to transmission mode, HIV-1 subtypes, and viral tropism was revisited. Varying mucosal barriers were not associated with differences in diversities of founder populations. CXCR4-using viruses are present during PHI but remain exceptional case

Study of Early Elevated Gas6 Plasma Level as a Predictor of Mortality in a Prospective Cohort of Patients with Sepsis.

Growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein interacting with anionic phospholipids and TAM tyrosine kinase receptors, is elevated in plasma of septic patients. Previous studies did not find different levels between survivors and non-survivors at admission because either they included a low number of patients (&lt;50) or a low number of non-survivors (5%). To determine, in a larger cohort of septic patients comprising an expected number of non-survivors, the performance of the plasma level of Gas6 and its soluble receptor Axl (sAxl) within 24 hours of admission to predict in-ICU mortality. Septic adults with or without shock. Gas6 and sAxl were prospectively measured by ELISA at day 0, 3, 7, and then weekly until discharge or death. We evaluated 129 septic patients, including 82 with and 47 without shock, with in-ICU mortality rate of 19.4% and in-hospital mortality rate of 26%. Gas6 level was higher in non-survivors than in survivors (238 vs. 167%, P = 0.003); this difference remained constant during the ICU stay. The area under the ROC curve for Gas6 (0.695 [95% CI: 0.58-0.81]) was higher than for sAxl, procalcitonin, CRP, IL-1beta, IL-6 and-alpha, and slightly higher than for IL-8, IL-10, SOFA and APACHEII scores in predicting in-ICU mortality. Considering 249% as a cut-off value, Gas6 measurement had a negative predictive value for mortality of 87%. It seems that Gas6 plasma level within 24 hours of ICU admission may predicts in-ICU mortality in patients with sepsis. If our result are confirmed in external validation, Gas6 plasma level measurement could contribute to the identification of patients who may benefit most from more aggressive management

Effectiveness of Transmitted Drug Resistance Testing Before Initiation of Antiretroviral Therapy in HIV-Positive Individuals

BACKGROUND For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS We included individuals from the HIV-CAUSAL Collaboration who enrolled <6 months of HIV diagnosis between 2006 and 2015, were ART-naive, and had measured CD4 count and HIV-RNA. Follow-up started at the date when all inclusion criteria were first met (baseline). We compared 2 strategies: (1) TDR testing within 3 months of baseline versus (2) no TDR testing. We used inverse probability weighting to estimate the 5-year proportion and hazard ratios (HRs) of virological suppression (confirmed HIV-RNA <50 copies/mL), and of AIDS or death under both strategies. RESULTS Of 25,672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17,189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). CONCLUSIONS TDR prevalence was low. Although TDR testing improved virological response, we found no evidence that it reduced the incidence of AIDS or death in first 5 years after diagnosis

Impactos sobre o aleitamento materno em crianças do município de Vespasiano durante o período de isolamento social associado à Pandemia do COVID-19

Introdução: O aleitamento materno é fundamental para a saúde infantil, oferecendo benefícios nutricionais, imunológicos e cognitivos. Dessa forma, a amamentação apresenta um papel importante na redução de comorbidade e mortalidade nas crianças. Durante a pandemia da COVID-19, a Atenção Primária, por meio as consultas de puericultura, foram prejudicas na função de acompanhar e incentivar o aleitamento materno exclusivo. Objetivo geral: Analisar o impacto do isolamento social devido à pandemia na prática de aleitamento materno em crianças de até 2 anos atendidas em três unidades de saúde. Método: Trata-se de uma coorte retrospectiva, com base na coleta de dados em prontuários de puericulturas realizadas em 3 unidades de saúde, entre março e dezembro de 2020, de pacientes de 0 a 2 anos. Os critérios de exclusão foram pacientes com contraindicação à amamentação ou prontuários com informações incompletas. Resultados: O aleitamento materno exclusivo até o sexto mês de vida, foi identificado em 38,8% da amostra. A idade de amamentação materna exclusiva entre as crianças variou de 0,3 meses a 8 meses. A idade média foi de 4,7 meses. Discussão: A adesão ao aleitamento materno exclusivo foi baixa, em comparação com as recomendações da Organização Mundial da Saúde, evidenciando a lacuna entre as diretrizes de saúde e a prática real. Aspectos como falta de suporte, questões culturais e retorno ao trabalho contribuem para essa disparidade. Em 2020, observa-se um aumento significativo no aleitamento materno exclusivo, possivelmente relacionado ao maior convívio entre mãe e bebê, sendo uma influência positiva, mas o estresse pandêmico pode impactar negativamente a amamentação. As limitações da pesquisa incluem representatividade da amostra e falta de detalhes sobre a escolha alimentar. Conclusão: Conclui-se que há uma baixa adesão ao aleitamento materno exclusivo e que é preciso reforçar estratégias mais específicas para apoiá-la. O acesso aos serviços de saúde é importante para orientar e incentivar o aleitamento materno

Thrombin Generation Is Associated with Venous Thromboembolism Recurrence, but Not with Major Bleeding and Death in the Elderly: A Prospective Multicenter Cohort Study

It is currently unknown whether thrombin generation is associated with venous thromboembolism (VTE) recurrence, major bleeding, or mortality in the elderly. Therefore, our aim was to prospectively study the association between thrombin generation and VTE recurrence, major bleeding, and mortality in elderly patients with acute VTE. Consecutive patients aged ≥65 years with acute VTE were followed for 2 years, starting from 1 year after the index VTE. Primary outcomes were VTE recurrence, major bleeding, and mortality. Thrombin generation was assessed in 551 patients 1 year after the index VTE. At this time, 59% of the patients were still anticoagulated. Thrombin generation was discriminatory for VTE recurrence, but not for major bleeding and mortality in non-anticoagulated patients. Moreover, peak ratio (adjusted subhazard ratio 4.09, 95% CI, 1.12-14.92) and normalized peak ratio (adjusted subhazard ratio 2.18, 95% CI, 1.28-3.73) in the presence/absence of thrombomodulin were associated with VTE recurrence, but not with major bleeding and mortality after adjustment for potential confounding factors. In elderly patients, thrombin generation was associated with VTE recurrence, but not with major bleeding and/or mortality. Therefore, our study suggests the potential usefulness of thrombin generation measurement after anticoagulation completion for VTE to help identify among elderly patients those at higher risk of VTE recurrence