TNFAIP3-interacting protein 1 polymorphisms and their association with symptomatic human respiratory syncytial virus infection and bronchiolitis in infants younger than one year from South Africa: A case-control study.

OBJECTIVES: This study analyzed the association of TNFAIP3-interacting protein 1 (TNIP1) polymorphisms with the symptomatic human respiratory syncytial virus (HRSV) infection and bronchiolitis in infants. METHODS: A case-control study was conducted involving 129 hospitalized infants with symptomatic HRSV infection (case group) and 161 healthy infants (control group) in South Africa (2016-2018). Six TNIP1 polymorphisms (rs869976, rs4958881, rs73272842, rs3792783, rs17728338, and rs999011) were genotyped. Genetic associations were evaluated using logistic regression adjusted by age and gender. RESULTS: Both rs73272842 G and rs999011 C alleles were associated with reduced odds for symptomatic HRSV infection (adjusted odd ratio [aOR] = 0.68 [95% confidence interval {CI} = 0.48-0.96] and aOR = 0.36 [95% CI = 0.19-0.68], respectively] and bronchiolitis (aOR = 0.71 [95% CI = 0.50-1.00] and aOR = 0.38 [95% CI = 0.22-0.66], respectively). The significance of these associations was validated using the BCa Bootstrap method (P <0.05). The haplotype GC (composed of rs73272842 and rs999011) was associated with reduced odds of symptomatic HRSV infection (aOR = 0.53 [95% CI = 0.37-0.77]) and bronchiolitis (aOR = 0.62 [95% CI = 0.46-0.84]), which were validated by the BCa Bootstrap method (P = 0.002 for both). CONCLUSION: TNIP1 rs73272842 G allele and rs999011 C allele were associated with reduced odds of symptomatic HRSV infection and the development of bronchiolitis in infants, suggesting that TNIP1 polymorphisms could impact susceptibility to HRSV illness.

MicroRNA signature from extracellular vesicles of HCV/HIV co-infected individuals differs from HCV mono-infected.

Hepatitis C virus (HCV) coinfection with human immunodeficiency virus (HIV) has a detrimental impact on disease progression. Increasing evidence points to extracellular vesicles (EVs) as important players of the host-viral cross-talk. The microRNAs (miRNAs), as essential components of EVs cargo, are key regulators of normal cellular processes and also promote viral replication, viral pathogenesis, and disease progression. We aimed to characterize the plasma-derived EVs miRNA signature of chronic HCV infected and HIV coinfected patients to unravel the molecular mechanisms of coinfection. EVs were purified and characterized from 50 plasma samples (21 HCV mono- and 29 HCV/HIV co-infected). EV-derived small RNAs were isolated and analyzed by massive sequencing. Known and de novo miRNAs were identified with miRDeep2. Significant differentially expressed (SDE) miRNA identification was performed with generalized linear models and their putative dysregulated biological pathways were evaluated. Study groups were similar for most clinical and epidemiological characteristics. No differences were observed in EVs size or concentration between groups. Therefore, HCV/HIV co-infection condition did not affect the concentration or size of EVs but produced a disturbance in plasma-derived EVs miRNA cargo. Thus, a total of 149 miRNAs were identified (143 known and 6 de novo) leading to 37 SDE miRNAs of which 15 were upregulated and 22 downregulated in HCV/HIV co-infected patients. SDE miRNAs regulate genes involved in inflammation, fibrosis, and cancer, modulating different biological pathways related to HCV and HIV pathogenesis. These findings may help to develop new generation biomarkers and treatment strategies, in addition to elucidate the mechanisms underlying virus-host interaction. KEY MESSAGES: HCV and HCV/HIV displayed similar plasma-EV size and concentration. EVs- derived miRNA profile was characterized by NGS. 37 SDE miRNAs between HCV and HCV/HIV were observed. SDE miRNAs regulate genes involved in inflammation, fibrosis and cancer.

HCV spontaneous clearers showed low senescence profile in people living with HIV under long ART.

Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) increases immune activation, inflammation, and oxidative stress that could lead to premature senescence. Different HCV infections, either acute or chronic infection, could lead to distinct premature cellular senescence in people living with HIV (PLWHIV). Observational study in 116 PLWHIV under antiretroviral treatment with different HCV status: (i) n = 45 chronically infected with HCV (CHC); (ii) n = 36 individuals who spontaneously clarify HCV (SC); (iii) n = 35 HIV controls. Oxidative stress biomarkers were analyzed at lipid, DNA, protein, and nitrates levels, as well as antioxidant capacity and glutathione reductase enzyme. Replicative senescence was evaluated by relative telomere length (RTL) measurement. Additionally, 26 markers of Senescence-Associated Secretory Phenotype (SASP) were analyzed by multiplex immunoassays (Luminex xMAP technology). Differences were evaluated by generalized linear model (GLMs) adjusted by most significant covariates. The SC group had a senescence signature similar to the HIV control group and slightly lower SASP levels. However, significant differences were observed with respect to the CHC group, where an increase in the nitrate concentration [adjusted arithmetic mean ratio, aAMR = 1.73 (1.27-2.35), p < 0.001, q = 0.009] and the secretion of 13 SASP-associated factors [granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-ß, interleukin (IL)-1ß, IL-2, IL-8, IL-13, tumor necrosis factor (TNF)-α, IL-1α, IL-1RA, IL-7, IL-15, C-X-C motif chemokine ligand 10 (IP-10), stem cell factor (SCF); q < 0.1)] was detected. The CHC group also showed higher values of IL-1α, IP-10, and placental growth factor 1 (PIGF-1) than HIV controls. The SC group showed a slightly lower senescence profile than the HIV group, which could indicate a more efficient control of viral-induced senescence due to their immune strengths. Chronic HCV infection in PLWHIV led to an increase in nitrate and elevated SASP biomarkers favoring the establishment of viral persistence.

Diagnostic Performance of the HCV Core Antigen Test To Identify Hepatitis C in HIV-Infected Patients: a Systematic Review and Meta-Analysis.

The standard algorithm for diagnosing hepatitis C virus (HCV) infection has two steps, an HCV antibody test for screening and a nucleic acid amplification test (NAAT) for confirmation. However, the HCV core antigen (HCVcAg) detection assay is an alternative for one-step diagnosis. We aimed to evaluate the diagnostic performance of the Abbott ARCHITECT HCV Ag assay to detect active hepatitis C in serum/plasma in people living with HIV/AIDS (PLWHA), through a systematic review and meta-analysis. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched until 20 September 2022 (PROSPERO, CRD42022348351). We included studies evaluating Abbott ARCHITECT HCV Ag assay (index assay) versus NAATs (reference test) in PLWHA coinfected with HCV who did not receive antiviral treatment for HCV. Meta-analysis was performed with the MIDAS module using Stata and random-effects models. The QUADAS-2 tool evaluated the risk of bias. The bivariate analysis was conducted on 11 studies with 2,407 samples. Pooled sensitivity was 0.95 (95% CI = 0.92 to 0.97), specificity 0.97 (95% CI = 0.93 to 0.99), positive likelihood ratio 37.76 (95% CI = 12.84 to 111.02), and negative likelihood ratio 0.06 (95% CI = 0.04 to 0.09). The area under the curve was 0.97 (95% CI = 0.20 to 1.00). For low prevalence (≤5%), the posttest probability that an individual with a positive test was a true positive ranged from 4% to 67%, whereas, at high prevalence (≥10%), the posttest probability was between 81% and 87%, indicating that a confirmatory test should be necessary, particularly with prevalence values of ≤1%. Regardless of prevalence, the probability that an individual with a negative test was a false negative was close to zero, indicating that the individual was not infected with HCV. In conclusion, the accuracy of the Abbott ARCHITECT HCV Ag assay was very good for HCV screening in serum/plasma samples from PLWHA. The clinical utility to confirm HCV infection was acceptable in high-prevalence settings (≥10%) but poor in low-prevalence settings (≤1%). Furthermore, it was excellent in excluding active HCV infection.

HCV eradication with DAAs differently affects HIV males and females: A whole miRNA sequencing characterization.

Gender-specific consequences after HCV eradication are unexplored. MicroRNAs (miRNAs) play a crucial role in the immune response against viral infections. However, few have highlighted miRNA role in sex-biased disease or therapy response. We aim to assess gender differences reflected in the miRNA expression of HIV/HCV-coinfected patients who achieve sustained virological response (SVR) with direct acting antivirals (DAAs). We conducted a prospective study of miRNA expression in PBMCs from 28 chronic HIV/HCV-coinfected patients (HIV/HCV) at baseline and after achieving SVR with DAAs. Sixteen HIV-monoinfected patients (HIV) and 36 healthy controls (HC) were used as controls. Identification of significant differentially expressed (SDE) miRNAs was performed with generalized linear model and mixed GLMs. We also explored putative dysregulated biological pathways. At baseline, the HIV/HCV patients showed differences in the miRNA profile concerning the HIV group (165 and 102 SDE miRNAs for males and females, respectively). Gender-stratified analysis of HIV/HCV group at baseline versus at SVR achievement showed higher differences in males (80 SDE miRNAs) than in females (55 SDE miRNAs). After SVR, HIV/HCV group showed similar values to HIV individuals, especially in females (1 SDE miRNA). However, ten miRNAs in males remained dysregulated, which were mainly involved in cancer, fatty acid, and inflammatory pathways. Taken together, our results show gender-biased dysregulation in the miRNA expression profile of PBMCs after HCV eradication with DAAs. These differences were normalized in females, while miRNA profile and their target-related pathways in males lack of normalization, which may be related to a high-risk of developing liver-related complications.

CEACAM7 polymorphisms predict genetic predisposition to mortality in post-surgical septic shock patients.

We carried out a retrospective exploratory study on 173 patients who underwent major surgery and developed septic shock after surgery. Our findings suggest that CEACAM7 rs1001578, rs10409040, and rs889365 polymorphisms could influence septic shock-related death in individuals who underwent major surgery.

Different HCV Exposure Drives Specific miRNA Profile in PBMCs of HIV Patients.

Micro RNAs (miRNAs) are essential players in HIV and HCV infections, as both viruses modulate cellular miRNAs and interact with the miRNA-mediated host response. We aim to analyze the miRNA profile of HIV patients with different exposure to HCV to explore specific signatures in the miRNA profile of PBMCs for each type of infection. We massively sequenced small RNAs of PBMCs from 117 HIV+ infected patients: 45 HIV+ patients chronically infected with HCV (HIV/HCV+), 36 HIV+ that spontaneously clarified HCV after acute infection (HIV/HCV-) and 36 HIV+ patients without previous HCV infection (HIV). Thirty-two healthy patients were used as healthy controls (HC). Differential expression analysis showed significantly differentially expressed (SDE) miRNAs in HIV/HCV+ (n = 153), HIV/HCV- (n = 169) and HIV (n = 153) patients. We found putative dysregulated pathways, such as infectious-related and PI3K signaling pathways, common in all contrasts. Specifically, putatively targeted genes involved in antifolate resistance (HIV/HV+), cancer-related pathways (HIV/HCV-) and HIF-signaling (HIV) were identified, among others. Our findings revealed that HCV strongly influences the expression profile of PBMCs from HIV patients through the disruption of its miRNome. Thus, different HCV exposure can be identified by specific miRNA signatures in PBMCs.

Age-Adjusted Endothelial Activation and Stress Index for Coronavirus Disease 2019 at Admission Is a Reliable Predictor for 28-Day Mortality in Hospitalized Patients With Coronavirus Disease 2019.

Background: Endothelial Activation and Stress Index (EASIX) predict death in patients undergoing allogeneic hematopoietic stem cell transplantation who develop endothelial complications. Because coronavirus disease 2019 (COVID-19) patients also have coagulopathy and endotheliitis, we aimed to assess whether EASIX predicts death within 28 days in hospitalized COVID-19 patients. Methods: We performed a retrospective study on COVID-19 patients from two different cohorts [derivation (n = 1,200 patients) and validation (n = 1,830 patients)]. The endpoint was death within 28 days. The main factors were EASIX [(lactate dehydrogenase * creatinine)/thrombocytes] and aEASIX-COVID (EASIX * age), which were log2-transformed for analysis. Results: Log2-EASIX and log2-aEASIX-COVID were independently associated with an increased risk of death in both cohorts (p < 0.001). Log2-aEASIX-COVID showed a good predictive performance for 28-day mortality both in the derivation cohort (area under the receiver-operating characteristic = 0.827) and in the validation cohort (area under the receiver-operating characteristic = 0.820), with better predictive performance than log2-EASIX (p < 0.001). For log2 aEASIX-COVID, patients with low/moderate risk (<6) had a 28-day mortality probability of 5.3% [95% confidence interval (95% CI) = 4-6.5%], high (6-7) of 17.2% (95% CI = 14.7-19.6%), and very high (>7) of 47.6% (95% CI = 44.2-50.9%). The cutoff of log2 aEASIX-COVID = 6 showed a positive predictive value of 31.7% and negative predictive value of 94.7%, and log2 aEASIX-COVID = 7 showed a positive predictive value of 47.6% and negative predictive value of 89.8%. Conclusion: Both EASIX and aEASIX-COVID were associated with death within 28 days in hospitalized COVID-19 patients. However, aEASIX-COVID had significantly better predictive performance than EASIX, particularly for discarding death. Thus, aEASIX-COVID could be a reliable predictor of death that could help to manage COVID-19 patients.

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients.

OBJECTIVE: To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. METHODS: We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). RESULTS: HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3). CONCLUSION: HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.

OLFM4 polymorphisms predict septic shock survival after major surgery.

BACKGROUND: Higher expression of olfactomedin-4 (OLFM4), a gene regulated by nuclear factor-kappa B (NF-κB), has been related to a higher risk of organ failure and death in patients with septic shock. We aimed to evaluate the association between OLFM4 single nucleotide polymorphisms (SNPs) and septic shock-related death in 175 patients who underwent major surgery, as well as its performance in predicting mortality. MATERIALS AND METHODS: We carried out a retrospective study. A total of seven OLFM4 SNPs were genotyped by Agena Bioscience's MassARRAY platform. Statistical analysis was performed by Kaplan-Meier and Cox regression tests. The diagnostic performance for predicting septic shock-related death was evaluated by the area under the receiver-operating characteristic (AUROC) curve. RESULTS: Patients with rs17552047 A allele and rs1891944 TT genotype had higher survival than patients with rs17552047 G allele (P-value = .024) and patients with rs1891944 CC/CT genotype (P-value = .038). However, only rs17552047 was associated with a lower risk of death under an additive inheritance model (adjusted hazard ratio [aHR] = 0.44, 95% CI = 0.27-0.71). The multivariate model with the most significant clinical variables (lactate, chronic kidney disease, peritonitis, heart disease and elective surgery) showed an AUROC of 0.776 for predicting septic shock-related death. When we added the OLFM4 rs17552047 SNP to the previous model, the AUROC was 0.811 and was close to reaching significant differences with the previous model (P-value = .065). CONCLUSION: OLFM4 rs17552047 A allele predicts septic shock survival in patients who underwent major surgery. Furthermore, rs17552047, together with clinical variables, could be useful to predict the outcome of septic shock.

IFNL3 rs12980275 Polymorphism Predicts Septic Shock-Related Death in Patients Undergoing Major Surgery: A Retrospective Study.

Interferon lambda 3 (IFNL3, previously called IL-28B) is a cytokine with effects against viral and bacterial pathogens. We aimed to analyze the IFNL3 rs12980275 SNP in patients who underwent major surgery, in order to establish its relationship with susceptibility to septic shock and septic shock-related death in these patients. We performed a case-control study on 376 patients to establish the association between IFNL3 rs12980275 SNP and the susceptibility to develop septic shock. Besides, we performed a longitudinal study among 172 septic shock patients using survival analysis with one censoring point of 28-days mortality. The IFNL3 rs12980275 polymorphism was genotyped by Agena Bioscience's MassARRAY platform. IFNL3 rs12980275 polymorphism was not associated with higher susceptibility to infection and septic shock development. Regarding survival analysis, the Kaplan-Meier analysis showed that patients with IFNL3 rs12980275 AA genotype had higher survival than patients with GG genotype (p = 0.003). The Cox regression analysis adjusted by the most relevant clinical and epidemiological characteristics showed that the GG genotype (recessive model) and the presence of the G allele (additive model) were associated with higher risk of death [adjusted hazard ratio (aHR) = 2.15, p = 0.034; aHR = 1.50, p = 0.030, respectively]. In conclusion, IFNL3 rs12980275 polymorphism was associated with septic shock-related death in patients who underwent major surgery. The A allele was linked to protection, and the G allele was associated with an increased risk of death. This is a first preliminary study that suggests for the first time a role of IFNL3 polymorphisms in the prognosis of septic shock.

DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS naïve HIV-infected patients: a retrospective study.

BACKGROUND: Most of the circulating Vitamin D (VitD) is transported bound to vitamin D-binding protein (DBP), and several DBP single nucleotide polymorphisms (SNPs) have been related to circulating VitD concentration and disease. In this study, we evaluated the association among DBP SNPs and AIDS progression in antiretroviral treatment (ART)-naïve-HIV-infected patients. METHODS: We performed a retrospective study in 667 patients who were classified according to their pattern of AIDS progression (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)) and 113 healthy blood donors (HIV, HCV, and HBV negative subjects). We genotyped seven DBP SNPs (rs16846876, rs12512631, rs2070741, rs2282679, rs7041, rs1155563, rs2298849) using Agena Bioscience's MassARRAY platform. The genetic association was evaluated by Generalized Linear Models adjusted by age at the moment of HIV diagnosis, gender, risk group, and VDR rs2228570 SNP. Multiple testing correction was performed by the false discovery rate (Benjamini and Hochberg procedure; q-value). RESULTS: All SNPs were in HWE (p > 0.05) and had similar genotypic frequencies for DBP SNPs in healthy-controls and HIV-infected patients. In unadjusted GLMs, we only found significant association with AIDS progression in rs16846876 and rs12512631 SNPs. In adjusted GLMs, DBP rs16846876 SNP showed significant association under the recessive inheritance model [LTNPs vs. RPs (adjusted odds ratio (aOR) = 3.53; q-value = 0.044) and LTNPs vs. MPs (aOR = 3.28; q-value = 0.030)] and codominant [LTNPs vs. RPs (aOR = 4.92; q-value = 0.030) and LTNPs vs. MPs (aOR = 3.15; q-value = 0.030)]. Also, we found DBP rs12512631 SNP showed significant association in the inheritance model dominant [LTNPs vs. RPs (aOR = 0.49; q-value = 0.031) and LTNPs vs. MPs (aOR = 0.6; q-value = 0.047)], additive [LTNPs vs. RPs (aOR = 0.61; q-value = 0.031)], overdominant [LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)], and codominant [LTNPs vs. RPs (aOR = 0.52; q-value = 0.036) and LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)]. Additionally, we found a significant association between DBP haplotypes (composed by rs16846876 and rs12512631) and AIDS progression (LTNPs vs RPs): DBP haplotype AC (aOR = 0.63; q-value = 0.028) and the DBP haplotype TT (aOR = 1.64; q-value = 0.028). CONCLUSIONS: DBP rs16846876 and rs12512631 SNPs are related to the patterns of clinical AIDS progression (LTNP, MP, and RP) in ART-naïve HIV-infected patients. Our findings provide new knowledge about AIDS progression that may be relevant to understanding the pathogenesis of HIV infection.

TNFAIP3, TNIP1, and MyD88 Polymorphisms Predict Septic-Shock-Related Death in Patients Who Underwent Major Surgery.

BACKGROUND: In many immune-related diseases, inflammatory responses and several clinical outcomes are related to increased NF-κB activity. We aimed to evaluate whether SNPs related to the NF-κB signaling pathway are associated with higher susceptibility to infection, septic shock, and septic-shock-related death in European patients who underwent major surgery. METHODS: We performed a case-control study on 184 patients with septic shock and 212 with systemic inflammatory response syndrome, and a longitudinal substudy on septic shock patients. Thirty-three SNPs within genes belonging to or regulating the NF-κB signaling pathway were genotyped by Agena Bioscience's MassARRAY platform. RESULTS: No significant results were found for susceptibility to infection and septic shock in the multivariate analysis after adjusting for multiple comparisons. Regarding septic-shock-related death, patients with TNFAIP3 rs6920220 AA, TNIP1 rs73272842 AA, TNIP1 rs3792783 GG, and TNIP1 rs7708392 CC genotypes had the highest risk of septic-shock-related death in the first 28 and 90 days. Also, the MyD88 rs7744 GG genotype was associated with a higher risk of death during the first 90 days. Haplotype analysis shows us that patients with the TNIP1 GAG haplotype (composed of rs73272842, rs3792783, and rs7708392) had a lower risk of death in the first 28 days and the TNIP1 AGC haplotype was associated with a higher risk of death in the first 90 days. CONCLUSIONS: The SNPs in the genes TNFAIP3, TNIP1, and MyD88 were linked to the risk of septic-shock-related death in patients who underwent major surgery.

Genetic variants upstream of TNFAIP3 in the 6q23 region are associated with liver disease severity in HIV/HCV-coinfected patients: A cross-sectional study.

BACKGROUND: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. METHODS: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). RESULTS: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively). CONCLUSIONS: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.

Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

Association of CD14 rs2569190 polymorphism with mortality in shock septic patients who underwent major cardiac or abdominal surgery: A retrospective study.

The aim of this study was to investigate the relationship between the CD14 rs2569190 polymorphism and death related to septic shock in white European patients who underwent major cardiac or abdominal surgery. We carried out a retrospective study in 205 septic shock patients. The septic shock diagnosis was established by international consensus definitions. The outcome variable was the death within 28, 60 and 90 days after septic shock diagnosis. The CD14 rs2569190 polymorphism was analyzed by Agena Bioscience's MassARRAY platform. For the genetic association analysis with survival was selected a recessive inheritance model (GG vs. AA/AG). One hundred thirteen out of 205 patients (55.1%) died with a survival median of 39 days (95%CI = 30.6; 47.4). Patients with rs2569190 GG genotype had shorter survival probability than rs2569190 AA/AG genotype at 60 days (62.3% vs 50%; p = 0.035), and 90 days (62.3% vs 52.6%; p = 0.046). The rs2569190 GG genotype was associated with increased risk of septic shock-related death in the first 60 days (adjusted hazard ratio (aHR) = 1.67; p = 0.016) and 90 days (aHR = 1.64; p = 0.020) compared to rs2569190 AA/AG genotype. In conclusion, the presence of CD14 rs2569190 GG genotype was associated with death in shock septic patients who underwent major surgery. Further studies with bigger sample size are required to verify this relationship.

ADAR1 polymorphisms are related to severity of liver fibrosis in HIV/HCV-coinfected patients.

The adenosine deaminase acting on RNA (ADAR1) gene is an interferon-stimulated gene involved in liver injury protection. Our aim was to analyze the association of polymorphisms within this gene with the severity of liver disease in European HIV/HCV-coinfected patients. We performed a cross-sectional study in 220 patients that underwent a liver biopsy. Five SNPs in the ADAR1 gene (rs1127326, rs1127317, rs1127314, rs1127313, rs2229857) were genotyped by GoldenGate assay. The outcome variables were fibrosis stage and necroinflammatory activity grade by METAVIR-score, aspartate aminotransferase to platelet ratio index (APRI), FIB-4 index, and fibrosis progression rate (FPR). In multivariate analysis, fibrosis progression rate (FPR) (aAMRs = 0.97) decreased in a dose-dependent manner with the presence of rs2229857_T, rs1127313_G, rs1127314_G and rs1127317_G; while rs1127326_T allele had only significant associations with FIB-4 (aAMRs ≤ 0.63) and FPR (aAMRs ≤ 0.97). Moreover, carriers of rs2229857_T, rs1127314_G, rs1127317_G, and rs1127326_T alleles were protected against advanced fibrosis (F ≥ 3) (adjusted ORs (aORs) ≤ 0.44), APRI ≥ 1.5 (aORs ≤ 0.33), and FPR ≥ 0.075 (aORs ≤ 0.45). rs1127313_G carriers showed lower odds of having F ≥ 3 (aORs = 0.39), FIB4 ≥ 3.25 (aOR = 0.22) and FPR ≥ 0.075 (aORs = 0.44). In conclusion, ADAR1 polymorphisms protected against severe liver disease in HIV/HCV-coinfected patients. These results could be used to improve therapeutic decision-making in clinical practice.

IL-6 rs1800795 polymorphism is associated with septic shock-related death in patients who underwent major surgery: a preliminary retrospective study.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, being the primary cause of death from infection, especially if not recognized and treated promptly. The aim of this study was to analyze whether IL-6 rs1800795 polymorphism is associated with septic shock-related death in European white patients who underwent major surgery. METHODS: We performed a retrospective study on 202 septic shock patients who underwent major cardiac or abdominal surgery. The septic shock was established according to the international septic shock definition. The primary outcome variable was the death within 90 days after diagnosis of septic shock. The IL-6 rs1800795 polymorphism was genotyped by Sequenom's MassARRAY platform. RESULTS: The median age of the patients was 73 years, 63.4% were male, and more than 40% of patients had heart disease and hypertension. Overall, the survival analysis showed that 111 (55%) patients died with a survival median of 39 days (95% CI 30.7; 47.2). The genetic analysis association with survival was performed under a recessive genetic model (CC vs. GG/CG). Patients with IL-6 rs1800795 CC genotype had higher mortality rate than the IL-6 rs1800795 GG/CG genotype at days 7 [31.6% (6/19) vs. 10.4% (19/183); log-rank test (p = 0.005)] and 28 [57.9% (11/19) vs. 33.3% (61/183); log-rank test (p = 0.009)], and 90 [68.4% (13/19) vs. 53.5% (98/183); log-rank test (p = 0.006)]. The IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death during the first 7 days [adjusted hazard ratio (aHR 4.65; p = 0.002), 28 days (aHR 2.50; p = 0.006), and 90 days (aHR 2.28; p = 0.006)] with septic shock. When patients were stratified by type of surgery, those with IL-6 rs1800795 CC genotype who underwent cardiac surgery had higher risk of death during the first 7 days (aHR 18.39; p = 0.001) and 28 days (aHR 6.1; p = 0.025) than IL-6 rs1800795 GG/GC carrier, whereas patients with IL-6 rs1800795 CC genotype who underwent abdominal surgery had higher risk of death during all follow-up (aHR 1.98; p = 0.050) than IL-6 rs1800795 GG/GC carrier. CONCLUSIONS: The presence of IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death in patients who underwent major cardiac or abdominal surgery. These findings need robust validation in bigger independent cohorts.

IL-1B rs16944 polymorphism is related to septic shock and death.

BACKGROUND: IL-1ß is a primary mediator of systemic inflammatory response syndrome (SIRS) and it may lead to shock septic. Our aim was to analyse whether IL-1B rs16944 polymorphism is associated with the onset of septic shock and death after major surgery. MATERIALS AND METHODS: We performed a case-control study on 467 patients who underwent major cardiac or abdominal surgery. Of them, 205 patients developed septic shock (cases, SS group) and 262 patients developed SIRS (controls, SIRS group). The primary outcome variables were the development of septic shock and death within 90 days after diagnosis of septic shock. The IL-1B rs16944 polymorphism was genotyped by Sequenom's MassARRAY platform. The association analysis was performed under a recessive genetic model (AA vs. GG/GC). RESULTS: The frequency of septic shock was higher in patients with IL-1B rs16944 AA genotype than in patients with IL-1B rs16944 GG/AG genotype when all patients were taken into account (63·6% vs. 41·8%; P = 0·006), cardiac surgery (52·2% vs. 33·3%; P = 0·072) and abdominal surgery (76·2% vs. 50·2%; P = 0·023). However, the IL-1B rs16944 AA genotype was only associated with higher likelihood of septic shock in the analysis of all population [adjusted odds ratio (aOR) = 2·26 (95%CI = 1·03; 4·97; P = 0·042], but not when it was stratified by cardiac surgery (P = 0·175) or abdominal surgery (P = 0·467). Similarly, IL-1B rs16944 AA genotype was also associated with higher likelihood of septic shock-related death in all population [aOR = 2·67 (95%CI = 1·07; 4·97); P = 0·035]. CONCLUSIONS: IL-1B rs16944 AA genotype seems to be related to the onset of septic shock and death in patients who underwent major surgery.