HIV reservoir and premature aging: risk factors for aging-associated illnesses in adolescents and young adults with perinatally acquired HIV.

Despite receiving antiretroviral therapy (ART), an increasing number of adolescents and young adults with perinatally acquired HIV (PHIVAYA) are at risk of developing premature senescence and aging-associated illnesses, including cancer. Given this concern, it is crucial to assess aging biomarkers and their correlation with the HIV reservoir in order to comprehensively characterize and monitor these individuals. Fifty-five PHIVAYA (median age: 23, interquartile range [IQR]: 20-27 years, and 21 [18-23] years on ART at the time of study sampling) were studied along with 23 age-matched healthy controls. The PHIVAYA exhibited significantly higher percentages of activated, senescent, exhausted CD4 and CD8 T cells, shorter telomeres, reduced thymic output, and higher levels of circulating inflammatory markers (PAMPs, DAMPs, and pro-inflammatory cytokines IL-6, IL-8, and TNFα) as well as denervation biomarkers (neural cell adhesion molecule 1 [NCAM1] and C-terminal Agrin fragment [CAF]), compared to controls. HIV-DNA levels positively correlated with activated, senescent, exhausted CD4 and CD8 T cells, circulating biomarkers levels, and inversely with regulatory T and B cells and telomere length. According to their viremia over time, PHIVAYA were subgrouped into 14 Not Suppressed (NS)-PHIVAYA and 41 Suppressed (S)-PHIVAYA, of whom 6 who initiated ART within one year of age and maintained sustained viral suppression overtime were defined as Early Suppressed (ES)-PHIVAYA and the other 35 as Late Suppressed (LS)-PHIVAYA. ES-PHIVAYA exhibited significantly lower HIV-DNA reservoir, decreased percentages of senescent and exhausted CD4 and CD8 T cells, reduced levels of circulating inflammatory and denervation biomarkers, but longer telomere compared to LS- and NS-PHIVAYA. They differed significantly from healthy controls only in a few markers, including higher percentages of regulatory T and B cells, and higher levels of DAMPs. Overall, these results underscore the importance of initiating ART early and maintaining viral suppression to limit the establishment of the viral reservoir and to counteract immune and cellular premature aging. These findings also suggest new approaches for minimally invasive monitoring of individuals at high risk of developing premature aging and age-related illnesses.

Integrating platelet reactivity in the age, creatinine and ejection fraction score to predict clinical outcomes following percutaneous coronary intervention in patients with chronic coronary syndrome: the PR-ACEF score.

To evaluate if integrating platelet reactivity (PR) evaluation in the original age, creatinine and ejection fraction (ACEF) score could improve the diagnostic accuracy of the model in patients with stable coronary artery disease (CAD). We enrolled patients treated with percutaneous coronary intervention between 2010 and 2011. High PR was included in the model (PR-ACEF). Co-primary end points were a composite of death/myocardial infarction (MI) and major adverse cardiovascular events (MACE). Overall, 471 patients were enrolled. Compared to the ACEF score, the PR-ACEF showed an improved diagnostic accuracy for death/MI (AUC 0.610 vs 0.670, p < 0.001) and MACE (AUC 0.572 vs 0.634, p < 0.001). These findings were confirmed using internal validation with bootstrap resampling. At 5 years, the PR-ACEF value > 1.75 was independently associated with death/MI [HR 3.51, 95% CI (1.97-6.23)] and MACE [HR 2.77, 95% CI (1.69-4.53)]. The PR-ACEF score was effective in improving the diagnostic performance of the ACEF score at the long-term follow-up.

Impact of baseline kidney function on the effects of sodium-glucose co-transporter-2 inhibitors on kidney and heart failure outcomes: A systematic review and meta-analysis of randomized controlled trials.

AIM: To determine whether the magnitude of the cardiorenal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2is) varies with baseline kidney function. METHODS: We searched randomized, placebo-controlled trials testing the effects of SGLT2is on renal and cardiovascular outcomes. Efficacy outcomes, stratified by baseline estimated glomerular filtration rate (eGFR) categories, included renal disease progression, a composite heart failure (HF) outcome and mortality. RESULTS: Thirteen trials testing SGLT2is in 90 402 participants with available eGFR data were included. The risk of bias was judged as low for all trials. SGLT2is reduced the relative risks of renal disease progression by 27% to 57% and of HF outcomes by 13% to 32% across different eGFR categories, with an overall low heterogeneity. Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2is' renal protection (P = .003). The greatest risk reduction was in participants with an eGFR of 90 ml/min/1.73m2 or higher (HR 0.43, 95% CI: 0.32-0.58) and the smallest was in those with an eGFR of less than 30 ml/min/1.73m2 (HR 0.73, 95% CI: 0.62-0.86, P < .001). Conversely, for HF, the greatest risk reduction was in those with an eGFR of less than 30 ml/min/1.73m2 (HR 0.68, 95% CI: 0.48-0.96) and the smallest was in those with an eGFR of 90 ml/min/1.73m2 or higher (HR 0.87, 95% CI: 0.56-1.34). CONCLUSIONS: SGLT2is reduce the risk of renal and HF outcomes for all eGFR categories. The greatest benefits in terms of kidney protection may be achieved by early initiation of SGLT2is in people with preserved eGFR. The greatest risk reduction for HF outcomes is observed in people with lower eGFR values.

Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia.

Adult T-cell leukemia-lymphoma (ATL), is a highly malignant T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), characterized by a poor prognosis. Two viral proteins, Tax-1 and HBZ play important roles in the pathogenesis of ATL. While Tax-1 can be found in both cytoplasm and nucleus of HTLV-1 infected patients, HBZ is exclusively localized in the cytoplasm of HTLV-1 asymptomatic carriers and patients with chronic neurologic disease HAM/TSP, and only in the nucleus of ATL cell lines, suggesting that the nuclear localization of HBZ can be a hallmark of neoplastic transformation. To clarify this crucial point, here we investigated in detail the pattern of HBZ expression in ATL patients. We made use of our monoclonal antibody 4D4-F3, that at present is a uniquely reported reagent, among the few described, able to detect endogenous HBZ by immunofluorescence and confocal microscopy in cells from asymptomatic carriers, HAM/TSP and ATL patients. We found that HBZ localizes both in the cytoplasm and in the nucleus of cells of ATL patients irrespective of their clinical status, with a strong preference for the cytoplasmic localization. Also Tax-1 localized in both compartments. As HBZ is exclusively localized in the cytoplasm in asymptomatic carriers and in non-neoplastic pathologies, this finding shows that neoplastic transformation consequent to HTLV-1 infection is accompanied and associated with the capacity of HBZ to translocate to the nucleus, which suggests a role of cytoplasmic-to-nuclear translocation in HTLV-1-mediated oncogenesis.

Metabolic rewiring and redox alterations in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.

Early risk of mortality, cardiovascular events, and bleeding in patients with newly diagnosed atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is independently associated with a 1.5- to 2.0-fold higher risk of all-cause death and increased morbidity, in particular for heart failure and stroke. Previous studies have shown that the annual rate of death in AF patients is ∼5%; however, emerging data indicate that the risk of death, but also of thromboembolic and bleeding complications, is highest early after the diagnosis, especially during the first month. In light of these observations, patients with newly diagnosed AF deserve close monitoring and may benefit from a comprehensive care targeting modifiable risk factors for death, such as heart failure, diabetes, renal impairment, and vascular disease. Aim of this report is to focus on timing and causes of death as well as on temporal trends of cardiovascular and bleeding complications in patients with newly diagnosed AF.

Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.

BACKGROUND: Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. METHODS: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. RESULTS: Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56-0.89; P=0.003). CONCLUSIONS: The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.

Cardiovascular effects of SGLT-2 inhibitors: What we have learned from cardiovascular outcome trials and what we still need to understand.

The recent results of the DECLARE-TIMI 58 trial forces a profound reflection about the cardiovascular protection conferred by SGLT-2 inhibitors. DECLARE-TIMI 58, the largest cardiovascular outcome trial in diabetes, failed to show a significant reduction in the risk of major adverse cardiovascular events (MACEs) conferred by dapagliflozin compared with placebo. However, a lower rate of hospitalization for heart failure was reported. Whilst the lack of benefits on MACE may seem in contrast with the results of previous SGLT-2 inhibitors cardiovascular outcome trials, DECLARE clearly delineates the real cardiovascular effects of SGLT-2 inhibitors, which mainly tackle heart failure. Differences in study design and population enrolled are crucial to correctly value each molecule and to translate results of clinical trials in daily clinical practise.

Comparison of Lipid-Lowering Medications and Risk for Cardiovascular Disease in Diabetes.

PURPOSE OF THE REVIEW: To summarize available evidence regarding lipid-lowering interventions for the prevention of cardiovascular disease in patients with diabetes. RECENT FINDINGS: Statins and non-statin therapies that act through upregulation of LDL receptor expression are associated with similar cardiovascular risk reduction per decrease in LDL cholesterol. In subjects with diabetes, with or without established cardiovascular disease, each 39 mg/dl reduction in LDL cholesterol observed with statins is associated with a 21% relative reduction in the risk of major coronary events at 5 years. Statins remain the first-line lipid-lowering agents for the management of dyslipidemia in individuals with diabetes; however, the addition of non-statin therapies to lower LDL cholesterol, such as ezetimibe and PCSK-9 inhibitors, to maximally tolerated statin therapy is recommended in patients with atherosclerotic cardiovascular disease and baseline LDL cholesterol over 70 mg/dl. Recent data support even lower LDL cholesterol targets (< 55 mg/dl) to further reduce the risk of cardiovascular events especially in subjects with diabetes and documented cardiovascular disease.

Impact of platelet reactivity on 5-year clinical outcomes following percutaneous coronary intervention: a landmark analysis.

We investigated the impact of suboptimal platelet reactivity on clinical outcomes after percutaneous coronary intervention (PCI). We enrolled 500 patients with stable coronary artery disease undergoing elective PCI. Platelet reactivity was measured before PCI using the VerifyNow P2Y12 assay. Primary endpoint was the incidence of ischemic or bleeding events at 1 month and 5 years. Patients with high platelet reactivity (HPR) showed significantly higher rates of ischemic events both during the 1st month after PCI (HR 2.06, 95% CI 1.02-4.06), and beyond 1 month compared with patients without HPR (HR 1.73, 95% CI 1.02-2.95). Conversely, compared with patients without low platelet reactivity (LPR), patients with LPR presented significantly higher rates of bleeding only during the 1st month (HR 3.67, 95% CI 1.68-8.02). In conclusion, pre-procedural HPR is associated with ischemic events even beyond the 1st month after PCI. The association of LPR with bleeding events seems to be confined to the periprocedural period.

The left atrial appendage: from embryology to prevention of thromboembolism.

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence.

UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. IMPORTANCE: HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel cis-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.

Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study-level meta-analysis of phase III randomized trials.

In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely characterized. We performed a meta-analysis to clarify whether in these patients the strategy of oral anticoagulation should be tailored to diabetes status. In this study-level meta-analysis, we included 4 randomized phase III trials comparing NOACs and warfarin in patients with nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall considered. Incidence of the following outcome measures was evaluated during the follow-up: stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios [RR] 0.80, 95% CI 0.68-0.93; P = .004) and nondiabetic patients (RR 0.83, 0.73-0.93; P = .001) (P for interaction .72). No interaction between diabetes status and benefits of NOACs was found for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (P for interaction >.05 for each comparison). Reduction of vascular death rates with NOACs was significant in diabetic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72-0.96; P = .01), in whom absolute the reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although no interaction was present (P = .23). Results of this meta-analysis support the safety and efficacy of NOACs compared with warfarin in diabetic patients with nonvalvular AF.

Extended duration dual antiplatelet therapy in patients with myocardial infarction: A study-level meta-analysis of controlled randomized trials.

BACKGROUND: Whether dual antiplatelet therapy (DAPT) is beneficial beyond 1 year after myocardial infarction (MI) is not demonstrated; in particular, available studies may be individually underpowered for end points at low incidence, that is, major and fatal bleeding or mortality. We thus assessed the effectiveness and safety of prolonged DAPT after MI over the long term. METHODS: We conducted a systematic search to identify randomized trials on the topic; 3 studies and 21,534 post-MI patients receiving placebo or aspirin plus P2Y12 inhibition for ≥2 years were included. Incidence of the following outcome measures was evaluated: major adverse cardiac events (MACE), major bleeding, fatal bleeding, and cardiovascular and noncardiovascular death. RESULTS: Occurrence of MACE was lower in patients treated with prolonged DAPT: 6.3% vs 7.9% in those without prolonged DAPT (odds ratios 0.74, 95% CI 0.60-0.91, P = .005); in the former, there was also a significant 16% reduction in cardiovascular mortality. Increase in major bleeding with extended duration DAPT was not significant in the overall analysis (1.5% vs 1.0%; P = .10), but became significant in the analysis restricted to patients receiving ticagrelor or prasugrel as second antiplatelet agent (odds ratios 2.16, 95% CI 1.63-2.86); prolonged use of DAPT did not raise rates of fatal bleeding or noncardiovascular mortality. CONCLUSION: Prolonged DAPT after MI reduces MACE and cardiovascular mortality over the long term; this was paralleled by higher risk of nonfatal major bleeding mainly with the newer, more potent P2Y12 antagonists. Tailoring duration of DAPT after MI on the comparative evaluation of both ischemic and bleeding risk is mandatory in this setting.

Safety and Efficacy of Switching From Clopidogrel to Prasugrel in Patients Undergoing Percutaneous Coronary Intervention: A Study-level Meta-analysis From 15 Studies.

BACKGROUND: There is poor evidence on clinical outcome of switching from clopidogrel to prasugrel in patients undergoing percutaneous coronary intervention. OBJECTIVES: Data on the topic are limited and we performed a study-level meta-analysis to assess safety and efficacy of such strategy. METHODS: A total of 15 studies and 3974 patients were included. The following comparisons were performed: prasugrel switching versus prasugrel only therapy; and prasugrel switching versus clopidogrel only therapy. Outcome measures were overall bleeding, major bleeding, and major adverse cardiac events (MACE). RESULTS: There was no statistically significant increased bleeding risk in the prasugrel switching versus prasugrel only group [overall bleeding: OR 1.07, 95% confidence interval (CI), 0.69-1.66; P = 0.77; major bleeding: OR 0.69, 95% CI, 0.32-1.49; P = 0.34]; MACE rates were also comparable. Incidence of safety end points was similar in the prasugrel switching and clopidogrel only groups (overall bleeding: OR 1.27, 95% CI, 0.75-2.15; P = 0.37; major bleeding: OR 0.70, 95% CI, 0.29-1.68; P = 0.42); occurrence of MACE was 3.8% in the prasugrel switching versus 8.3% in the clopidogrel only group (P = 0.23). No statistically significant difference in the safety outcomes was present stratifying by clinical presentation. CONCLUSIONS: Switching from clopidogrel to prasugrel does not increase bleeding complications during follow-up of patients undergoing percutaneous coronary intervention; however, the strength of the data is not sufficient to make definitive clinical recommendations.

Impact of the high-frequency cutoff of bandpass filtering on ECG quality and clinical interpretation: A comparison between 40Hz and 150Hz cutoff in a surgical preoperative adult outpatient population.

BACKGROUND: In 1990 the American Heart Association (AHA) established a standard 0.05 to 150Hz bandwidth for the routine recording of 12-lead electrocardiograms (ECGs). However, subsequent studies have indicated a very high prevalence of deviations from the recommended cutoffs. OBJECTIVE: This prospective observational study investigates the impact of 40Hz compared to 150Hz high-frequency cutoffs on ECG quality and clinical interpretation in a single-center surgical outpatient population. METHODS: 1582 consecutive adult patients underwent two standard 12-lead ECG tracings using different high-frequency cutoffs (40Hz and 150Hz). Two blinded cardiologists randomly reviewed and interpreted the recordings according to pre-defined parameters (PR and ST segment, Q and T wave abnormalities). An arbitrary score, ranging from 1 to 3, was established to evaluate the perceived quality of the recordings and the non-interpretable ECGs were noted. The tracings were then matched to compare interpretations between 40 and 150Hz filters. RESULTS: A 40Hz high-frequency cutoff resulted in an increased rate of optimal quality ECGs compared to the 150Hz cutoff (93.4% vs 54.6%; p<0.001) and a lower rate of non-interpretable traces (0.25% vs 4.80%; p<0.001). Analyzing the morphologic parameters, no significant differences between the filter settings were found, except for a higher incidence of the J-point elevation in the 40Hz high-frequency cutoff (p=0.007) and a higher incidence of left ventricular hypertrophy in the 150Hz high-frequency cutoff (7.4% vs 5.4%, p<0.001). The latter was noted only in ECGs with borderline QRS amplitudes (between 3.3 and 3.7mV; p<0.001). CONCLUSION: Despite current recommendations, the large deviation from standard high-frequency cutoff in clinical practice does not seem to significantly affect ECG clinical interpretation and a 40Hz high-frequency cutoff of the band-pass filtering may be acceptable in a low risk population, allowing for a better quality of tracings.

Identification of novel monocistronic HTLV-1 mRNAs encoding functional Rex isoforms.

BACKGROUND: Human T cell leukemia virus type 1 (HTLV-1) gene expression is controlled by the key regulatory proteins Tax and Rex. The concerted action of these proteins results in a two-phase kinetics of viral expression that depends on a time delay between their action. However, it is difficult to explain this delay, as Tax and Rex are produced from the same mRNA. In the present study we investigated whether HTLV-1 may produce novel mRNA species capable of expressing Rex and Tax independently. FINDINGS: Results revealed the expression of three alternatively spliced transcripts coding for novel Rex isoforms in infected cell lines and in primary samples from infected patients. One mRNA coded for a Tax isoform and a Rex isoform, and two mRNAs coded for Rex isoforms but not Tax. Functional assays showed that these Rex isoforms exhibit activity comparable to canonic Rex. An analysis of the temporal expression of these transcripts upon ex vivo culture of cells from infected patients and cell lines transfected with a molecular clone of HTLV-1 revealed early expression of the dicistronic tax/rex mRNAs followed by the monocistronic mRNAs coding for Rex isoforms. CONCLUSION: The production of monocistronic HTLV-1 mRNAs encoding Rex isoforms with comparable activity to canonical Rex, but with distinct timing, would support a prolonged duration of Rex function with gradual loss of Tax, and is consistent with the two-phase expression kinetics. A thorough understanding of these regulatory circuits will shed light on the basis of viral latency and provide groundwork to develop strategies for eradicating persistent infections.

Statin pretreatment and risk of in-hospital atrial fibrillation among patients undergoing cardiac surgery: a collaborative meta-analysis of 11 randomized controlled trials.

AIMS: Statin pretreatment in patients undergoing cardiac surgery is understood to prevent postoperative atrial fibrillation (AF). However, this is based on observational and limited randomized trial evidence, resulting in uncertainty about any genuine anti-arrhythmic benefits of these agents in this setting. We therefore aimed to quantify precisely the association between statin pretreatment and postoperative AF among patients undergoing cardiac surgery. METHODS AND RESULTS: A detailed search of MEDLINE and PubMed databases (1st January 1996 to 31st July 2012) was conducted, followed by a review of the reference lists of published studies and correspondence with trial investigators to obtain individual-participant data for meta-analysis. Evidence was combined across prospective, randomized clinical trials that compared the risk of postoperative AF among individuals randomized to statin pretreatment or placebo/control medication before elective cardiac surgery. Postoperative AF was defined as episodes of AF lasting ≥5 min. Overall, 1105 participants from 11 trials were included; of them, 552 received statin therapy preoperatively. Postoperative AF occurred in 19% of these participants when compared with 36% of those not treated with statins (odds ratio 0.41, 95% confidence interval 0.31-0.54, P < 0.00001, using a random-effects model). Atrial fibrillation prevention by statin pretreatment was consistent across different subgroups. CONCLUSION: Short-term statin pretreatment may reduce the risk of postoperative AF among patients undergoing cardiac surgery.

Rethinking weight loss treatments as cardiovascular medicine in obesity, a comprehensive review.

The global escalation of obesity has made it a worldwide health concern, notably as a leading risk factor for cardiovascular disease (CVD). Extensive evidence corroborates its association with a range of cardiac complications, including coronary artery disease, heart failure, and heightened vulnerability to sudden cardiac events. Additionally, obesity contributes to the emergence of other cardiovascular risk factors including dyslipidaemia, type 2 diabetes, hypertension, and sleep disorders, further amplifying the predisposition to CVD. To adequately address CVD in patients with obesity, it is crucial to first understand the pathophysiology underlying this link. We herein explore these intricate mechanisms, including adipose tissue dysfunction, chronic inflammation, immune system dysregulation, and alterations in the gut microbiome.Recent guidelines from the European Society of Cardiology underscore the pivotal role of diagnosing and treating obesity to prevent CVD. However, the intricate relationship between obesity and CVD poses significant challenges in clinical practice: the presence of obesity can impede accurate CVD diagnosis while optimizing the effectiveness of pharmacological treatments or cardiac procedures requires meticulous adjustment, and it is crucial that cardiologists acknowledge the implications of excessive weight while striving to enhance outcomes for the vulnerable population affected by obesity. We, therefore, sought to overcome controversial aspects in the clinical management of heart disease in patients with overweight/obesity and present evidence on cardiometabolic outcomes associated with currently available weight management interventions, with the objective of equipping clinicians with an evidence-based approach to recognize and address CVD risks associated with obesity.