Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Cross-Linking-Induced Permanently Perpendicular Helix Orientation in Surface-Grafted Polyglutamate Films

Using a chemical cross-linking procedure, surface-grafted polyglutamate films with a permanently perpendicular helix orientation were prepared. A surface-grafted R-helical polyglutamate film containing polymerizable side groups was synthesized by ring-opening terpolymerization of 50 molar% γ-methyl-L-glutamate N-carboxyanhydride (NCA), 30% γ-stearyl-L-glutamate NCA and 20% γ-4-vinylbenzyl-L-glutamate NCA initiated from a silicon substrate functionalized with primary amino groups. The average tilt angle of the end-grafted helices in this film is approximately 66°, indicating a nearly parallel helix orientation with respect to the substrate surface. After swelling of the grafted terpolyglutamate film in stearyl methacrylate and subsequent radical cross-linking, the average helix tilt angle decreases to about 11°, indicating an almost perpendicular helix orientation. The film thickness increases accordingly from 151 Å before to approximately 390 Å after cross-linking. Extensive solvent treatment of the cross-linked film shows that the perpendicular helix orientation is permanent.

Abdominal Compressions Increase Vital Organ Perfusion During CPR in Dogs: Relation With Efficacy of Thoracic Compressions

Study objective: Abdominal compressions can be interposed between the thoracic compressions of standard CPR (SCPR). The resulting interposed abdominal compression CPR (IAC-CPR) may increase blood pressures and patient survival, particularly if applied as a primary technique after in-hospital cardiac arrest. We used a predominant cardiac compression canine model to study the effects of IAC-CPR on blood pressures and total and vital organ perfusion as a function of time after cardiac arrest and efficacy of SCPR. Design: In a crossover design, we measured blood pressures and total and regional blood flow (radioactive microspheres) during 6-minute episodes of mechanical SCPR and IAC-CPR, both early (4 to 16 minutes) and late (18 to 30 minutes) after induction of ventricular fibrillation in eight dogs (weight, 25 to 33 kg) under neuroleptanalgesia/anesthesia. Results: During IAC-CPR, the ascending aorticright atrial pressure gradient increased (P<.05), and retrograde pressure pulses contributed to the rise of ascending aortic pressure. Within 2 minutes after the start of IAC-CPR, end-tidal CO 2 fraction increased by 0.6±0.4 vol% (P<.05), suggesting enhanced venous return. IAC-CPR enhanced (P<.05) total forward blood flow (574±406 versus 394±266 mL/minute during SCPR for the early phase) and vital organ perfusion (including myocardium), in both early and late phases. The IAC-CPR-induced augmentation of blood flow was greater if perfusion was relatively high during SCPR. Conclusion: Compared with predominant cardiac compressions alone (SCPR), the addition of interposed abdominal compressions (IAC-CPR) improves total and vital organ oxygen delivery through enhanced venous return and perfusion pressures. [Hoekstra OS, van Lambalgen AA, Groeneveld ABJ, van den Bos GC, Thijs LG: Abdominal compressions increase vital organ perfusion during CPR in dogs: Relation with efficacy of thoracic compressions. Ann Emerg Med March1995;25:375-385.]

Betaglycan (TGFBR3) up-regulation correlates with increased TGF-β signaling in Marfan patient fibroblasts in vitro

Background: Marfan syndrome (MFS), a congenital connective tissue disorder leading to aortic aneurysm development, is caused by fibrillin-1 (FBN1) gene mutations. Transforming growth factor beta (TGF-β) might play a role in the pathogenesis. It is still a matter of discussion if and how TGF-β up-regulates the intracellular downstream pathway, although TGF-β receptor 3 (TGFBR3 or Betaglycan) is thought to be involved. We aimed to elucidate the role of TGFBR3 protein in TGF-β signaling in Marfan patients. Methods: Dermal fibroblasts of MFS patients with haploinsufficient (HI; n=9) or dominant negative (DN; n=4) FBN1 gene mutations, leading to insufficient or malfunctioning fibrillin-1, respectively, were used. Control cells (n=10) were from healthy volunteers. We quantified TGFBR3 protein expression by immunofluorescence microscopy and gene expression of FBN1, TGFB1, its receptors, and downstream transcriptional target genes by quantitative polymerase chain reaction. Results: Betaglycan protein expression in FBN1 mutants pooled was higher than in controls (P=.004) and in DN higher than in HI (P=.015). In DN, significantly higher mRNA expression of FBN1 (P=.014), SMAD7 (P=.019), HSP47 (P=.023), and SERPINE1 (P=.008), but a lower HSPA5 expression (P=.029), was observed than in HI. A pattern of higher expression was noted for TGFB1 (P=.059), FN1 (P=.089), and COL1A1 (P=.089) in DN as compared to HI. TGFBR3 protein expression in cells, both presence in the endoplasmic reticulum and amount of vesicles per cell, correlated positively with TGFB1 mRNA expression (Rs=0.60, P=.017; Rs=0.55, P=.029; respectively). TGFBR3 gene expression did not differ between groups. Conclusion: We demonstrated that activation of TGF-β signaling is higher in patients with a DN than an HI FBN1 gene mutation. Also, TGFBR3 protein expression is increased in the DN group and correlates positively with TGFB1 expression in groups pooled. We suggest that TGFBR3 protein expression is involved in up-regulated TGF-β signaling in MFS patients with a DN FBN1 gene mutation