Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine—a Staccato trial substudy

Objectives Stavudine is widely used in Thailand and is associated with mitochondrial toxicity. Here, we evaluated the effect of switching from stavudine/didanosine to tenofovir/lamivudine on measures of metabolic and mitochondrial toxicity in Thai patients. Methods Thirty-five Thai patients with full HIV RNA suppression were switched from stavudine/didanosine to tenofovir/lamivudine while receiving saquinavir/ritonavir 1600/100 mg once daily. Patients were assessed at the time of switch and 24 and 48 weeks after for lipids, liver enzymes, lactate, mitochondrial DNA content and limb/total fat mass by dual energy X-ray absorptiometry (DEXA) scanning. Results Forty-eight weeks after the switch, there were significant reductions in lipids and lactate, but no change in liver enzymes. There was reversal of lipoatrophy, as shown by rises in limb fat mass (+0.38 kg, P = 0.006) and total fat mass (+0.69 kg, P = 0.02) on DEXA scan. Patients perceived weight improvement, but did not report reversal of lipoatrophy of individual body parts. The mitochondrial DNA/nuclear DNA ratio rose (+1.06, P < 0.0001). Conclusions After the nucleoside reverse transcriptase inhibitor switch, reversal of mitochondrial toxicity was consistent with switch studies of mainly Caucasian patients, although the peripheral mononuclear cell mitochondrial DNA rise exceeded previous report

Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Ageing

Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with leukocyte telomere length (LTL), a potential marker of cellular ageing. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviours and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviours, and body mass index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL (r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood. Copyright © 2016 European Association of Personality Psycholog

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

Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients

Background: Mitochondrial dysfunction may be causally related to the pathogenesis of organ failure in critically ill patients. Decreased mitochondrial DNA (mtDNA) levels have been associated with mitochondrial dysfunction and were investigated here in relation to short-term (31-day) survival. Methods: This was a prospective longitudinal cohort study of 28 mechanically ventilated critically ill adults admitted to a single center tertiary care intensive care unit (ICU) with hypotension secondary to cardiogenic (N = 13), septic (N = 14) or hypovolemic (N = 1) disease processes. Clinical data and blood were collected at baseline and patients were followed until they expired or left the ICU. Blood was collected every Monday, Wednesday and Friday, and the buffycoat relative mtDNA/nuclear DNA (nDNA) ratio was determined. An archived pool of healthy controls was also studied. Results: At baseline, the patients' mtDNA/nDNA ratio was 30% lower than a pool of 24 healthy controls (0.76 versus 1.09) and was not different between short-term survivors and non-survivors (0.74 ± 0.05 (N = 16) versus 0.79 ± 0.06 (N = 12), p = 0.49). By day 4, the percent mtDNA/nDNA change from baseline in survivors was significantly different from that in non-survivors (+29.5% versus -5.7%, p = 0.03). It also tended to be higher in survivors at last measurement (+38.4% versus +7.1%, p = 0.06). There was a weak correlation between within patient mtDNA/nDNA and platelet count (r = 0.20, p = 0.03) but not with Sequential Organ Failure Assessment (SOFA) scores (r = 0.12, p = 0.23). The mtDNA associations remained after adjustment for platelet. Conclusion: Blood mtDNA levels appeared initially low, increased over time in patients who ultimately survived, and remained low in those who did not. This is consistent with mitochondrial recovery being associated with survival and warrants further investigation as a marker of mitochondrial alterations and outcome in critical illness.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofNon UBCReviewedFacult

Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women--Preliminary Findings of a Prospective Association.

Leukocyte telomere length (LTL) shortens with age, and is a prospective marker of mortality related to cardiovascular disease. Many health behaviors and social environmental factors have been found to be associated with LTL. Several of these are also associated with conscientiousness, a dispositional personality trait. Conscientiousness is a propensity to be planful, adhere to social norms, and inhibit pre-potent responses. Like LTL, conscientiousness is prospectively related to mortality, possibly through cumulative effects on health over the life course via multiple pathways. As a result, we hypothesized that childhood levels of conscientiousness would predict LTL prospectively in adulthood. We selected a sample of 60 women in the Hawaii Personality and Health Cohort; 30 described by their teachers as high on conscientiousness in childhood and 30 described as low on the trait. Dried blood spot samples collected in adulthood 40 years later were used as sources of DNA for the LTL assay. Conscientiousness was associated with longer LTL (p = .02). Controlling for age did not account for this association. Controlling for education and physiological dysregulation partially attenuated the association, and the effect remained significant when accounting for differences in LTL across cultural groups. These results represent the first evidence that childhood personality prospectively predicts LTL 40 years later in adulthood. Our findings would be consistent with a mediation hypothesis whereby conscientiousness predicts life paths and trajectories of health that are reflected in rates of LTL erosion across the lifespan

Plots of adult LTL for high and low childhood conscientiousness groups Bee swarm plots illustrating differences in adult LTL (T/S ratio) across extreme groups for high (<i>n</i> = 29) and low (<i>n</i> = 29) childhood conscientiousness.

<p>Group means are displayed as horizontal line.</p

Sample characteristics of the subsample in comparison to the female clinic sample and for the high versus low childhood conscientiousness groups.

<p><i>Note</i>. Values reported are means (SD) or n (%). These are provided for the full sample as well as the high and low childhood conscientiousness groups combined and separately. Five participants were missing highest grade, 3 in the high child conscientiousness group and 2 in the low group. Ten participants were missing scores on adult conscientiousness, 4 in the high child conscientiousness group and 6 in the low group. Sixteen participants were missing complete data on physical activity, 10 in the high child conscientiousness group and 6 in the low group. Eight participants were missing data on smoking, 5 in the high child conscientiousness group and 3 in the low group.</p><p>*Subsample analyses exclude the two samples stored on neonatal paper noted in the text</p><p>^†Physiological Dysregulation reported in z scores; higher scores indicate poorer health</p><p>^‡Educational Attainment assessed on a 9-point scale where 1 = 8th grade or less; 9 = postgraduate or professional degree</p><p>^§Smoking was coded into five categories (0–4) based on life-time smoking history where 0 = ≤ 100 cigarettes, 1 = previously smoked < 8 Pack years, 2 = previously smoked ≥ 8 pack years, 3 = current smoker at ≤ ½ pack a day, 4 = current smoker > ½ pack a day</p><p>**Physical activity is a weighted sum of three items assessing number of instances of mild, moderate, and strenuous exercise in a typical week over the previous year</p><p>^††Adult conscientiousness measured using sums of 24 items scored on a 5 point scale</p><p>Sample characteristics of the subsample in comparison to the female clinic sample and for the high versus low childhood conscientiousness groups.</p

Plots of adult LTL for high and low childhood conscientiousness groups Bee swarm plots illustrating differences in adult LTL (T/S ratio) across extreme groups for high (<i>n</i> = 29) and low (<i>n</i> = 29) childhood conscientiousness.

<p>Group means are displayed as horizontal line.</p

Eligibility and selection of the pilot sample.

<p>Eligibility and selection of the pilot sample.</p