The Human Serum Metabolome

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

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

Provision of immediate postpartum contraception to women living with HIV in the Eastern Cape, South Africa; a cross-sectional analysis

Abstract Background Universal access to contraception is an important strategy adopted by the South African government to reduce the high rate of unintended pregnancies, especially in women living with HIV. In this article, we describe the choices of contraception and also, examine the influencing factors of the choices of contraception in the immediate postpartum period in parturient women with HIV in the Eastern Cape, South Africa. Methods In this prospective cross-sectional study, 1617 parturient women with HIV completed a survey on the choice of contraception received in the immediate postpartum period (within 72 h) across three large maternity services in the Eastern Cape between September 2015 to May 2016. Additional information was extracted from their medical records. Choices of contraception were categorised as; short-acting (injectables), long-acting reversible (intrauterine device and implants) and permanent contraception (tubal ligation). Adjusted and unadjusted logistic regression models were employed to determine the influencing factors of the choices of contraception received by the cohort. Results Participants were predominantly single (69.1%), unemployed (75.1%), had a grade 7–12 level of education (88.4%) and were HIV positive before their index pregnancy (81.3%). The prevalence of immediate postpartum contraception was high (n = 1507; 93.2%) with Injectables being the preferred choice in the majority of the participants (n = 1218; 75.3%). After controlling for all relevant covariates, single marital status was associated with a higher likelihood of immediate postpartum contraceptive initiation (AOR; 1.82 95% CI 1.10–3.03). Overall, women were more likely to initiate a long-acting reversible and irreversible methods when older than 35 years and having had more than two children. Conclusions We found a high prevalence of immediate postpartum contraception with a preference for Injectables in the study setting. Long-term monitoring of this cohort will elucidate on contraceptive discontinuation and risk of unintended pregnancies in the region. Plain English Summary Ensuring universal access to contraceptives is an important strategy to reduce the rate of unintended pregnancies at the population level. This strategy was adopted by the South African government with a vision of stemming the tide of unintended pregnancies among women living with HIV. In this study, the choices of contraception adopted by women living with HIV following the delivery of their babies were explored. In addition, the study highlights the factors that predict these choices. Participants were asked the choice of contraception they had received prior to being discharged from the maternity centres where they had delivered their babies. The various types of contraception were then categorised by their duration of action. Three distinct groups emerged; short-acting injectables, long acting reversible contraceptives and permanent methods. Of the 1617 women included in the study, 1117 were single and 1314 knew their HIV status prior to the onset of the index pregnancy. Almost all the women (1507 out of 1617) received one form of contraception before leaving the hospital. Many women (1218 out of 1617) chose injectable contraception (short-acting contraception) over the other types of contraception. Women who were older than 34 years and who had three or more children were more likely to choose a long-acting reversible contraceptive and permanent method over the short-acting contraception or nothing. In conclusion, given the short duration of action of the predominant method adopted by these women, a long-term follow up of the study participants will provide more information on the continued use of contraception and risk for unintended pregnancies. </jats:sec

Provision of Immediate Postpartum Contraception to Women living with HIV in the&amp;nbsp;&amp;nbsp;Eastern Cape, South Africa; A Cross-sectional Analysis

Abstract Background: Universal access to contraception is an important strategy adopted by the South African government to reduce the high rate of unintended pregnancies, especially in women living with HIV. In this article, we describe the choices of contraception and also, examine the influencing factors of the choices of contraception in the immediate postpartum period in parturient women with HIV in the Eastern Cape, South Africa.Methods: In this prospective cross-sectional study, 1617 parturient women with HIV completed a survey on the choice of contraception received in the immediate postpartum period (within 72 hours) across three large maternity services in the Eastern Cape between September 2015 to May 2016. Additional information was extracted from their medical records. Choices of contraception were categorised as; short-acting (injectables), long-acting reversible (intrauterine device and implants) and permanent contraception (tubal ligation). Adjusted and unadjusted logistic regression models were employed to determine the influencing factors of the choices of contraception received by the cohort.Results: Participants were predominantly single (69.1%), unemployed (75.1%), had a grade 7-12 level of education (88.4%) and were HIV positive before their index pregnancy (81.3%). The prevalence of immediate postpartum contraception was high (n=1507; 93.2%) with Injectables being the preferred choice in the majority of the participants (n= 1218; 75.3%). After controlling for all relevant covariates, single marital status was associated with a higher likelihood of immediate postpartum contraceptive initiation (AOR;1.82 95% CI;1.10-3.03). Overall, women were more likely to initiate a long-acting reversible and irreversible methods when older than 35 years and having had more than two children.Conclusions: We found a high prevalence of immediate postpartum contraception with a preference for Injectables in the study setting. Long-term monitoring of this cohort will elucidate on contraceptive discontinuation and risk of unintended pregnancies in the region.</jats:p

Determinants of Immediate Postpartum Contraception among Parturient Women with HIV in the Eastern Cape, South Africa; A Prospective Cross-sectional Study

Abstract Background: Universal access to contraception is an important strategy adopted by the South African government in order to reduce the rate of unintended pregnancies in women with HIV. In this article, we describe the choices of contraception and also, examine the influencing factors of the choices of contraception in the immediate postpartum period in parturient women with HIV in the Eastern Cape, South Africa.Methods: In this prospective cross-sectional study, 1617 parturient women with HIV completed a survey on the choice of contraception received in the immediate postpartum period (within 72 hours) across three large maternity services in the Eastern Cape between September 2015 to May 2016. Additional information was extracted from their medical records. Choices of contraception were categorised as; short-acting, long-acting reversible and permanent contraception. Adjusted and unadjusted multinomial regression models were employed to determine the influencing factors of the choices of contraception received by the cohort. Results: Participants were predominantly single (69.1%), unemployed (75.1%), had a grade 7-12 level of education (88.4%) and were HIV positive before their index pregnancy (81.3%).The uptake rate of immediate postpartum contraception was high (n=1507; 93.2%) with injectables being the preferred choice in the majority of the participants (n= 1218; 75.3%). Caesarean delivery was associated with higher odds of initiating long-acting reversible (AOR: 7.79; 95% CI:4.04-15.04) and permanent contraception (AOR: 6.52; 95% CI: 3.48-12.22).Conclusions: We found a high uptake of immediate postpartum contraception with a preference for injectables in the study setting. Long-term monitoring of this cohort will elucidate on the loss to follow-up and risk of unintended pregnancies in the region.</jats:p