Riviste scientifiche

[Department of Error] Department of Error

The Lancet - Sa, 23/05/2020 - 00:00
Clark H, Coll-Seck A M, Banerjee A, et al. A future for the world's children? A WHO-UNICEF–Lancet Commission. Lancet 2020; 395: 605–58—In this Commission, the affiliation details for S Peterson, D B Hipgrave, and J Requejo were incorrect and have been changed to “UNICEF Headquarters, Programme Division, Health Section (S Peterson MD, D B Hipgrave PhD), and Division of Data, Analysis, Planning and Monitoring, Data and Analytics Section, New York, USA (J Requejo PhD)”. Affiliation details for ZA Bhutta (Center of Excellence in Women and Child Health, the Aga Khan University, Karachi, Pakistan) have been added.

[Articles] Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

The Lancet - Sa, 23/05/2020 - 00:00
Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.

[Clinical Picture] Alternative causes of ankle pain in a patient with enthesopathy and X-linked hypophosphataemia

The Lancet - Sa, 23/05/2020 - 00:00
A 43-year-old Australian-born, white man was referred to our unit because of increasing pain in both his ankles. The pain had developed approximately 7 days earlier. 3 days before the pain started, he had been admitted to hospital with cellulitis of his upper arm; he had been treated for septicaemia and acute kidney injury caused by an infection with Streptococcus pyogenes.

[Review] Urinary tract infections in children

The Lancet - Sa, 23/05/2020 - 00:00
Urinary tract infections (UTIs) in children are among the most common bacterial infections in childhood. They are equally common in boys and girls during the first year of life and become more common in girls after the first year of life. Dividing UTIs into three categories; febrile upper UTI (acute pyelonephritis), lower UTI (cystitis), and asymptomatic bacteriuria, is useful for numerous reasons, mainly because it helps to understand the pathophysiology of the infection. A single episode of febrile UTI is often caused by a virulent Escherichia coli strain, whereas recurrent infections and asymptomatic bacteriuria commonly result from urinary tract malformations or bladder disturbances.

Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: A systematic review and meta-analysis

PLoS Medicine - Ve, 22/05/2020 - 23:00

by Jane L. Tarry-Adkins, Catherine E. Aiken, Susan E. Ozanne

Background

Fetal growth in gestational diabetes mellitus (GDM) is directly linked to maternal glycaemic control; however, this relationship may be altered by oral anti-hyperglycaemic agents. Unlike insulin, such drugs cross the placenta and may thus have independent effects on fetal or placental tissues. We investigated the association between GDM treatment and fetal, neonatal, and childhood growth.

Methods and findings

PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and Cochrane databases were systematically searched (inception to 12 February 2020). Outcomes of GDM-affected pregnancies randomised to treatment with metformin, glyburide, or insulin were included. Studies including preexisting diabetes or nondiabetic women were excluded. Two reviewers independently assessed eligibility and risk of bias, with conflicts resolved by a third reviewer. Maternal outcome measures were glycaemic control, weight gain, and treatment failure. Offspring anthropometric parameters included fetal, neonatal, and childhood weight and body composition data. Thirty-three studies (n = 4,944), from geographical locations including Europe, North Africa, the Middle East, Asia, Australia/New Zealand, and the United States/Latin America, met eligibility criteria. Twenty-two studies (n = 2,801) randomised women to metformin versus insulin, 8 studies (n = 1,722) to glyburide versus insulin, and 3 studies (n = 421) to metformin versus glyburide. Eleven studies (n = 2,204) reported maternal outcomes. No differences in fasting blood glucose (FBS), random blood glucose (RBS), or glycated haemoglobin (HbA1c) were reported. No studies reported fetal growth parameters. Thirty-three studies (n = 4,733) reported birth weight. Glyburide-exposed neonates were heavier at birth (58.20 g, 95% confidence interval [CI] 10.10–106.31, p = 0.02) with increased risk of macrosomia (odds ratio [OR] 1.38, 95% CI 1.01–1.89, p = 0.04) versus neonates of insulin-treated mothers. Metformin-exposed neonates were born lighter (−73.92 g, 95% CI −114.79 to −33.06 g, p < 0.001) with reduced risk of macrosomia (OR 0.60, 95% CI 0.45–0.79, p < 0.001) than insulin-exposed neonates. Metformin-exposed neonates were born lighter (−191.73 g, 95% CI −288.01 to −94.74, p < 0.001) with a nonsignificant reduction in macrosomia risk (OR 0.32, 95% CI 0.08–1.19, I2 = 0%, p = 0.09) versus glyburide-exposed neonates. Glyburide-exposed neonates had a nonsignificant increase in total fat mass (103.2 g, 95% CI −3.91 to 210.31, p = 0.06) and increased abdominal (0.90 cm, 95% CI 0.03–1.77, p = 0.04) and chest circumferences (0.80 cm, 95% CI 0.07–1.53, p = 0.03) versus insulin-exposed neonates. Metformin-exposed neonates had decreased ponderal index (−0.13 kg/m3, 95% CI −0.26 to −0.00, p = 0.04) and reduced head (−0.21, 95% CI −0.39 to −0.03, p = 0.03) and chest circumferences (−0.34 cm, 95% CI −0.62 to −0.05, p = 0.02) versus the insulin-treated group. Metformin-exposed neonates had decreased ponderal index (−0.09 kg/m3, 95% CI −0.17 to −0.01, p = 0.03) versus glyburide-exposed neonates. Study limitations include heterogeneity in dosing, heterogeneity in GDM diagnostic criteria, and few studies reporting longitudinal growth outcomes.

Conclusions

Maternal randomisation to glyburide resulted in heavier neonates with a propensity to increased adiposity versus insulin- or metformin-exposed groups. Metformin-exposed neonates were lighter with reduced lean mass versus insulin- or glyburide-exposed groups, independent of maternal glycaemic control. Oral anti-hyperglycaemics cross the placenta, so effects on fetal anthropometry could result from direct actions on the fetus and/or placenta. We highlight a need for further studies examining the effects of intrauterine exposure to antidiabetic agents on longitudinal growth, and the importance of monitoring fetal growth and maternal glycaemic control when treating GDM. This review protocol was registered with PROSPERO (CRD42019134664/CRD42018117503).

Antibody and cellular responses to HIV vaccine regimens with DNA plasmid as compared with ALVAC priming: An analysis of two randomized controlled trials

PLoS Medicine - Ve, 22/05/2020 - 23:00

by Zoe Moodie, Stephen R. Walsh, Fatima Laher, Lucas Maganga, Michael E. Herce, Sarita Naidoo, Mina C. Hosseinipour, Craig Innes, Linda-Gail Bekker, Nicole Grunenberg, Philipp Mann, Chenchen Yu, Allan C. deCamp, Maurine D. Miner, Nicole L. Yates, Jack Heptinstall, Nonhlanhla N. Mkhize, One Dintwe, Nicole Frahm, Kristen W. Cohen, Mary Allen, Julia Hutter, Ralf Wagner, Giuseppe Pantaleo, M. Juliana McElrath, Georgia D. Tomaras, Lynn Morris, David C. Montefiori, Erica Andersen-Nissen, Glenda E. Gray, Peter B. Gilbert, James G. Kublin, the NIAID HVTN 100 and HVTN 111 trial teams

Background

DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle.

Methods and findings

The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%–32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42–3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51–6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67–2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48–2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%–56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%–63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%–82.7%, p < 0.001 for Gag LAI/ZM96). The study’s main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non–vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects.

Conclusions

In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy.

Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial

PLoS Medicine - Ve, 22/05/2020 - 23:00

by Catherine S. Todd, Heidi E. Jones, Nontokozo Langwenya, Donald R. Hoover, Pai-Lien Chen, Gregory Petro, Landon Myer

Background

Women living with HIV (WLHIV) have lower rates of contraceptive use than noninfected peers, yet concerns regarding contraceptive efficacy and interaction with antiretroviral therapy (ART) complicate counseling. Hormonal contraceptives may increase genital tract HIV viral load (gVL) and sexual transmission risk to male partners. We compared gVL, plasma VL (pVL), and intrauterine contraceptive (IUC) continuation between the levonorgestrel intrauterine system (LNG-IUS) and copper intrauterine device (C-IUD) in Cape Town, South Africa.

Methods and findings

In this double-masked, randomized controlled noninferiority trial, eligible WLHIV were ages 18–40, not pregnant or desiring pregnancy within 30 months, screened and treated (as indicated) for reproductive tract infections (RTIs) within 1 month of enrollment, and virologically suppressed using ART or above treatment threshold at enrollment (non-ART). Between October 2013, and December 2016, we randomized consenting women within ART groups, using 1:1 permuted block randomization stratified by ART use, age (18–23, 24–31, 32–40), and recent injectable progestin contraceptive (IPC) exposure, and provided the allocated IUC. At all visits, participants provided specimens for gVL (primary outcome), pVL, RTI, and pregnancy testing. We assessed gVL and pVL across 6 and 24 months controlling for enrollment measures, ART group, age, and RTI using generalized estimating equation and generalized linear models (non-ART group pVL and hemoglobin) in as-treated analyses. We measured IUC discontinuation rates with Kaplan-Meier estimates and Cox proportional hazards models. We enrolled 71 non-ART (36 LNG-IUS, 31 C-IUD; 2 declined and 2 were ineligible) and 134 ART-using (65 LNG-IUS, 67 C-IUD; 1 declined and 1 could not complete IUC insertion) women. Participant median age was 31 years, and 95% had 1 or more prior pregnancies. Proportions of women with detectable gVL were not significantly different comparing LNG-IUS to C-IUD across 6 (adjusted odds ratio [AOR]: 0.78, 95% confidence interval [CI] 0.44–1.38, p = 0.39) and 24 months (AOR: 1.03, 95% CI: 0.68–1.57, p = 0.88). Among ART users, proportions with detectable pVL were not significantly different at 6 (AOR = 0.83, 95% CI 0.37–1.86, p = 0.65) and 24 months (AOR = 0.94, 95% CI 0.49–1.81, p = 0.85), whereas among non-ART women, mean pVL was not significantly different at 6 months (−0.10 log10 copies/mL, 95% CI −0.29 to 0.10, p = 0.50) between LNG-IUS and C-IUD users. IUC continuation was 78% overall; C-IUD users experienced significantly higher expulsion (8% versus 1%, p = 0.02) and elective discontinuation (adjusted hazard ratio: 8.75, 95% CI 3.08–24.8, p < 0.001) rates. Sensitivity analysis adjusted for differential IUC discontinuation found similar gVL results. There were 39 serious adverse events (SAEs); SAEs believed to be directly related to IUC use (n = 7) comprised 3 pelvic inflammatory disease (PID) cases and 4 pregnancies with IUC in place with no discernible trend by IUC arm. Mean hemoglobin change was significantly higher among LNG-IUS users across 6 (0.57 g/dL, 95% CI 0.24–0.90; p < 0.001) and 24 months (0.71 g/dL, 95% CI 0.47–0.95; p < 0.001). Limitations included not achieving non-ART group sample size following change in ART treatment guidelines and truncated 24 months’ outcome data, as 17 women were not yet eligible for their 24-month visit at study closure. Also, a change in VL assay during the study may have caused some discrepancy in VL values because of different limits of detection.

Conclusions

In this study, we found that the LNG-IUS did not increase gVL or pVL and had low levels of contraceptive failure and associated PID compared with the C-IUD among WLHIV. LNG-IUS users were significantly more likely to continue IUC use and had higher hemoglobin levels over time. The LNG-IUS appears to be a safe contraceptive with regard to HIV disease and may be a highly acceptable option for WLHIV.

Trial registration

ClinicalTrials.gov NCT01721798.

Variations in use of childbirth interventions in 13 high-income countries: A multinational cross-sectional study

PLoS Medicine - Ve, 22/05/2020 - 23:00

by Anna E. Seijmonsbergen-Schermers, Thomas van den Akker, Eva Rydahl, Katrien Beeckman, Annick Bogaerts, Lorena Binfa, Lucy Frith, Mechthild M. Gross, Björn Misselwitz, Berglind Hálfdánsdóttir, Deirdre Daly, Paul Corcoran, Jean Calleja-Agius, Neville Calleja, Miriam Gatt, Anne Britt Vika Nilsen, Eugene Declercq, Mika Gissler, Anna Heino, Helena Lindgren, Ank de Jonge

Background

Variations in intervention rates, without subsequent reductions in adverse outcomes, can indicate overuse. We studied variations in and associations between commonly used childbirth interventions and adverse outcomes, adjusted for population characteristics.

Methods and findings

In this multinational cross-sectional study, existing data on 4,729,307 singleton births at ≥37 weeks in 2013 from Finland, Sweden, Norway, Denmark, Iceland, Ireland, England, the Netherlands, Belgium, Germany (Hesse), Malta, the United States, and Chile were used to describe variations in childbirth interventions and outcomes. Numbers of births ranged from 3,987 for Iceland to 3,500,397 for the USA. Crude data were analysed in the Netherlands, or analysed data were shared with the principal investigator. Strict variable definitions were used and information on data quality was collected. Intervention rates were described for each country and stratified by parity. Uni- and multivariable analyses were performed, adjusted for population characteristics, and associations between rates of interventions, population characteristics, and outcomes were assessed using Spearman’s rank correlation coefficients. Considerable intercountry variations were found for all interventions, despite adjustments for population characteristics. Adjustments for ethnicity and body mass index changed odds ratios for augmentation of labour and episiotomy. Largest variations were found for augmentation of labour, pain relief, episiotomy, instrumental birth, and cesarean section (CS). Percentages of births at ≥42 weeks varied from 0.1% to 6.7%. Rates among nulliparous versus multiparous women varied from 56% to 80% versus 51% to 82% for spontaneous onset of labour; 14% to 36% versus 8% to 28% for induction of labour; 3% to 13% versus 7% to 26% for prelabour CS; 16% to 48% versus 12% to 50% for overall CS; 22% to 71% versus 7% to 38% for augmentation of labour; 50% to 93% versus 25% to 86% for any intrapartum pain relief, 19% to 83% versus 10% to 64% for epidural anaesthesia; 6% to 68% versus 2% to 30% for episiotomy in vaginal births; 3% to 30% versus 1% to 7% for instrumental vaginal births; and 42% to 70% versus 50% to 84% for spontaneous vaginal births. Countries with higher rates of births at ≥42 weeks had higher rates of births with a spontaneous onset (rho = 0.82 for nulliparous/rho = 0.83 for multiparous women) and instrumental (rho = 0.67) and spontaneous (rho = 0.66) vaginal births among multiparous women and lower rates of induction of labour (rho = −0.71/−0.66), prelabour CS (rho = −0.61/−0.65), overall CS (rho = −0.61/−0.67), and episiotomy (multiparous: rho = −0.67). Variation in CS rates was mainly due to prelabour CS (rho = 0.96). Countries with higher rates of births with a spontaneous onset had lower rates of emergency CS (nulliparous: rho = −0.62) and higher rates of spontaneous vaginal births (multiparous: rho = 0.70). Prelabour and emergency CS were positively correlated (nulliparous: rho = 0.74). Higher rates of obstetric anal sphincter injury following vaginal birth were found in countries with higher rates of spontaneous birth (nulliparous: rho = 0.65). In countries with higher rates of epidural anaesthesia (nulliparous) and spontaneous births (multiparous), higher rates of Apgar score < 7 were found (rhos = 0.64). No statistically significant variation was found for perinatal mortality. Main limitations were varying quality of data and missing information.

Conclusions

Considerable intercountry variations were found for all interventions, even after adjusting for population characteristics, indicating overuse of interventions in some countries. Multivariable analyses are essential when comparing intercountry rates. Implementation of evidence-based guidelines is crucial in optimising intervention use and improving quality of maternity care worldwide.

All five of Earth's largest mass extinctions linked to global warming

New Scientist - Ve, 22/05/2020 - 20:04
There have been five particularly large extinction events in Earth’s history, and for the first time all of them have been linked to global warming

Fake news gets shared more when it is angry and anxiety-inducing

New Scientist - Ve, 22/05/2020 - 12:00
An analysis of fake news shared on social media service Weibo has found that posts flagged as fake news were more like to contain words associated with anger than real news

Which animals are benefitting from coronavirus lockdowns?

New Scientist - Ve, 22/05/2020 - 11:22
It isn’t true that dolphins have returned to Venice, but bees are benefitting from lower air pollution, and a drop in ocean traffic could be good for whales

Coronavirus drugs: how well is the hunt for covid-19 treatments going?

New Scientist - Ve, 22/05/2020 - 00:56
Hundreds of trials are testing known antiviral drugs, as well as those that block immune responses to coronavirus, but we may need to build a covid-19 treatment from scratch

Bees force plants to flower early by cutting holes in their leaves

New Scientist - Gi, 21/05/2020 - 21:00
Hungry bumblebees can make plants flower up to a month earlier than usual by cutting holes in their leaves, which may help them adapt to climate change

Population of world’s strangest plant threatened by climate change

New Scientist - Gi, 21/05/2020 - 20:10
Hardy and resilient welwitschia is unlike anything else on Earth, but climate change appears to be pushing these plants past their limits

How the coronavirus pandemic is affecting wildlife and conservation

New Scientist - Gi, 21/05/2020 - 19:59
Poaching is up, zoos are running out of money and conservation funding has been slashed. But there’s hope the pandemic could make biodiversity a higher priority

HPV vaccine linked to fewer premature births in Australia

New Scientist - Gi, 21/05/2020 - 19:49
An estimated 2000 premature births seem to have been prevented by widespread HPV vaccination in Australia, possibly by protecting against damage to the cervix

A large moon might be hugging an object in the outer solar system

New Scientist - Gi, 21/05/2020 - 15:25
A trans-Neptunian object known as 2002 TC302 appears to have a large moon at an unusually close orbit

Sugary drink warnings: A meta-analysis of experimental studies

PLoS Medicine - Me, 20/05/2020 - 23:00

by Anna H. Grummon, Marissa G. Hall

Background

Policymakers worldwide are considering requiring warnings for sugary drinks. A growing number of experimental studies have examined sugary drink warnings’ impacts, but no research to our knowledge has synthesized this literature. To inform ongoing policy debates, this study aimed to identify the effects of sugary drink warnings compared with control conditions.

Methods and findings

We systematically searched 7 databases on June 21, 2019, and October 25, 2019. We also searched reference lists of relevant articles. Two investigators independently screened titles, abstracts, and full texts to identify peer-reviewed articles that used an experimental protocol to examine the effects of sugary drink warnings compared to a control condition. Two investigators independently extracted study characteristics and effect sizes from all relevant full-text articles. We meta-analyzed any outcome assessed in at least 2 studies, combining effect sizes using random effects meta-analytic procedures. Twenty-three experiments with data on 16,241 individuals (mean proportion female, 58%) were included in the meta-analysis. Most studies took place in Latin America (35%) or the US or Canada (46%); 32% included children. Relative to control conditions, sugary drink warnings caused stronger negative emotional reactions (d = 0.69; 95% CI: 0.25, 1.13; p = 0.002) and elicited more thinking about the health effects of sugary drinks (d = 0.65; 95% CI: 0.29, 1.01; p < 0.001). Sugary drink warnings also led to lower healthfulness perceptions (d = −0.22; 95% CI: −0.27, −0.17; p < 0.001) and stronger disease likelihood perceptions (d = 0.15; 95% CI: 0.06, 0.24; p = 0.001). Moreover, sugary drink warnings reduced both hypothetical (d = −0.32; 95% CI: −0.44, −0.21; p < 0.001) and actual consumption and purchasing behavior (d = −0.17; 95% CI: −0.30, −0.04; p = 0.012). Statistically significant effects were not observed for perceptions of added sugar or positive sugary drink attitudes (p’s > 0.10). Moderation analyses revealed that health warnings (e.g., “Beverages with added sugar contribute to obesity”) led to greater reductions in hypothetical sugary drink purchases than did nutrient warnings (e.g., “High in sugar”; d = −0.35 versus −0.18; Qb = 4.04; p = 0.04). Limitations of this study include that we did not review grey literature and that we were unable to conduct moderation analyses for several prespecified moderators due to an insufficient number of studies.

Conclusions

This international body of experimental literature supports sugary drink warnings as a population-level strategy for changing behavior, as well as emotions, perceptions, and intentions.

Protocol Registry

PROSPERO ID 146405.

Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study

PLoS Medicine - Me, 20/05/2020 - 23:00

by Mi Lai, Ying Liu, Gabriele V. Ronnett, Anne Wu, Brian J. Cox, Feihan F. Dai, Hannes L. Röst, Erica P. Gunderson, Michael B. Wheeler

Background

Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development.

Methods and findings

The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20–45 years—33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6–9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case–control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820–0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period.

Conclusions

In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM.

Trial registration

ClinicalTrials.gov Identifier: NCT01967030.

Tiny robots can travel through rushing blood to deliver drugs

New Scientist - Me, 20/05/2020 - 21:00
Robots smaller than a red blood cell can move against the flow of blood when directed by magnets, which could help deliver drugs directly to cancer cells
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