Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial.

BACKGROUND: The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks' gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic. METHODS: This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0-28+ 6 weeks' gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0-28+ 6 weeks' gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. DISCUSSION: Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks' postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age. TRIAL REGISTRATION: ISRCTN84264977 . Date assigned: 15/09/2010.

Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans.

BACKGROUND: Little is known about the role of amino acids in cellular signaling pathways, especially as it pertains to pathways that regulate the rate of aging. However, it has been shown that methionine or tryptophan restriction extends lifespan in higher eukaryotes and increased proline or tryptophan levels increase longevity in C. elegans. In addition, leucine strongly activates the TOR signaling pathway, which when inhibited increases lifespan. RESULTS: Therefore each of the 20 proteogenic amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine and aspartate extended lifespan at least to a small extent at one or more of the 3 concentrations tested with serine and proline showing the largest effects. 11 of the amino acids were less potent at higher doses, while 5 even decreased lifespan. Serine, proline, or histidine-mediated lifespan extension was greatly inhibited in eat-2 worms, a model of dietary restriction, in daf-16/FOXO, sir-2.1, rsks-1 (ribosomal S6 kinase), gcn-2, and aak-2 (AMPK) longevity pathway mutants, and in bec-1 autophagy-defective knockdown worms. 8 of 10 longevity-promoting amino acids tested activated a SKN-1/Nrf2 reporter strain, while serine and histidine were the only amino acids from those to activate a hypoxia-inducible factor (HIF-1) reporter strain. Thermotolerance was increased by proline or tryptophan supplementation, while tryptophan-mediated lifespan extension was independent of DAF-16/FOXO and SKN-1/Nrf2 signaling, but tryptophan and several related pyridine-containing compounds induced the mitochondrial unfolded protein response and an ER stress response. High glucose levels or mutations affecting electron transport chain (ETC) function inhibited amino acid-mediated lifespan extension suggesting that metabolism plays an important role. Providing many other cellular metabolites to C. elegans also increased longevity suggesting that anaplerosis of tricarboxylic acid (TCA) cycle substrates likely plays a role in lifespan extension. CONCLUSIONS: Supplementation of C. elegans with 18 of the 20 individual amino acids extended lifespan, but lifespan often decreased with increasing concentration suggesting hormesis. Lifespan extension appears to be caused by altered mitochondrial TCA cycle metabolism and respiratory substrate utilization resulting in the activation of the DAF-16/FOXO and SKN-1/Nrf2 stress response pathways.

How and when to refer a child for specialist paediatric palliative care.

Specialist paediatric palliative care is a relatively new area of paediatrics, and the interface with other disciplines can occasionally pose challenges for referrers due to lack of information about the diverse services available. Although services vary on a regional basis, there are common principles which may be used to guide and support referrals. Children may be referred to palliative care services via a number of routes from community-based primary care to regional tertiary centres. Identifying those most likely to benefit from the finite resources available can be a challenge, and healthcare professional's negative attitudes to palliative care have been further identified as a potentially modifiable barrier. This article aims to clarify the role of specialist paediatric palliative care, identify who should be eligible for such care, describe the services available (including those from children's hospices) and provide a tool for assessing some of the most challenging referrals. Many of the documents referenced can be downloaded from the Together for Short Lives website, and in many cases, there is no charge.

Provider perspectives on implementing a student health and counseling center intervention for sexual violence.

Objective: To describe provider experiences with implementation of the GIFTSS (Giving Information for Trauma Support and Safety) intervention. Participants: Health and counseling center staff from participating campuses attended trainings between August 2015 and August 2016. Interviews were conducted between May and August 2017. Methods: Providers (n = 230) completed surveys prior to and six months following a 3-hour training on the intervention. Structured phone interviews were conducted with a purposively selected subset of 14 providers. Results: Overall, staff found the intervention acceptable. Implementation barriers noted were time and competing patient priorities. Providers noted variation based on patient and visit characteristics. Clinic commitment, particularly in adopting strategies for universal dissemination of the GIFTSS card, was seen as helpful. Conclusion: Implementation of a brief trauma-informed intervention in campus health and counseling centers was feasible and acceptable to most providers. Opportunities to change organizational culture regarding ensuring adequate time and safety for patients are discussed.

Postpartum-Specific Vital Sign Reference Ranges.

OBJECTIVE: To estimate normal ranges for postpartum maternal vital signs. METHODS: We conducted a multicenter prospective longitudinal cohort study in the United Kingdom. We recruited women before 20 weeks of gestation without significant comorbidities and with accurately dated singleton pregnancies. Women recorded their own blood pressure, heart rate, oxygen saturation and temperature daily for 2 weeks postpartum. Trained midwives measured participants' vital signs including respiratory rate around postpartum days 1, 7, and 14. RESULTS: From August 2012 to September 2016, we screened 4,279 pregnant women; 1,054 met eligibility criteria and chose to take part. Postpartum vital sign data were available for 909 women (86.2%). Median, or 50th centile (3rd-97th centile), systolic and diastolic blood pressures increased from the day of birth: 116 mm Hg (88-147) and 74 mm Hg (59-93) to a maximum median of 121 mm Hg (102-143) and 79 mm Hg (63-94) on days 5 and 6 postpartum, respectively, an increase of 5 mm Hg (95% CI 3-7) and 5 mm Hg (95% CI 4-6), respectively. Median (3rd-97th centile) systolic and diastolic blood pressure returned to 116 mm Hg (98-137) and 75 mm Hg (61-91) by day 14 postpartum. The median (3rd-97th centile) heart rate was highest on the day of birth, 84 beats per minute (bpm) (59-110) decreasing to a minimum of 75 bpm (55-101) 14 days postpartum. Oxygen saturation, respiratory rate, and temperature did not change in the 2 weeks postbirth. Median (3rd-97th centile) day-of-birth oxygen saturation was 96% (93-98). Median (3rd-97th centile) day-of-birth respiratory rate was 15 breaths per minute (10-22). Median (3rd-97th centile) day-of-birth temperature was 36.7°C (35.6-37.6). CONCLUSION: We present widely relevant, postpartum, day-specific reference ranges which may facilitate early detection of abnormal blood pressure, heart rate, respiratory rate, oxygen saturation and temperature during the puerperium. Our findings could inform construction of an evidence-based modified obstetric early warning system to better identify unwell postpartum women. CLINICAL TRIAL REGISTRATION: ISRCTN, 10838017.

Gestation-Specific Vital Sign Reference Ranges in Pregnancy.

OBJECTIVE: To estimate normal ranges for maternal vital signs throughout pregnancy, which have not been well defined in a large contemporary population. METHODS: We conducted a three-center, prospective, longitudinal cohort study in the United Kingdom from August 2012 to September 2017. We recruited women at less than 20 weeks of gestation without significant comorbidities with accurately dated singleton pregnancies. We measured participants' blood pressure (BP), heart rate, respiratory rate, oxygen saturation and temperature following standardized operating procedures at 4-6 weekly intervals throughout pregnancy. RESULTS: We screened 4,279 pregnant women, 1,041 met eligibility criteria and chose to take part. Systolic and diastolic BP decreased slightly from 12 weeks of gestation: median or 50th centile (3rd-97th centile) 114 (95-138); 70 (56-87) mm Hg to reach minimums of 113 (95-136); 69 (55-86) mm Hg at 18.6 and 19.2 weeks of gestation, respectively, a change (95% CI) of -1.0 (-2 to 0); -1 (-2 to -1) mm Hg. Systolic and diastolic BP then rose to a maximum median (3rd-97th centile) of 121 (102-144); 78 (62-95) mm Hg at 40 weeks of gestation, a difference (95% CI) of 7 (6-9) and9 (8-10) mm Hg, respectively. The median (3rd-97th centile) heart rate was lowest at 12 weeks of gestation: 82 (63-105) beats per minute (bpm), rising progressively to a maximum of 91 (68-115) bpm at 34.1 weeks. SpO2 decreased from 12 weeks of gestation: median (3-97 centile) 98% (94-99%) to 97% (93-99%) at 40 weeks. The median (3-97 centile) respiratory rate at 12 weeks of gestation was 15 (9-22), which did not change with gestation. The median (3-97 centile) temperature at 12 weeks of gestation was 36.7 (35.6-37.5)°C, decreasing to a minimum of 36.5 (35.3-37.3)°C at 33.4 weeks. CONCLUSION: We present widely relevant, gestation-specific reference ranges for detecting abnormal BP, heart rate, respiratory rate, oxygen saturation and temperature during pregnancy. Our findings refute the existence of a clinically significant BP drop from 12 weeks of gestation. CLINICAL TRIAL REGISTRATION: ISRCTN, ISRCTN10838017.

A cluster-randomized trial of a college health center-based alcohol and sexual violence intervention (GIFTSS): Design, rationale, and baseline sample.

INTRODUCTION: Sexual violence (SV) on college campuses is common, especially alcohol-related SV. This is a 2-arm cluster randomized controlled trial to test a brief intervention to reduce risk for alcohol-related sexual violence (SV) among students receiving care from college health centers (CHCs). Intervention CHC staff are trained to deliver universal SV education to all students seeking care, to facilitate patient and provider comfort in discussing SV and related abusive experiences (including the role of alcohol). Control sites provide participants with information about drinking responsibly. METHODS: Across 28 participating campuses (12 randomized to intervention and 16 to control), 2292 students seeking care at CHCs complete surveys prior to their appointment (baseline), immediately after (exit), 4months later (T2) and one year later (T3). The primary outcome is change in recognition of SV and sexual risk. Among those reporting SV exposure at baseline, changes in SV victimization, disclosure, and use of SV services are additional outcomes. Intervention effects will be assessed using generalized linear mixed models that account for clustering of repeated observations both within CHCs and within students. RESULTS: Slightly more than half of the participating colleges have undergraduate enrollment of ≥3000 students; two-thirds are public and almost half are urban. Among participants there were relatively more Asian (10 v 1%) and Black/African American (13 v 7%) and fewer White (58 v 74%) participants in the intervention compared to control. CONCLUSIONS: This study will offer the first formal assessment for SV prevention in the CHC setting. Clinical Trials #: NCT02355470.

Pregnancy physiology pattern prediction study (4P study): protocol of an observational cohort study collecting vital sign information to inform the development of an accurate centile-based obstetric early warning score.

INTRODUCTION: Successive confidential enquiries into maternal deaths in the UK have identified an urgent need to develop a national early warning score (EWS) specifically for pregnant or recently pregnant women to aid more timely recognition, referral and treatment of women who are developing life-threatening complications in pregnancy or the puerperium. Although many local EWS are in use in obstetrics, most have been developed heuristically. No current obstetric EWS has defined the thresholds at which an alert should be triggered using evidence-based normal ranges, nor do they reflect the changing physiology that occurs with gestation during pregnancy. METHODS AND ANALYSIS: An observational cohort study involving 1000 participants across three UK sites in Oxford, London and Newcastle. Pregnant women will be recruited at approximately 14 weeks' gestation and have their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation and temperature) measured at 4 to 6-week intervals during pregnancy. Vital signs recorded during labour and delivery will be extracted from hospital records. After delivery, participants will measure and record their own vital signs daily for 2 weeks. During the antenatal and postnatal periods, vital signs will be recorded on an Android tablet computer through a custom software application and transferred via mobile internet connection to a secure database. The data collected will be used to define reference ranges of vital signs across normal pregnancy, labour and the immediate postnatal period. This will inform the design of an evidence-based obstetric EWS. ETHICS AND DISSEMINATION: The study has been approved by the NRES committee South East Coast-Brighton and Sussex (14/LO/1312) and is registered with the ISRCTN (10838017). All participants will provide written informed consent and can withdraw from the study at any point. All data collected will be managed anonymously. The findings will be disseminated in international peer-reviewed journals and through research conferences.

Metabolome and proteome changes with aging in Caenorhabditis elegans.

To expand the understanding of aging in the model organism Caenorhabditis elegans, global quantification of metabolite and protein levels in young and aged nematodes was performed using mass spectrometry. With age, there was a decreased abundance of proteins functioning in transcription termination, mRNA degradation, mRNA stability, protein synthesis, and proteasomal function. Furthermore, there was altered S-adenosyl methionine metabolism as well as a decreased abundance of the S-adenosyl methionine synthetase (SAMS-1) protein. Other aging-related changes included alterations in free fatty acid levels and composition, decreased levels of ribosomal proteins, decreased levels of NADP-dependent isocitrate dehydrogenase (IDH1), a shift in the cellular redox state, an increase in sorbitol content, alterations in free amino acid levels, and indications of altered muscle function and sarcoplasmic reticulum Ca(2+) homeostasis. There were also decreases in pyrimidine and purine metabolite levels, most markedly nitrogenous bases. Supplementing the culture medium with cytidine (a pyrimidine nucleoside) or hypoxanthine (a purine base) increased lifespan slightly, suggesting that aging-induced alterations in ribonucleotide metabolism affect lifespan. An age-related increase in body size, lipotoxicity from ectopic yolk lipoprotein accumulation, a decline in NAD(+) levels, and mitochondrial electron transport chain dysfunction may explain many of these changes. In addition, dietary restriction in aged worms resulting from sarcopenia of the pharyngeal pump likely decreases the abundance of SAMS-1, possibly leading to decreased phosphatidylcholine levels, larger lipid droplets, and ER and mitochondrial stress. The complementary use of proteomics and metabolomics yielded unique insights into the molecular processes altered with age in C. elegans.

D-beta-hydroxybutyrate extends lifespan in C. elegans.

The ketone body beta-hydroxybutyrate (ßHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of ßHB supplementation on the lifespan ofC. elegans nematodes. ßHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented ßHB-mediated lifespan extension. ßHB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. ßHB did not extend lifespan in a genetic model of dietary restriction indicating that ßHB is likely functioning through a similar mechanism. ßHB addition also upregulated ΒHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and ßHB dehydrogenase activity induced by ßHB addition, suggesting that F55E10.6 functions as an inducible ßHB dehydrogenase. Furthermore, ßHB supplementation increased worm thermotolerance and partially prevented glucose toxicity. It also delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-ßHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.

Malate and fumarate extend lifespan in Caenorhabditis elegans.

Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. Malate can be synthesized from fumarate by the enzyme fumarase and further oxidized to oxaloacetate by malate dehydrogenase with the accompanying reduction of NAD. Addition of fumarate also extended lifespan, but succinate addition did not, although all three intermediates activated nuclear translocation of the cytoprotective DAF-16/FOXO transcription factor and protected from paraquat-induced oxidative stress. The glyoxylate shunt, an anabolic pathway linked to lifespan extension in C. elegans, reversibly converts isocitrate and acetyl-CoA to succinate, malate, and CoA. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II. Reduction of fumarate to succinate is coupled with the oxidation of FADH2 to FAD. Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors.