bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs
Authors: Bhatt Sasmira , Alison Beth J. , Wallace Euan M. , Crossley Kelly J. , Gill Andrew W. , Kluckow Martin , te Pas Arjan B. , Morley Colin J. , Polglase Graeme R. , Hooper Stuart B. 
Published: February 2013

Key points
Delayed cord clamping improves circulatory stability in preterm infants at birth, but the underlying reason is not known.
In a new preterm lamb study we investigated whether delayed cord clamping until ventilation had been initiated improved pulmonary, cardiovascular and cerebral haemodynamic stability.
We demonstrated that ventilation prior to cord clamping markedly improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped, thus further stabilising the cerebral haemodynamic transition.
These results show that delaying cord clamping until after ventilation onset leads to a smoother transition to newborn life, and probably underlies previously demonstrated benefits of delayed cord clamping.
Abstract  Delayed cord clamping improves circulatory stability in preterm infants at birth, but the underlying physiology is unclear. We investigated the effects of umbilical cord clamping, before and after ventilation onset, on cardiovascular function at birth. Prenatal surgery was performed on lambs (123 days) to implant catheters into the pulmonary and carotid arteries and probes to measure pulmonary (PBF), carotid (CaBF) and ductus arteriosus blood flows. Lambs were delivered at 126 ± 1 days and: (1) the umbilical cord was clamped at delivery and ventilation was delayed for about 2 min (Clamp 1st; n = 6), and (2) umbilical cord clamping was delayed for 3–4 min, until after ventilation was established (Vent 1st; n = 6). All lambs were subsequently ventilated for 30 min. In Clamp 1st lambs, cord clamping rapidly (within four heartbeats), but transiently, increased pulmonary and carotid arterial pressures (by ∼30%) and CaBF (from 30.2 ± 5.6 to 40.1 ± 4.6 ml min−1 kg−1), which then decreased again within 30–60 s. Following ventilation onset, these parameters rapidly increased again. In Clamp 1st lambs, cord clamping reduced heart rate (by ∼40%) and right ventricular output (RVO; from 114.6 ± 14.4 to 38.8 ± 9.7 ml min−1 kg−1), which were restored by ventilation. In Vent 1st lambs, cord clamping reduced RVO from 153.5 ± 3.8 to 119.2 ± 10.6 ml min−1 kg−1, did not affect heart rates and resulted in stable blood flows and pressures during transition. Delaying cord clamping for 3–4 min until after ventilation is established improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped. As a result, cardiac output remains stable, leading to a smoother cardiovascular transition throughout the early newborn period.
PET/CT imaging evidence of FUS‐mediated (18)F‐FDG uptake changes in rat brain
Authors: Kim Hyungmin , Park Mi‐Ae , Wang Shuyan , Chiu Alan , Fischer Krisztina , Yoo Seung‐Schik 
Published: February 2013

Purpose:Transcranial focused ultrasound (FUS) delivers highly focused acoustic energy to a small region of the brain in a noninvasive manner. Recent studies have revealed that FUS, which is administered either in pulsed or continuous waves, can elicit or suppress neural tissue excitability. This neuromodulatory property of FUS has been demonstratedvia direct motion detection, electrophysiological recordings, functional magnetic resonance imaging (fMRI), confocal imaging, and microdialysis sampling of neurotransmitters. This study presents new evidence of local increase in glucose metabolism induced by FUS to the rat brain using FDG (18‐fludeoxyglucose) positron emission tomography (PET).Methods:Sprague–Dawley rats underwent sonication to a unilateral hemispheric area of the brain prior to PET scan. The pulsed sonication (350 kHz, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, and duration of 300 ms) was applied in 2 s intervals for 40 min immediately after the FDG injectionvia tail vein. Subsequently, the PET was acquired in dynamic list‐mode to image FDG activity for an hour, and reconstructed into a single volume representing standardized uptake value (SUV). The raw SUV as well as its asymmetry index (AI) were measured from five different volume‐of‐interests (VOIs) of the brain for both hemispheres, and compared between sonicated and unsonicated groups.Results:Statistically significant hemispheric changes in SUV were observed only at the center of sonication focus within the FUS group [pairedt‐test; t(7) = 3.57, p < 0.05]. There were no significant hemispheric differences in SUV within the control group in any of the VOIs. A statistically significant elevation in AI (t‐test; t(7) = 3.40, p < 0.05) was observed at the center of sonication focus (7.9 ± 2.5%, the deviations are in standard error) among the FUS group when compared to the control group (−0.8 ± 1.2%).Conclusions:Spatially distinct increases in the glucose metabolic activity in the rat brain is present only at the center of sonication focus, suggesting localized functional neuromodulation mediated by the sonication.
The effect of flattening filter free delivery on endothelial dose enhancement with gold nanoparticles
Authors: Detappe Alexandre , Tsiamas Panagiotis , Ngwa Wilfred , Zygmanski Piotr , Makrigiorgos Mike , Berbeco Ross 
Published: February 2013

Purpose:The aim of this study is to quantify and to compare the dose enhancement factor from gold nanoparticles (AuNP) to tumor endothelial cells for different concentrations of AuNP, and clinical MV beam configurations.Methods:Tumor endothelial cells are modeled as slabs measuring 10 × 10 × 2μm. A spherical AuNP is simulated on the surface of the endothelial cell, within the blood vessel. 6 MV photon beams with and without the flattening filter are investigated for different field sizes, depths in material and beam modulation. The incident photon energy spectra for each configuration is generated using EGSnrc. The dose enhancement in the tumor endothelial cell is found using an analytical calculation. The endothelial dose enhancement factor is defined to be the ratio of the dose deposited with and without AuNPs.Results:It is found that clinical beam parameters may be chosen to maximize the effect of gold nanoparticles during radiotherapy. This effect is further amplified ∼20% by the removal of the flattening filter. Modulation of the clinical beam with the multileaf collimator tends to decrease the proportion of low energy photons, therefore providing less enhancement than the corresponding open field.Conclusions:The results of this work predict a dose enhancement to tumor blood vessel endothelial cells using conventional therapeutic (MV) x‐rays and quantify the relative change in enhancement with treatment depth and field size.
A population-level prediction tool for the incidence of first-episode psychosis: translational epidemiology based on cross-sectional data
Authors: Kirkbride James B , Jackson Daniel , Perez Jesus , Fowler David , Winton Francis , Coid Jeremy W , Murray Robin M , Jones Peter B 
Published: February 2013

ObjectivesSpecialist early intervention services (EIS) for people aged 14–35 years with first episodes of psychosis (FEP) have been commissioned throughout England since 2001. A single estimate of population need was used everywhere, but true incidence varies enormously according to sociodemographic factors. We sought to develop a realistically complex, population-based prediction tool for FEP, based on precise estimates of epidemiological risk.Design and participantsData from 1037 participants in two cross-sectional population-based FEP studies were fitted to several negative binomial regression models to estimate risk coefficients across combinations of different sociodemographic and socioenvironmental factors. We applied these coefficients to the population at-risk of a third, socioeconomically different region to predict expected caseload over 2.5 years, where the observed rates of ICD-10 F10-39 FEP had been concurrently ascertained via EIS.SettingEmpirical population-based epidemiological data from London, Nottingham and Bristol predicted counts in the population at-risk in the East Anglia region of England.Main outcome measuresObserved counts were compared with predicted counts (with 95% prediction intervals (PI)) at EIS and local authority district (LAD) levels in East Anglia to establish the predictive validity of each model.ResultsA model with age, sex, ethnicity and population density performed most strongly, predicting 508 FEP participants in EIS in East Anglia (95% PI 459, 559), compared with 522 observed participants. This model predicted correctly in 5/6 EIS and 19/21 LADs. All models performed better than the current gold standard for EIS commissioning in England (716 cases; 95% PI 664–769).ConclusionsWe have developed a prediction tool for the incidence of psychotic disorders in England and Wales, made freely available online (http://www.psymaptic.org), to provide healthcare commissioners with accurate forecasts of FEP based on robust epidemiology and anticipated local population need. The initial assessment of some people who do not require subsequent EIS care means additional service resources, not addressed here, will be required.
LIVING AND DYING WITH LIVER FAILURE: A SERIAL INTERVIEW STUDY
Authors: Kimbell B , Kendall M , Boyd K , Murray S A 
Published: February 2013

IntroductionIn the UK, the incidence of liver disease is increasing dramatically and by 2030 is predicted to kill more people than heart disease. In order to effectively treat this growing patient population we need to understand their experiences. However, research in this area is still underdeveloped.Aims and MethodsTo better understand the experiences, goals and support needs of patients with chronic liver failure, and to what extent existing services are perceived to meet these. We recruited 15 patients with advanced liver disease with a range of aetiologies. Up to three in-depth interviews are undertaken with patients and their informal carers over the course of 1 year. One-off interviews are also undertaken with their professional carers. The data are analysed thematically using Grounded Theory and NVivo 9.ResultsInitial results indicate a high level of unmet physical needs and comorbidities. Considerable uncertainty, anxiety and confusion exist amongst patients regarding their disease and its likely progression. Interprofessional and doctor-patient communication is challenging, and advance care planning largely absent.ConclusionsThis study is the first serial interview study of people with advanced progressive liver disease. They have a high and prolonged burden of physical, social and psychological unmet needs, and like heart failure and COPD patients receive much less support and palliative care than cancer sufferers.
THE BEHAVIOUR AND PAIN (BEPAID) STUDY: DEMENTIA PATIENTS WHO DIE IN THE ACUTE HOSPITAL
Authors: Lord K , White N , Scott S , Sampson E L 
Published: February 2013

IntroductionPeople with dementia admitted to acute hospitals often receive poor care, many of whom die in this setting. The BePaid study (Behaviour and Pain in Dementia) is funded jointly by Alzheimer's Society and the BUPA Foundation.Aims and MethodsA longitudinal cohort study in two London hospitals providing evidence about mortality rates, pain and carer satisfaction using the following tools: Pain Assessment in Advanced Dementia (PAINAD), medical notes review and carer questionnaire.Results230 patients were recruited, with a mortality rate of 13%. 70% of deaths were documented as expected, with 77% of those individuals being put on the Liverpool Care Pathway. Only 17% of patients that subsequently died were referred to the palliative care team during their admission and 27% died with a pressure sore (grades 1–4). 50% of patients were noted by clinicians to be in pain in the last 48 h of life. Mean pain score throughout admission for these that died was 2.69 on the PAINAD, in comparison to 1.49 for those who were discharged. Of those that died, 45% of carers were a little dissatisfied/ dissatisfied with the overall quality of care provided on the ward.ConclusionsRecognising and planning for dying in the acute setting is challenging for clinicians. Palliative Care Teams are not being regularly involved in this process. The data highlights the importance of assessing and managing pain until the end of life. Hospitals need to focus on working with relatives to improve satisfaction with overall quality of care for those whose relatives are dying.
MORECARE CAPACITY: MENTAL CAPACITY AND PROCESSES OF CONSENT FOR RESEARCH ON END-OF-LIFE CARE
Authors: Stone K , Hotopf M , Koffman J , Lewis P , Wee B , Bernal W , Higginson IJ , Evans C J 
Published: February 2013

IntroductionA major barrier to improving end-of-life care (EoLC) is the inclusion of those near to death in research studies. The Mental Capacity Act 2005 clarified concepts on involving adults lacking capacity in research and there are examples of innovative approaches but uncertainty surrounds best research practice. This paper systematically appraises the evidence on the challenges and solutions for adults lacking capacity to participate in research on EoLC.Aims and MethodsA meta-synthesis of the literature on capacity and consent in research on palliative and EoLC to examine the challenges and solutions and identify best practice. A systematic literature appraisal searching five electronic databases and grey literature email survey. Search terms included consent and capacity (and synonyms) within three patient groups: palliative care, mental health and accident and emergency. Selection criteria: primary research concerning adults with compromised capacity and processes of consent in research. A short-semi structured email survey to leading national and international researchers (n=317) to capture ‘out of view’ best practice.Results9916 references were identified, 107 included for full paper review in the palliative care group. Four main themes were identified: (1) timing, (2) proxies and supportive decision making, (3) research resource and expertise, and (4) ethical consideration. 63% of survey respondents had undertaken research involving adults with compromised capacity with assent being the most common approach used.ConclusionsThe meta-synthesis provides guidance on key challenges and solutions to involving those at the end-of-life in research including timing, proxies and supportive decision making, resources for research and ethical considerations.
HANDLE WITH CARE: ADVANCE CARE PLANNING FOR CHILDREN AND YOUNG PEOPLE WITH PALLIATIVE CARE NEEDS
Authors: Mitchell S , Dale J 
Published: February 2013

IntroductionACP for children with life-limiting illnesses presents one of the most complex and ethically challenging scenarios in medicine. Currently most children who die, do so in hospital and most commonly on PICU, despite growing evidence that family preferences are for end-of-life care at home.Aims and MethodsTo investigate current practice related to ACP on PICU, and how this might be improved. A qualitative study was carried out in a PICU setting. Semi-structured interviews were conducted and thematic content analysis carried out on transcriptions.ResultsEight consultants and six senior nurses. Themes emerged around ‘the significance of the death of a child’. ACP is a dynamic, MDT process which is essential to improve care for children with life-limiting conditions. It is currently lacking. As a result, children endure intensive care which is ultimately futile. The GP has an increasingly important role.ConclusionsACP is needed for paediatric patients with life-limiting conditions to improve care, avoid potentially harmful interventions and deliver choice to families. The palliative care population in paediatrics represent a complex group with a diverse range of diagnoses, family situation and multicultural differences. The numbers of children and young people with palliative care needs is rising, and with advances in paediatric medicine the mortality rate is falling. Some are outliving their own life expectancies and transitioning in to adult services, presenting a new challenge for adult palliative care services. There is opportunity for knowledge to be shared between adult and paediatric practitioners in this increasingly relevant area.
REMOTE AND RURAL: THE FORGOTTEN INEQUITY
Authors: Layden J , Bunch H , Hekerem D , Millar L , Maxwell V 
Published: February 2013

IntroductionRemote rural Scotland is 18% of the population and 94% of the land mass. With a lower demand for specialist healthcare, patients are at significant risk of being hidden and forgotten. Barriers to equitable access in remote rural communities includes: poor transport infrastructure, lack of OOH cover and recruitment from a limited pool.Aims and MethodsInnovative service models have been developed in partnership with NHS Boards to address the palliative care needs of Scotland's remote and rural communities. Service models deliver improvements to the quality of end of life care, increase the number of patients dying in their preferred place and reduce unplanned hospital admissions. Two examples are presented.ResultsOptimal Utilisation of remote rural Resources (Argyll and Bute) involves a bank of Marie Curie nurses working to a more flexible contract, complementing existing staff to enable a fast, local and consistent response to palliative care needs. Staff receive some online training which overcomes the difficulties in arranging training within remote rural services. Blended Multi-visit model (Deeside)—a shared community nursing and Marie Curie role, with the flexibility for staff to split their time between a generalist and specialist palliative care role. This enables the service to meet patient needs whilst minimising staff travelling time.ConclusionsThe service models focus on integration and partnership, which takes account of a less predictable demand, the geography and capitalising on the limited local resources. A complete understanding of remote rural communities is essential to develop innovative palliative care services that respond to patient needs.
‘NEW’ POPULATION, NEW CHALLENGES: YOUNG ADULTS IN PALLIATIVE CARE
Authors: Sivell S , Lidstone V , Taubert M , Thompson C , Nelson A 
Published: February 2013

IntroductionThe prognosis of life-limiting conditions of childhood has improved in recent years with an increase in the number of young people accessing adult specialist palliative care (SPC) services. However, little is known about the learning needs and requirements of SPC teams to help provide them with the knowledge and skills to provide care to young people.Aims and MethodsTo identify the training needs of SPC teams and inform the development of an education package for SPC teams.Online Delphi Process:Collated expert opinion on the format, delivery and content of the education package.Round 1: content analysis of free text responses. Rounds 2 and 3: median and mean scores calculated to score the relevance/importance of each item. IQR scores assessed the extent of agreement about the scored relevance of each items. Items where no agreement was reached in Round 2 were put forward to Round 3 for re-rating.Focus groups:Focus groups were held with young people (pre- and post-transition), parents/carers of young people post-transition and staff from a local adult hospice and analysed using thematic analysis.ResultsDelphi:Consensus was reached on the frequency of delivery, who could deliver the training, format of the package and content.Focus Groups:Discussions centred around: challenges of caring for young people; barriers to transition; education and training of staff; facilitating transition.ConclusionsRecommendations include a continuous/rolling programme of education, tailored for content and mode of delivery and incorporated into working practice. A template to guide handover and a single point of contact would facilitate the transition process.
MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models
Authors: Tovar Christian , Graves Bradford , Packman Kathryn , Filipovic Zoran , Xia Brian Higgins Mingxuan , Tardell Christine , Garrido Rosario , Lee Edmund , Kolinsky Kenneth , To Kwong-Him , Linn Michael , Podlaski Frank , Wovkulich Peter , Vu Binh , Vassilev Lyubomir T. 
Published: February 2013

Abstract
MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (KD ∼ 11 nmol/L), blocking its interactions with p53 in vitro. A crystal structure of the RG7112–MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic concentrations caused dose-dependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53. Cancer Res; 73(8); 2587–97. ©2013 AACR.
Increased Circulation of Galectin-3 in Cancer Induces Secretion of Metastasis-Promoting Cytokines from Blood Vascular Endothelium
Authors: Chen Chen , Duckworth Carrie A. , Zhao Qicheng , Pritchard David Mark , Rhodes Jonathan M. , Yu Lu-Gang 
Published: February 2013

AbstractPurpose: Cytokines such as interleukin (IL)-6 and granulocyte colony-stimulating factor (G-CSF) are important metastasis promoters. This study has investigated the functional significance of the increased circulation of galectin-3, a common feature in patients with cancer and in particular those with metastasis, on cytokine secretion from the blood vascular endothelium in cancer.Experimental Design: The effects of galectin-3 on secretion of cytokines from human microvascular lung endothelial cells were assessed in vitro by cytokine array and in vivo in mice. The consequences of galectin-3–induced cytokine secretion on endothelial cell behaviors were determined, and the relationship between the levels of circulating galectin-3 and cytokines in patients with colorectal cancer with and without metastasis was investigated.Results: Galectin-3 at pathologic concentrations found in patients with cancer induces secretion of IL-6, G-CSF, sICAM-1, and granulocyte macrophage colony-stimulating factor from blood vascular endothelial cells in vitro and in mice. These cytokines autocrinely/paracrinely interact with the vascular endothelium to increase the expressions of endothelial cell surface adhesion molecules integrinαvβ1, E-selectin, ICAM-1, and VCAM-1, resulting in increased cancer cell–endothelial adhesion and increased endothelial cell migration and tubule formation. In patients with metastatic colon cancer, higher serum galectin-3 levels correlated significantly with increased serum G-CSF, IL-6, and sICAM1 concentrations.Conclusion: The increased circulation of galectin-3 in patients with cancer induces secretion of several metastasis-promoting cytokines from the blood vascular endothelium that enhances endothelial cell activities in metastasis. Targeting the actions of circulating galectin-3 in patients with cancer therefore represents a promising therapeutic strategy to reduce metastasis and improve survival. Clin Cancer Res; 19(7); 1693–704. ©2013 AACR.