Detection of large-scale X-ray bubbles in the Milky Way halo.

The halo of the Milky Way provides a laboratory to study the properties of the shocked hot gas that is predicted by models of galaxy formation. There is observational evidence of energy injection into the halo from past activity in the nucleus of the Milky Way1-4; however, the origin of this energy (star formation or supermassive-black-hole activity) is uncertain, and the causal connection between nuclear structures and large-scale features has not been established unequivocally. Here we report soft-X-ray-emitting bubbles that extend approximately 14 kiloparsecs above and below the Galactic centre and include a structure in the southern sky analogous to the North Polar Spur. The sharp boundaries of these bubbles trace collisionless and non-radiative shocks, and corroborate the idea that the bubbles are not a remnant of a local supernova5 but part of a vast Galaxy-scale structure closely related to features seen in γ-rays6. Large energy injections from the Galactic centre7 are the most likely cause of both the γ-ray and X-ray bubbles. The latter have an estimated energy of around 1056 erg, which is sufficient to perturb the structure, energy content and chemical enrichment of the circumgalactic medium of the Milky Way.

Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma.

INTRODUCTION: Immune checkpoint inhibition (ICI) has improved patients' outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance. METHODS: Stage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included. RESULTS: In the majority of patients, the progressive tumor lesion contained higher CD8+ T cell counts/mm2 and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion. In the acquired tumor lesions, high CD8+/mm2 and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found. CONCLUSION: Intrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

BluePrint molecular subtypes predict response to neoadjuvant pertuzumab in HER2-positive breast cancer.

BACKGROUND: The introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain which patients derive most benefit. In this study, we determine the prognostic value of BluePrint subtyping in HER2-positive breast cancer. Additionally, we evaluate its use as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab. METHODS: From a cohort of patients with stage II-III HER2-positive breast cancer who were treated with neoadjuvant chemotherapy and trastuzumab with or without pertuzumab, 836 patients were selected for microarray gene expression analysis, followed by readout of BluePrint standard (HER2, Basal and Luminal) and dual subtypes (HER2-single, Basal-single, Luminal-single, HER2-Basal, Luminal-HER2, Luminal-HER2-Basal). The associations between subtypes and pathological complete response (pCR), overall survival (OS) and breast cancer-specific survival (BCSS) were assessed, and pertuzumab benefit was evaluated within the BluePrint subgroups. RESULTS: BluePrint results were available for 719 patients. In patients with HER2-type tumors, the pCR rate was 71.9% in patients who received pertuzumab versus 43.5% in patients who did not (adjusted Odds Ratio 3.43, 95% CI 2.36-4.96). Additionally, a significantly decreased hazard was observed for both OS (adjusted hazard ratio [aHR] 0.45, 95% CI 0.25-0.80) and BCSS (aHR 0.46, 95% CI 0.24-0.86) with pertuzumab treatment. Findings were similar in the HER2-single subgroup. No significant benefit of pertuzumab was seen in other subtypes. CONCLUSIONS: In patients with HER2-type or HER2-single-type tumors, pertuzumab significantly improved the pCR rate and decreased the risk of breast cancer mortality, which was not observed in other subtypes. BluePrint subtyping may be valuable in future studies to identify patients that are likely to be highly sensitive to HER2-targeting agents.

Incidence and sociodemographic, living environment and maternal health associations with stillbirth in a tertiary healthcare setting in Kano, Northern Nigeria.

BACKGROUND: Almost two million stillbirths occur annually, most occurring in low- and middle-income countries. Nigeria is reported to have one of the highest stillbirth rates on the African continent. The aim was to identify sociodemographic, living environment, and health status factors associated with stillbirth and determine the associations between pregnancy and birth factors and stillbirth in the Murtala Mohammed Specialist Hospital, Kano, Nigeria. METHODS: A three-month single-site prospective observational feasibility study. Demographic and clinical data were collected. We fitted bivariable and multivariable models for stillbirth (yes/no) and three-category livebirth/macerated stillbirth/non-macerated stillbirth outcomes to explore their association with demographic and clinical factors. FINDINGS: 1,998 neonates and 1,926 mothers were enrolled. Higher odds of stillbirth were associated with low-levels of maternal education, a further distance to travel to the hospital, living in a shack, maternal hypertension, previous stillbirth, birthing complications, increased duration of labour, antepartum haemorrhage, prolonged or obstructed labour, vaginal breech delivery, emergency caesarean-section, and signs of trauma to the neonate following birth. INTERPRETATION: This work has obtained data on some factors influencing stillbirth. This in turn will facilitate the development of improved public health interventions to reduce preventable deaths and to progress maternal health within this site.

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Views of the public about Snacktivity™: a small changes approach to promoting physical activity and reducing sedentary behaviour.

BACKGROUND: Many people do not meet the recommended health guidance of participation in a minimum of 150-300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2-5 min bouts of physical activity 'snacks' throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public. METHODS: A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region. RESULTS: A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25-0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity 'snacks' were preferred to those which were strength based. CONCLUSIONS: The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts.

The Nasal Microbiome in ANCA-Associated Vasculitis: Picking the Nose for Clues on Disease Pathogenesis.

PURPOSE OF REVIEW: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular. RECENT FINDINGS: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.

A qualitative focus group study concerning perceptions and experiences of Nigerian mothers on stillbirths.

OBJECTIVE: To explore the experiences and perceptions of stillbirth among mothers from a tertiary medical centre in Kano, Northern Nigeria. DESIGN: Qualitative, interpretative. SETTING: Tertiary healthcare facility, Murtala Muhammad Specialist Hospital (MMSH), Kano, Northern Nigeria. SAMPLE: Mothers who had given birth to a liveborn baby at the MMSH in the prior 6 months (n = 31). In order to capture the experiences and perception of stillbirth within this cohort we approached mothers who had in a previous pregnancy experienced a stillbirth. Of the 31 who attended 16 had a previous stillbirth. METHODS: Semi-structured Focus Group Discussions, consisting of open-ended questions about stillbirth, beliefs, experiences and influences were held in MMSH, conducted over 1 day. RESULTS: Our findings highlight that this is a resource-poor tertiary facility serving an ever-growing population, increasing strain on the hospital and healthcare workers. Many of the participants highlighted needing permission from certain family members before accessing healthcare or medical treatment. We identified that mothers generally have knowledge on self-care during pregnancy, yet certain societal factors prevented that from being their priority. Judgement and blame was a common theme, yet a complex area entwined with traditions, superstitions and the pressure to procreate with many mothers described being made to feel useless and worthless if they did not birth a live baby. CONCLUSIONS: As access to healthcare becomes easier, there are certain traditions, family and social dynamics and beliefs which conflict with scientific knowledge and act as a major barrier to uptake of healthcare services. The findings highlight the need for investment in maternity care, appropriate health education and public enlightenment; they will help inform appropriate interventions aimed at reducing stigma around stillbirth and aide in educating mothers about the importance of appropriate health seeking behaviour. Stillbirths are occurring in this area of the world unnecessarily, globally there has been extensive research conducted on stillbirth prevention. This research has highlighted some of the areas which can be tackled by modifying existing successful interventions to work towards reducing preventable stillbirths.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-ß, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs.

Turbulent heating in galaxy clusters brightest in X-rays.

The hot (10(7) to 10(8) kelvin), X-ray-emitting intracluster medium (ICM) is the dominant baryonic constituent of clusters of galaxies. In the cores of many clusters, radiative energy losses from the ICM occur on timescales much shorter than the age of the system. Unchecked, this cooling would lead to massive accumulations of cold gas and vigorous star formation, in contradiction to observations. Various sources of energy capable of compensating for these cooling losses have been proposed, the most promising being heating by the supermassive black holes in the central galaxies, through inflation of bubbles of relativistic plasma. Regardless of the original source of energy, the question of how this energy is transferred to the ICM remains open. Here we present a plausible solution to this question based on deep X-ray data and a new data analysis method that enable us to evaluate directly the ICM heating rate from the dissipation of turbulence. We find that turbulent heating is sufficient to offset radiative cooling and indeed appears to balance it locally at each radius-it may therefore be the key element in resolving the gas cooling problem in cluster cores and, more universally, in the atmospheres of X-ray-emitting, gas-rich systems on scales from galaxy clusters to groups and elliptical galaxies.

Disposition and metabolism of 2,2'-dimorpholinodiethyl ether in sprague dawley rats and B6C3F1/N mice after oral, intravenous administration, and dermal application.

The specialty amine catalyst 2,2'-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75-93%) and some in feces (∼4-8%). The total radioactivity in tissues at 24 h and 72 h (males only) following oral administration was 8-10% and ∼4%, respectively, suggesting considerable tissue distribution. A moderate amount of the total tissue radioactivity in kidney and liver were unextractable suggesting covalent binding of [14C]DMDEE-derived products in tissue macromolecules. Absorption following a single dermal application in rats was significant (∼64%) with a similar disposition pattern to oral. The oral and dermal disposition of [14C]DMDEE in male and female mice was similar to rats. Urinary products of DMDEE identified were oxidative metabolism of the morpholine ring. Coadministration of DMDEE with nitrite in rats didn't produce the rodent carcinogen, N-nitrosomorpholine.

Review of diseases and health management in zebrafish Danio rerio (Hamilton 1822) in research facilities.

The use of zebrafish (Danio rerio) in biomedical research has expanded at a tremendous rate over the last two decades. Along with increases in laboratories using this model, we are discovering new and important diseases. We review here the important pathogens and diseases based on some 20 years of research and findings from our diagnostic service at the NIH-funded Zebrafish International Resource Center. Descriptions of the present status of biosecurity programmes and diagnostic and treatment approaches are included. The most common and important diseases and pathogens are two parasites, Pseudoloma neurophilia and Pseudocapillaria tomentosa, and mycobacteriosis caused by Mycobacterium chelonae, M. marinum and M. haemophilum. Less common but deadly diseases are caused by Edwardsiella ictaluri and infectious spleen and kidney necrosis virus (ISKNV). Hepatic megalocytosis and egg-associated inflammation and fibroplasia are common, apparently non-infectious, in zebrafish laboratories. Water quality diseases include supersaturation and nephrocalcinosis. Common neoplasms are spindle cell sarcomas, ultimobranchial tumours, spermatocytic seminomas and a small-cell carcinoma that is caused by a transmissible agent. Despite the clear biosecurity risk, researchers continue to use fish from pet stores, and here, we document two novel coccidia associated with significant lesions in zebrafish from one of these stores.

Anatomical relationship between mitral valve annulus and circumflex artery and its surgical implications.

BACKGROUND: Performing surgical procedures around the mitral valve (MV) annulus can cause iatrogenic lesions on the circumflex artery (Cx). The risk of this iatrogenesis comes from the proximity between this vessel and the MV annulus. OBJECTIVE: To evaluate the relation between the MV annulus and the Cx at different spots of its path and highlight the risks of its damage. METHODS: Fifty cadaveric adult human hearts were studied. Each heart was categorized depending on coronary dominance, and Cx was classified in type 1 (Cx giving off only the left posterior ventricular artery) and type 2 (Cx reaching the crux cordis and giving off the posterior interventricular branch). Three reference spots were chosen: A- when Cx begins to run across the coronary sulcus; B- immediately before the left posterior ventricular artery emerges and C- in the midpoint of the two previous points; to measure the diameter of the Cx and the MV annulus. Values of P<0.05 were considered significant. RESULTS: A total of 43 (86%) hearts were classified in type 1. These hearts showed that the diameter of the Cx in spot A is bigger than in the B and C spots (P=0.001). The 7 hearts (14%) classified in type 2 did not exhibit a difference in the diameter of the Cx in the A, B and C spots (NS). Also, the thickness of the fibrous annulus, in type 1 and type 2 hearts were not different between the three spots (NS). CONCLUSION: The present study showed that the diameter of the Cx varies depending on the heart type. This knowledge might improve the success rate of cardiac surgeries and decrease the rates of iatrogenic Cx lesions.

Tissue diagnosis during colorectal cancer surgery using optical sensing: an in vivo study.

BACKGROUND: In colorectal cancer surgery there is a delicate balance between complete removal of the tumor and sparing as much healthy tissue as possible. Especially in rectal cancer, intraoperative tissue recognition could be of great benefit in preventing positive resection margins and sparing as much healthy tissue as possible. To better guide the surgeon, we evaluated the accuracy of diffuse reflectance spectroscopy (DRS) for tissue characterization during colorectal cancer surgery and determined the added value of DRS when compared to clinical judgement. METHODS: DRS spectra were obtained from fat, healthy colorectal wall and tumor tissue during colorectal cancer surgery and results were compared to histopathology examination of the measurement locations. All spectra were first normalized at 800 nm, thereafter two support vector machines (SVM) were trained using a tenfold cross-validation. With the first SVM fat was separated from healthy colorectal wall and tumor tissue, the second SVM distinguished healthy colorectal wall from tumor tissue. RESULTS: Patients were included based on preoperative imaging, indicating advanced local stage colorectal cancer. Based on the measurement results of 32 patients, the classification resulted in a mean accuracy for fat, healthy colorectal wall and tumor of 0.92, 0.89 and 0.95 respectively. If the classification threshold was adjusted such that no false negatives were allowed, the percentage of false positive measurement locations by DRS was 25% compared to 69% by clinical judgement. CONCLUSION: This study shows the potential of DRS for the use of tissue classification during colorectal cancer surgery. Especially the low false positive rate obtained for a false negative rate of zero shows the added value for the surgeons. Trail registration This trail was performed under approval from the internal review board committee (Dutch Trail Register NTR5315), registered on 04/13/2015, https://www.trialregister.nl/trial/5175 .

Comparative disposition of dimethylaminoethanol and choline in rats and mice following oral or intravenous administration.

Dimethylaminoethanol (DMAE) and its salts have been used to treat numerous disorders in humans and hence safety of its use is a concern. DMAE is a close structural analog of choline, an essential nutrient. Exposure to DMAE may affect choline uptake and synthesis. The current investigation characterizes: 1) the absorption, distribution, metabolism, and excretion (ADME) of DMAE in Wistar Han rats and B6C3F1 mice following a single gavage or intravenous (IV) administration of 10, 100 or 500 mg/kg [14C]DMAE, and 2) the ADME of [14C]choline (160 mg/kg) and the effect on its disposition following pre-treatment with DMAE (100 or 500 mg/kg). In both rats and mice, following gavage administration, DMAE was excreted in urine (16-69%) and as exhaled CO2 (3-22%). The tissue retention was moderate (21-44%); however, the brain concentrations were low and there was no accumulation. Serum choline levels were not elevated following administration of DMAE. The DMAE metabolites in urine were DMAE N-oxide and N,N-dimethylglycine; the carcinogen, N-N-dimethylnitrosamine, was not detected. The pattern of disposition of [14C]choline following gavage administration was similar to that of [14C]DMAE. Prior treatment with DMAE had minimal effects on choline disposition. The pattern of disposition of [14C]DMAE and [14C]choline following IV administration was similar to gavage administration. There were minimal dose-, sex- or species-related effects following gavage or IV administration of [14C]DMAE or [14C]choline. Data from the current study did not support previous reports that: 1) DMAE alters choline uptake and distribution, or 2) that DMAE is converted into choline in vivo.

The cost-effectiveness of universal late-pregnancy screening for macrosomia in nulliparous women: a decision analysis.

OBJECTIVE: To identify the most cost-effective policy for detection and management of fetal macrosomia in late-stage pregnancy. DESIGN: Health economic simulation model. SETTING: All English NHS antenatal services. POPULATION: Nulliparous women in the third trimester treated within the UK NHS. METHODS: A health economic simulation model was used to compare long-term maternal-fetal health and cost outcomes for two detection strategies (universal ultrasound scanning at approximately 36 weeks of gestation versus selective ultrasound scanning), combined with three management strategies (planned caesarean section versus induction of labour versus expectant management) of suspected fetal macrosomia. Probabilities, costs and health outcomes were taken from literature. MAIN OUTCOME MEASURES: Expected costs to the NHS and quality-adjusted life-years (QALYs) gained from each strategy, calculation of net benefit and hence identification of most cost-effective strategy. RESULTS: Compared with selective ultrasound, universal ultrasound increased QALYs by 0.0038 (95% CI 0.0012-0.0076), but also costs by £123.50 (95% CI 99.6-149.9). Overall, the health gains were too small to justify the cost increase given current UK thresholds cost-effective policy was selective ultrasound coupled with induction of labour where macrosomia was suspected. CONCLUSIONS: The most cost-effective policy for detection and management of fetal macrosomia is selective ultrasound scanning coupled with induction of labour for all suspected cases of macrosomia. Universal ultrasound scanning for macrosomia in late-stage pregnancy is not cost-effective. TWEETABLE ABSTRACT: Universal late-pregnancy ultrasound screening for fetal macrosomia is not warranted.

Disposition of fullerene C60 in rats following intratracheal or intravenous administration.

Fullerene C60 is used in a variety of industrial and consumer capacities. As part of a comprehensive evaluation of the toxicity of fullerene C60 by the National Toxicology Program, the disposition following intratracheal (IT) instillation and intravenous (IV) administration of 1 or 5 mg/kg b.wt. fullerene C60 was investigated in male Fischer 344 rats. Following IT instillation, fullerene C60 was detected in the lung as early as 0.5 h post-exposure with minimal clearance over the 168 h period; the concentration increased ≥20-fold with a 5-fold increase in the dose. Fullerene C60 was not detected in extrapulmonary tissues. Following IV administration, fullerene C60 was rapidly eliminated from the blood and was undetectable after 0.5 h post-administration. The highest tissue concentrations of fullerene C60 occurred in the liver, followed by the spleen, lung and kidney. Fullerene C60 was cleared slowly from the kidney and the lung with estimated half-lives of 24 and 139 h, respectively. The liver concentration of fullerene C60 did not change much with time; over 90% of the fullerene C60 remained there over the study duration up to 168 h. Fullerene C60 was also not detected in urine or feces. These data support the hypothesis that fullerene C60 accumulates in the body and therefore has the potential to induce detrimental health effects following exposure.

Implementation of the Family Nurse Partnership programme in England: experiences of key health professionals explored through trial parallel process evaluation.

BACKGROUND: The Family Nurse Partnership (FNP) programme was introduced to support young first-time mothers. A randomised trial found FNP added little short-term benefit compared to usual care. The study included a comprehensive parallel process evaluation, including focus groups, conducted to aid understanding of the introduction of the programme into a new service and social context. The aim of the focus groups was to investigate views of key health professionals towards the integration and delivery of FNP programme in England. METHODS: Focus groups were conducted separately with Family Nurses, Health Visitors and Midwives at trial sites during 2011-2012. Transcripts from audio-recordings were analysed thematically. RESULTS: A total of 122 professionals participated in one of 19 focus groups. Family Nurses were confident in the effectiveness of FNP, although they experienced practical difficulties meeting programme fidelity targets and considered that programme goals did not sufficiently reflect client or community priorities. Health Visitors and Midwives regarded FNP as well-resourced and beneficial to clients, describing their own services as undervalued and struggling. They wished to work closely with Family Nurses, but felt excluded from doing so by practical barriers and programme protection. CONCLUSION: FNP was described as well-resourced and delivered by highly motivated and well supported Family Nurses. FNP eligibility, content and outcomes conflicted with individual client and community priorities. These factors may have restricted the potential effectiveness of a programme developed and previously tested in a different social milieu. Building Blocks ISRCTN23019866 Registered 20/04/2009.

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.