Intrapartum-related perinatal deaths in births planned in midwifery-led settings in Great Britain: findings and recommendations from the ESMiE confidential enquiry.

OBJECTIVE: To review quality of care in births planned in midwifery-led settings, resulting in an intrapartum-related perinatal death. DESIGN: Confidential enquiry. SETTING: England, Scotland and Wales. SAMPLE: Intrapartum stillbirths and intrapartum-related neonatal deaths in births planned in alongside midwifery units, freestanding midwifery units or at home, sampled from national perinatal surveillance data for 2015/16 (alongside midwifery units) and 2013-16 (freestanding midwifery units and home births). METHODS: Multidisciplinary panels reviewed medical notes for each death, assessing and grading quality of care by consensus, with reference to national standards and guidance. Data were analysed using thematic analysis and descriptive statistics. RESULTS: Sixty-four deaths were reviewed, 30 stillbirths and 34 neonatal deaths. At the start of labour care, 23 women were planning birth in an alongside midwifery unit, 26 in a freestanding midwifery unit and 15 at home. In 75% of deaths, improvements in care were identified that may have made a difference to the outcome for the baby. Improvements in care were identified that may have made a difference to the mother's physical and psychological health and wellbeing in 75% of deaths. Issues with care were identified around risk assessment and decisions about planning place of birth, intermittent auscultation, transfer during labour, resuscitation and neonatal transfer, follow up and local review. CONCLUSIONS: These confidential enquiry findings do not address the overall safety of midwifery-led settings for healthy women with straightforward pregnancies, but suggest areas where the safety of care can be improved. Maternity services should review their care with respect to our recommendations. TWEETABLE ABSTRACT: Confidential enquiry of intrapartum-related baby deaths highlights areas where care in midwifery-led settings can be made even safer.

Geomembrane applications for controlling diffusive migration of petroleum hydrocarbons in cold region environments.

Laboratory permeation tests examine the migration of aromatic hydrocarbons (benzene, toluene, ethylbenzene and xylenes (BTEX)) at 2, 7 and 14 °C through three different types of geomembrane (high density polyethylene (HDPE), linear low density polyethylene (LLDPE) and polyvinyl chloride (PVC)). Tests on both virgin and exhumed field samples provide permeation parameters (partitioning (Sgf), diffusion (Dg), and permeation (Pg) coefficients) for the three geomembranes. These results are combined with published values for the same geomembranes at 23 °C to establish an Arrhenius relationship that can be used to estimate diffusion parameters at temperatures other than those for which tests were conducted. Tests on an HDPE geomembrane sample exhumed after 3 years from a landfill site in the Canadian Arctic showed no significant difference in diffusion characteristics compared to an otherwise similar unaged and unexposed HDPE geomembrane. Contaminant transport modeling for benzene through HDPE, LLPDE and PVC in a simulated landfill cover show that for the conditions examined the presence of any of the three geomembranes below the 2 m thick soil cover substantially reduced the contaminant flux compared to the soils alone for realistic degrees of saturation in the cover soil. For these same realistic cold climate cases, of the three geomembranes examined, the HDPE geomembrane was the most effective at controlling the contaminant flux out of the landfill. An increase in soil cover and liner temperature by 2 °C (from potential climate change effects) above those currently measured at an Arctic landfill showed an increase in contaminant transport through the cover system for all geomembranes due to the increase surface temperature (especially in the summer months). Modeling of the addition of an extra 0.5 m of soil cover, as a mitigation measure for the effects of climate change, indicates that the main benefit of adding this unsaturated soil was to reduce the geomembrane temperature and that this did reduce the magnitude of the increase in contaminant transport.

Transfers of women planning birth in midwifery units: data from the birthplace prospective cohort study.

OBJECTIVE: To examine the percentage of women transferred, reasons for transfer and factors associated with the transfer of women planning birth in midwifery units (MUs). DESIGN: Prospective cohort study. SETTING: All freestanding midwifery units (FMUs) and alongside midwifery units (AMUs) in England. PARTICIPANTS: Twenty-nine thousand, two hundred and forty-eight eligible women with a singleton, term and 'booked' pregnancy, planning birth in an MU between April 2008 and April 2010. METHODS: Multivariable logistic regression was used to explore the sociodemographic and clinical characteristics associated with transfer. MAIN OUTCOME MEASURES: Transfer during labour or within 24 hours of birth. RESULTS: Over one in four women were transferred from AMUs and over one in five from FMUs. In both types of MU, compared with multiparous women aged 25-29 years, nulliparous women aged <20 years had higher odds of transfer (FMU-adjusted odds ratio [OR], 4.5; 95% confidence interval [CI], 3.10-6.57; AMU-adjusted OR, 2.6; 95% CI, 2.18-2.06), and the odds of transfer increased with increasing age. Nulliparous women aged ≥ 35 years in FMUs had 7.4 times the odds of transfer (95% CI, 5.43-10.10) and, in AMUs, 6.0 times the odds of transfer (95% CI, 4.81-7.41). Starting labour care after 40 weeks of gestation and the presence of complicating conditions at the start of labour care were also independently associated with a higher risk of transfer. CONCLUSIONS: Transfer from MUs is common, especially for first-time mothers. This study provides evidence on the maternal characteristics associated with an increased risk of transfer, which can be used to inform women's choices about place of birth.

Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model.

PURPOSE: Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity. MATERIALS AND METHODS: The effect of mild heat (40 degrees C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40 degrees C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome. RESULTS: Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy. CONCLUSIONS: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine, and daily interferon-alpha: a description of a phase I-II protocol.

PURPOSE: The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-alpha). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration. MATERIALS AND METHODS: The protocol design derived from a schedule-optimized preclinical regimen. Drugs were administered together, and also with thermal therapy in a schedule that optimized the therapeutic index. Eligible patients were those with therapy-resistant, metastatic or advanced solid malignancies. Beginning at 40 mg/m(2), the cisplatin dose was escalated by 10 mg/m(2) to the maximally tolerated dose (MTD) in successive cohorts of 3 patients. A treatment cycle consisted of cisplatin on day one, followed by thermal therapy and simultaneous gemcitabine 36 hours later; then a second dose of gemcitabine one week later; and daily IFN- alpha. RESULTS: Thirty-seven patients were treated on protocol. The MTD of cisplatin in the thermochemotherapy regimen was established to be 60 mg/m(2). The dose limiting toxicities (DLT) were peripheral neuropathy and ototoxicity. Complete and partial responses combined were 43%. The therapy improved the quality of life of responding patients. CONCLUSION: The protocol was well tolerated and was associated with antitumor activity in patients with a variety of advanced metastatic solid tumors. Tumor response occurred with the thermochemotherapy treatment despite treating malignancies that had progressed on the same chemotherapy drugs administered as standard treatment. Notably, good responses were observed in patients with high-grade neuroendocrine and pancreas cancers. This regimen will be tested in a phase II study.

The importance of schedule in whole body thermochemotherapy.

PURPOSE: To determine an effective triple-agent schedule combining fever-range whole body thermal therapy (FR-WB-TT) with cisplatin and gemcitabine by optimizing the timing of drug with heat, and drug with drug. MATERIALS AND METHODS: Using an orthotopically implanted syngeneic breast adenocarcinoma in an immunologically normal female Fischer rat model, we investigated various schedules of a thermochemotherapy regimen combining FR-WB-TT with chemotherapy agents, cisplatin and gemcitabine. Differently timed combinations of a) cisplatin with FR-WB-TT, b) gemcitabine with FR-WB-TT, and c) cisplatin with gemcitabine were examined for anti-tumor efficacy and toxicity. A combination of the three agents based on the optimal two-agent schedules was then tested. RESULTS: The greatest primary tumor and axillary metastasis growth delay and lowest toxicity was induced with administration of cisplatin 24 h prior to gemcitabine and cisplatin 24 h prior to simultaneous gemcitabine and FR-WB-TT. Administering cisplatin 24 h prior to gemcitabine was more effective and less toxic than giving the two drugs simultaneously or gemcitabine prior to cisplatin. Survival was greatest when gemcitabine and FR-WB-TT were administered 24 h after cisplatin, even with reduced drug doses. One complete cure resulted from the triple agent treatment. CONCLUSIONS: The relative timing of agents in multiple modality treatments is critically important in achieving tumor control or cures, and in reducing toxicity. Optimizing the relative timing of multiple agents in thermochemotherapy allows use of lower drug doses to achieve maximal anti-tumor efficacy and minimal toxicity.

The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases.

Many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumour diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival. It is hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day 12 after implantation. The metronomic CPT-11 was combined with long-duration, low-temperature, fever-range whole body hyperthermia (FR-WBH). This systemic hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological activity. Both the group treated with FR-WBH alone and the combined FR-WBH + CPT-11 group had delayed onset and reduced incidence of axillary lymph node metastases compared to control (p < 0.05). Combination therapy of FR-WBH + CPT-11 resulted in a significantly greater inhibition of axillary lymph node metastasis volume compared to both control and CPT-11 alone (p < 0.02) at day 16. Interestingly, none of the therapies significantly affected inguinal lymph node metastases. Lung metastases were decreased by 36% at the time of death in rats treated with FR-WBH + CPT-11, by 25% in the CPT-11 alone group and by 14% in the FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly longer (35%) than control animals (p < 0.04). Neither significant body weight loss nor gastrointestinal toxicity was observed in any group. These data suggest that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be safely combined to reduce distant lymph node and lung metastases and, thus, to increase survival.

Prevalence, age of onset and demographic relationships of different areca nut habits amongst children in Tower Hamlets, London.

OBJECTIVE: To examine prevalence and demographic relationships of different areca nut habits amongst children. DESIGN: Self-administered questionnaire. SUBJECTS: Children aged between 11 and 15. Of 800 questionnaires distributed, 704 were fully completed (88%). SETTING: Two secondary schools in the London district of Tower Hamlets. MEASURES: Demographic, areca nut habits used, age first used, still using, frequency of use. RESULTS: Users of any areca nut habit were exclusively from the South Asian population. Of this population, 77% had engaged in a habit, and dependent upon habit between 54 and 92% of these still remained current users. The highest prevalence of current use for boys and girls respectively was for areca nut alone (36%, 43%), followed by mistee pan (35%, 29%), betel-quid (27%, 26%) and pan masala (14%, 16%). Of the current users, 44% engaged in one habit only, 24% two, 20% three and 13% all four. The highest period of risk for starting to use areca nut alone, betel-quid and mistee pan was between ages 5 and 12, whilst for pan masala it was after 10. Boys had a significantly higher risk of beginning use before 10 (P < .001) and a higher frequency of use for pan masala (P< .01), areca nut alone (P< .05) and betel-quid (P = .06) than girls. The frequency of using each habit was between 3 and 5 episodes per week, however boys use pan masala approximately 10 times per week. CONCLUSION: South Asian children may already be experienced users of areca nut. Greater attention should be directed towards identifying signs of oral submucous fibrosis, oral cancer and other potentially malignant lesions within the South Asian population.

Boron stimulates yeast (Saccharomyces cerevisiae) growth.

Boron is required for the growth of vascular plants and embryonic development in fish. The molecular basis of boron's essentiality, however, remains unknown for both. The objective of this study was to determine whether yeast (Saccharomyces cerevisiae) could be used as a model for the evaluation of intracellular boron trafficking. Three experiments were conducted to assess the effect of boron supplementation on yeast growth. Cultures were grown in low boron media containing 0.04 micromol B/L. After 24 h, a new flask was inoculated with this culture; it was allowed to reach early log phase growth (9 h) and was then divided between two flasks. One flask was supplemented with ultrapure boric acid to achieve a concentration of 185 micromol B/L (+B); the other was supplemented with an equivalent volume of ultrapure water (NB). Boron significantly stimulated cell growth rate into the stationary phase of growth. Yeast cell boron concentrations decreased in both treatments over the course of the experiment, but analysis by inductively coupled plasma-mass spectrometry (ICPMS) did not detect differences in cellular concentration between the boron supplemented (B) and nonsupplemented (NB) groups. Ethanol concentrations did not differ between the two treatments, demonstrating that boron-stimulated growth was not a secondary effect of alcohol dehydrogenase inhibition. The demonstration of boron-dependent growth stimulation in yeast suggests that Saccharomyces cerevisiae can be used as a model system for the study of intracellular boron trafficking.

The response of trout and zebrafish embryos to low and high boron concentrations is U-shaped.

Fish in the embryo-larval stage of development have been shown to be sensitive to boron (B) at both ends of the dose-response curve (1,2). The present study evaluated the health effects of low and high B concentrations on rainbow trout (Oncorhynchus mykiss), a cold water species, and zebrafish (Danio rerio), a warm water species. Rainbow trout embryos were incubated from day 1 until 2 wk posthatch in Type 1 ASTM ultrapure-grade water (12.5 degrees C) supplemented with only B (0-500 microM) as boric acid, or together with CaCO3 (0-2 mM) to increase water hardness. Embryonic growth was stimulated by B in a dose-dependent manner at all Ca concentrations (p < 0.001). Chronic exposures below 9 micromol B/L impaired embryonic growth and above 10 mmol B/L caused death (p < 0.001). Thus, the safe range of exposure for the rainbow trout was between the adverse effect concentrations of 9 micromol B/L and 10 mmol B/L. Zebrafish were maintained for 6 mo in ultrapure water containing <0.2 micromol B/L to determine the effect of low-level exposure. High-level exposure was assessed by exposing zygotes, derived from parents maintained at 46 micromol B/L, to graded concentrations of boric acid up to a concentration of 75 mmol B/L from fertilization until they were free feeding (96 h). Fertilization occurred, but zygotes failed to survive when water contained <0.2 micromol B/L (p < 0.001). Death occurred at and above 9.2 mmol B/L. Thus, the safe range of B exposure for zebrafish was between the adverse effect concentrations of 0.2 micromol B/L and 9.2 mmol B/L. The dose-response for both species was thus U-shaped.

Calcium absorption, endogenous excretion, and endocrine changes during and after long-term bed rest.

Negative calcium balance is a known consequence of bed rest, and is manifested in elevated urine and fecal calcium (Ca). Elevated fecal Ca can result from either decreased absorption, increased endogenous fecal excretion, or both. We measured the Ca absorption and endogenous fecal excretion in eight healthy male volunteers before and during 4 months of bed rest. Dual isotope (n = 6) or single isotope (n = 2) methods in conjunction with Ca balance were used to calculate true and net Ca absorption and endogenous fecal excretion. Stool Ca increased from 797 mg/day (mean intake 991 mg/day) to 911 mg/day during bed rest, whereas urine Ca excretion increased from 174 to 241 mg/day. True Ca absorption decreased from 31 +/- 7% of Ca intake pre-bed rest to 24 +/- 2% during bed rest, (p < 0.05) and returned toward pre-bed rest values within 5-6 weeks following reambulation. Endogenous fecal excretion did not change significantly, and therefore, most of the increased fecal Ca resulted from changes in absorption. However, in one individual, endogenous fecal Ca excretion was the major contributor to Ca loss. Ionized Ca and pyridinium crosslinks increased and 1,25(OH)2 vitamin D decreased during bed rest, similar to the decrease in Ca absorption; parathyroid hormone (PTH), calcitonin, serum albumin, phosphorus, and total serum Ca were unchanged. Although alkaline phosphatase, osteocalcin, and PTH were unchanged during bed rest, they were elevated during reambulation. These changes accompanied by increased Ca absorption and balance and decreased ionized and total serum Ca suggest a rebound in bone formation following immobilization.

Eddy current correction in volume-localized MR spectroscopy.

The quality of volume-localized magnetic resonance spectroscopy is affected by eddy currents caused by gradient switching. Eddy currents can be reduced with improved gradient systems; however, it has been suggested that the distortion due to eddy currents can be compensated for during postprocessing with a single-frequency reference signal. The authors propose modifying current techniques for acquiring the single-frequency reference signal by using relaxation weighting to reduce interference from components that cannot be eliminated by digital filtering alone. Additional sequences with T1 or T2 weighting for reference signal acquisition are shown to have the same eddy current characteristics as the original signal without relaxation weighting. The authors also studied a new eddy current correction method that does not require a single-frequency reference signal. This method uses two free induction decays (FIDs) collected from the same volume with two sequences with opposite gradients. Phase errors caused by eddy currents are opposite in these two FIDs and can be canceled completely by combining the FIDs. These methods were tested in a phantom. Eddy current distortions were corrected, allowing quantitative measurement of structures such as the -CH = CH- component, which is otherwise undetectable.

Cardiac manifestations in disorders of fat and carnitine metabolism in infancy.

The prognosis of patients with cardiomyopathy associated with hypocarnitinemia is uncertain. Cardiac hemodynamics, histologic findings and response to oral L-carnitine therapy were retrospectively evaluated in 11 children with cardiomyopathy associated with abnormal carnitine metabolism. Three had systemic carnitine deficiency, two familial hypocarnitinemia with neutropenia, three transient neonatal hypocarnitinemia and three a carnitine insufficiency syndrome. Six had a hypertrophic and five a dilated cardiomyopathy. Hypotonia was present in seven (64%). The cardiothoracic ratio was greater than 0.60 in eight (73%). The most frequent abnormality on the electrocardiogram was ST-T wave inversion in the left precordial leads with various degrees of left ventricular hypertrophy. Echocardiographically, two patients with hypertrophic cardiomyopathy had decreased left ventricular function and two patients with dilated cardiomyopathy had increased thickness of the left ventricular wall. Histologic evaluation (two autopsies and one endomyocardial biopsy) revealed striking lipid accumulation within hypertrophied myocytes. Six of eight patients on carnitine replacement therapy had improvement echocardiographically during a 3 month to 2 year follow-up period. In summary, both hypertrophic and dilated cardiomyopathy can result from abnormal carnitine metabolism. The determination of plasma carnitine concentrations and fatty acid metabolism by-products should be performed in all patients with either form of cardiomyopathy of unknown etiology because carnitine supplementation may lead to improvement.

The prediction of compatibility/incompatibility in blends of ethyl cellulose with hydroxypropyl methylcellulose or hydroxypropyl cellulose using 2-dimensional solubility parameter maps.

Typical two dimensional solubility parameter maps for ethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose have been constructed using literature data. The maps of the polymers showed some degree of overlap indicating some mutual compatibility. Compatibility between ethyl cellulose and hydroxypropyl cellulose was greater than between ethyl cellulose and hydroxypropyl methylcellulose. The maps may also be used to predict the effect of added plasticizers.

Spironolactone therapy in infants with congestive heart failure secondary to congenital heart disease.

The efficacy of treatment with spironolactone for congestive heart failure secondary to congenital heart disease was studied in 21 infants under 1 year of age. All received digoxin and chlorothiazide. In addition, group A (n = 10) was given supplements of potassium and group B (n = 11) received spironolactone. Daily clinical observations of vital signs, weight, hepatomegaly, and vomiting were recorded. Paired t test analysis showed significant reduction in liver size and weight (P less than 0.01) and respiratory rate (P less than 0.05) in group B, and less significant decreases in group A. The incidence of vomiting was slightly lower in group B. We conclude that the addition of spironolactone hastens and enhances the response to standard treatment with digoxin and chlorothiazide in infants with congestive heart failure.