The surprisingly large neutron capture cross-section of 88Zr.

The probability that a nucleus will absorb a neutron-the neutron capture cross-section-is important to many areas of nuclear science, including stellar nucleosynthesis, reactor performance, nuclear medicine and defence applications. Although neutron capture cross-sections have been measured for most stable nuclei, fewer results exist for radioactive isotopes, and statistical-model predictions typically have large uncertainties1. There are almost no nuclear data for neutron-induced reactions of the radioactive nucleus 88Zr, despite its importance as a diagnostic for nuclear security. Here, by exposing 88Zr to the intense neutron flux of a nuclear reactor, we determine that 88Zr has a thermal neutron capture cross-section of 861,000 ± 69,000 barns (1σ uncertainty), which is five orders of magnitude larger than the theoretically predicted value of 10 barns2. This is the second-largest thermal neutron capture cross-section ever measured and no other cross-section of comparable size has been discovered in the past 70 years. The only other nuclei known to have values greater than 105 barns3-6 are 135Xe (2.6 × 106 barns), a fission product that was first discovered as a poison in early reactors7,8, and 157Gd (2.5 × 105 barns), which is used as a detector material9,10, a burnable reactor poison11 and a potential medical neutron capture therapy agent12. In the case of 88Zr neutron capture, both the target and the product (89Zr) nuclei are radioactive and emit intense γ-rays upon decay, allowing sensitive detection of miniscule quantities of these radionuclides. This result suggests that as additional measurements with radioactive isotopes become feasible with the operation of new nuclear-science facilities, further surprises may be uncovered, with far-reaching implications for our understanding of neutron capture reactions.

Heimdallr, Baldr, and Solarstein: designing the next generation of VLTI instruments in the Asgard suite.

High angular resolution imaging is an increasingly important capability in contemporary astrophysics. Of particular relevance to emerging fields such as the characterization of exoplanetary systems, imaging at the required spatial scales and contrast levels results in forbidding challenges in the correction of atmospheric phase errors, which in turn drives demanding requirements for precise wavefront sensing. Asgard is the next-generation instrument suite at the European Southern Observatory's Very Large Telescope Interferometer (VLTI), targeting advances in sensitivity, spectral resolution, and nulling interferometry. In this paper, we describe the requirements and designs of three core modules: Heimdallr, a beam combiner for fringe tracking, low order wavefront correction, and visibility science; Baldr, a Zernike wavefront sensor to correct high order atmospheric aberrations; and Solarstein, an alignment and calibration unit. In addition, we draw generalizable insights for designing such system and discuss integration plans.

Diverging trends for onset of acute myocardial infarction, heart failure, stroke and mortality in young males: role of changes in obesity and fitness.

BACKGROUND: As opposed to the decreasing overall rates of coronary heart disease (CHD) incidence and overall cardiovascular disease (CVD) mortality, heart failure (HF) and stroke incidence are increasing in young people, potentially due to rising rates of obesity and reduced cardiorespiratory fitness (CRF). OBJECTIVES: We investigated trends in early major CVD outcomes in a large cohort of young men. METHODS: Successive cohorts of Swedish military conscripts from 1971 to 1995 (N = 1,258,432; mean age, 18.3 years) were followed, using data from the National Inpatient and Cause of Death registries. Cox proportional hazard models were used to analyse changes in 21-year CVD event rates. RESULTS: 21-year CVD and all-cause mortality and incidence of acute myocardial infarction (AMI) decreased progressively. Compared with the cohort conscripted in 1971-1975 (reference), the hazard ratios (HRs) for the last 1991-1995 cohort were 0.50 [95% confidence interval (CI) 0.42-0.59] for CVD mortality; 0.57 (95% CI 0.54-0.60) for all-cause mortality; and 0.63 (95% CI 0.53-0.75) for AMI. In contrast, the incidence of ischaemic stroke, intracerebral haemorrhage and HF increased with HRs of 1.43 (95% CI 1.17-1.75), 1.30 (95% CI 1.01-1.68) and 1.84 (95% CI 1.47-2.30), respectively. During the period, rates of obesity increased from 1.04% to 2.61%, whilst CRF scores decreased slightly. Adjustment for these factors influenced these secular trends only moderately. CONCLUSION: Secular trends of young-onset CVD events demonstrated a marked shift from AMI and CVD mortality to HF and stroke incidence. Trends were significantly, though moderately, influenced by changing baseline BMI and CRF.

Scotland's 2009-2015 methadone-prescription cohort: Quintiles for daily dose of prescribed methadone and risk of methadone-specific death.

AIMS: As methadone clients age, their drug-related death (DRD) risks increase, more than doubling at 45+ years for methadone-specific DRDs. METHODS: Using Community Health Index (CHI) numbers, mortality to 31 December 2015 was ascertained for 36 347 methadone-prescription clients in Scotland during 2009-2015. Cohort entry, quantity of prescribed methadone and daily dose (actual or recovered by effective, simple rules) were defined by clients' first CHI-identified methadone prescription after 30 June 2009 and used in proportional hazards analysis. As custodian of death records, National Records of Scotland identified non-DRDs from DRDs. Methadone-specific DRD means methadone was implicated but neither heroin nor buprenorphine. RESULTS: The cohort's 192 928 person-years included 1857 non-DRDs and 1323 DRDs (42%), 546 of which were methadone specific. Actual/recovered daily dose was available for 26 533 (73%) clients who experienced 420 methadone-specific DRDs. Top quintile for daily dose at first CHI-identified methadone prescription was >90 mg. Age 45+ years at cohort-entry (hazard ratio vs 25-34 years: 3.1, 95% confidence interval: 2.4-4.2), top quintile for baseline daily dose of prescribed methadone (vs 50-70 mg: 1.9, 1.1-3.1) and being female (1.3, 1.0-1.6) significantly increased clients' risk of methadone-specific DRD. CONCLUSION: Extra care is needed when methadone daily dose exceeds 90 mg. Females' higher risk for methadone-specific DRD is new and needs validation. Further analyses of prescribed daily dose linked to mortality for large cohorts of methadone clients are needed internationally, together with greater pharmacodynamic and pharmacokinetic understanding of methadone by age and sex. Balancing age-related risks is challenging for prescribers who manage chronic opiate dependency against additional uncertainty about the nature, strength and pharmacological characteristics of drugs from illegal markets.

Obesity in adolescent men increases the risk of venous thromboembolism in adult life.

BACKGROUND: As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long-term risks associated with adolescent obesity. OBJECTIVES: This study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE). METHODS: Nationwide register-based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to <35 kg m-2 ) and 7236 severely obese (BMI ≥ 35 kg m-2 ). The participants were followed until a first registered diagnosis of VTE. RESULTS: During a median follow-up of 28 years (interquartile interval, 20 to 36 years), 11 395 cases of deep vein thrombosis and 7270 cases of pulmonary embolism were recorded. Compared with men with a BMI of 18.5 to <20 kg m-2 , men with higher BMI in young adulthood showed an incrementally increasing risk of VTE that was moderately but significantly increased already at normal BMI levels. Adolescent obese men with a BMI of 30 to 35 kg m-2 had an adjusted hazard ratio of 2.93 (95% confidence interval, 2.65 to 3.24) for VTE. Severely obese men with a BMI of ≥35 kg m-2 had a hazard ratio of 4.95 (95% confidence interval, 4.16 to 5.90). CONCLUSIONS: Men who were obese or severely obese in young adulthood had a marked increase in risk of VTE.

A bioluminescent reporter for the halophilic archaeon Haloferax volcanii.

Haloarchaea have evolved to thrive in hypersaline environments. Haloferax volcanii is of particular interest due to its genetic tractability; however, few in vivo reporters exist for halophiles. Haloarchaeal proteins evolved characteristics that promote proper folding and function at high salt concentrations, but many mesophilic reporter proteins lack these characteristics. Mesophilic proteins that acquire salt-stabilizing mutations, however, can lead to proper function in haloarchaea. Using laboratory-directed evolution, we developed and demonstrated an in vivo luciferase that functions in the hypersaline cytosol of H. volcanii.

Effect of zinc on oropharyngeal mucositis in children with acute leukemia undergoing chemotherapy.

BACKGROUND: Oropharyngeal mucositis (OM) is one of the main side-effects of oncological therapy. There is no treatment to prevent its occurrence, but some zinc-based therapies have been proven to help in decreasing its intensity. The objective of this study was to determine the effect of zinc in OM in children with acute leukemia in the early stages of oncological treatment. MATERIAL AND METHODS: This quasi-experimental study evaluated OM in 2 groups (control group: conventional hospital management, and experimental group: administration of 50 mg of zinc gluconate daily plus conventional hospital management). OM severity was recorded at a two-month follow-up. RESULTS: Forty-nine patients (26 in the control group and 23 in the experimental group) were included. The mean age of the patients was 11.1 ± 2.7 years; 65.3% had a diagnosis of pre-B acute lymphoblastic leukemia. The incidences of OM in the control group and the experimental group were 46.2% and 26.1%, respectively, but the difference was not significant. Based on a negative binomial regression model, females had, on average, 1.5 more days with OM (p = 0.002), and patients assigned to the experimental group had, on average, 2 less days with OM than the control group (p = 0.001). The pain score was higher in the control group (p = 0.0009), as was the mean score on the WHO scale (p = 0.0012). CONCLUSIONS: Zinc facilitated a reduction in the severity and duration of OM; further studies focusing on children are needed to confirm the effects of this trace element.

Risk of exposure to air pollution among British children with and without intellectual disabilities.

BACKGROUND: Exposure to outdoor air pollution is a well-established risk factor for a range of adverse health conditions. No previous study has quantified the extent to which children with intellectual disability (ID) may be exposed to outdoor air pollution. METHODS: Secondary analysis of data extracted from the UK's Millennium Cohort Study, a nationally representative sample of over 18 000 UK children born 2000-2002. RESULTS: Averaging across ages, children with IDs were 33% more likely to live in areas with high levels of diesel particulate matter, 30% more likely to live in areas with high levels of nitrogen dioxide, 30% more likely to live in areas with high levels of carbon monoxide and 17% more likely to live in areas with high levels of sulphur dioxide. CONCLUSIONS: Levels of exposure to outdoor air pollution among children with ID are significantly higher than those of families of children without ID. Exposure to outdoor air pollution may be one of the pathways that contributes to the health inequities experienced by people with IDs.

An evidence-based treatment algorithm for colorectal polyp cancers: results from the Scottish Screen-detected Polyp Cancer Study (SSPoCS).

OBJECTIVES: Colorectal polyp cancers present clinicians with a treatment dilemma. Decisions regarding whether to offer segmental resection or endoscopic surveillance are often taken without reference to good quality evidence. The aim of this study was to develop a treatment algorithm for patients with screen-detected polyp cancers. DESIGN: This national cohort study included all patients with a polyp cancer identified through the Scottish Bowel Screening Programme between 2000 and 2012. Multivariate regression analysis was used to assess the impact of clinical, endoscopic and pathological variables on the rate of adverse events (residual tumour in patients undergoing segmental resection or cancer-related death or disease recurrence in any patient). These data were used to develop a clinically relevant treatment algorithm. RESULTS: 485 patients with polyp cancers were included. 186/485 (38%) underwent segmental resection and residual tumour was identified in 41/186 (22%). The only factor associated with an increased risk of residual tumour in the bowel wall was incomplete excision of the original polyp (OR 5.61, p=0.001), while only lymphovascular invasion was associated with an increased risk of lymph node metastases (OR 5.95, p=0.002). When patients undergoing segmental resection or endoscopic surveillance were considered together, the risk of adverse events was significantly higher in patients with incomplete excision (OR 10.23, p<0.001) or lymphovascular invasion (OR 2.65, p=0.023). CONCLUSION: A policy of surveillance is adequate for the majority of patients with screen-detected colorectal polyp cancers. Consideration of segmental resection should be reserved for those with incomplete excision or evidence of lymphovascular invasion.

Factors influencing the decision to attend screening for cancer in the UK: a meta-ethnography of qualitative research.

Background: This review aimed to better understand experiences of being invited to cancer screening and associated decision-making. Methods: Qualitative evidence explaining UK cancer screening attendance decisions was systematically identified. Data were extracted and meta-ethnography used to identify shared themes, synthesize findings and generate higher level interpretations. Results: Thirty-four studies met inclusion criteria. They related to uptake of breast, cervical, colorectal, prostate, ovarian and lung cancer screening. Three primary themes emerged from the synthesis. 'Relationships with the health service' shaped decisions, influenced by trust, compliance with power, resistance to control or surveillance and perceived failures to meet cultural, religious and language needs. 'Fear of cancer screening' was both a motivator and barrier in different ways and to varying degrees. Strategies to negotiate moderate fear levels were evident. 'Experiences of risk' included the creation of alternative personal risk discourses and the use of screening as a coping strategy, influenced by disease beliefs and feelings of health and wellness. Conclusions: The findings highlight the importance of the provider-patient relationship in screening uptake and enrich our understanding of how fear and risk are experienced and negotiated. This knowledge can help promote uptake and improve the effectiveness of cancer screening.

Validity, Reliability, and Diagnostic Accuracy of Ratings of Perceived Exertion to Identify Dependence in Performing Self-care Activities in Older Women.

BACKGROUND: Dependence in self-care activities among older women has been previously evaluated through performance-based tests. However, these tests have presented inability to accurately distinguish between dependent and independent older adults in performing activities of daily living. AIM: To examine the validity, reliability, and diagnostic accuracy of rating of perceived exertion (RPE) to identify dependence in performing self-care activities in older women. METHODS: Thirty-five older women performed two different constant-load tasks (walking on treadmill at 4 km/h for five minutes and arm curls with two kg for one minute), reporting RPE at the end, in four sessions. Performance-based tests (30-second chair stand and 6-minute walk) were also evaluated. Katz Index and Lawton and Brody questionnaires were applied to evaluate the dependence level in performing basic and instrumental activities of daily living. RESULTS: RPE was greater on the first session (RPE 14 ± 2) than second session (RPE 13 ± 2), while it was similar through other sessions, with high values of intraclass coefficient correlation (0.96-0.99). Basic activities of daily living and instrumental activities of daily living presented high correlations with RPE measures (0.75-0.82), whereas performance-based tests presented moderate correlations (0.47-0.59). RPE responses explained the most variance in identifying dependence in self-care activities and presented high diagnostic accuracy to differentiate dependent from independent older women. So the hypotheses had been confirmed that RPE responses in constant-load exercise are better predictors of dependence in self-care activities than performance-based tests. CONCLUSIONS: RPE of constant-load physical tasks was valid, reliable, and accurate in identifying dependence in performing self-care activities in older women; therefore, it is possible to use the perceived exertion to identify dependence in performing activities of daily living in older women.

Limited evidence of abnormal intra-colonic pressure profiles in diverticular disease - a systematic review.

AIM: Abnormal colonic pressure profiles and high intraluminal pressures are postulated to contribute to the formation of sigmoid colon diverticulosis and the pathophysiology of diverticular disease. This study aimed to review evidence for abnormal colonic pressure profiles in diverticulosis. METHOD: All published studies investigating colonic pressure in patients with diverticulosis were searched in three databases (Medline, Embase, Scopus). No language restrictions were applied. Any manometry studies in which patients with diverticulosis were compared with controls were included. The Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control studies was used as a measure of risk of bias. A cut-off of five or more points on the NOS (fair quality in terms of risk of bias) was chosen for inclusion in the meta-analysis. RESULTS: Ten studies (published 1962-2005) met the inclusion criteria. The studies followed a wide variety of protocols and all used low-resolution manometry (sensor spacing range 7.5-15 cm). Six studies compared intra-sigmoid pressure, with five of six showing higher pressure in diverticulosis vs controls, but only two reached statistical significance. A meta-analysis was not performed as only two studies were above the cut-off and these did not have comparable outcomes. CONCLUSION: This systematic review of manometry data shows that evidence for abnormal pressure in the sigmoid colon in patients with diverticulosis is weak. Existing studies utilized inconsistent methodology, showed heterogeneous results and are of limited quality. Higher quality studies using modern manometric techniques and standardized reporting methods are needed to clarify the role of colonic pressure in diverticulosis.

The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

BACKGROUND: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. RESULTS: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. CONCLUSION: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. CLINICALTRIALSGOV: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.

Measurement of Uranium Isotope Ratios in Keratinous Materials: A Noninvasive Bioassay for Special Nuclear Material.

Hair, toenail, and fingernail are noninvasive, integrative biological monitors routinely used to assess mineral intake.1-4 In this study, we demonstrate the feasibility of distinguishing between exposure to natural, depleted, and enriched U by measuring the (235)U/(238)U, (234)U/(238)U, and (236)U/(238)U ratios in the hair, fingernails, and toenails of occupationally exposed workers and control volunteers. The exposure history of cases and controls to non-natural U was assessed through voluntary self-reporting using a simple questionnaire. The measured U isotope ratios and U concentration in the hair, toenail, and fingernail of cases were compared to a nonexposed control group. No difference was observed in the uranium concentration between the two groups. Significant differences between the cases and the control group were observed in the (235)U/(238)U and (236)U/(238)U isotope ratios but not the (234)U/(238)U. This is the first time that hair, fingernail, and toenail have been demonstrated to be sensitive to occupational exposure to enriched and depleted U, a result with significant implications for proliferation compliance monitoring.

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation-Chemoembolization Therapy in Rats.

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm3 ± 1.01, 3.96 cm3 ± 1.75, and 6.13 cm3 ± 2.27 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P < .05). Conclusion CA4P pretreatment caused a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the efficacy of anti-HCC treatment with PTA-CET in rats. © RSNA, 2016 Online supplemental material is available for this article.

Assessment and validation of a defined fluid restriction protocol in the use of subcutaneous desmopressin for children with inherited bleeding disorders.

INTRODUCTION: Despite the availability of subcutaneous desmopressin (1-deamino-8-d-arginine vasopressin, SC-DDAVP) as a haemostatic agent for children with mild bleeding disorders, few publications specifically address the safety or efficacy of this mode of administration. AIM: Our aim was to assess whether a defined fluid restriction protocol was effective in preventing hyponatremia in children receiving perioperative SC-DDAVP, and to document adequate biological and clinical response in this setting. METHODS: We retrospectively analysed a cohort of children with mild bleeding disorders prescribed SC-DDAVP over a 5-year period following institution of a 'two-thirds maintenance' fluid restriction protocol. RESULTS: Sixty-nine patients received SC-DDAVP following this protocol, including 15 with mild haemophilia A, 49 with von Willebrand disease (VWD) and five with platelet storage pool disorder. In patients who underwent formal preoperative assessment a complete or partial response was observed in 28/29 with type 1 VWD and 14/15 with mild haemophilia A. Perioperative SC-DDAVP provided excellent haemostasis in all patients, with no requirement for factor concentrate or blood products. Mild asymptomatic hyponatremia was detected in seven children who received multiple doses of DDAVP (lowest sodium 129 mmol L(-1) ); however, adherence to the prescribed fluid restriction protocol was questionable in six of these cases. Symptomatic hyponatremia was not observed. CONCLUSION: Subcutaneous desmopressin was well-tolerated, with no serious side-effects observed, and good biological responses in preoperative trials. A two-thirds maintenance fluid regimen was effective at preventing symptomatic hyponatremia in our cohort, and is now the standard protocol for fluid restriction post-DDAVP administration in our centre.

Sleep disturbance in patients taking opioid medication for chronic back pain.

Poor sleep is an increasingly recognised problem with chronic pain and further increases the effect on daily function. To identify the relationship between chronic pain, opioid analgesia and sleep quality, this study investigated activity and sleep patterns in patients taking opioid and non-opioid analgesia for chronic back pain. Thirty-one participants (10 healthy controls, 21 patients with chronic pain: 6 on non-opioid medication; 15 on opioid medication) were assessed using actigraphy, polysomnography and questionnaires. Patients with chronic pain subjectively reported significant sleep and wake disturbances as shown by decreased overall sleep quality (Pittsburgh Sleep Quality Index, p < 0.001), increased symptoms of insomnia (Insomnia Severity Index, p < 0.001) and increased fatigue (Fatigue Severity Scale, p = 0.002). They also spent increased time in bed (p = 0.016), took longer to get to sleep (p = 0.005) and had high interindividual variability in other measures of activity but no overall irregular rest-activity pattern. Patients on high doses of opioids (> 100 mg morphine-equivalent/day) demonstrated distinctly abnormal brain activity during sleep suggesting that polysomnography is necessary to detect sleep disturbance in this population in the absence of irregular rest-activity behaviour. Night-time sleep disturbance is common in individuals suffering from chronic pain and may be further exacerbated by opioid treatment. Considerations must be made regarding the appropriate use of combined actigraphy and miniaturised polysomnography for future population-based studies.

ttm-1 encodes CDF transporters that excrete zinc from intestinal cells of C. elegans and act in a parallel negative feedback circuit that promotes homeostasis.

Zinc is an essential metal involved in a wide range of biological processes, and aberrant zinc metabolism is implicated in human diseases. The gastrointestinal tract of animals is a critical site of zinc metabolism that is responsible for dietary zinc uptake and distribution to the body. However, the role of the gastrointestinal tract in zinc excretion remains unclear. Zinc transporters are key regulators of zinc metabolism that mediate the movement of zinc ions across membranes. Here, we identified a comprehensive list of 14 predicted Cation Diffusion Facilitator (CDF) family zinc transporters in Caenorhabditis elegans and demonstrated that zinc is excreted from intestinal cells by one of these CDF proteins, TTM-1B. The ttm-1 locus encodes two transcripts, ttm-1a and ttm-1b, that use different transcription start sites. ttm-1b expression was induced by high levels of zinc specifically in intestinal cells, whereas ttm-1a was not induced by zinc. TTM-1B was localized to the apical plasma membrane of intestinal cells, and analyses of loss-of-function mutant animals indicated that TTM-1B promotes zinc excretion into the intestinal lumen. Zinc excretion mediated by TTM-1B contributes to zinc detoxification. These observations indicate that ttm-1 is a component of a negative feedback circuit, since high levels of cytoplasmic zinc increase ttm-1b transcript levels and TTM-1B protein functions to reduce the level of cytoplasmic zinc. We showed that TTM-1 isoforms function in tandem with CDF-2, which is also induced by high levels of cytoplasmic zinc and reduces cytoplasmic zinc levels by sequestering zinc in lysosome-related organelles. These findings define a parallel negative feedback circuit that promotes zinc homeostasis and advance the understanding of the physiological roles of the gastrointestinal tract in zinc metabolism in animals.