Epidemiology of migraine.

Migraine affects over a billion people worldwide and brings with it a huge burden of disability. It is a disease which disproportionally affects the working age population which heightens its economic impact, both at the individual family level and the societal level. Women are significantly more affected by migraine at every age and in all social and geographical groups. At the most severe end of the spectrum, chronic migraine is associated with poorer overall physical and mental health as well as increased risk of unemployment and lower household income. Estimates of the incidence and prevalence of migraine vary with sex, race, ethnicity, geography, socioeconomic, and educational status, suggesting there are many factors at play. In many cases, it is not clear whether these factors are causative of migraine, the effects of migraine, or (as is most likely) a combination of both. Future studies should aim to clarify these links, so that modifiable factors can be addressed where possible and those at risk of developing chronic migraine might receive targeted treatment at an early stage.

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache.

Background: Many patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective. Objective: To assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients. Method: We prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3 months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies. Results: 17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3 months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month. Conclusion: This study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies.

Identifying women who may benefit from higher dose omega-3 supplementation during pregnancy to reduce their risk of prematurity: exploratory analyses from the ORIP trial.

OBJECTIVES: The risk factors for prematurity are multifactorial and include low omega-3 status. Omega-3 supplementation in pregnancy has been found to reduce prematurity risk, particularly among women with low omega-3 levels. This study aimed to identify maternal characteristics that predict whether women with a singleton pregnancy will benefit from omega-3 supplementation to reduce their risk of prematurity. DESIGN: Exploratory analyses of a multicentre, double-blind randomised trial. SETTING: 6 tertiary care centres in four states in Australia. PARTICIPANTS: 5328 singleton pregnancies in 5305 women recruited before 20 weeks of gestation. INTERVENTIONS: Fish oil capsules containing 900 mg omega-3 long-chain polyunsaturated fatty acids per day versus vegetable oil capsules consumed from enrolment until 34 weeks' gestation. OUTCOME MEASURES: Early preterm birth (EPTB, <34 weeks' gestation) and preterm birth (PTB, <37 weeks' gestation) analysed using logistic regression models with interactions between treatment group and a range of maternal biological, clinical and demographic characteristics. RESULTS: Omega-3 supplementation reduced the odds of EPTB for women with low total omega-3 status in early pregnancy (OR=0.30, 95% CI 0.10-0.93). No additional maternal characteristics influenced whether omega-3 supplementation reduced the odds of EPTB. For PTB, women were more likely to benefit from omega-3 supplementation if they were multiparous (OR=0.65, 95% CI 0.49-0.87) or avoided alcohol in the lead up to pregnancy (OR=0.62, 95% CI 0.45-0.86). CONCLUSIONS: Our results support previous findings that women with low total omega-3 levels in early pregnancy are most likely to benefit from taking omega-3 supplements to reduce their risk of EPTB. Understanding how other maternal characteristics influence the effectiveness of omega-3 supplementation on reducing PTB requires further investigation. TRIAL REGISTRATION NUMBER: ACTRN12613001142729.

Recent advances in policy and practice translation of the evidence for additional omega-3 fatty acids and prematurity.

PURPOSE OF REVIEW: This is a review of the most up-to-date research on the effectiveness of omega-3 fatty acids for reducing the risk of prematurity in well nourished women with access to high-quality obstetric care. It will provide an overview of the translation of the evidence on omega-3 screening into policy, and the latest research on how to implement the policy into practice. RECENT FINDINGS: Findings of the included clinical studies support that omega-3 supplementation for women with a singleton pregnancy who have a low omega-3 status reduces the risk of early preterm birth. SUMMARY: There is evidence that screening and providing appropriate advice to women with a singleton pregnancy who have a low omega-3 status can reduce their risk of early preterm birth, and avoiding supplementation for women who are replete will avoid unnecessary supplementation and potential harm.

Translating n-3 polyunsaturated fatty acid status from whole blood to plasma and red blood cells during pregnancy: Translating n-3 status across blood fractions in pregnancy.

Women with low n-3 (omega-3) status in pregnancy can reduce their risk of early preterm birth (<34 weeks' gestation) through n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation. As investigators measure fatty acid status in different blood fractions, equations are needed to compare results across studies. Similarly, derived cut-points for defining low and replete n-3 status are needed to assist clinical interpretation during early pregnancy. Our aims were to develop equations to convert the percentage of total n-3 fatty acids, EPA+DHA and DHA between whole blood, plasma and red blood cells (RBC), and to derive cut-points for defining low and replete total n-3 fatty acid status in plasma and RBC from those already established in whole blood. Using blood samples from 457 pregnant women in a multicentre randomised controlled trial, equations for these interconversions were developed using simple linear regression models. Measures of n-3 fatty acid status in whole blood and plasma were strongly related (R2 > 0.85), while more moderate relationships were observed between measures in whole blood and RBC (R2 0.55 - 0.71), or plasma and RBC (R2 0.55 - 0.63). Using the conversion equations, established cut-points for low and replete n-3 status in whole blood (<4.2% and >4.9% of total fatty acids) converted to <3.7% and >4.3% of plasma total fatty acids, and to <7.3% and >8.1% of RBC total fatty acids. Agreement to define low and replete n-3 status was better between whole blood and plasma, rather than between whole blood and RBC. Our data also show that total n-3 fatty acids in plasma and serum are interchangeable. We conclude that either whole blood or plasma total n-3 fatty acids can be used to define low status in pregnancy and identify women who will most benefit from n-3 LCPUFA supplementation to reduce their risk of early birth. Further research is needed to determine the clinical utility of other fatty acid measures in various blood lipid fractions.

BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma.

Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial-5 y OS 45% vs. 80%, p = 0.011-and CNS9904, a radiotherapy-led trial-OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients.

Omega-3 fatty acids to prevent preterm birth: Australian pregnant women's preterm birth awareness and intentions to increase omega-3 fatty acid intake.

BACKGROUND: Preterm birth is the leading cause of death in children under five. A recent Cochrane review found a 42% reduction in early preterm birth (< 34 weeks' gestation) and 11% reduction in preterm birth (< 37 weeks' gestation) with omega-3 fatty acid supplementation. To assist in the development of implementation strategies to increase pregnant women's omega-3 fatty acid intake, we assessed the awareness of Australian pregnant women about preterm birth, their nutrition and supplementation behaviours during pregnancy, and intentions to increase omega-3 fatty acid intake. METHODS: A ten-minute survey was conducted online to assess the knowledge, attitudes, behaviours, and intentions of Australian pregnant women across three domains: (1) preterm birth; (2) nutrition and supplementation during pregnancy; and (3) omega-3 fatty acid consumption to prevent preterm birth. Participants were recruited from Survey Sampling International's research panels. RESULTS: Of the 763 women who completed the survey, less than two-thirds had heard of preterm birth. Over 55% of respondents had changed their diet during pregnancy and a prenatal dietary supplement was consumed by 82% of the women surveyed. Respondents' main source of information about preterm birth and nutrition during pregnancy was from a health professional. When asked about their intentions to increase their omega-3 fatty acid intake following a health professional's recommendation, the vast majority of participants indicated they would increase their omega-3 fatty acid intake (90%). When a hypothetical scenario was presented of an omega-3 fatty acid supplement being offered from a health service at no cost, the number of respondents who selected they would increase their intake through supplementation increased from 54 to 79%. CONCLUSIONS: The main information source for women about preterm birth and dietary supplementation recommendations during pregnancy is their health professional. Therefore, informing women about ways to prevent preterm birth, including the role of omega-3 fatty acids, should occur during antenatal visits. The results from our study are useful for clinicians caring for pregnant women and for the next stage of translation of the Cochrane review findings - the design of implementation strategies to increase the intake of omega-3 fatty acids during pregnancy where needed.

Aspergillus niger infection in an immunosuppressed patient confined solely to the brain.

A 68-year-old woman with a background of hypertension, stroke and rheumatoid arthritis presented to her local hospital after a 4-week history of gradual deterioration and increasing confusion with new onset right-sided weakness. Her initial CT scan revealed a rim enhancing mass lesion with surrounding oedema in the left parietal lobe for which she underwent CT stealth-guided biopsy. Microbiology culture of the 2 biopsy samples yielded Aspergillus niger and she was started on the antifungal agent voriconazole. MRI 2 weeks after the procedure also demonstrated radiological findings consistent with intracranial aspergillosis. She later developed leucopenia with neutrophils of 1.5×109/L and her methotrexate and voriconazole were stopped. Voriconazole was changed to oral posaconazole. She did not undergo surgical resection and has continued to improve clinically on posaconazole, with recovery in her white cell count.

Different intensities of glycaemic control for pregnant women with pre-existing diabetes.

BACKGROUND: The optimal glycaemic control target in pregnant women with pre-existing diabetes is unclear, although there is a clear link between high glucose concentrations and adverse birth outcomes. OBJECTIVES: To assess the effects of different intensities of glycaemic control in pregnant women with pre-existing type 1 or type 2 diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2016) and planned to search reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials comparing different glycaemic control targets in pregnant women with pre-existing diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted data extraction, assessed risk of bias and checked for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included three trials, all in women with type 1 diabetes (223 women and babies). All three trials were at high risk of bias due to lack of blinding, unclear methods of randomisation and selective reporting of outcomes. Two trials compared very tight (3.33 to 5.0 mmol/L fasting blood glucose (FBG)) with tight-moderate (4.45 to 6.38 mmol/L) glycaemic control targets, with one trial of 22 babies reporting no perinatal deaths orserious perinatal morbidity (evidence graded low for both outcomes). In the same trial, there were two congenital anomalies in the very tight, and none in the tight-moderate group, with no significant differences in caesarean section between groups (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.49 to 1.73; evidence graded very low). In these two trials, glycaemic control was not significantly different between the very tight and tight-moderate groups by the third trimester, although one trial of 22 women found significantly less maternal hypoglycaemia in the tight-moderate group.In a trial of 60 women and babies comparing tight (≤ 5.6 mmol/L FBG); moderate (5.6 to 6.7 mmol/L); and loose (6.7 to 8.9 mmol/L) glycaemic control targets, there were two neonatal deaths in the loose and none in the tight or moderate groups (evidence graded very low). There were significantly fewer women with pre-eclampsia (evidence graded low), fewer caesarean sections (evidence graded low) and fewer babies with birthweights greater than 90th centile (evidence graded low) in the combined tight-moderate compared with the loose group.The quality of the evidence was graded low or very low for important outcomes, because of design limitations to the studies, the small numbers of women included, and wide confidence intervals crossing the line of no effect. Many of the important outcomes were not reported in these studies. AUTHORS' CONCLUSIONS: In a very limited body of evidence, few differences in outcomes were seen between very tight and tight-moderate glycaemic control targets in pregnant women with pre-existing type 1 diabetes, including actual glycaemic control achieved. There is evidence of harm (increased pre-eclampsia, caesareans and birthweights greater than 90th centile) for 'loose' control (FBG above 7 mmol/L). Future trials comparing interventions, rather than glycaemic control targets, may be more feasible. Trials in pregnant women with pre-existing type 2 diabetes are required.

Barriers and enablers to implementing antenatal magnesium sulphate for fetal neuroprotection guidelines: a study using the theoretical domains framework.

BACKGROUND: Strong evidence supports administration of magnesium sulphate prior to birth at less than 30 weeks' gestation to prevent very preterm babies dying or developing cerebral palsy. This study was undertaken as part of The WISH (Working to Improve Survival and Health for babies born very preterm) Project, to assess health professionals' self-reported use of antenatal magnesium sulphate, and barriers and enablers to implementation of 2010 Australian and New Zealand clinical practice guidelines. METHODS: Semi-structured, one-to-one interviews were conducted with obstetric and neonatal consultants and trainees, and midwives in 2011 (n = 24) and 2012-2013 (n = 21) at the Women's and Children's Hospital, South Australia. Transcribed interview data were coded using the Theoretical Domains Framework (describing 14 domains related to behaviour change) for analysis of barriers and enablers. RESULTS: In 2012-13, health professionals more often reported 'routinely' or 'sometimes' administering or advising their colleagues to administer magnesium sulphate for fetal neuroprotection (86% in 2012-13 vs. 46% in 2011). 'Knowledge and skills', 'memory, attention and decision processes', 'environmental context and resources', 'beliefs about consequences' and 'social influences' were key domains identified in the barrier and enabler analysis. Perceived barriers were the complex administration processes, time pressures, and the unpredictability of preterm birth. Enablers included education for staff and women at risk of very preterm birth, reminders and 'prompts', simplified processes for administration, and influential colleagues. CONCLUSIONS: This study has provided valuable data on barriers and enablers to implementing magnesium sulphate for fetal neuroprotection, with implications for designing and modifying future behaviour change strategies, to ensure optimal uptake of this neuroprotective therapy for very preterm infants.

Different intensities of glycaemic control for pregnant women with pre-existing diabetes.

BACKGROUND: The optimal glycaemic control target in pregnant women with pre-existing diabetes is unclear, although there is a clear link between high glucose concentrations and adverse birth outcomes. OBJECTIVES: To assess the effects of different intensities of glycaemic control in pregnant women with pre-existing type 1 or type 2 diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2012). SELECTION CRITERIA: We included randomised controlled trials comparing different glycaemic control targets in pregnant women with pre-existing diabetes. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias, and extracted data. MAIN RESULTS: We included three trials all in women with type 1 diabetes (223 women and babies), and all with a high risk of bias. Two trials compared very tight (3.33 to 5.0 mmol/L fasting blood glucose (FBG)) with tight-moderate (4.45 to 6.38) glycaemic control targets, with one trial of 22 babies reporting no perinatal deaths or serious perinatal morbidity. In the same trial, there were two birth defects in the very tight and none in the tight-moderate group with no significant differences in caesarean section between groups (risk ratio 0.92, 95% confidence interval (CI) 0.49 to 1.73). In these two trials glycaemic control was not significantly different between the very tight and tight-moderate groups by the third trimester, although one trial of 22 women found significantly less maternal hypoglycaemia in the tight-moderate group.In a trial of 60 women and babies comparing tight (≤ 5.6 mmol/L FBG); moderate (5.6 to 6.7); and loose (6.7 to 8.9) glycaemic control targets, there were two neonatal deaths in the loose and none in the tight or moderate groups. There were significantly fewer women with pre-eclampsia, fewer caesareans and fewer birthweights greater than 90th centile in the combined tight-moderate compared with the loose group. AUTHORS' CONCLUSIONS: In a very limited body of evidence, few differences in outcomes were seen between very tight and tight-moderate glycaemic control targets in pregnant women with pre-existing type 1 diabetes, including actual glycaemic control achieved. There is evidence of harm (increased pre-eclampsia, caesareans and birthweights greater than 90th centile) for 'loose' control (FBG above 7 mmol/L). Future trials comparing interventions, rather than glycaemic control targets, may be more feasible particularly for pregnant women with type 2 diabetes.

Different intensities of glycaemic control for pregnant women with pre-existing diabetes.

BACKGROUND: The optimal glycaemic control target in pregnant women with pre-existing diabetes is unclear, although there is a clear link between high glucose concentrations and adverse birth outcomes. OBJECTIVES: To assess the effects of different intensities of glycaemic control in pregnant women with pre-existing type 1 or type 2 diabetes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 May 2010). SELECTION CRITERIA: We included randomised controlled trials comparing different glycaemic control targets in pregnant women with pre-existing diabetes. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias, and extracted data. MAIN RESULTS: We included three trials all in women with type 1 diabetes (223 women and babies), and all with a high risk of bias. Two trials compared very tight (3.33 to 5.0 mmol/L fasting blood glucose (FBG)) with tight-moderate (4.45 to 6.38) glycaemic control targets, with one trial of 22 babies reporting no perinatal deaths or serious perinatal morbidity. In the same trial, there were two birth defects in the very tight and none in the tight-moderate group with no significant differences in caesarean section between groups (risk ratio 0.92, 95% confidence interval (CI) 0.49 to 1.73). In these two trials glycaemic control was not significantly different between the very tight and tight-moderate groups by the third trimester, although one trial of 22 women found significantly less maternal hypoglycaemia in the tight-moderate group.In a trial of 60 women and babies comparing tight (

Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial.

BACKGROUND: The visual and mental development of preterm infants improved after feeding them milk enriched with docosahexaenoic acid (DHA) in amounts matching the fetal accretion rate. OBJECTIVE: The objective was to evaluate whether feeding preterm infants milk with a higher DHA content than that used in current practice influences language or behavior in early childhood. DESIGN: This was a follow-up study in a subgroup of infants enrolled in the DINO (Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome) trial. In a double-blind randomized controlled trial, infants born at <33 wk of gestation were fed milk containing 1% of total fatty acids as DHA (higher-DHA group) or approximately 0.3% DHA (control group) until reaching full-term equivalent age. The longer-term effects of the intervention on language, behavior, and temperament were measured by using the MacArthur Communicative Development Inventory (MCDI) at 26-mo corrected age, the Strengths and Difficulties Questionnaire (SDQ), and the Short Temperament Scale for Children (STSC) between 3- and 5-y corrected age. RESULTS: Mean (+/-SD) MCDI scores did not differ significantly (adjusted P = 0.8) between the higher-DHA group (308 +/- 179, n = 60) and the control group (316 +/- 192, n = 67) per the Vocabulary Production subscale. Composite scores on the SDQ and STSC did not differ between the higher-DHA group and the control group [SDQ Total Difficulties: higher-DHA group (10.3 +/- 6.0, n = 61), control group (9.5 +/- 5.5, n = 64), adjusted P = 0.5; STSC score: higher-DHA group (3.1 +/- 0.7, n = 61), control group (3.0 +/- 0.7, n = 64), adjusted P = 0.3]. CONCLUSIONS: Feeding preterm infants milk containing 3 times the standard amount of DHA did not result in any clinically meaningful change to language development or behavior when assessed in early childhood. Whether longer-term effects of dietary DHA supplementation can be detected remains to be assessed. This trial was registered with the Australia and New Zealand Clinical Trial Registry at www.anzctr.org.au as 12606000327583.