Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia.

INTRODUCTION: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known. METHODS: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function. RESULTS: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365). CONCLUSIONS: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

The World Rugby and International Rugby Players Contact Load Guidelines: From conception to implementation and the future.

Managing training load in rugby union is crucial for optimising performance and injury prevention. Contact training warrants attention because of higher overall injury and head impact risk, yet players must develop physical, technical, and mental skills to withstand the demands of the game. To help coaches manage contact loads in professional rugby, World Rugby and International Rugby Players convened an expert working group. They conducted a global survey with players to develop contact load guidelines. This commentary aims to describe the contact load guidelines and their implementation, and identify areas where future work is needed to support their evolution.

Anastomosis Groups of Rhizoctonia solani and Binucleate Rhizoctonia Associated with Potatoes in Idaho.

A survey of the relative incidence of anastomosis groups (AGs) of Rhizoctonia spp. associated with potato disease was conducted in Idaho, the leading potato producing state in the U.S.A. In total, 169 isolates of Rhizoctonia solani and seven binucleate Rhizoctonia (BNR) isolates were recovered from diseased potato plants. The AG of each isolate was determined through real-time PCR assays for AG 3-PT and phylogenetic analysis of the internal transcribed spacer region of ribosomal DNA. AG 3-PT was the predominant AG, accounting for 85% of isolates recovered, followed by AG 2-1 (5.7%) and AG 4 HG-II (4.5%). Two different subsets of AG 2-1 isolates were recovered (subset 2 and 3). Three isolates each of AG A and AG K were recovered, as well as one isolate each of AG 5 and AG W. An experiment carried out under greenhouse conditions with representative isolates of the different AGs recovered from Idaho potatoes showed differences in aggressiveness between AGs to potato stems, with AG 3-PT being the most aggressive followed by an isolate of AG 2-1 (subset 3). The three BNR isolates representative of AG A, AG K, and AG W appeared to be less aggressive to potato stems than the R. solani isolates except for the AG 2-1 (subset 2) isolate. This is the first comprehensive study of the relative incidences of Rhizoctonia species associated with Idaho potatoes and the first study to report the presence of BNR AG W outside of China.

The Theory of Planned Behavior and the USDA Summer Food Service Program.

OBJECTIVE: Examine the impact of the Summer Food Service Program (SFSP) on the intentions to positively change fruit and vegetable consumption in a rural, low-income adolescent population using the Theory of Planned Behavior. DESIGN: Quantitative data collected via a pre-post intervention survey to determine predictors of positive nutrition behaviors and changes in self-reported fruit and vegetable consumption. SETTING: A mid-sized university. PARTICIPANTS: Fifty-seven high school students. Participants were primarily female (n = 36) and white (n = 56). INTERVENTION: Participants followed the standards of the SFSP for 5 weeks and were provided with mandatory and optional nutrition education sessions. MAIN OUTCOME MEASURE: Intentions to change nutrition behaviors. ANALYSIS: Multiple regression. RESULTS: Paired-sample t test showed a significant increase in knowledge from pretest (mean [M] = 11.18, SD = 1.68) to posttest (M = 12.91, SD = 1.76); t[56] = -8.09, P < 0.001; (t[56] = -8.09, P < 0.001) and in self-reported fruit and vegetable intake from pretest (M = 13.96, SD = 4.23) to posttest (M = 16.80, SD = 5.42); (t[56] = -3.20, P = 0.002). Regression demonstrated that all constructs of the Theory of Planned Behavior were significant (F[4, 52] = 14.56, P < 0.001 with an R2 of 0.53) for their effects on behavior intentions with perceived behavioral control being the most salient predictor. CONCLUSIONS AND IMPLICATIONS: Opportunities for shaping adolescent nutrient intake and eating behaviors during enrollment in the SFSP exist. Reinforcing positive attitudes, subjective norms, and perceived behavioral control may help to increase nutrition behavioral intentions and nutrition behaviors.

Urine dicarboxylic acids change in pre-symptomatic Alzheimer's disease and reflect loss of energy capacity and hippocampal volume.

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.

On demand delivery and analysis of single molecules on a programmable nanopore-optofluidic device.

Nanopore-based single nanoparticle detection has recently emerged as a vibrant research field with numerous high-impact applications. Here, we introduce a programmable optofluidic chip for nanopore-based particle analysis: feedback-controlled selective delivery of a desired number of biomolecules and integration of optical detection techniques on nanopore-selected particles. We demonstrate the feedback-controlled introduction of individual biomolecules, including 70S ribosomes, DNAs and proteins into a fluidic channel where the voltage across the nanopore is turned off after a user-defined number of single molecular insertions. Delivery rates of hundreds/min with programmable off-times of the pore are demonstrated using individual 70S ribosomes. We then use real-time analysis of the translocation signal for selective voltage gating of specific particles from a mixture, enabling selection of DNAs from a DNA-ribosome mixture. Furthermore, we report optical detection of nanopore-selected DNA molecules. These capabilities point the way towards a powerful research tool for high-throughput single-molecule analysis on a chip.

Wind Turbine Electromagnetic Energy: Exploring Risk of Harm to Human Health.

The risk of harm to human health associated with radio/electromagnetic energy exposure is debated globally. Physicians and health practitioners may be presented with increasing numbers of patients with multisystem complaints, which may be initially confusing. Some residents living in proximity to wind energy facilities report harm they associate with exposure to radio/electromagnetic energy. Although authorities, physicians, and researchers express concerns regarding exposure to radio/electromagnetic energy in general, research specific to wind turbines is limited. Current regulations may be limited in scope and not include all devices that emit and/or utilize radio/electromagnetic energy. We recommend that government regulators advise the public of potential risks of exposure and establish limits that incorporate all sources of radio/electromagnetic energy, including wind turbines. Until these limits are established, governments should take precautionary and proactive measures to protect public health, with additional attention given to vulnerable population groups such as children and the older adults.

Optical trapping assisted detection rate enhancement of single molecules on a nanopore optofluidic chip.

We use optical trapping to deliver molecular targets to the vicinity of a nanopore for high-throughput single molecule analysis on an optofluidic chip. DNA detection rates increase over 80× to enable detection at attomolar concentrations.

A dramatic case of a woman discovered after 7 months of untreated catatonia.

Described is an unusually severe case of catatonia in the context of a major depressive episode. The patient is a 49-year-old Caucasian female who was living with her husband in an urban apartment. In March 2015, she experienced a major depressive episode in the context of financial hardship after being dismissed from her job. She became catatonic and did not leave her apartment for 7 months. For the first 4 months she lay in bed, then after losing bowel and bladder continence, she was transferred by her husband to the bedroom floor where she lay prone for another 3 months before paramedics were notified. She subsequently underwent a 4-month admission to an intensive care unit, surgical ward, and psychiatric ward. This case shows the extreme extent of psychiatric and physical sequelae that can result from prolonged delay of treatment of severe catatonia in the context of depression.

Note: Eliminating stripe artifacts in light-sheet fluorescence imaging.

We report two techniques to mitigate stripe artifacts in light-sheet fluorescence imaging. The first uses an image processing algorithm called the multidirectional stripe remover method to filter stripes from an existing image. The second uses an elliptical holographic diffuser with strong scattering anisotropy to prevent stripe formation during image acquisition. These techniques facilitate accurate interpretation of image data, especially in denser samples. They are also facile and cost-effective.

Setting targets leads to greater long-term weight losses and 'unrealistic' targets increase the effect in a large community-based commercial weight management group.

BACKGROUND: Setting personal targets is an important behavioural component in weight management programmes. Normal practice is to encourage 'realistic' weight loss, although the underlying evidence base for this is limited and controversial. The present study investigates the effect of number and size of weight-loss targets on long-term weight loss in a large community sample of adults. METHODS: Weight change, attendance and target weight data for all new UK members, joining from January to March 2012, were extracted from a commercial slimming organisation's electronic database. RESULTS: Of the 35 380 members who had weight data available at 12 months after joining, 69.1% (n = 24 447) had a starting body mass index (BMI) ≥30 kg m-2 . Their mean (SD) weight loss was 12.9% (7.8%) and, for both sexes, weight loss at 12 months was greater for those who set targets (P < 0.001). Those that set ≥4 targets achieved the greatest loss (P < 0.001). The odds ratio for weight loss ≥10% at 12 months was 10.3 (95% confidence interval = 9.7-11.1, P < 0.001) where targets had been set compared to none. At the highest quintile of target size, the size of the first target explained 47.2% (P < 0.001) of the variance in weight loss achieved at 12 months. The mean (SD) BMI reduction in those with a target >25% was 7.6 (4.0) kg m-2 . A higher percentage of obese members did not set targets (P < 0.001) compared to those with a BMI <30 kg m-2 . CONCLUSIONS: Much of the variance in weight loss achieved in this population was explained by the number of targets set and the size of the first target. Although obese people were less likely to set targets, doing so increased the likelihood of achieving clinically significant weight loss and, for some 'unrealistic' targets, improved the results.

Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

Amniotic fluid levels of phospholipase A2 in fetal rats with retinoic acid induced myelomeningocele: the potential "second hit" in neurologic damage.

OBJECTIVES: There is growing evidence of ongoing, in utero neurological damage in fetuses with myelomeningocele (MMC). Phospholipase A2 (PLA2) has known neurotoxic properties and is predominantly present in its secretory isoform (sPLA2) in meconium, the passage of which is increased in MMC fetuses. The objective of this study was to determine if amniotic fluid (AF) levels of PLA2 are elevated in a rat model of MMC. METHODS: Timed pregnant Sprague-Dawley rats were gavage fed 60 mg/kg/bodyweight retinoic acid (RA) in olive oil at embryonic day 10 (E10). Amniocentesis was performed at multiple gestational time points on MMC fetuses, RA-exposed fetuses without MMC and control fetuses. AF PLA2 levels were analyzed by a fluorescent enzyme activity assay. PLA2 isoforms were determined by measuring activity in the presence of specific inhibitors. RESULTS: There was no difference in AF PLA2 activity between groups on E15. PLA2 activity was significantly increased in MMC fetuses on E17, E19 and E21 (p < 0.001). Secretory PLA2 primarily accounted for the overall greater activity. CONCLUSIONS: PLA2 levels are elevated in the AF of fetal rats with MMC and may contribute to ongoing neural injury. This pathway may be a useful drug target to limit ongoing damage and better preserve neurologic function.

Granular dynamics during impact.

We study the impact of a projectile onto a bed of 3 mm grains immersed in an index-matched fluid. We vary the amount of prestrain on the sample, strengthening the force chains within the system. We find this affects only the prefactor of the linear depth-dependent term in the stopping force. We propose a simple model to account for the strain dependence of this term, owing to increased pressure in the pile. Interestingly, we find that the presence of the fluid does not affect the impact dynamics, suggesting that dynamic friction is not a factor. Using a laser sheet scanning technique to visualize internal grain motion, we measure the trajectory of each grain throughout an impact. Microscopically, our results indicate that weaker initial force chains result in more irreversible, plastic rearrangements, suggesting static friction between grains does play a substantial role in the energy dissipation.

Evaluation of a low-cost commercially available extraction device for assessing lead bioaccessibility in contaminated soils.

The U.S. EPA's in vitro bioaccessibility (IVBA) method 9200.1-86 defines a validated analytical procedure for the determination of lead bioaccessibility in contaminated soils. The method requires the use of a custom-fabricated extraction device that uses a heated water bath for sample incubation. In an effort to improve ease of use, increase sample throughput, and reduce equipment acquisition and maintenance costs, an alternative low-cost, commercially available extraction device capable of sample incubation via heated air and end-over-end rotation was evaluated. An intra-laboratory study was conducted to compare lead bioaccessibility values derived using the two extraction devices. IVBA values were not statistically different (α = 0.05) between the two extraction devices for any of the soils (n = 6) evaluated in this study, with an average difference in mean lead IVBA of 0.8% (s.d. = 0.5%). The commercially available extraction device was able to generate accurate lead IVBA data as compared to the U.S. EPA's expected value for a National Institute of Standards and Technology standard reference material soil. The relative percent differences between high and low IVBA values for each soil, a measure of instrument precision, were also not statistically different (α = 0.05) between the two extraction devices. The statistical agreement of lead IVBA values observed using the two extraction devices supports the use of a low-cost, commercially available extraction device as a reliable alternative to a custom-fabricated device as required by EPA method 9200.1-86.

Voluntary exercise can strengthen the circadian system in aged mice.

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2(luc)/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption.

Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine.

OBJECTIVE: To assess the efficacy and safety of adding propranolol to topiramate in chronic migraine subjects inadequately controlled with topiramate alone. METHODS: This was a double-blind, placebo-controlled, randomized clinical trial conducted through the National Institute of Neurological Disorders and Stroke Clinical Research Collaboration, expected to randomize 250 chronic migraine subjects inadequately controlled (≥10 headaches/month) with topiramate (50-100 mg/day) to either propranolol LA (long acting) (240 mg/day) or placebo. Primary outcome was 28-day moderate to severe headache rate reduction at 6 months (weeks 16 to 24) compared with baseline (weeks -4 to 0). RESULTS: A planned interim analysis was performed after 48 sites randomized 171 subjects. The data and safety monitoring board recommended ending the trial after determining that it would be highly unlikely for the combination to result in a significant reduction in 28-day headache rate compared with topiramate alone if all 250 subjects were randomized. No safety concerns were identified. At study closure, 191 subjects were randomized. The 6-month reduction in moderate to severe 28-day headache rate and total 28-day headache rate for combination therapy vs topiramate alone was not significantly different: 4.0 vs 4.5 days (moderate to severe 28-day headache rate; p = 0.57) and 6.2 vs 6.1 days (total 28-day headache rate; p = 0.91). CONCLUSIONS: This study does not provide evidence that the addition of propranolol LA to topiramate adds benefit when chronic migraine is inadequately controlled with topiramate alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that propranolol LA, added to topiramate, is ineffective in chronic migraine patients who fail topiramate monotherapy.

The experiences of cancer patients.

OBJECTIVES: To assess the needs of cancer patients for information about their condition and to understand the psychological impact of their illness. BACKGROUND: The discussion of prognosis and treatment options in the palliative setting is an important and difficult part of oncology practice. To evaluate this, we examined the experiences of cancer patients of the physical and psychological impact of their disease on their life, and their opinions on the communication of end-of-life decisions and treatment options. METHODS: A patient questionnaire was designed that encompassed communication regarding treatment and prognosis, quality-of-life attitudes subsequent to cancer diagnosis, end-of-life care and cancer drug funding. One hundred and twenty-five patients with a diagnosis of cancer were asked to participate and 96 questionnaires were completed and available for analysis. The questionnaire consisted of 63 questions and was completed in both an inpatient and outpatient setting. RESULTS: This survey brought to light a number of controversial issues in cancer service provision, highlighting the emotional and psychological changes brought about by a cancer diagnosis. Major concerns of our patients include fear of death and pain, changes in interpersonal relationships and financial constraints. Only 66% of the patients wanted to be given a prognosis by their clinicians and just 70% of the patients recalled being given a detailed prognosis. 11% of the patients were not prepared to undergo palliative treatment. In all, 7% were not prepared to accept treatment for 1 year and 2% for 5 years of life in exchange for the potential side effects of cytotoxic chemotherapy. 12% of the patients would not want to be in possession of the information that they were in the terminal phase of the illness with a short time to live and 16% would not want this discussed with their next of kin. CONCLUSION: This study informs medical professionals about the importance of tailoring information to the needs of the individual patient, and we feel it provides insights into the successes and failures of our communication with cancer patients. It is important that difficult discussions are personalized to the individual patients' wishes. These can vary dramatically both in the area of disclosure of bad news in prognosis and in end-of-life decision making. This study provides compelling evidence for good advanced care planning at an early stage in the management of patients with terminal cancers.

Restricted wheel access following a light cycle inversion slows re-entrainment without internal desynchrony as measured in Per2Luc mice.

Circadian rhythms are physiological and behavioral oscillations that have period lengths of approximately 24 h. In mammals, circadian rhythms are driven by a master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). These rhythms can be entrained to light:dark cycles through photic and non-photic cues. Current research suggests that the SCN re-entrains rapidly to new light:dark (LD) cycles with the first photic cues, whereas peripheral tissues re-entrain more slowly, leading to a transient state of internal disorder while the organism adjusts to the new timing of photic input. To assess internal temporal order during the readjustment we used dim light to slow the rate of re-entrainment following a 12-h inversion of the LD cycle. We also used a wheel-restriction paradigm, which can block behavioral evidence of re-entrainment. Per2(Luc) mice were entrained to a 12:12 dim LD cycle with wheel access ad libitum. Following a 12-h shift in the LD cycle, some animals were subjected to wheel restriction; wheels were locked during the new dark period and available during the new light period. Other mice had wheels available ad lib throughout the experiment. Behavioral actograms of general locomotor activity as measured with motion sensors indicated that mice with ad lib access to wheels were able to re-entrain at a rate significantly faster than mice with restricted wheel access. Up to 2 weeks following the LD inversion many wheel-restricted animals were still active predominantly in the new light period. Phase of the PER2::LUC bioluminescence rhythms in SCN and four peripheral tissues (lung, esophagus, thymus, and spleen), measured ex vivo on days 2, 9, and 16 following the inversion, indicated that within each condition the SCN and peripheral tissues shifted at the same rate, whereas the rate of re-entrainment for the tissues differed between conditions. Ex vivo data showed that the PER2::LUC peaks in SCN and peripheral tissues were closely linked to time of activity onset in both groups. Thus, this wheel restriction protocol is capable of reducing and in some cases apparently hindering photic re-entrainment of the circadian system, verifying this protocol as a mechanism for study of photic/non-photic entrainment interactions. Our results suggest that LD inversion under dim light and a wheel-restriction protocol does not induce internal desynchrony, indicating that slowing the rate of shift by limiting both entrainment inputs may induce less "jet lag".