The effectiveness of interventions to reduce peripheral blood culture contamination in acute care: a systematic review protocol.

BACKGROUND: Blood cultures are an integral part of the diagnosis of bacteremia in unwell patients. The treatment of bacteremia involves the rapid and accurate identification of the causative agent grown from the blood cultures collected. Contamination of blood cultures with non-pathogenic microbes such as skin commensals causes false positive results and subsequent unnecessary and potentially harmful interventions. While guidelines for blood culture quality recommend no more than 2-3% contamination rate, rates up to 12% are reported in the literature. There have been a number of methods proposed to reduce the contamination of blood cultures, including educational interventions, changing of skin cleansing preparations and introduction of blood culture collection packs in acute care settings. This protocol outlines methods to identify and evaluate interventions to reduce blood culture contamination in the acute care setting. METHODS: The reviewers will conduct a systematic search of literature in CINHAL, PubMed, EMBASE and the Cochrane Central register of controlled trials. Unpublished works will be identified in ProQuest Dissertations and Theses. Articles will be assessed for relevance based on their title and abstract. Remaining relevant citations will have their full text retrieved and assessed against eligibility criteria. All studies that meet the eligibility criteria will have their methodological quality appraised. Assessments for relevance and methodological quality will be conducted independently by two reviewers. If appropriate, data will be analysed using the Mantel-Haenszel method under a random effects model. Heterogeneity of the studies will be assessed using the I 2 and chi-squared statistic. Meta-analysis will be attempted if the data is suitable. DISCUSSION: This review will identify and summarise the interventions previously described in the literature aimed at reducing peripherally collected blood culture contamination rates in acute care. These findings have the potential to lead to multifaceted interventions based on previous evidence to reduce blood culture contamination in the acute setting. Reductions in the proportion of contaminated blood cultures have the potential to save money, unrequired treatment (particularly antimicrobials) and hospital bed days. SYSTEMATIC REVIEW REGISTRATION: In accordance with guidelines outlined in the PRISMA-P methodology, this protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on December 8, 2017, and last updated on January 4, 2018 (registration number CRD42017081650).

An anthropomorphic soft skeleton hand exploiting conditional models for piano playing.

The development of robotic manipulators and hands that show dexterity, adaptability, and subtle behavior comparable to human hands is an unsolved research challenge. In this article, we considered the passive dynamics of mechanically complex systems, such as a skeleton hand, as an approach to improving adaptability, dexterity, and richness of behavioral diversity of such robotic manipulators. With the use of state-of-the-art multimaterial three-dimensional printing technologies, it is possible to design and construct complex passive structures, namely, a complex anthropomorphic skeleton hand that shows anisotropic mechanical stiffness. We introduce a concept, termed the "conditional model," that exploits the anisotropic stiffness of complex soft-rigid hybrid systems. In this approach, the physical configuration, environment conditions, and conditional actuation (applied actuation) resulted in an observable conditional model, allowing joint actuation through passivity-based dynamic interactions. The conditional model approach allowed the physical configuration and actuation to be altered, enabling a single skeleton hand to perform three different phrases of piano music with varying styles and forms and facilitating improved dynamic behaviors and interactions with the piano over those achievable with a rigid end effector.

Comparing the survival rate of juvenile Chinook salmon migrating through hydropower systems using injectable and surgical acoustic transmitters.

Acoustic telemetry is one of the primary technologies for studying the behavior and survival of fishes throughout the world. The size and performance of the transmitter are key limiting factors. The newly developed injectable transmitter is the first acoustic transmitter that can be implanted via injection instead of surgery. A two-part field study was conducted to evaluate the performance of the injectable transmitter and its effect on the survival of implanted fish. The injectable transmitter performed well and similarly to the proceeding generation of commercially-available JSATS transmitters tested concurrently. Snake River subyearling Chinook salmon smolts implanted with the injectable transmitter had a higher survival probability from release to each of eleven downstream detection arrays, because reach-specific survival estimates were significantly higher for the injectable group in three of the eleven reaches examined. Overall, the injectable group had a 0.263 (SE = 0.017) survival probability over the entire 500 km study area compared to 0.199 (0.012) for the surgically implanted group. The reduction in size and ability to implant the new transmitter via injection has reduced the tag or tagging effect bias associated with studying small fishes. The information gathered with this new technology is helping to evaluate the impacts of dams on fishes.

Anatomical variation in the position of the brachiocephalic trunk (innominate artery) with respect to the trachea: a computed tomography-based study and literature review of Innominate Artery Compression Syndrome.

Respiratory compromise due to tracheal compression by the brachiocephalic trunk (BT), a condition first labeled as Innominate Artery Compression Syndrome (IACS), has been controversially attributed to an anomalous origin of this vessel to the left of, and hence crossing, the trachea. The aim of this study was to establish the normal relationship between the BT and trachea in infants, children, and young adults without obstructive respiratory symptoms. One hundred and eighty-one computed tomography (CT) examinations of the thorax, in three age groups, were reviewed. In axial cross section, the origin of the BT from the aortic arch was identified. The BT origin, with respect to the trachea, was recorded as for a clock face, approximated to the nearest half hour. There were 62 CTs in Group 1 (1 day to 3 years of age), 48 CTs in Group 2 (10-15 years), and 71 examinations in Group 3 (20-40 years). In 96.8% of Group 1, 91.7% of Group 2, and 74.6% of Group 3 the BT origin was to the left of the trachea, between the half past twelve and 3 o'clock positions. The BT origin occurred more the left in Group 1 when compared with the other two groups (P < 0.001). An origin of the BT to the left of the trachea is a normal finding in children and young adults without obstructive respiratory symptoms. There is a tendency for the origin to become progressively more rightward with age.

Ocean fertilization: a potential means of geoengineering?

The oceans sequester carbon from the atmosphere partly as a result of biological productivity. Over much of the ocean surface, this productivity is limited by essential nutrients and we discuss whether it is likely that sequestration can be enhanced by supplying limiting nutrients. Various methods of supply have been suggested and we discuss the efficacy of each and the potential side effects that may develop as a result. Our conclusion is that these methods have the potential to enhance sequestration but that the current level of knowledge from the observations and modelling carried out to date does not provide a sound foundation on which to make clear predictions or recommendations. For ocean fertilization to become a viable option to sequester CO2, we need more extensive and targeted fieldwork and better mathematical models of ocean biogeochemical processes. Models are needed both to interpret field observations and to make reliable predictions about the side effects of large-scale fertilization. They would also be an essential tool with which to verify that sequestration has effectively taken place. There is considerable urgency to address climate change mitigation and this demands that new fieldwork plans are developed rapidly. In contrast to previous experiments, these must focus on the specific objective which is to assess the possibilities of CO2 sequestration through fertilization.

The alpha7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice.

While activation of alpha7 nicotinic receptors protects neurons from a variety of apoptotic insults in vitro, little is known about this neuroprotective action in vivo, especially under amyloidogenic conditions that mimic Alzheimer's disease. We therefore investigated the effects of 4OH-GTS-21, a selective partial agonist for these receptors, on septohippocampal cholinergic and GABAergic neuron survival following fimbria fornix (FFX) lesions in three strains of mice: C57BL/6J wild type mice; human presenilin-1 mutant M146L (PS1) transgenic mice; and mice expressing both mutant PS1 and Swedish mutant K670N/M671L amyloid precursor protein (APP). Initial studies to demonstrated that 4OH-GTS-21 is likely brain permeant based on its ability to improve passive avoidance and Morris water task behaviors in nucleus basalis-lesioned rats. In FFX-lesioned mice, twice per day i.p. injections of 1 mg/kg of 4OH-GTS-21 for 2 weeks promoted the survival and prevented the atrophy of septal cholinergic neurons. Septal parvalbumin-staining GABAergic neurons were not protected by this treatment, although they also express alpha7 nicotinic receptors, suggesting an indirect, nerve growth factor (NGF)-mediated mechanism. No protection of cholinergic neurons was observed in similarly treated PS1 or APP/PS1 transgenic mice. 4OH-GTS-21 treatment actually reduced cholinergic neuronal size in APP/PS1 mice. Hippocampal amyloid deposition was not affected by FFX lesions or treatment with this alpha7 nicotinic receptor agonist in APP/PS1 mice under these conditions. These results indicate that brain alpha7 nicotinic receptors are potential targets for protecting at-risk brain neurons in Alzheimer's disease, perhaps via their effects on NGF receptors; however, this protection may be sensitive under some conditions to environmental factors such as inhibitory amyloid-peptides.

alpha7 Nicotinic receptor gene delivery into mouse hippocampal neurons leads to functional receptor expression, improved spatial memory-related performance, and tau hyperphosphorylation.

Brain alpha7 nicotinic receptors have become therapeutic targets for Alzheimer's disease (AD) based on their memory-enhancing and neuroprotective actions. This study investigated the feasibility of increasing neuronal alpha7 receptor functions using a gene delivery approach based on neuron-selective recombinant adeno-associated virus (rAAV)-derived vectors. In order to determine whether alpha7 receptor-mediated cytotoxicity was dependent on receptor density, rat alpha7 nicotinic receptors were expressed at high concentrations in GH4C1 cells as measured with nicotine-displaceable [3H]methyllycaconitine (MLA) binding. The potency of GTS-21 (an alpha7 receptor agonist) to induce cell loss was similar in these cells to that seen in pheochromocytoma (PC12) cells expressing nine-times-lower receptor levels, suggesting that cytotoxicity was more dependent on agonist concentration than receptor density. Hippocampal transduction with rat alpha7 nicotinic receptors increased [3H]MLA binding in this region in wild type and alpha7 receptor-knockout (KO) mice without apparent cytotoxicity. No difference was observed in Kd values for MLA binding between endogenous and transgenic receptors. Single cell recordings demonstrated that dentate granule cells that normally have no alpha7 receptor response did so following alpha7 receptor gene delivery in wild type mice. Recovery of alpha7 function was also observed in stratum oriens and stratum radiatum neurons of KO mice following gene delivery. Wild type mice exhibited improved acquisition performance in the Morris water task 1 month after bilateral hippocampal transductions with the rat alpha7 receptor gene compared with green fluorescent protein-transduced controls. However, both groups reached similar training levels and there was no difference in subsequent probe performance. Finally, this gene delivery approach was used to test whether alpha7 receptors affect tau-phosphorylation. Chronic (i.e. 2 month but not 2 week) expression of high levels of alpha7 receptors in hippocampus increased AT8 staining characteristic of hyperphosphorylated tau in that region, indicating that endogenous agonist-mediated receptor activation may be able to modulate this process.

The relationship between enamel softening and erosion caused by soft drinks at a range of temperatures.

OBJECTIVES: Investigations of the erosive potential of soft drinks are usually performed at room or body temperature, but drinks are more frequently served chilled, with ice, or hot. Since the rate of chemical reactions usually increases with temperature, it is predicted that erosion is more severe at high temperatures and reduced at low temperatures. The aim of this study was to investigate the correlation between enamel softening, enamel erosion, and temperature. METHODS: Atomic force microscopy nanoindentation and non-contact optical profilometry were used to assess changes in enamel nanomechanical properties after 5 min and erosive material loss after 30 min exposure to two different non-carbonated soft drinks at 4, 25, 50 and 75 degrees C. RESULTS: For one drink (Robinson's Original Juice Drink), there was a statistically significant difference between nanomechanical properties and erosion depth at all temperatures, with softening and erosion increasing with temperature. For another drink (Ribena ToothKind Juice Drink), there was a slight softening and virtually no material loss, and temperature had no statistically significant impact on erosion. There was a good linear correlation (R2 = 0.94) between nanomechanical properties and material loss. CONCLUSIONS: The difference between the drinks can be explained by their composition. For the erosive drink, material loss increased, and nanohardness decreased, approximately linearly with temperature. The correlation between softening and erosion demonstrated that nanomechanical properties after very short erosion times can be considered a good predictor of bulk material loss after considerably longer erosion times.

New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation.

We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.

A methodology for testing the erosive potential of sports drinks.

OBJECTIVES: The aim of the study was to develop and test a methodology in situ, which simulated the consumption of sports drinks. A secondary aim was to assess the acceptability of the method to sedentary participants. METHODS: To select the sports drink for the study in situ, five commercially available sports drinks were examined for erosive potential in vitro. The study in situ was a single centre, 2-period, 2-treatment crossover study to compare the erosive effect of a commercially available sports drink (Test), with that of mineral water (Control), over 10 day periods on 10 healthy volunteers. Subjects wore upper removable appliances containing two human enamel specimens from 9 a.m. to 5 p.m. The regimen of intake of the drinks was 350 ml in 10, 5-min rest, 650 ml in 25, 5-min rest, 500 ml in 10 and 5-min rest. Measurements of enamel loss were made on samples after 5 and 10 days by profilometry. RESULTS: The in situ study showed a statistically significant difference in erosive potential between the test and control beverages. No specimen exposed to the control beverage displayed appreciable erosion. Erosion occurred with the test drink, but to a variable degree between subjects. The subjects unanimously found the drinking regimen unpleasant. CONCLUSIONS: The sports drink caused significantly more erosion in situ than water and as seen in other studies, there was marked variation in susceptibility to erosion between subjects. The new drinking regimen was designed to simulate pre, during and post-exercise intake. Although all the sedentary subjects participating in this study reported that they found the volume of fluids consumed over a short period of time excessive it is unlikely that this would prove problematic in the exercise environment.

The protective effect of fluoride treatments against enamel erosion in vitro.

Fluoride is known to reduce enamel solubility during the caries process. The aim of this investigation was to determine whether fluoride preparations affect erosion attributed to citric acid and citric acid-based soft drinks. Flat enamel specimens embedded in epoxy resin were prepared from caries free, human third molar teeth extracted from patients aged 18-35 years. Specimens were polished to have a profile within a tolerance of +/-0.3 microm measured on a profilometer. Specimens were taped to leave a 2 mm window of exposed enamel. Groups of specimens were exposed to citric acid and soft drinks with and without the addition of sodium fluoride or exposed to the same solutions after pre-treatment with fluoride products. Enamel loss was measured by profilometer after 10, 20 and 30 min of acid exposure. The different acidic solutions varied significantly in the amount of erosion produced both with and without the addition of fluoride. In addition, the different fluoride products differed significantly in the protective effect afforded. Both fluoride application methods reduced in mean terms, enamel erosion at all time points and by all acidic solutions. The majority of differences were <25% and as the study was powered to show differences as significant at or above this level few reached statistical significance. Fluoride applied to enamel either in acidic solutions or as a pre-treatment, reduces enamel erosion; however, the actual clinical benefit appears low. More studies are required, including investigations in situ.

Modification of soft drinks with xanthan gum to minimise erosion: a study in situ.

OBJECTIVE: To compare the erosive effect of a new blackcurrant/calcium drink with xanthan gum, on enamel in situ, with a low erosive product, a conventional fruit beverage and water. DESIGN: The study was single centre, randomised, single blind, 4 treatment crossover design. SETTING: This study, conducted in 2000, employed volunteers working at the Bristol Dental Hospital, UK. SUBJECTS, MATERIALS AND METHODS: 16 subjects (>or=18 years) wore two enamel samples in a removable acrylic appliance. The drinks tested were (A) New blackcurrant/calcium/gum drink (test product), (B) Original blackcurrant/calcium drink, (C) Conventional blackcurrant drink (positive control) and (D) Water (negative control), for 15 day study periods. Drinking was supervised, with 250 ml imbibed four times/day between 9.00am-5.00pm. Profile measurements of specimens were made at baseline, 5, 10 and 15 days. MAIN OUTCOME MEASURES: Paired t-tests compared erosion by surfometry with selected pairs of formulations. RESULTS: Of 16 screened subjects (3 male, 13 female), mean age 34.2 years, 1 subject failed to complete the study. A caused significantly less enamel loss than C, with no statistically significant differences from B at any time points measured. Of 43 treatment emergent adverse events, none were considered related to the study formulations. CONCLUSIONS: A retained low erosive properties similar to B, with additional benefits of taste flexibility and beverage stability.

Cutaneous haemangioma: prevalence and sonographic characteristics of associated hepatic haemangioma.

AIMS: To determine the prevalence of hepatic haemangiomas (HH) occurring with multiple or large cutaneous haemangiomas (CH), and compare the ultrasound (US) characteristics of HH with morphology of concurrent CH. MATERIALS AND METHODS: Retrospective and prospective sonographic and clinical analysis was undertaken on 69 patients referred for US to exclude silent HH. This comprised 62 patients referred over 6 years with six or more CH or one large CH (#10878;5 cm) and seven patients referred over 1 year with three to five small CH. RESULTS: HH occurred in 45% miliary CH and 40% mixed small and large CH, but also in 12-14% of patients with one large or three or more small CH. None had HH progression. There was association between HH sonographic characteristics and CH number and morphology. CONCLUSION: Clinically silent HH occurred in nearly one in four of infants presenting overall with six or more small CH or large CH. Previous studies have documented HH mortality between 18 and 80%, although this was not shown in our study. Therefore, if clinical suspicion exists, US is indicated to enable early steroid treatment if significant HH are present.

Cytoskeletal responsiveness to progestins is dependent on progesterone receptor A levels.

Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian hormones, which are implicated in cancer development and progression. In human breast and endometrial tumors, there is disrupted expression of progesterone receptor (PR) isoforms and predominance of one isoform, usually PRA. PRA predominance is an early event in carcinogenesis, and in cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in cancers. Progestin treatment of PR-positive breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-progestin RU38486. Altered tropomyosin (Tm) isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5 isoform levels, and transfection of Tm5a mimicked progestin-mediated cell rounding in PRA-overexpressing cells. Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of progestin, and discrete focal localization was evident in cells with PRA predominance. Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with cancer development and progression may be regulated in part by altered PRA expression which develops early in carcinogenesis.

Functional analysis of the actin-binding protein, tropomyosin 1, in neuroblastoma.

Tropomyosin 1 (TM1) is downregulated in a number of transformed cell types, and exogenous expression of TM1 can restore actin organisation and reverse cellular transformation. We find that TM1 is also downregulated in human neuroblastoma cell lines, correlating with increasing malignancy. However, exogenous TM1 does not restore actin cytoskeleton organisation in neuroblastoma cells.

Development of low erosive carbonated fruit drinks 2. Evaluation of an experimental carbonated blackcurrant drink compared to a conventional carbonated drink.

OBJECTIVE: Previous studies demonstrated that a non-carbonated blackcurrant juice drink with added calcium produced little erosion of enamel in vitro and in situ by comparison with other low pH fruit drinks. The aim of this study is to evaluate the erosive effects in situ of an experimental formulation carbonated drink with added calcium, compared to a conventional carbonated drink over a 20 day period using a similar design as in previous studies. METHOD: The study was a single centre, single blind, randomised placebo controlled three cell crossover design involving 15 volunteers. The test drinks were an experimental carbonated ready-to-drink (RTD) blackcurrant drink, a conventional carbonated RTD orange drink and water. Two enamel samples were retained in situ, in the midline of the hard palate on an upper removable acrylic appliance. Drinks were 250 ml volumes consumed four times per day during 20 working days. Measurements of enamel loss were made on enamel samples after days 2, 5, 10, 15 and 20 by profilometry. RESULTS: The experimental carbonated blackcurrant drink caused significantly less enamel loss than the conventional carbonated orange drink at all time points measured, but was not significantly different from water at days 2, 5 and 20. CONCLUSIONS: This study has shown that it is possible to modify carbonated soft drinks in a manner similarly shown with non-carbonated soft drinks, to minimise dental erosion.

Development of low erosive carbonated fruit drinks. 1. Evaluation of two experimental orange drinks in vitro and in situ.

OBJECTIVES: To determine the in vitro erosive potential and in situ erosive effect of two new formulation low calorie carbonated orange drinks with that of two conventional diet products and water. METHODS: In the in vitro study, six specimens of deciduous and permanent enamel were randomly allocated to each of the five products and a '4h' protocol employed. In the in situ study, 15 healthy volunteers participated in a single centre, single blind, 5-phase crossover study, conducted according to Good Clinical Practice, and employing a validated model. RESULTS: The in vitro erosive potential of the experimental formulations was less than that of the comparators at all time points. Conversely, the observed erosive potential of both experimental formulations was greater than that of the control. Consistent statistically significant differences were found in relation to permanent enamel only. Unfortunately, the in situ study did not produce results entirely consistent with those of the in vitro study. Notably, a generally progressive loss of enamel was observed in specimens exposed to the control. CONCLUSIONS: The data from the in vitro study show the experimental formulations to have low comparative erosivity. However, the methodologies in vitro and in situ somewhat unusually do not correlate in ranking the erosivity of drinks. The results of this study should therefore be viewed with caution, further research being clearly warranted.

Evaluation of spinal ultrasound in spinal dysraphism.

AIMS: The aims of this study were to evaluate the role of spinal ultrasound in detecting occult spinal dysraphism (OSD) in neonates and infants, and to determine the degree of agreement between ultrasound and magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: Eighty-five consecutive infants had spinal ultrasound over 31 months. Of these, 15 patients (age 1 day-7 months, mean 40 days; nine male) had follow-up MRI. Ultrasound and MRI findings were correlated retrospectively. RESULTS: Six out of 15 (40%) ultrasound examinations showed full agreement with MRI, seven of 15 (47%) had partial agreement, and two of 15 (13%) had no agreement. In the present series ultrasound failed to visualize: four of four dorsal dermal sinuses, three of four fatty filum terminales, one of one terminal lipoma, two of four partial sacral agenesis, three of four hydromyelia and one of 10 low-lying cords. CONCLUSION: Agreement between ultrasound and MRI was good, particularly for the detection of low-lying cord (90%). Therefore we recommend ultrasound as a first-line screening test for OSD. If ultrasound is abnormal, equivocal or technically limited, MRI is advised for full assessment.

Plasmid delivery in the rat brain.

Neurodegenerative diseases as a class do not have effective pharmacotherapies. This is due in part to a poor understanding of the pathologies of the disease processes, and the lack of effective medications. Gene delivery is an attractive possibility for treating these diseases. For the paradigm to be effective, efficient, safe and versatile vectors are required. In this study we evaluated three plasmid delivery systems for transgene expression in the rat hippocampus. Two of these systems were designed to have enhanced intracellular biodegradability. It was hypothesized that this system would be less toxic and could increase the free (non-vector) associated plasmids within the cell, leading to increased transgene activity. Polyethylenimine (PEI) and r-AAV-2 (recombinant adeno associated virus-2) were used as positive, non-viral and viral controls respectively, in the in vivo experiments. The results from the studies indicate there is a distinct difference between the various vectors in terms of total cells transfected, type of cell transfected, and toxicity. Non-viral systems were effective at transfecting both neurons and glia cells within the hippocampus, while the r-AAV-2 transfected mainly neurons. In summary, plasmid-mediated systems are effective for transgene expression within the brain and deserve further study.