A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.

Exogenous melatonin can be helpful for treatment of some sleep disorders. However, immediate-release formulations are rapidly absorbed and cleared from the body making it difficult to provide coverage for an entire sleep period. Extended-release melatonin formulations can better mimic the naturally occurring melatonin profile and increase efficacy, but few studies have reported on their pharmacokinetics. To assess the pharmacokinetics of extended-release melatonin, we conducted a randomized, double-blind, crossover study of extended-release melatonin (4 mg) compared to immediate-release melatonin (4 mg) in 18 healthy adults, ages 18-65 years. Participants received immediate-release or extended-release melatonin in clinic after an 8 h fast, and blood samples were taken over a 10-h period. After a 7-day washout period, the same procedures were repeated with the melatonin form not previously received. Extended-release melatonin had a longer time to peak concentration (1.56 vs 0.6 h) and elimination half-life (1.63 vs 0.95 h) compared with immediate-release melatonin. Maximum concentration was lower for extended-release melatonin compared with immediate-release melatonin (7581 pg/mL vs 13120 pg/mL). Extended-release melatonin raised melatonin levels in as little as 15 min and sustained elevated melatonin levels (>300 pg/mL) for 6 h before falling below 50 pg/mL by 9 h. No clinically relevant adverse events were observed, and safety parameters remained within normal ranges for both formulations. The pharmacokinetic profile of this extended-release melatonin formulation suggests that it could be used for future efficacy studies of melatonin and sleep outcomes. This trial is registered at ClinicalTrials.gov, NCT04067791.

Higher intake of certain nutrients among older adults is associated with better cognitive function: an analysis of NHANES 2011-2014.

BACKGROUND: An increasing number of adults are over the age of 65, and there is concern about the increasing prevalence of age-associated cognitive decline and poor mental health status in older adults in the United States. Several nutrients are known to have important biological roles in brain health and neurological function, but many individuals fall short of recommended intake levels. The objective of this study was to examine the association between nutrient intake and cognitive function. We also explored whether nutrient intake was associated with depression. METHODS: This cross-sectional study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 and included participants ≥ 60 years of age who had reliable day 1 dietary recall data and either valid cognitive function data (n = 2713) or valid depression score data (n = 2943). The sample was stratified by gender, and cognitive functioning test (CFT) composite z-scores were analyzed by quartiles. Depression status was assessed using the Patient Health Questionnaire (PHQ-9). RESULTS: Higher intake and adequacy of a number of different nutrients from food were associated with higher cognitive function in both males and females. Nutrients that showed the most consistent associations with cognitive function across intake and adequacy analyses for food in both males and females were vitamin A, vitamin E, thiamin, riboflavin, vitamin B6, folate, magnesium, potassium, zinc, vitamin K, and lutein and zeaxanthin (p < 0.05 for all). These associations were positive with increasing intake and adequacy being associated with higher CFT composite z-scores. Analysis of nutrient intake and depression yielded results that differed by gender. In females, the nutrients that showed consistent inverse associations with depression scores across both intake and adequacy analyses for food were vitamin A, vitamin C, magnesium, vitamin K, potassium, and dietary fiber (p < 0.05 for all). In males, no significant associations between nutrient intake from food and depression scores were observed. CONCLUSIONS: Our findings suggest that older adults with sufficient intakes of certain essential nutrients have higher cognitive function. Future studies are needed to confirm whether a well-balanced diet and/or dietary supplements which emphasize these nutrients are effective for prevention of age-related declines in cognitive function and mood.

Lower Intakes of Key Nutrients Are Associated with More School and Workplace Absenteeism in US Children and Adults: A Cross-Sectional Study of NHANES 2003-2008.

The influence of individual macro- and micronutrients on absenteeism in the United States is largely unknown. The objective of this study was to determine whether nutritional status or nutrient intake were associated with absenteeism from school and work due to illness or injury. Data from NHANES 2003-2008 were used to assess nutrient intake from food and food plus supplements, nutritional biomarker levels, and school and work absenteeism per year in children and adults. Negative binomial regression models were used to predict mean days of missed work per year and to estimate incidence rate ratios (IRRs) of absenteeism by nutrient biomarker status. Of 7429 children, 77% reported missing school days (mean 4.0 days). Of 8252 adults, 51% reported missing work days (mean 4.9 days). Children and adults who reported more absent days had a significantly lower intake of protein and several essential micronutrients from the diet. When nutrients from supplements were included, this negative association was retained for protein, selenium, choline, and DHA in children and for protein, selenium, vitamin K, choline, potassium, fiber, octadecatrienoic acid, and lycopene in adults. Future studies are needed to ascertain whether dietary interventions, such as access to healthier food options and/or dietary supplements, can reduce absenteeism.

Diverse Durham collection phages demonstrate complex BREX defense responses.

Bacteriophages (phages) outnumber bacteria ten-to-one and cause infections at a rate of 1025 per second. The ability of phages to reduce bacterial populations makes them attractive alternative antibacterials for use in combating the rise in antimicrobial resistance. This effort may be hindered due to bacterial defenses such as Bacteriophage Exclusion (BREX) that have arisen from the constant evolutionary battle between bacteria and phages. For phages to be widely accepted as therapeutics in Western medicine, more must be understood about bacteria-phage interactions and the outcomes of bacterial phage defense. Here, we present the annotated genomes of 12 novel bacteriophage species isolated from water sources in Durham, UK, during undergraduate practical classes. The collection includes diverse species from across known phylogenetic groups. Comparative analyses of two novel phages from the collection suggest they may be founding members of a new genus. Using this Durham phage collection, we determined that particular BREX defense systems were likely to confer a varied degree of resistance against an invading phage. We concluded that the number of BREX target motifs encoded in the phage genome was not proportional to the degree of susceptibility. IMPORTANCE Bacteriophages have long been the source of tools for biotechnology that are in everyday use in molecular biology research laboratories worldwide. Phages make attractive new targets for the development of novel antimicrobials. While the number of phage genome depositions has increased in recent years, the expected bacteriophage diversity remains underrepresented. Here we demonstrate how undergraduates can contribute to the identification of novel phages and that a single City in England can provide ample phage diversity and the opportunity to find novel technologies. Moreover, we demonstrate that the interactions and intricacies of the interplay between bacterial phage defense systems such as Bacteriophage Exclusion (BREX) and phages are more complex than originally thought. Further work will be required in the field before the dynamic interactions between phages and bacterial defense systems are fully understood and integrated with novel phage therapies.

Telemedical Interdisciplinary Care Team Evaluation and Treatment of People With Low Back Pain: A Retrospective Observational Study.

Objective: To evaluate the effects of an interdisciplinary care team (ICT) model delivered by telemedicine on patients with low back pain (LBP). Design: Retrospective analysis of deidentified pre-existing data. Setting: Retrospective observational study of patients presenting with LBP to a nationwide telemedicine practice using an ICT model. Participants: Over a 9-month period all patients with a diagnosis related to LBP and who had an ICT evaluation (medical doctor, advanced practice provider, health coach, and physical therapist) were included in the study (n=36). A minimum of 2 follow-up physical therapy visits were required for inclusion. Interventions: Patients were evaluated for LBP, received a diagnosis, and were offered a multidisciplinary treatment plan. Additional real-time audio visual medical, health coaching, registered dietician, and physical therapy services were received as deemed clinically appropriate. Main Outcome Measures: Baseline, 30 day, and final pain (mean 81 day) measurements via numerical pain rating scale (NPRS). Baseline and final Patient-Reported Outcomes Measurement Information System (PROMIS)-10 Global Mental/Physical domains. Secondary Outcome Measures: Use of prescription medication, referral for imaging, need for injections, or surgery. Results: 36 patients met criteria. Pain levels included mild (n=6, 16.7%), moderate (n=19, 52.8%), and severe (n=11, 30.6%). Clinically significant pain improvements were noted in 83.3% (n=25) of those with moderate or severe pain. PROMIS Mental and Physical Health categorization from Fair/Poor to Good/Excellent significantly improved over time. The initial 20% (n=7) in Fair/Poor Mental Health improved to 6.3% (n=2) at finish, while the 80% (n=28) in Good/Excellent Mental Health at start improved to 93.8% (n=30) at finish. Regarding Physical Health, 51.4% (n=18) rated Fair/Poor at start and 31.3% (n=10) at finish, while the 48.6% (n=17) rated Good/Excellent at start improved to 68.8% (n=22) at finish. The need for prescription medication was low (n=6, 16.7%) and spinal imaging orders were negligible (n=1, 2.8%). Injections were warranted in 11.4% (n=4) of patients and surgical referral with operative treatment in 2.8% (n=1). Conclusion: Interdisciplinary care delivered through telemedicine can significantly improve pain and support improved health-related quality of life in patients with LBP, with low rates of imaging, prescription, and interventional use.

Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape.

The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.

Awareness of inappropriate use related to antimicrobial resistance among medical doctors by country economic status: A systematic review.

BACKGROUND: Antimicrobial resistance (AMR) is promoted by inappropriate use and is a greater burden for low to middle income countries (LMIC) than high income countries (HIC). OBJECTIVE: This systematic review aimed to compare the awareness of inappropriate use related to AMR among medical doctors from LMIC and HIC using published knowledge, attitude and practice (KAP) studies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, sequential systematic literature search of PubMed and Web of Science databases for articles published since inception up to June 1, 2022 for KAP studies involving medical doctors. Using fifteen KAP items related to promoting AMR, data on proportion of participants responding affirmatively was extracted and reported using means, ranges and 95% confidence intervals (CI). RESULTS: Forty-two studies met the inclusion criteria and involved 13,089 medical doctors from 11HIC and 21LMIC. All were cross-sectional studies, 71.4% involved non-probability sampling and 78.6% were of satisfactory quality. Knowledge items showed mean proportion of more medical doctors responding correctly. Similar affirmation trends were observed for attitude and prescribing practice items. Awareness appeared similar between medical doctors of the economic groups, except for a greater interest in training for LMIC (95.4%; 95%CI 93.0%, 97.9%) versus HIC (81.7%; 95%CI 65.6%, 97.9%). Countries with poor proportions were identified in both economic groups. CONCLUSION: For identified studies, trends suggest good awareness among medical doctors of the known inappropriate use and perceived threat of AMR, as well as prescribing practices to reduce the risk of AMR. Trends were similar across HIC and LMIC; however, countries with evidence of poor awareness exist in both economic groups.

Neurophysiologic monitoring during cervical traction in a pediatric patient with severe cognitive disability and atlantoaxial instability.

Background: Surgical management of atlantoaxial instability (AAI) in pediatric patients with Down syndrome is associated with high neurological morbidity. Moreover, Down syndrome cognitive impairment coupled to AAI removes traditional verbal communication to relay evolving symptoms and aid in neurologic examination. It is not clear whether surgical adjuncts can alter clinical outcomes in this vulnerable population. Case Description: Herein, we report the case of a 6-year-old patient with significant developmental delay and severe AAI that was successfully managed by stabilization with guidance of neurophysiologic investigations in the perioperative phase. Conclusion: Perioperative neurophysiologic monitoring is safe, useful, and reliable in pediatric patients with trisomy 21 undergoing cervical traction and occipitocervical instrumented fusion for AAI.

An exploration into two-dimensional metal oxides, and other 2D materials, synthesised via liquid metal printing and transfer techniques.

Two-dimensional (2D) metal oxides can be difficult to synthesise, and scaling up production using traditional methods is challenging. However, a new liquid metal-based technique, that utilises both "top-down" and "bottom-up" processes, has recently been introduced. These liquids oxidise to form an oxide surface "skin" which may be exfoliated as a 2D flake and subsequently used in various electronic devices and chemical reactions.

Total estimated usual nutrient intake and nutrient status biomarkers in women of childbearing age and women of menopausal age.

BACKGROUND: Women of childbearing age (WCBA) and women of menopausal age (WMENO) have distinct nutritional needs. Understanding nutrient intake and status in these life stages is critical for tailoring dietary recommendations. OBJECTIVES: The objectives of this study were to evaluate total estimated usual nutrient intakes from food and food plus supplements and to compare these to established recommendations for WCBA and WMENO life stages and examine associations between self-reported estimated usual intakes and nutrient status biomarkers. METHODS: Twenty-four-hour dietary recall data from 2011-2016 NHANES were used to estimate usual intake of nutrients from food and food plus supplements for WCBA (aged 15-44 y, n = 4,134) and WMENO (aged 40-65 y, n = 3,438). Estimates of mean usual intake were derived and compared across clinically defined nutrient biomarker categories. RESULTS: Both young (aged 15-30 y) and older (aged 31-44 y) WCBA had intakes from food below the Estimated Average Requirement (EAR) for calcium (49% and 44%, respectively), magnesium (62%, 44%), and vitamins A (50%, 44%), C (47%, 46%), D (>97%, >97%), and E (92%, 88%). Similarly, perimenopausal (aged 40-50 y) and menopausal (aged 51-65 y) women had intakes from food below the EAR for calcium (48% and 74%, respectively), magnesium (50%, 49%), and vitamins A (44%, 37%), C (44%, 41%), D (>97%, >97%), and E (88%, 86%). Nutrient gaps decreased with supplement usage. For folate, vitamins D and B-12, and DHA, women in the lowest biomarker category (indicating increased risk of deficiency) had significantly lower intake from food (315.2 ± 25.9 compared with 463.8 ± 5.2 µg dietary folate equivalents, 3.5 ± 0.1 compared with 4.2 ± 0.1 µg, 3.6 ± 0.2 compared with 4.3 ± 0.1 µg, and 0.037 ± 0.005 compared with 0.070 ± 0.006 g, respectively; P < 0.01) of the corresponding nutrient compared with the highest biomarker category. CONCLUSIONS: Substantial percentages of WCBA and WMENO are not meeting recommendations for multiple nutrients, whereas supplement usage partially fills nutrient gaps. Dietary intake was positively associated with most nutrient status biomarkers. Specific guidance is needed to ensure adequate nutrient intakes and nutrient status during these critical life stages.

Genome-wide Association Analysis Across 16,956 Patients Identifies a Novel Genetic Association Between BMP6, NIPAL1, CNGA1 and Spondylosis.

STUDY DESIGN: A case-control genome-wide association study (GWAS) on spondylosis. OBJECTIVE: Leveraging Geisinger's MyCode initiative's multimodal dataset, we aimed to identify genetic associations with degenerative spine disease. SUMMARY OF BACKGROUND DATA: Degenerative spine conditions are a leading cause of global disability; however, the genetic underpinnings of these conditions remain under-investigated. Previous studies using candidate-gene approach suggest a genetic risk for degenerative spine conditions, but large-scale GWASs are lacking. METHODS: We identified 4434 patients with a diagnosis of spondylosis using ICD diagnosis codes with genotype data available. We identified a population-based control of 12,522 patients who did not have any diagnosis for osteoarthritis. A linear-mix, additive genetic model was employed to perform the genetic association tests adjusting for age, sex, and genetic principal components to account for the population structure and relatedness. Gene-based association tests were performed and heritability and genetic correlations with other traits were investigated. RESULTS: We identified a genome-wide significant locus at rs12190551 (odds ratio = 1.034, 95% confidence interval 1.022-1.046, P = 8.5 × 10-9, minor allele frequency = 36.9%) located in the intron of BMP6. Additionally, NIPAL1 and CNGA1 achieved Bonferroni significance in the gene-based association tests. The estimated heritability was 7.19%. Furthermore, significant genetic correlations with pain, depression, lumbar spine bone mineral density, and osteoarthritis were identified. CONCLUSION: We demonstrated the use of a massive database of genotypes combined with electronic health record data to identify a novel and significant association spondylosis. We also identified significant genetic correlations with pain, depression, bone mineral density, and osteoarthritis, suggesting shared genetic etiology and molecular pathways with these phenotypes.Level of Evidence: N/A.

Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005-2016 NHANES.

A well-functioning immune system is essential for human health and well-being. Micronutrients such as vitamins A, C, D, E, and zinc have several functions throughout the immune system, yet inadequate nutrient intakes are pervasive in the US population. A large body of research shows that nutrient inadequacies can impair immune function and weaken the immune response. Here, we present a new analysis of micronutrient usual intake estimates based on nationally representative data in 26,282 adults (>19 years) from the 2005-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the prevalence of inadequacy (% of population below estimated average requirement [EAR]) in four out of five key immune nutrients is substantial. Specifically, 45% of the U.S. population had a prevalence of inadequacy for vitamin A, 46% for vitamin C, 95% for vitamin D, 84% for vitamin E, and 15% for zinc. Dietary supplements can help address nutrient inadequacy for these immune-support nutrients, demonstrated by a lower prevalence of individuals below the EAR. Given the long-term presence and widening of nutrient gaps in the U.S.-specifically in critical nutrients that support immune health-public health measures should adopt guidelines to ensure an adequate intake of these micronutrients. Future research is needed to better understand the interactions and complexities of multiple nutrient shortfalls on immune health and assess and identify optimal levels of intake in at-risk populations.

Transforaminal Endoscopic Approach for Large-Sample Tumor Biopsy using Beveled Working Channel for Core Technique: A Technical Note.

BACKGROUND: Identifying the histopathological diagnosis of a spinal tumor is the necessary step prior to pursuing subsequent treatment. Both minimally invasive and open spinal procedures have been described as useful methods of obtaining tumor tissue for diagnosis but differ by their limitations. Minimally invasive techniques, such as computed tomography-guided biopsies, can expose the patient to radiation, and the tissue obtained may be nondiagnostic. Tubular and open procedures require collateral soft-tissue damage and may require bony removal leading to iatrogenic injury. Endoscopic approaches to the spine can be employed to avoid treatment delay in diagnosis, decrease length of stay, and provide adequate tissue for diagnosis. METHODS: We describe the surgical planning, tumor localization, and transforaminal endoscopic approach for tissue diagnosis of a lumbar spinal mass in a patient with a known history of Hodgkin lymphoma and non-Hodgkin lymphoma after a nondiagnostic computed tomography- guided biopsy. Final histopathological diagnosis of the lumbar spinal mass was consistent with large B-cell non-Hodgkin lymphoma. CONCLUSIONS: We demonstrate the application of an endoscopic transforaminal approach in spine oncology. We also describe our technique on how we use a beveled working channel to obtain a large tissue core sample for definitive diagnosis.

A Latent Profile Analysis of Young Adult Lifestyle Behaviors.

Objective: The aim of this study was to identify lifestyle profiles of young adult males and females based on their alcohol, diet, and exercise behaviors and then link these profiles with health. Method: We used the nationally representative 2017 Behavioral Risk Factor Surveillance System (BRFSS; N = 17,286; 47% female; Mage = 23.22; SD = 3.16; 65% white) to examine profiles of alcohol use, daily fruit and vegetable intake, fried potato intake, and exercise per week using latent profile analysis. Participants also reported the days their general, physical, and mental health were poor and BMI. Results: Five distinct profiles for both males and females were identified: Healthy Eaters/Exercisers, Moderates, Unhealthy Eaters, Medium Drinkers, and Heavy Drinkers. Heavy Drinkers and Unhealthy Eaters reported the most days of poor mental and physical health. Conclusions: Heavy drinkers and unhealthy eaters had the highest number of days of poor health, which also places them at risk for a host of health adversities throughout adulthood. Examining motivations behind young adults' patterns of consumption and activity is an important future direction to identify mechanisms for healthy lifestyle promotion during the transition to adulthood.

Micronutrient Inadequacy in Short Sleep: Analysis of the NHANES 2005-2016.

One third of U.S. adults report short sleep (<7 h), which has been linked to negative health outcomes. Inadequate intake of micronutrients across the U.S. adult population has been reported, and a relationship between sleep conditions and micronutrient intake is emerging. This cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES 2005-2016) (n = 26,211) showed that participants with short sleep duration had a lower usual intake (Food + Supplements) of calcium, magnesium, and vitamin D in all adults aged 19+ years, and vitamin K in adults aged 19-50 years, even after adjusting for covariates. In addition, participants reporting short sleep had a higher percentage of individuals with intake lower than the estimated average requirement (EAR) across multiple nutrients. Age and gender differences were observed in the prevalence of inadequate intake across multiple nutrients. Adults aged 51-99 years with short sleep duration had inadequate intake with respect to more nutrients. In females there was an association between short sleep and a higher prevalence of inadequate intake (Food + Spp) for calcium, magnesium, and vitamins A, C, D, E, and K (above adequate intake). Conversely, males reporting short sleep only had an inadequate intake of vitamin D. Overall, we demonstrate that short sleep is associated with increased nutrient inadequacy, emphasizing the possible need for dietary supplementation.

Proteomic Analysis of 3T3-L1 Adipocytes Treated with Insulin and TNF-α.

Insulin resistance is an indication of early stage Type 2 diabetes (T2D). Insulin resistant adipose tissues contain higher levels of insulin than the physiological level, as well as higher amounts of intracellular tumor necrosis factor-α (TNF-α) and other cytokines. However, the mechanism of insulin resistance remains poorly understood. To better understand the roles played by insulin and TNF-α in insulin resistance, we performed proteomic analysis of differentiated 3T3-L1 adipocytes treated with insulin (Ins), TNF-α (TNF), and both (Ins + TNF). Out of the 693 proteins identified, the abundances of 78 proteins were significantly different (p < 0.05). Carnitine parmitoyltransferase-2 (CPT2), acetyl CoA carboxylase 1 (ACCAC-1), ethylmalonyl CoA decarboxylase (ECHD1), and methylmalonyl CoA isomerase (MCEE), enzymes required for fatty acid ß-oxidation and respiratory electron transport, and ß-glucuronidase, an enzyme responsible for the breakdown of complex carbohydrates, were down-regulated in all the treatment groups, compared to the control group. In contrast, superoxide dismutase 2 (SOD2), protein disulfide isomerase (PDI), and glutathione reductase, which are the proteins responsible for cytoskeletal structure, protein folding, degradation, and oxidative stress responses, were up-regulated. This suggests higher oxidative stress in cells treated with Ins, TNF, or both. We proposed a conceptual metabolic pathway impacted by the treatments and their possible link to insulin resistance or T2D.

Maternal Omega-3 Nutrition, Placental Transfer and Fetal Brain Development in Gestational Diabetes and Preeclampsia.

Omega-3 fatty acids, particularly docosahexaenoic fatty acid (DHA), are widely recognized to impact fetal and infant neurodevelopment. The impact of DHA on brain development, and its inefficient synthesis from the essential alpha-linolenic acid (ALA), has led to recommended DHA intakes of 250-375 mg eicosapentaenoic acid + DHA/day for pregnant and lactating women by the Dietary Guidelines for Americans. Despite these recommendations, the intake of omega-3s in women of child-bearing age in the US remains very low. The low maternal status of DHA prior to pregnancy could impair fetal neurodevelopment. This review focuses on maternal omega-3 status in conditions of gestational diabetes mellitus (GDM) and preeclampsia, and the subsequent impact on placental transfer and cord blood concentration of omega-3s. Both GDM and preeclampsia are associated with altered maternal omega-3 status, altered placental omega-3 metabolism, reduced cord blood omega-3 levels and have an impact on neurodevelopment in the infant and on brain health later in life. These findings indicate lower DHA exposure of the developing baby may be driven by lower placental transfer in both conditions. Thus, determining approaches which facilitate increased delivery of DHA during pregnancy and early development might positively impact brain development in infants born to mothers with these diseases.

Cerebrospinal fluid untargeted metabolomic profiling of aneurysmal subarachnoid hemorrhage: an exploratory study.

INTRODUCTION: Despite advancements in medical and surgical therapies, clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH) continue to be poor. Currently, aSAH pathophysiology remains poorly understood. No aSAH biomarkers are commonly used in the clinical setting. This exploratory study used metabolomics profiling to identify global metabolic changes and metabolite predictors of long-term outcome using cerebrospinal fluid (CSF) samples of aSAH patients. METHODS AND METHODS: Gas chromatography time-of-flight mass spectrometry was applied to CSF samples collected from 15 consecutive high-grade aSAH patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated vasospasm timeframe). Metabolite levels at both time points were compared and correlated with vasospasm status and Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons. RESULTS: Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively. CONCLUSIONS: Our preliminary study suggests that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate 2-hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis.

A Review of Cerebral Shunts, Current Technologies, and Future Endeavors.

Objective. The use of cerebrospinal shunts is the standard of care for hydrocephalus. However, shunts are extremely vulnerable to failure and lack noninvasive methods to monitor their viability. We review current shunt technologies and attempts to improve their function. Methods. A PubMed search was performed to find literature on shunts and shunt function. Company brochures and websites were also used. Results. Fixed and variable pressure valves from four major companies are discussed. Also reviewed are siphon resistive devices, intracranial pressure sensors, and recent attempts on the development of cerebrospinal fluid sensors, including a micromechanical flow sensor we have recently developed. Conclusions. While variable pressure valves and siphon resistive devices have both had considerable success in dealing with variable intracranial pressure, a more sophisticated, continuous monitoring system is needed to ensure shunt viability and patient safety. An integrated flow sensor may provide the ability to track fluid flow and determine shunt functionality.