ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

Lower pro- to anti-inflammatory ratios associated with reduced neurocognitive flexibility in symptomatic adolescents with bipolar disorder.

INTRODUCTION: Peripheral inflammatory markers, such as C-reactive protein (CRP), are elevated among adolescents and adults with bipolar disorder (BD), particularly during symptomatic episodes. Neurocognition, predominantly in the domain of executive function, is also impaired among adults and youth with BD. In adults with BD, CRP is negatively associated with neurocognitive functioning. We aim to investigate this relationship in BD adolescents. METHODS: Serum levels of CRP and five other inflammatory markers (interleukin (IL)-1ß, IL-6, IL-10, IL-4 and tumor necrosis factor α (TNF)) were examined in 60 adolescents with BD (34 symptomatic, 26 asymptomatic) age- and sex-matched to 51 healthy controls (HC). Diagnoses were confirmed using semi-structured interviews. Pro- to anti-inflammatory marker ratios were also examined. Neurocognitive flexibility was assessed via the intra/extradimensional shift (IED) task from the CANTAB battery. Multivariate linear regression controlled for age, sex and race. RESULTS: Within symptomatic BD adolescents, but not asymptomatic BD or HC adolescents, lower IL-6/IL-10 and lower CRP/IL-10 ratios were significantly associated with worse performance on the neurocognitive flexibility task (p = 0.03 and p = 0.04, respectively). Both models accounted for 13.3% of variance in neurocognitive flexibility. No significant CRP by diagnosis interaction effects were observed on neurocognitive flexibility. LIMITATIONS: Limited sample-size restricted ability to separate the symptomatic BD adolescents into varying mood states. CONCLUSION: More balanced pro- to anti-inflammatory ratios were associated with better neurocognitive flexibility in symptomatic BD adolescents. Prospective studies are warranted to assess the direction of these findings.

Call to action regarding the vascular-bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders.

OBJECTIVES: The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. METHODS: An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. RESULTS: The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. CONCLUSIONS: Further research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

Comparison of Qualitative and Quantitative Assessments of Iliac Artery Tortuosity and Calcification.

INTRODUCTION: During endovascular aneurysm repair, the iliac artery typically serves as a conduit for device delivery. The degree of tortuosity and calcification in the iliac artery ultimately determines whether the device can successfully traverse the vessel. These 2 parameters can be assessed using qualitative approaches or calculated using quantitative methods based on the Society for Vascular Surgery (SVS) reporting standards. The objective of this study was to determine whether qualitative methods are sufficient to accurately assess iliac artery tortuosity and calcification by calculating interobserver variability and comparing them to the SVS Reporting Standards. METHODS: Three vascular surgeons reviewed preoperative computed tomography scans for 50 patients who underwent fenestrated endovascular aneurysm repair and qualitatively assessed left and right iliac artery tortuosity and calcification. Iliac artery geometries were segmented from these image sets. Tortuosity index and calcification length ratio were calculated and categorized based on the SVS Reporting Standards. RESULTS: Interobserver variability was calculated for the qualitative assessments using interclass correlation coefficients. For tortuosity index, among the 3 observers, good agreement was found for the left iliac artery and fair agreement was found for the right. For calcification length ratio, excellent agreement was found for both iliac arteries. When compared to the quantitative assessment, the qualitative assessments underpredicted tortuosity in 2.3% of cases, matched the quantitative values in 16.7% of cases, and overpredicted tortuosity in 81.0% of cases. The qualitative assessments underpredicted calcification in 46.3% of cases, matched the quantitative values in 49.3% of cases, and overpredicted calcification in 4.3% of cases. CONCLUSION: Qualitative assessment of iliac artery tortuosity showed fair-to-good interobserver agreement and poor agreement to SVS Reporting Standards. Qualitative assessment of iliac artery calcification showed excellent interobserver agreement and fair agreement to SVS Reporting Standards. These trends should be considered when qualitative reporting methodologies are used.

Retinal photography: A window into the cardiovascular-brain link in adolescent bipolar disorder.

OBJECTIVE: The burden of cardiovascular disease in bipolar disorder (BD) exceeds what can be explained by traditional cardiovascular risk factors (CVRFs), lifestyle, and/or medications. Moreover, neurocognitive deficits are a core feature of BD, and are also related to CVRFs. We examined retinal vascular photography, a proxy for cerebral microvasculature, in relation to CVRFs, peripheral microvascular function, and neurocognition among BD adolescents. METHODS: Subjects were 30 adolescents with BD and 32 healthy controls (HC). Retinal photography was conducted using a Topcon TRC 50 DX, Type IA camera, following pupil dilation. Retinal arteriolar and venular caliber was measured, from which the arterio-venular ratio (AVR) was computed. All measures were conducted masked to participant diagnosis. Peripheral arterial tonometry measured endothelial function. Neurocognition was assessed using the Cambridge Neuropsychological Tests Automated Battery. RESULTS: AVR was not significantly different between groups (Cohen's d=0.18, p=0.103). Higher diastolic blood pressure (BP) was associated with lower (worse) AVR in BD (r=-0.441, p=0.015) but not HC (r=-0.192, p=0.293). Similarly, in the BD group only, higher (better) endothelial function was associated with higher AVR (r=0.375, p=0.041). Hierarchical regression models confirmed that, independent of covariates, retinal vascular caliber was significantly associated with diastolic BP and endothelial function in BD. Within the BD group, mood scores were significantly negatively correlated with AVR (ß=-0.451, p=0.044). LIMITATIONS: This study's limitations include a small sample size, a cross-sectional study design, and a heterogeneous sample. CONCLUSION: Retinal photography may offer unique insights regarding the cardiovascular and neurocognitive burden of BD. Larger longitudinal studies are warranted.

Inflammatory Markers and Brain-Derived Neurotrophic Factor as Potential Bridges Linking Bipolar Disorder and Cardiovascular Risk Among Adolescents.

OBJECTIVE: Bipolar disorder (BD) is associated with increased rates of cardiovascular disease (CVD). Brain-derived neurotrophic factor (BDNF) and inflammatory markers are leading biomarkers in BD. We examined whether these biomarkers underlie the link between BD and CVD proxies among adolescents with bipolar spectrum disorders. METHODS: Subjects were 60 adolescents, 13-19 years old (40 with BD and 20 healthy controls [HCs]). Semistructured interviews determined diagnoses based on DSM-IV. Serum was assayed for BDNF, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Carotid intima media thickness (cIMT) and flow-mediated dilation were assessed using ultrasound. Procedures were conducted at a subspecialty clinic (January 2011-May 2014). RESULTS: Adolescents with BD had significantly greater waist circumference (BD: 81.72 cm [11.67 cm], HC: 75.64 cm [8.63 cm]; U = 547.5, P = .021), body mass index (BMI) (BD: 25.50 kg/m²undefined[5.29 kg/m²], HC: 21.76 kg/m² [3.43 kg/m²]; U = 608.5, P < .0001), pulse pressure (BD: 42.31 mm Hg [10.57 mm Hg], HC: 33.84 mm Hg [6.69 mm Hg]; U = 561.5, P < .001), and IL-6 (BD: 8.93 pg/mL [7.71 pg/mL], HC: 4.96 pg/mL [6.38 pg/mL]; U = 516.0, P < .0001) than HC adolescents. Subjects with BD-I (n = 14) and BD-II (n = 16) had greater IL-6 versus HCs (F3,51 = 5.29, P = .003). Controlling for BMI and age did not alter these findings. IL-6 was higher in symptomatic (n = 19) and asymptomatic BD (n = 21) versus that found in HCs (F2,52 = 7.96, P = .001). In symptomatic BD, lower BDNF was associated with greater mean cIMT (ρ = -0.507, P = .037). CONCLUSIONS: This study found evidence of increased inflammation among adolescents with BD. While present findings suggest a potential interplay between symptomatic status, biomarkers, and atherosclerosis proxies, there were no significant differences in cIMT or flow-mediated dilation in adolescents with BD compared to HCs. This may indicate that there is potential opportunity for CVD prevention strategies in adolescents with BD.

Correlates of Adolescent-reported and Parent-reported Family Conflict Among Canadian Adolescents With Bipolar Disorder.

BACKGROUND: Family conflict exacerbates the course of bipolar disorder (BP) among adults. However, few studies have examined family conflict among adolescents with BP, and fewer have looked at adolescent-reported and parent-reported family conflict separately. METHODS: Subjects were 89 adolescents, aged 13 to 19 years, with a diagnosis of BP on the basis of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (KSADS-PL). Subjects were divided into high-conflict and low-conflict groups using a median split on the Conflict Behavior Questionnaire (child report and parent report). The χ(2) analyses and independent samples t tests were performed for univariate analyses. Multivariable logistic regression analyses were performed on variables with P<0.2. RESULTS: Parent-reported and adolescent-reported Conflict Behavior Questionnaire scores were significantly correlated (r=0.50, P<0.001). High parent-reported family conflict was positively associated with recent manic symptoms, externalizing comorbidities, and dimensional scores reflecting emotional dysregulation. High adolescent-reported family conflict was positively associated with recent manic symptoms and emotional dysregulation, and negatively associated with socioeconomic status and lifetime psychiatric hospitalization. Bipolar subtype was significantly associated with high versus low family conflict. LIMITATIONS: The limitations of this study included being a cross-sectional study, use of a medium-sized sample, and lack of a control group. CONCLUSIONS: Despite substantial agreement between adolescents and parents regarding the amount of family conflict, there were meaningful differences in the factors associated with adolescent-reported and parent-reported conflict. These findings demonstrate the importance of ascertaining family conflict from adolescents as well as from parents. Moreover, these findings can potentially inform family therapy, which is known to be effective for adolescents with BP.

The Impact of Selective Dopamine D2, D3 and D4 Ligands on the Rat Gambling Task.

Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug had modest effects on latency measures suggesting that D4 may contribute in some ways to decision making under this task.

Cardiovascular and psychiatric characteristics associated with oxidative stress markers among adolescents with bipolar disorder.

INTRODUCTION: In the field of bipolar disorder (BD) research there is an absence of validated biomarkers and limited understanding of the biology underlying excessive and premature cardiovascular disease (CVD). Oxidative stress is a potential biomarker in both BD and CVD. OBJECTIVE: To examine psychiatric and cardiovascular characteristics associated with peripheral oxidative stress markers among adolescents with BD, who are at high risk for CVD. METHODS: Participants were 30 adolescents, 13-19years old, with BD and without CVD. Ultrasonography was used to evaluate vascular function and structure. Traditional CVD risk factors were also measured. Psychiatric assessments were conducted via semi-structured interview. Serum levels of oxidative stress (lipid hydroperoxides (LPH) and protein carbonylation (PC)) were assayed. RESULTS: Compared to published data on adults with BD, adolescents had significantly lower levels of LPH and PC (t52(11.34), p<0.0001; t58(29.68), p<0.0001, respectively). Thicker mean and maximum carotid intima media thickness was associated with greater levels of LPH (r=.455, p=.015; r=.620, p<0.0001, respectively). LPH was associated with diastolic blood pressure (r=-.488, p=0.008) and pulse pressure (r=.543, p=0.003). Mood symptoms and medication were not significantly associated with oxidative stress. CONCLUSION: Adolescents with BD have lower levels of oxidative stress compared to adults with BD, supporting prevailing illness staging theories for BD. Oxidative stress is robustly associated with a proxy measure of atherosclerosis and may explain in part the increased risk of CVD in BD.

Non-invasive vascular imaging is associated with cardiovascular risk factors among adolescents with bipolar disorder.

Cardiovascular disease (CVD) is exceedingly prevalent among adults with bipolar disorder (BD), implicating BD adolescents as a high-risk group for CVD. Non-invasive ultrasound measures of vascular structure (via carotid intima media thickness [cIMT]) and function (via flow-mediated dilation [FMD]) predict future CVD, and are associated with traditional CVD risk factors among adolescents without mood disorders. This study examined, for the first time, the association of cIMT and FMD with CVD risk factors among adolescents with BD. The presence of multiple potential confounds among adolescents with BD, including various medications and mood states, informs the need to demonstrate whether cIMT and FMD are associated with CVD risk factors in this population specifically. Participants were 30 adolescents, 13-19 years old, with BD, without CVD. High-resolution ultrasonography was used to evaluate vascular structure (cIMT) and function (FMD). Analyses examined associations of cIMT and FMD with traditional CVD risk factors. cIMT was significantly positively associated with systolic blood pressure and waist circumference. FMD was significantly negatively associated with waist circumference, body mass index, triglycerides, and glucose, and positively associated with high-density lipoprotein. cIMT and FMD are associated with traditional CVD risk factors among adolescents with BD. Irrespective of numerous potential confounds, non-invasive vascular ultrasound approaches may be used as CVD risk proxies among adolescents with BD as they are for other adolescents.

Correlates of psychiatric hospitalization in a clinical sample of Canadian adolescents with bipolar disorder.

OBJECTIVE: To identify factors associated with psychiatric hospitalization among adolescents with bipolar disorder (BD). METHODS: Participants were 100 adolescents, ages 13-19, who fulfilled DSM-IV criteria for bipolar I disorder [(BD-I), n=26], bipolar II disorder [(BD-II), n=40], or operationalized criteria for BD not otherwise specified [(BD-NOS), n=34], via the Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (KSADS-PL). Demographic, clinical, and family history variables were measured via clinical interview with the participant and a parent or guardian. RESULTS: The lifetime prevalence of psychiatric hospitalization was 50%. Significant predictors of psychiatric hospitalization in univariate analyses included older age, BD-I, history of suicide attempt, psychosis, lifetime use of second generation antipsychotics (SGAs), lithium, SSRI antidepressants and any medication. BD-II was negatively associated with psychiatric hospitalization. In multivariable analyses, older age, history of suicide attempt, psychosis and use of SGAs were positively associated with hospitalization, whereas BD-II was negatively associated with hospitalization. CONCLUSIONS: Psychiatric hospitalization in adolescents with BD is highly prevalent and associated with older age and proxies for greater illness severity. Further studies are needed to identify strategies for reducing the need for psychiatric hospitalizations among adolescents with BD.

The Affordable Care Act 2010: educational needs of bedside nurses.

The Patient Protection and Affordable Care Act of 2010 (ACA) significantly impacts bedside nurses who must participate in organizational change and provide resources to patients. A health reform educational needs assessment was distributed to nurses from a midsized community hospital located in an elevated-need and medically underserved area in New England. Many nurses indicated that more knowledge was needed and they lacked information about the educational incentives. Health policy professional development opportunities are required to inform bedside nursing practice.