2 Minute Medicine Rewind January 27, 2020

Electronic Cigarette and JUUL Use Among Adolescents and Young Adults

1. The use of electronic cigarettes is highly prevalent among adolescents and young adults through the advent of JUUL, which has unique implications for this young and susceptible age group.

Evidence Rating Level: 1 (Excellent)

Adverse effects of nicotine on overall health, as well as neurodevelopment during critical stages, are well-known. However, adolescents and young adults are facing greater peer and societal pressures with the advent of electronic cigarettes (e-cigarettes), including JUUL and products that add flavors to their products. Given that e-cigarettes are now more popular on a sales basis than traditional cigarettes, this study of two nationally-representative longitudinal samples of adolescents and young adults sought to determine the prevalence of e-cigarette use and risk factors associated with their use. This particular study sample was extracted from the Truth Longitudinal Cohort, which was designed to determine the effectiveness of its similarly-named prevention media campaign. Analyses included 14,379 participants from Wave 7 (mean [SD] age = 24.3 [0.9] years, 51% female) and 12,114 participants from Wave 8 (mean [SD] age = 24.5 [0.10] years, 50.1% female). Approximately 61.6% of this sample was Caucasian, 51.1% were between the ages of 25 and 34 years, and 76.9% were either “living comfortably” or “meeting needs with a little left over”. Lastly, 78.8% of the sample reported not living with anyone else who smokes in any form. Findings showed that 33.2% of Wave 8 reported use of any type of e-cigarette, 12.4% of whom reported current use. JUUL use was highest among the 18-20-year-old age group, with a significant difference between those who have used JUUL at least once and those who currently use (difference 11.1%, p<0.001). Hispanic participants were the ethnic group with the highest use rates of e-cigarettes and JUUL, as were males and those who identified as gay, lesbian, or bisexual. Participants who believed that cigarettes were more harmful than e-cigarettes had the highest lifetime use (21.6%) and current use (12.4%). Comparing Waves 7 and 8, which were exactly one year apart, there was a significant increase in lifetime e-cigarette use (difference 3.6%, p<0.001) as well as current e-cigarette use (difference 4.3%, p<0.001). Lifetime JUUL use increased during this year by 123.7% (p<0.001), with current use rates significantly increasing for each age group except for the group 15 to 17 years of age. Compared to the oldest age group studied (25 to 34 years), all younger groups demonstrated greater odds of lifetime use (adjusted OR range = 1.82 to 4.91, p<0.05) and current use (adjusted OR range = 10.11 to 20.64, p<0.01). Wave 8 smokers in general were more likely to have used JUUL than those who reported no smoking in Wave 7 (adjusted OR range = 2.20 to 3.60, p<0.01; adjusted OR range = 2.22 to 3.03, p<0.5, respectively). Sensation-seeking behavior was also significantly associated with greater odds of lifetime use (adjusted OR = 1.75, p<0.01) and current use (adjusted OR = 1.94, p<0.01) of JUUL. Lastly, those with friends also demonstrated greater odds of JUUL lifetime (adjusted OR = 1.84, p<0.01) and current use (adjusted OR = 2.53, p<0.01). This study highlights the prominence of JUUL in the e-cigarette trend and the risk factors associated with use among adolescents and young adults. Given the risks involved, particularly among these age groups, prevention efforts must be targeted to ensure that use rates do not continue to rise.

Characterization of Alzheimer Disease Biomarker Discrepancies Using Cerebrospinal Fluid Phosphorylated Tau and AV1451 Positron Emission Tomography

1. Flortaucipir-PET and CSF modalities for assessing tau pathology not only differ in results in early Alzheimer’s dementia (AD) but suprathreshold CSF P-tau may be indicative of early AD that is unrecognizable via cognitive testing.

2. CSF P-tau may provide evidence of disease progression that early fortaucipir-PET cannot sufficiently detect.

Evidence Rating Level: 1 (Excellent)

Both amyloid-β (Aβ) and tau pathologies are characteristic biomarkers of Alzheimer’s disease (AD). Aβ accumulation is evaluated through cerebrospinal fluid (CSF) and positron emission tomography (PET), with results from these two modalities often being used interchangeably. Due to the similar but unidentical information obtained from these procedures, this cohort study sought to evaluate tau pathology with CSF and fluorine 18-labeled flortaucipir (AV1451) PET to determine whether or not they offer different information related to disease progression and cognitive decline in AD. A total of 322 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent both CSF and PET evaluations of tau pathology within 25 months of analyses (mean [SD] age = 73.08 [7.37] years, 56% female). Of these, 66.1% were cognitively healthy, 30.4% had mild cognitive impairment (MCI), and 3.4% had AD dementia. PET regions of interest (ROI) were established to determine positivity (standard uptake value ratio ≥1.37) and included the bilateral entorhinal, amygdala, fusiform, inferior, and middle cortices due to evidence supporting their roles in AD. Thresholds were calculated for CSF phosphorylated tau (P-tau; ≥26.64 pg/mL). Approximately 65% of participants were CSF^–/PET^–, 19.5% CSF⁺/PET^–, 4.6% CSF^–/PET⁺, and 10.5% CSF⁺/PET⁺. Findings suggested that a categorization of CSF⁺/PET^– resulted in a significantly faster five-year accumulation of P-tau and increased PET binding in RIOs compared to CSF^–/PET^– participants (CSF+/PET- time-by-group interaction β [SE] 0.06 [0.03] pg/mL/mo, p = 0.02; CSF⁺/PET⁺ time-by-group interaction β [SD] 0.11 [0.03] pg/mL/mo, p<0.001). When either measure indicated tau positivity, there was evidence of elevated Aβ-PET burden. Estimated model intercepts suggested that P-tau may precede the five-year period during which these analyses began (CSF⁺/PET^– β [SD] 17.65 [2.82], p<0.001; CSF⁺/PET⁺ β [SE] 29.45 [3.33], p<0.001). Further all CSF⁺/PET⁺ participants were Aβ positive and 76% were diagnosed with either MCI or AD. This study provides evidence that flortaucipir-PET and CSF modalities for assessing tau pathology not only differ but also that suprathreshold CSF P-tau may be indicative of early AD dementia  unrecognizable via cognitive testing. Essentially, CSF P-tau may provide evidence of disease progression that early fortaucipir-PET cannot sufficiently detect. 

Assessment of the Predictive Value of Outpatient Smartphone Videos for Diagnosis of Epileptic Seizures

1. Expert review of smartphone videos possesses additive, predictive value for the diagnosis of epileptic seizures, with the ability to maintain confidentiality in the sharing of these files.

Evidence Rating Level: 2 (Good)

Video electroencephalogram (EEG) monitoring (VEM) is the ideal diagnostic standard for epileptic seizures when diagnosis is unclear through medical history, laboratory assessments, and witnessed seizures. However, misdiagnosis is common, 20% to 30% of patients who undergo VEM have nonepileptic seizures, and many patients face barriers to this procedure. This diagnostic study conducted across eight tertiary care epilepsy centers sought to evaluate reviewer accuracy in diagnosing epileptic seizures through smartphone videos, as well as identify psychogenic nonepileptic seizures. A total of 44 participants met inclusion criteria (mean [range] age = 45.1 [20-82] years, 70.5% female). Participants completed one diagnostic VEM session in an epilepsy monitoring unit prior to diagnosis by epilepsy and clinical neurophysiology experts. Final VEM-verified diagnoses included psychogenic nonepileptic seizures (30), epileptic seizures (11), and physiologic nonepileptic events (3). A total of 530 smartphone videos were reviewed by 19 reviewers (10 epilepsy experts, 9 senior neurology residents). While both of these groups demonstrated similar diagnostic specificity for epileptic seizures (88.3% and 93.3%, respectively), experts demonstrated greater sensitivity (76.8% and 41.5%). For psychogenic nonepileptic seizures, experts demonstrated greater specificity and sensitivity than neurology residents. In spite of a significant difference in duration of smartphone videos (mean = 2.23 minutes) compared to a standard 60-minute history and physical examination (p<0.001), interpretation of these smartphone videos was accurate in predicting epileptic seizures in 89.1% of cases (specificity = 93.3%). Increased odds of accurate diagnosis existed when smartphone videos were combined with history and physical examination compared to history and physical alone (95% CI 1.01 to 54.3, p<0.02). Findings suggest that patients with epileptic seizures are 6.65 times more likely to receive an accurate diagnosis with smartphone video and those with psychogenic nonepileptic seizures were 2.58 times more likely to receive an accurate diagnosis. Residents reported greater diagnostic confidence overall but were less accurate across all metrics of study. This study strongly suggests that smartphone videos of seizure may provide additive and predictive value to experts when diagnosing these complicated disorders and should be considered when patients are unlikely to engage in VEM.

Prevalence and Genetic Profile of Isoniazid Resistance In Tuberculosis Patients: A Multicountry Analysis of Cross-Sectional Data

1. Following phenotypic testing and sequencing, prevalence of isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) is higher than that of rifampicin, suggesting that more accurate diagnostic screening methods are needed to more effectively detect and prevent the spread of TB.

Evidence Rating Level: 2 (Good)

Drug-resistant tuberculosis (TB) must be monitored and directly confronted to reduce the spread of resistance among other populations as tuberculosis represents one of the leading causes of infectious disease in the world. While both isoniazid and rifampicin are first-line medications for TB, resistance to either one is associated with an increased risk of treatment effectiveness. Only rifampicin resistance is sufficiently documented, reportedly occurring in up to 18% of previously-treated TB patients. The World Health Organization WHO established a treatment regimen for Hr-TB in 2018 that entails six-month use of pyrazinamide, rifampicin, levofloxacin, and ethambutol. This multinational review of data from the WHO between 2003 and 2017 aimed to determine the global prevalence of isoniazid-resistant, rifampicin-susceptible TB (Hr-TB) as well as associated drug resistance patterns across phenotypes and genotypes. Across 156 countries from which isoniazid data were available, 211,753 patients were included in subsequent analyses, suggesting a global prevalence of Hr-TB among previously-treated TB patients of 11.4% (95% CI 9.4% to 13.4%) and a prevalence of Hr-TB among new TB patients of 7.4% (95% CI 6.5% to 8.4%). Six countries possessed data on levofloxacin and pyrazinamide resistance among HR-TB patients, only two of which had cases of resistance to both of these anti-TB medications (Belarus 5.3%, 95% CI 0.1 to 26.0; Philippines 1.8%, 95% CI 0.2 to 6.4). Across all countries, 4,563 Hr-TB patients were included in sequencing data for relevant genomic regions. A total of 1,174 isolates resistant either by phenotypic testing or sequencing. Of these, 78.6% (95% CI 76.1% to 80.9%) had resistance-conferring katG gene mutations only, 14.6% (95% CI 12.7% to 16.8%) had mutations in both katG and inhA promoter region, and 6.8% (95% CI 5.4% to 8.4%) had mutations in only the inhA promoter region. This latter group may benefit from a higher dose of isoniazid. Overall, this study found that Hr-TB prevalence was higher than the known prevalence of rifampicin resistance across the countries with available data. Thus, current algorithm-based diagnostic techniques are likely to result in oversight and underestimation of Hr-TB patients. The 2018 WHO treatment recommendation for Hr-TB may be useful but will require more accurate and precise diagnostic screening procedures.

Decreased Frontal White-Matter Diffusion and Improved Cognitive Flexibility After Burr-Hole Surgery In Moyamoya Angiopathy

1. Burr-hole surgery for moyamoya angiopathy may be a process of indirect revascularization harboring potential to improve frontal cerebral perfusion and apparent diffusion coefficient values in normal-appearing white matter while also improving cognitive inflexibility as a component of executive dysfunction.

Evidence Rating Level: 2 (Good)

Moyamoya angiopathy (MMA) is a progressive neurological disease that results in a reduction of apparent diffusion coefficient (ADC) as well as stenosis and occlusion of the intracranial carotid artery in spite of seemingly normal frontal white matter (WM). Hypoperfusion of frontal regions is another pathological sign, with consequent risks of stroke and neurocognitive disorders including executive dysfunction. Studies of revascularization surgeries have generally been limited, specifically as they result to cognitive outcomes. This retrospective study of 14 adults with MMA (mean [SD] age = 38.1 [10.7] years, 64.3% female) within one hospital occurred between March 2008 and November 2015, aiming to determine cognitive changes in relation to ADC and cerebrovascular reserve (CVR) following burr-hole surgery due to its focus on perfusion of frontal areas rather than the lateral hemispheres. Surgery included a median of 7 burr-holes (range 4-9) through the frontal bone, perioperative antiplatelet drugs were limited, and low molecular weight heparin treatment was engaged 24 hours post-surgery until sufficient recovery. An average of four regions of interest (ROI) were utilized to calculate anterior ADC in normal WM, though ROIs were altered to avoid WM hyperintensities and ischemic lesions. Executive functioning and processing speed were evaluated with the Trail Making Test (Parts A and B), Stroop inhibition score, Modified Wisconsin Card Sorting Test (WCST), and verbal fluency. Frontal ADC reduced following surgery in 19 of 26 hemispheres – frontal ADC decreased post-surgery (difference -26 mm²/s, p<0.001) but no significant changes were observed in posterior ADC. Perfusion-weighted imaging could be interpreted in 24 of the 26 hemispheres that were operated on due to artifacts in one patient, though no changes were observed in subcortical or frontal CVR in the sample. Cognitively, the greatest impairments were in cognitive flexibility, conceptualization, and inhibition. Following surgery, 60% of patients demonstrated cognitive improvement in TMT B, defined as an increase of at least one standard deviation (TMT B median z-score change -1.47 to -0.21, p – 0.018), but not on other measures. ADC did not significantly differ between those who showed improvement and those who did not, nor did ADC differ among those whose performance improved. Overall, this study found that burr-hole surgery resulted in reduced ADC values in frontal regions with normal WM. While results normalized, though this was sustained at a higher level than other series (700^10-6mm²/s). ADC values may be a proxy for post-surgery cerebral perfusion and may harbor potential in improving cognitive flexibility. 

Efficacy of Digital Cognitive Behavioral Therapy for the Treatment of Insomnia Symptoms Among Pregnant Women: A Randomized Clinical Trial

1. Digital cognitive behavioral therapy for insomnia (CBT-I) resulted in significant decreases in severity of insomnia, depressive, and anxiety symptoms compared to standard treatment in pregnant women at no greater than 28 weeks’ gestation.

Evidence Rating Level: 2 (Good)

It is estimated that approximately 14% of pregnant women experience moderate-to-severe symptoms of insomnia. While often viewed as harmless, insomnia can negatively impact the quality of life of woman as well as increase risk of adverse birth outcomes. Given that there are limited treatment options for clinically significant symptoms, research must focus on interventions that are unlikely to increase odds of complications or negative outcomes. This randomized clinical trial evaluated the effectiveness of digital cognitive behavioral therapy for insomnia (CBT-I) in adult women meeting criteria for an insomnia disorder who reported no greater than 28 weeks’ gestation (n = 208, mean [SD] age = 33.6 [3.7] years; mean baseline gestational [SD] age = 17.6 [6.3] weeks). CBT-I involved six weekly sessions lasting approximately 20 minutes each, available via website or iOS app. It possessed five main components: sleep restriction, stimulus control, relaxation techniques, cognitive therapy, and sleep hygiene and education. A total of 103 women were randomly assigned to standard treatment (ST) and 105 women were randomly assigned to the CBT-I group – 68 women (64.8%) completed all six sessions. Women were predominantly Caucasian, married or cohabiting, possessed a college degree, and earned more than $100,000 per year. Participants completed the seven-item Insomnia Severity Index (ISI) as well as logged their own sleep efficiency, duration, quality, and disorder via diaries. Depressive symptoms were assessed with the 10-item Edinburgh Postnatal Depression Scale (EPDS) and anxiety symptoms were assessed with the Generalized Anxiety Disorder Scale-7. Participants were given no limitations related to adjunct treatments during treatment, including psychotherapeutic and pharmacological interventions. A mean of 7.97 [2.08] weeks were required to complete all six sessions of CBT-I. Women in the CBT-I group experienced significantly greater improvements in insomnia symptom severity between baseline and postintervention compared to ST (time-by-group interaction difference -0.36, 95% CI 00.48 to -0.23, χ² = 29.8, p<0.001, d = -1.03). Remission (defined as ISI <7) rates were higher among the CBT-I group than ST (difference 21.7%, χ²₁ = 9.8, p = 0.002). Caseness, global sleep quality, and sleep efficiency were all significantly greater in the CBT-I group; sleep duration did not significantly differ between groups (p = 0.07). The CBT-I group also experienced greater reductions in severity of depressive symptoms (difference -0.21, 95% CI -0.30 to -0.11, p<0.001) and anxiety symptoms (difference -0.188, 95% CI -0.26 to -0.10, p<0.001). Remission rates of these symptoms were significantly higher in the CBT-I group (difference 13.8%, χ²₁ – 3.9, p = 0.048). Three adverse outcomes occurred in the ST group (2 miscarriages, 1 stillbirth) but were reported as unrelated to the study. Three adverse outcomes also occurred in the CBT-I group (3 miscarriages in first trimester, one of these prior to beginning treatment), for which investigators cannot rule out the impact of treatment in spite of other likely explanations. Overall, this study suggests that digital CBT-I is an effective non-pharmacological intervention for pregnant women (<28 weeks’ gestation) experiencing insomnia, as well as co-occurring depressive and anxiety symptoms. Remission rates following CBT-I are also promising beyond overall improvement of symptom severity, even with the availability of other treatment options.

Image: PD

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