Adolescent Intentional Abuse Ingestions: Overall 10-Year Trends and Regional Variation.

OBJECTIVE: Adolescent intentional ingestions remain a significant public health problem in the United States with little research to date on the over-the-counter or prescription medicines that adolescents abuse. These data are important for anticipatory guidance by primary care providers, preventive health, and poison center outreach. METHODS: This was an observational study using the American Association of Poison Control Centers National Poison Data System. The study population consisted of all cases of patients aged 13 to 19 years from 2004 to 2013 with a coding of "intentional abuse." RESULTS: There were 95,695 patient calls that were coded for intentional abuse between 2004 and 2013 for adolescents aged 13 to 19 years. The most common agent reportedly ingested in intentional-abuse cases was antihistamine and/or decongestant with dextromethorphan, and this agent remained the most common throughout the 10-year study period. The next 4 most common agents remained similar across the study period as well and included ethanol, benzodiazepines, dextromethorphan alone, and marijuana. These 5 agents remained the most commonly reported across the study period for all US regions (West, Midwest, South Northeast, and US territories). CONCLUSIONS: Over a recent 10-year period, common cough preparations remain the most commonly reported intentional abuse ingestion among all years and regions for adolescents.

Pediatric Minor Traumatic Brain Injury With Intracranial Hemorrhage: Identifying Low-Risk Patients Who May Not Benefit From ICU Admission.

BACKGROUND: Pediatric patients with any severity of traumatic intracranial hemorrhage (tICH) are often admitted to intensive care units (ICUs) for early detection of secondary injury. We hypothesize that there is a subset of these patients with mild injury and tICH for whom ICU care is unnecessary. OBJECTIVES: To quantify tICH frequency and describe disposition and to identify patients at low risk of inpatient critical care intervention (CCI). METHODS: We retrospectively reviewed patients aged 0 to 17 years with tICH at a single level I trauma center from 2008 to 2013. The CCI included mechanical ventilation, invasive monitoring, blood product transfusion, hyperosmolar therapy, and neurosurgery. Binary recursive partitioning analysis led to a clinical decision instrument classifying patients as low risk for CCI. RESULTS: Of 296 tICH admissions without prior CCI in the field or emergency department, 29 had an inpatient CCI. The decision instrument classified patients as low risk for CCI when patients had absence of the following: midline shift, depressed skull fracture, unwitnessed/unknown mechanism, and other nonextremity injuries. This clinical decision instrument produced a high likelihood of excluding patients with CCI (sensitivity, 96.6%; 95% confidence interval, 82.2%-99.9%) from the low-risk group, with a negative likelihood ratio of 0.056 (95% confidence interval, -0.053-0.166). The decision instrument misclassified 1 patient with CCI into the low-risk group, but would have impacted disposition of 164 pediatric ICU admissions through 5 years (55% of the sample). CONCLUSIONS: A subset of low-risk patients may not require ICU admission. The proposed decision rule identified low-risk children with tICH who may be observable outside an ICU, although this rule requires external validation before implementation.

Relative Effectiveness of Dopamine Antagonists for Pediatric Migraine in the Emergency Department.

OBJECTIVE: Migraine headaches are common in the pediatric emergency department. The mainstay of abortive treatment consists of nonsteroidal anti-inflammatories and dopamine antagonists. The objective of this study was to compare the effectiveness of 3 commonly used dopamine antagonists to abort pediatric migraine. METHODS: This was a retrospective cohort study of all patients who presented to the pediatric emergency department at a tertiary care pediatric hospital between January 2010 and December 2013. Patients were treated for a migraine headache with a combination of ketorolac and one of the following dopamine antagonists: prochlorperazine, metoclopramide, or promethazine. The primary outcome was treatment failure and receiving non-evidence-based treatment defined by the need for opioids. Secondary outcomes included pain score reduction and return visit within 48 hours. RESULTS: There were 57 patients during this period with 67 visits that met inclusion criteria: 27 (40.3%) visits in which patients were treated with prochlorperazine, 23 (34.3%) visits in which patients were treated with metoclopramide, and 17 (25.4%) visits in which patients were treated with promethazine. Across visits, the mean age was 14.5 years, and 63% were women. Opioids were given for treatment failure in 8.7% of visits in which patients received prochlorperazine, 25% in which patients received metoclopramide, and 42.8% in which patients received promethazine. Patients treated with promethazine had significantly higher odds of needing opioids and experiencing less than 50% reduction in pain score compared with prochlorperazine after adjusting for patient characteristics. CONCLUSIONS: This study suggests variable efficacy among 3 commonly used dopamine antagonists for pediatric migraine headache. Promethazine seems least effective and results in higher use of opioids compared with other available dopamine antagonists.

Early Fever As a Predictor of Paroxysmal Sympathetic Hyperactivity in Traumatic Brain Injury.

OBJECTIVE: Paroxysmal sympathetic hyperactivity (PSH) is characterized by episodic, hyperadrenergic alterations in vital signs after traumatic brain injury (TBI). We sought to apply an objective scale to the vital sign alterations of PSH in order to determine whether 1 element might be predictive of developing PSH. SETTING/PARTICIPANTS/DESIGN: We conducted an observational study of consecutive TBI patients (Glasgow Coma Scale score ≤12) and monitored the cohort for clinical evidence of PSH. PSH was defined as a paroxysm of 3 or more of the following characteristics: (1) tachycardia, (2) tachypnea, (3) hypertension, (4) fever, (5) dystonia (rigidity or decerebrate posturing), and (6) diaphoresis, with no other obvious causation (ie, alcohol withdrawal, sepsis). MAIN MEASURES: The Modified Clinical Feature Severity Scale (mCFSS) was applied to each participant once daily for the first 5 days of hospitalization. RESULTS: Nineteen (11%) of the 167 patients met criteria for PSH. Patients with PSH had a higher 5-day cumulative mCFSS score than those without PSH (median [interquartile range] = 36 [29-42] vs 29 [22-35], P = .01). Of the 4 components of the mCFSS, elevated temperature appeared to be most predictive of the development of PSH, especially during the first 24 hours (odds ratio = 1.95; 95% confidence interval, 1.12-3.40). CONCLUSION: Early fever after TBI may signal impending autonomic dysfunction.

Risk-Adjusted Variation of Publicly Reported Emergency Department Timeliness Measures.

STUDY OBJECTIVE: The Centers for Medicare & Medicaid Services (CMS) recently published emergency department (ED) timeliness measures. These data show substantial variation in hospital performance and suggest the need for process improvement initiatives. However, the CMS measures are not risk adjusted and may provide misleading information about hospital performance and variation. We hypothesize that substantial hospital-level variation will persist after risk adjustment. METHODS: This cross-sectional study included hospitals that participated in the Emergency Department Benchmarking Alliance and CMS ED measure reporting in 2012. Outcomes included the CMS measures corresponding to median annual boarding time, length of stay of admitted patients, length of stay of discharged patients, and waiting time of discharged patients. Covariates included hospital structural characteristics and case-mix information from the American Hospital Association Survey, CMS cost reports, and the Emergency Department Benchmarking Alliance. We used a γ regression with a log link to model the skewed outcomes. We used indirect standardization to create risk-adjusted measures. We defined "substantial" variation as coefficient of variation greater than 0.15. RESULTS: The study cohort included 723 hospitals. Risk-adjusted performance on the CMS measures varied substantially across hospitals, with coefficient of variation greater than 0.15 for all measures. Ratios between the 10th and 90th percentiles of performance ranged from 1.5-fold for length of stay of discharged patients to 3-fold for waiting time of discharged patients. CONCLUSION: Policy-relevant variations in publicly reported CMS ED timeliness measures persist after risk adjustment for nonmodifiable hospital and case-mix characteristics. Future "positive deviance" studies should identify modifiable process measures associated with high performance.

Association of Overall Opioid Prescriptions on Adolescent Opioid Abuse.

BACKGROUND: Opioid abuse is a public health epidemic in the United States. Much literature has focused on the prescribing practices of physicians and opioid misuse by adults. However, there are limited data on the effect of opioid prescriptions on adolescent recreational ingestion of these medications. OBJECTIVES: The objective of this study was to assess for a relationship between opioid prescribing practices across the United States and adolescent opioid ingestion calls to poison centers. METHODS: This was an observational study using the National Poison Data System. The study population consisted of poison center calls regarding adolescents between 2005 and 2010 in the database with a coding of "intentional abuse" and an opioid ingestion. National opioid prescription estimates were generated using nationally representative outpatient and inpatient databases. RESULTS: There were 4186 adolescent opioid ingestion calls during the study period. There was a general increase between 2005 and 2010 in both teen opioid abuse calls (617 in 2005 to 782 in 2010) and national opioid prescriptions (approximately 78 million in 2005 to 108 million in 2010). For each opioid prescription increase per 100 persons per year, the annual teen opioid abuse calls increased by 1.8% (95% confidence interval 0.9-2.8%), equivalent to an absolute increase of about 0.04 to 0.05 calls per 100,000 teens annually. CONCLUSIONS: There appears to be an association between opioid prescriptions nationally and poison center calls for adolescent opioid ingestions. This is particularly important in this patient population because of impulsivity and early exposure to substance abuse. Providers should be aware of the nonmedical use of opioids by adolescents and educate patients accordingly.

The Effect of a Dedicated Psychiatric Team to Pediatric Emergency Mental Health Care.

BACKGROUND: Pediatric emergency department (PED) visits among children and adolescents with acute mental health needs have increased over the past decade with long wait times in the PED awaiting disposition. OBJECTIVE: The objective of this study was to evaluate the effect of a new pediatric mental health liaison program with the hypothesis that this model reduces length of stay (LOS) and hospitalization rates among pediatric mental health patients. METHODS: This was a pre- and postintervention retrospective study of the year prior to (June 2012-June 2013) and the year after (October 2013-October 2014) implementation of a new PED psychiatric team. All patients aged 1-18 years with a mental health International Classification of Diseases-9(th) Revision code were included. Patients who did not receive a Psychiatry consult in the PED were excluded. RESULTS: There were 83 encounters in the year prior to and 129 encounters in the year after the implementation of the liaison program. There was an increase in the suicidality of mental health patients during this time. There was a significant decrease in mean PED LOS of 27% (95% confidence interval [CI] 0-46%; p = 0.05) from pre- to postintervention period. The decrease in the proportion of patients admitted/transferred to an inpatient psychiatric facility in the postintervention year was statistically significant (odds ratio 0.35; 95% CI 0.17-0.71; p < 0.01). CONCLUSIONS: The use of a dedicated child psychiatrist and mental health social worker to the PED results in significantly decreased LOS and need for admission without any change in return visit rate. Larger, multicenter studies are needed to confirm these findings.

Maternal serum glycosylated fibronectin as a point-of-care biomarker for assessment of preeclampsia.

OBJECTIVE: We assessed the association of glycosylated fibronectin (GlyFn) with preeclampsia and its performance in a point-of-care (POC) test. STUDY DESIGN: GlyFn, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor 1 (sFlt1) levels were determined in serum samples from 107 pregnant women. In all, 45 were normotensive and 62 were diagnosed with preeclampsia. The ability of GlyFn to assess preeclampsia status and relationships between GlyFn and maternal characteristics and pregnancy outcomes were analyzed. RESULTS: GlyFn serum levels in the first trimester were significantly higher in women with preeclampsia (P < .01) and remained higher throughout pregnancy (P < .01). GlyFn, sFlt1, PlGF, and the sFlt1/PlGF ratio were significantly associated (P < .01) with preeclampsia status, and the classification performance of these analytes represented by area under the receiver operating characteristic curve was 0.99, 0.96, 0.94, and 0.98, respectively, with 95% confidence intervals of 0.98-1.00, 0.89-1.00, 0.86-1.00, and 0.94-1.00, respectively. Increased GlyFn levels were significantly associated with gestational age at delivery (P < .01), blood pressure (P = .04), and small-for-gestational-age neonates. Repeated-measures analysis of the difference in weekly GlyFn change in the third trimester demonstrated that mild preeclampsia was associated with a weekly change of 81.7 µg/mL (SE 94.1) vs 195.2 µg/mL (SE 88.2) for severe preeclampsia. The GlyFn POC demonstrated similar performance to a plate assay with an area under the receiver operating characteristic curve of 0.93 and 95% confidence interval of 0.85-1.00. CONCLUSION: GlyFn is a robust biomarker for monitoring of preeclampsia in both a standard and POC format, which supports its utility in diverse settings.

Do Emergency Medicine Residents Prefer Resident-initiated or Attending-initiated Feedback?

BACKGROUND: Real-time feedback is crucial to improving physician performance. Emerging theory suggests that learner-initiated feedback may be more effective in changing performance than attending-initiated feedback, but little is known about how residents perceive resident- versus attending-initiated feedback. OBJECTIVES: The primary aim was to determine whether residents' satisfaction varied by learner-versus attending-initiated feedback encounters. We hypothesized that residents would be more satisfied with resident-initiated feedback. METHODS: This was a multicenter study of five emergency medicine residency programs. We developed a milestones-based, real-time feedback intervention that provided behavioral anchors for ED subcompetencies and prompted a feedback discussion. The intervention was implemented at all sites for a 3-month period from March to November 2014. Residents were asked to initiate one card per shift; attendings were also invited to initiate encounters and, in either instance, asked to provide one specific suggestion for improvement. Residents confidentially rated their satisfaction with feedback on a 10-point scale. Reported satisfaction was categorized as "very satisfied" (score of 10) versus "less than very satisfied" (score < 10). Logistic regression was used to assess the difference in satisfaction between resident- versus attending-initiated feedback, and random effects were used to account for the clustering of repeated ratings within resident and by site. RESULTS: A total of 785 cards was collected from five sites. Participation varied by site (range = 21-487 cards per site). Of the 587 cards with both feedback initiator and satisfaction data, 67% (396/587) were resident-initiated, and median satisfaction score was 10 (range = 4-10). There was no difference in the odds of being "very satisfied" by resident- vesus attending-initiated encounters (odds ratio = 1.08, 95% confidence interval = 0.41 to 2.83). CONCLUSIONS: Our results suggest that residents are likely to be as satisfied with self-initiated feedback as attending-initiated feedback. Further research is needed to determine whether resident-initiated feedback is more likely to be incorporated into practice and result in objective performance improvements.

Estimating the Cost of Care for Emergency Department Syncope Patients: Comparison of Three Models.

INTRODUCTION: We sought to compare three hospital cost-estimation models for patients undergoing evaluation for unexplained syncope using hospital cost data. Developing such a model would allow researchers to assess the value of novel clinical algorithms for syncope management. METHODS: We collected complete health services data, including disposition, testing, and length of stay (LOS), on 67 adult patients (age 60 years and older) who presented to the emergency department (ED) with syncope at a single hospital. Patients were excluded if a serious medical condition was identified. We created three hospital cost-estimation models to estimate facility costs: V1, unadjusted Medicare payments for observation and/or hospital admission; V2: modified Medicare payment, prorated by LOS in calendar days; and V3: modified Medicare payment, prorated by LOS in hours. Total hospital costs included unadjusted Medicare payments for diagnostic testing and estimated facility costs. We plotted these estimates against actual cost data from the hospital finance department, and performed correlation and regression analyses. RESULTS: Of the three models, V3 consistently outperformed the others with regard to correlation and goodness of fit. The Pearson correlation coefficient for V3 was 0.88 (95% confidence interval [CI] 0.81, 0.92) with an R-square value of 0.77 and a linear regression coefficient of 0.87 (95% CI 0.76, 0.99). CONCLUSION: Using basic health services data, it is possible to accurately estimate hospital costs for older adults undergoing a hospital-based evaluation for unexplained syncope. This methodology could help assess the potential economic impact of implementing novel clinical algorithms for ED syncope.

Meta-analysis of the Impact of Patient Characteristics on Estimates of Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Lumbar Spinal Fusion.

STUDY DESIGN: Meta-analysis of individual patient data from randomized controlled trials of recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar spinal fusion. OBJECTIVE: To determine how patient characteristics impact estimates of effectiveness and harms of rhBMP-2 versus iliac crest bone graft (ICBG) in lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: Patient characteristics are thought to impact rates of fusion in spinal fusion surgery, but no analyses examining the effect of patient characteristics on efficacy and safety of rhBMP-2 as compared with ICBG have been conducted. METHODS: Using individual patient data obtained from the Yale Open Data Access Project, the impact of patient characteristics on the effects of rhBMP-2 on fusion, overall success, and harms were assessed using linear and generalized linear mixed effects models. RESULTS: Ten industry-sponsored randomized controlled trials of rhBMP-2 were included in the analysis. There is preliminary support for an association between rhBMP-2 and improved outcomes for smokers (P = 0.01), individuals under the age of 60 years (P < 0.01), and patients of normal weight (P = 0.03), but not in patients who are nonsmokers, over the age of 60 years, obese or severely obese. RhBMP-2 usage was associated with decreased harms in individuals with no previous back surgeries but this was not seen in individuals with a previous back surgery (P < 0.01). CONCLUSION: Effects of rhBMP-2 may vary according to patient characteristics. Future studies of rhBMP-2 should include planned subgroup analysis in patients over 60 years, smokers, patients that are obese and severely obese, and individuals with previous back surgeries to better identify those most likely to benefit. LEVEL OF EVIDENCE: 1.

Association of Early Stress Testing with Outcomes for Emergency Department Evaluation of Suspected Acute Coronary Syndrome.

BACKGROUND: Professional society guidelines suggest early stress testing (within 72 hours) after an emergency department (ED) evaluation for suspected acute coronary syndrome (ACS). However, there is increasing concern that current practice results in over-testing without evidence of benefit. We test the hypothesis that early stress testing improves outcomes. METHODS: We analyzed prospectively collected data from 9 EDs on patients with suspected ACS, 1999-2001. We excluded patients with an ED diagnosis of ACS. The primary outcome was 30-day major adverse cardiac events (MACEs), including all-cause death, acute myocardial infarction, and revascularization. We used the HEART score to determine pretest ACS risk (low, intermediate, and high). To mitigate potential confounding, patients with and without early stress testing were matched within pretest risk strata in a 1:2 ratio using propensity scores. RESULTS: Of 7127 potentially eligible patients, 895 (13%) received early stress testing. The analytic cohort included 895 patients with early stress testing matched to 1790 without early stress testing. The overall 30-day MACE rate in both the source and analytic population was 3%. There were no baseline imbalances after propensity score matching (P > 0.1 for more than 30 variables). There was no association between early stress testing and 30-day MACE [odds ratio, 1.0; 95% confidence interval (CI), 0.6-1.7]. There was no effect modification by pretest risk (low: odds ratio, 1.0; 95% CI, 0.2-3.7; intermediate: 1.2; 95% CI, 0.6-2.6; high: 0.4; 95% CI, 0.1-1.6). CONCLUSIONS: Early stress testing is not associated with reduced MACE in patients evaluated for suspected ACS. Early stress testing may have limited value in populations with low MACE rate.

Comparison of the HEART and TIMI Risk Scores for Suspected Acute Coronary Syndrome in the Emergency Department.

OBJECTIVES: The emergency department evaluation for suspected acute coronary syndrome (ACS) is common, costly, and challenging. Risk scores may help standardize clinical care and screening for research studies. The Thrombolysis in Myocardial Infarction (TIMI) and HEART are two commonly cited risk scores. We tested the null hypothesis that the TIMI and HEART risk scores have equivalent test characteristics. METHODS: We analyzed data from the Internet Tracking Registry of Acute Coronary Syndromes (i*trACS) from 9 EDs on patients with suspected ACS, 1999-2001. We excluded patients with an emergency department diagnosis consistent with ACS, or without sufficient data to calculate TIMI and HEART scores. The primary outcome was 30-day major adverse cardiovascular events, including all-cause death, acute myocardial infarction, and urgent revascularization. We describe test characteristics of the TIMI and HEART risk scores. RESULTS: The study cohort included 8255 patients with 508 (6.2%) 30-day major adverse cardiovascular events. Receiver operating curve and reclassification analyses favored HEART [c statistic: 0.753, 95% confidence interval (CI): 0.733-0.773; continuous net reclassification improvement: 0.608, 95% CI: 0.527-0.689] over TIMI (c statistic: 0.678, 95% CI: 0.655-0.702). A HEART score 0-3 [negative predictive value (NPV) 0.982, 95% CI: 0.978-0.986; positive predictive value (PPV) 0.103, 95% CI: 0.094-0.113; likelihood ratio (LR) positive 1.76; LR negative 0.28] demonstrates similar or superior NPV/PPV/LR compared with TIMI = 0 (NPV 0.978, 95% CI: 0.971-0.983; PPV 0.077, 95% CI: 0.071-0.084; LR positive 1.28; LR negative 0.35) and TIMI = 0-1 (NPV 0.963, 95% CI: 0.958-0.968; PPV 0.102, 95% CI: 0.092-0.113; LR positive 1.73; LR negative 0.58). CONCLUSIONS: The HEART score has better discrimination than TIMI and outperforms TIMI within previously published "low-risk" categories.

Reliability of Clinical Assessments in Older Adults With Syncope or Near Syncope.

OBJECTIVES: Clinical prediction models for risk stratification of older adults with syncope or near syncope may improve resource utilization and management. Predictors considered for inclusion into such models must be reliable. Our primary objective was to evaluate the inter-rater agreement of historical, physical examination, and electrocardiogram (ECG) findings in older adults undergoing emergency department (ED) evaluation for syncope or near syncope. Our secondary objective was to assess the level of agreement between clinicians on the patient's overall risk for death or serious cardiac outcomes. METHODS: We conducted a cross-sectional study at 11 EDs in adults 60 years of age or older who presented with unexplained syncope or near syncope. We excluded patients with a presumptive cause of syncope (e.g., seizure) or if they were unable or unwilling to follow-up. Evaluations of the patient's past medical history and current medication use were completed by treating provider and trained research associate pairs. Evaluations of the patient's physical examination and ECG interpretation were completed by attending/resident, attending/advanced practice provider, or attending/attending pairs. All evaluations were blinded to the responses from the other rater. We calculated the percent agreement and kappa statistic for binary variables. Inter-rater agreement was considered acceptable if the kappa statistic was 0.6 or higher. RESULTS: We obtained paired observations from 255 patients; mean (±SD) age was 73 (±9) years, 137 (54%) were male, and 204 (80%) were admitted to the hospital. Acceptable agreement was achieved in 18 of the 21 (86%) past medical history and current medication findings, none of the 10 physical examination variables, and three of the 13 (23%) ECG interpretation variables. There was moderate agreement (Spearman correlation coefficient, r = 0.40) between clinicians on the patient's probability of 30-day death or serious cardiac outcome, although as the probability increased, there was less agreement. CONCLUSIONS: Acceptable agreement between raters was more commonly achieved with historical rather than physical examination or ECG interpretation variables. Clinicians had moderate agreement in assessing the patient's overall risk for a serious outcome at 30 days. Future development of clinical prediction models in older adults with syncope should account for variability of assessments between raters and consider the use of objective clinical variables.

Salivary protein glycosylation as a noninvasive biomarker for assessment of glycemia.

Assessment of short-term glycemic control can facilitate monitoring of diabetes development in at-risk individuals and monitoring response to lifestyle modification or medication. We evaluated salivary protein glycosylation levels as a novel, noninvasive, short-term glycemic index in comparison to hemoglobin A1c (HbA1c), fructosamine, 1,5-anhydroglucitol (1,5-AG), and continuous glucose monitoring (CGM). Ten subjects with type 2 diabetes were monitored by CGM and saliva and blood were collected at baseline and days 1, 7, 14, 21, and 28 for determination of salivary protein glycosylation, serum fructosamine, and serum 1,5-anhydroglucitol (1,5-AG) levels, as well as HbA1c (baseline and day 28). Weekly, 14-day, 21-day, and 28-day summary blood glucose measures from CGM were computed and matched to the time of each study visit. Salivary protein glycosylation exhibited a moderate correlation with fructosamine (r = .65) and 1,5-AG (r = -.48) at baseline, and weak correlation with HbA1c (r = .3). Salivary protein glycosylation exhibited a stronger correlation than fructosamine and 1,5-AG with 7-, 14-, and 21-day average BG (r = .84, .84, and .69, respectively, vs -.37, -.28, and .00 [fructosamine] and .00, -.21, and -.57 [1,5-AG]), maximum BG (r = .79, .76, and .53 vs -.09, -.21, and -.05 [fructosamine] and -.32, -.27, and -.52 [1,5-AG]), and percentage of time over 140 mg/dL (r = .87, .79, and .59 vs -.26, -.32, and .07 [fructosamine] and -.04, -.10, and -.50 [1,5-AG]). Salivary protein glycosylation represents a promising noninvasive technology for monitoring short-term glycemic control.

Non-24-Hour Disorder in Blind Individuals Revisited: Variability and the Influence of Environmental Time Cues.

STUDY OBJECTIVES: To assess the interindividual and intraindividual variability in the circadian rhythms of blind individuals with non-24-h disorder and to quantify the influence of environmental time cues in blind subjects lacking entrainment (non-24-h individuals or N-24s). DESIGN: An observational study of 21 N-24s (11 females and 10 males, age 9-78 years) who kept a sleep/wake schedule of their choosing. Circadian phase was determined using the melatonin onset (MO) from plasma or saliva samples that were collected every 2 weeks. Melatonin concentrations were measured by radioimmunoassay. A total of 469 MO assessments were conducted over 5,536 days of study. The rate of drift of circadian phase was calculated using a series of MOs (total number of hours the MO drifted divided by the total number of days studied). Stability of the rest/activity rhythm was calculated using chi-squared periodogram analysis of wrist actigraphy data in 19 subjects. SETTING: Academic medical center. PARTICIPANTS: Paid volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects lacked entrainment such that circadian phase drifted an average (± standard deviation) of 0.39 ± 0.29 h later per day; however, there was notable intersubject and intrasubject variability in the rate of drift including relative coordination and periods of transient entrainment during which there was little to no drift in the circadian phase. A regular, reproducible, and significant oscillation in the rate of drift was detected in 14 of the 21 subjects. A significant non-24-h rest/activity rhythm was detected in 18 of 19 subjects. There was a strong correlation (r = 0.793, P = 0.0001) between the non-24-h rest/activity rhythm and the rate of drift of the circadian phase. CONCLUSIONS: Most N-24s are influenced by unidentified environmental time cues and the non-entrained biological clock in such N-24s is reflected in their rest/activity rhythms. These findings may have diagnostic and treatment implications: this disorder might be diagnosed with actigraphy alone, relative coordination and transient entrainment may result in misdiagnosis and responsiveness to environmental time cues may influence treatment success with oral melatonin. CITATION: Emens JS; Laurie AL; Songer JB; Lewy AJ. Non-24-hour disorder in blind individuals revisited: variability and the influence of environmental time cues. SLEEP 2013;36(7):1091-1100.

Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods.

In the absence of the entraining light-dark cycle, most totally blind humans free-run, albeit with relative coordination to nonphotic zeitgebers. Such blind free-runners (BFRs) often attempt to maintain a 24-h sleep-wake schedule and consequently suffer from recurrent sleep disruption and daytime somnolence. This study was conducted to determine the periods of the free-running melatonin rhythm and of the rest-activity cycle in 16 BFRs. It was found that the non-24-h component of the rest-activity rhythm correlated with the observed period of the circadian pacemaker.

Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model.

The phase shift hypothesis (PSH) states that most patients with SAD become depressed in the winter because of a delay in circadian rhythms with respect to the sleep/wake cycle: According to the PSH, these patients should preferentially respond to the antidepressant effects of bright light exposure when it is scheduled in the morning so as to provide a corrective phase advance and restore optimum alignment between the circadian rhythms tightly coupled to the endogenous circadian pacemaker and those rhythms that are related to the sleep/wake cycle. Recent support for the PSH has come from studies in which symptom severity was shown to correlate with the degree of circadian misalignment: it appears that a subgroup of patients are phase advanced, not phase delayed; however, the phase-delayed type is predominant in SAD and perhaps in other disorders as well, such as non-seasonal unipolar depression. It is expected that during the next few years the PSH will be tested in these and other conditions, particularly since healthy subjects appear to have more severe symptoms of sub-clinical dysphoria correlating with phase-delayed circadian misalignment; critically important will be the undertaking of treatment trials to investigate the therapeutic efficacy of morning bright light or afternoon/evening low-dose melatonin in these disorders in which symptoms are more severe as the dim light melatonin onset (DLMO) is delayed with respect to the sleep/wake cycle (non-restorative sleep should also be evaluated, as well as bipolar disorder). The possibility that some individuals (and disorders) will be of the phase-advanced type should be considered, taking into account that the correct timing of phase-resetting agents for them will be bright light scheduled in the evening and/or low-dose melatonin taken in the morning. While sleep researchers and clinicians are accustomed to phase-typing patients with circadian-rhythm sleep disorders according to the timing of sleep, phase typing based on the DLMO with respect to the sleep/wake cycle may lead to quite different recommendations for the optimal scheduling of phase-resetting agents, particularly for the above disorders and conditions.