Socioeconomic factors, sleep timing and duration, and amygdala resting-state functional connectivity in children.

Introduction: Reduced sleep health has been consistently linked with increased negative emotion in children. While sleep characteristics have been associated with neural function in adults and adolescents, much less is known about these associations in children while considering socioeconomic context. In this study, we examined the associations among socioeconomic factors, sleep duration and timing, and resting-state functional connectivity (rsFC) of the amygdala in children. Methods: Participants were typically-developing 5- to 9-year-olds from socioeconomically diverse families (61% female; N = 94). Parents reported on children's weekday and weekend bedtimes and wake-up times, which were used to compute sleep duration and midpoint. Analyses focused on amygdala-anterior cingulate cortex (ACC) connectivity followed by amygdala-whole brain connectivity. Results: Lower family income-to-needs ratio and parental education were significantly associated with later weekday and weekend sleep timing and shorter weekday sleep duration. Shorter weekday sleep duration was associated with decreased amygdala-ACC and amygdala-insula connectivity. Later weekend sleep midpoint was associated with decreased amygdala-paracingulate cortex and amygdala-postcentral gyrus connectivity. Socioeconomic factors were indirectly associated with connectivity in these circuits via sleep duration and timing. Discussion: These results suggest that socioeconomic disadvantage may interfere with both sleep duration and timing, in turn possibly altering amygdala connectivity in emotion processing and regulation circuits in children. Effective strategies supporting family economic conditions may have benefits for sleep health and brain development in children.

Polygenic risk for depression and anterior and posterior hippocampal volume in children and adolescents.

BACKGROUND: Depression has frequently been associated with smaller hippocampal volume. The hippocampus varies in function along its anterior-posterior axis, with the anterior hippocampus more strongly associated with stress and emotion processing. The goals of this study were to examine the associations among parental history of anxiety/depression, polygenic risk scores for depression (PGS-DEP), and anterior and posterior hippocampal volumes in children and adolescents. To examine specificity to PGS-DEP, we examined associations of educational attainment polygenic scores (PGS-EA) with anterior and posterior hippocampal volume. METHODS: Participants were 350 3- to 21-year-olds (46 % female). PGS-DEP and PGS-EA were computed based on recent, large-scale genome-wide association studies. High-resolution, T1-weighted magnetic resonance imaging (MRI) data were acquired, and a semi-automated approach was used to segment the hippocampus into anterior and posterior subregions. RESULTS: Children and adolescents with higher polygenic risk for depression were more likely to have a parent with a history of anxiety/depression. Higher polygenic risk for depression was significantly associated with smaller anterior but not posterior hippocampal volume. PGS-EA was not associated with anterior or posterior hippocampal volumes. LIMITATIONS: Participants in these analyses were all of European ancestry. CONCLUSIONS: Polygenic risk for depression may lead to smaller anterior but not posterior hippocampal volume in children and adolescents, and there may be specificity of these effects to PGS-DEP rather than PGS-EA. These findings may inform the earlier identification of those in need of support and the design of more effective, personalized treatment strategies. DECLARATIONS OF INTEREST: none. DECLARATIONS OF INTEREST: None.

Socioeconomic Disparities in Hypothalamic-Pituitary-Adrenal Axis Regulation and Prefrontal Cortical Structure.

Socioeconomic disadvantage during childhood predicts an increased risk for mental health problems across the life span. Socioeconomic disadvantage shapes multiple aspects of children's proximal environments and increases exposure to chronic stressors. Drawing from multiple literatures, we propose that childhood socioeconomic disadvantage may lead to adaptive changes in the regulation of stress response systems including the hypothalamic-pituitary-adrenal (HPA) axis. These changes, in turn, affect the development of prefrontal cortical (PFC) circuitry responsible for top-down control over cognitive and emotional processes. Translational findings indicate that chronic stress reduces dendritic complexity and spine density in the medial PFC and anterior cingulate cortex, in part through altered HPA axis regulation. Socioeconomic disadvantage has frequently been associated with reduced gray matter in the dorsolateral and ventrolateral PFC and anterior cingulate cortex and lower fractional anisotropy in the superior longitudinal fasciculus, cingulum bundle, and uncinate fasciculus during middle childhood and adolescence. Evidence of socioeconomic disparities in hair cortisol concentrations in children has accumulated, although null findings have been reported. Coupled with links between cortisol levels and reduced gray matter in the PFC and anterior cingulate cortex, these results support mechanistic roles for the HPA axis and these PFC circuits. Future longitudinal studies should simultaneously consider multiple dimensions of proximal factors, including cognitive stimulation, while focusing on epigenetic processes and genetic moderators to elucidate how socioeconomic context may influence the HPA axis and PFC circuitry involved in cognitive and emotional control. These findings, which point to modifiable factors, can be harnessed to inform policy and more effective prevention strategies.

Neighborhood Socioeconomic Disadvantage and White Matter Microstructure of the Arcuate Fasciculus and Uncinate Fasciculus in Adolescents.

Background: Neighborhood- or area-level socioeconomic disadvantage is associated with neural alterations across the life span. However, few studies have examined the effects of neighborhood disadvantage on white matter microstructure during adolescence, an important period of development that coincides with increased risk for psychopathology. Methods: In 200 adolescents (ages 13-20 years; 54.5% female, 4% nonbinary) recruited from 2 studies enriched for early adversity and depression, we examined whether neighborhood socioeconomic disadvantage derived from census tract data was related to white matter microstructure in several major white matter tracts. We also examined whether depressive symptoms and sex moderated these associations. Results: Greater neighborhood socioeconomic disadvantage was associated with lower fractional anisotropy (FA) in the left arcuate fasciculus (ß = -0.24, false discovery rate [FDR]-corrected p = .035) and right uncinate fasciculus (ß = -0.32, FDR-corrected p = .002) above and beyond the effects of family-level socioeconomic status. Depressive symptoms significantly moderated the association between left arcuate fasciculus FA and both neighborhood (ß = 0.17, FDR-corrected p = .026) and unemployment (ß = 0.22, FDR-corrected p = .004) disadvantage such that these associations were only significant in adolescents who reported less severe depression. Sex did not moderate the association between socioeconomic disadvantage and FA in these tracts. Conclusions: Greater neighborhood socioeconomic disadvantage, particularly poverty and educational attainment levels, was associated with lower FA in the arcuate fasciculus and uncinate fasciculus above and beyond the effects of family-level measures of socioeconomic status. These patterns were only observed in adolescents with low levels of depression, suggesting that we must be cautious about generalizing these findings to youths who struggle with mental health difficulties.

Socioeconomic disparities in sleep duration are associated with cortical thickness in children.

INTRODUCTION: Disrupted sleep has been consistently linked with lower academic achievement and worse mental health in children. Less is understood about sleep as a potential factor underlying socioeconomic differences in brain morphometry in children. The goals of this study were to investigate the associations among socioeconomic factors, sleep duration, and brain morphometry in children, and to examine the roles of the sleep environment and family routines in these associations. METHODS: Participants were 5- to 9-year-old children from socioeconomically diverse families (N = 94; 61% female). Parents reported on children's weekday and weekend sleep durations, sleep environment, and family routines. High-resolution, T1-weighted structural magnetic resonance imaging (MRI) data were acquired. Analyses focused on cortical thickness, cortical surface area, and amygdala and hippocampal volume. RESULTS: Results indicated that lower family income-to-needs ratio and parental education were significantly associated with shorter weekday sleep duration in children. Shorter weekday sleep duration was significantly associated with reduced thickness in the left middle temporal, right postcentral, and right superior frontal cortices and smaller basolateral but not centromedial amygdala volume. Family routines significantly mediated the associations of family income-to-needs ratio and parental education with weekday sleep duration in children. CONCLUSION: These results contribute to our understanding of sleep factors as proximal mechanisms through which socioeconomic context may alter neural development during childhood.

Cerebellar Mutism Syndrome in Children After Surgery for a Posterior Fossa Tumor: Patient Characteristics and Recovery.

Background: Cerebellar mutism syndrome (CMS) is a potential complication that may be experienced by children undergoing a resection of a posterior fossa tumor. Symptoms include mutism and emotional lability; additional symptoms may include hypotonia, difficulty swallowing, ataxia, and changes in cognition. The recovery of children experiencing CMS symptoms can be variable. In this retrospective chart review study, we identified the presenting characteristics of CMS in a cohort of children and compared them to matched-controls who did not develop CMS and examined recovery patterns during the year after diagnosis. Methods: Patients were identified through the program database. Children between ages 3 and 18 years who had a craniotomy for a posterior fossa tumor at our institution were included. For each CMS case, two control cases were selected to match the type of central nervous system tumor, sex, age group, and surgery date. Patient characteristics were abstracted from the patient's electronic medical record and the CMS survey was used to score CMS cases. Results: Seventeen children with CMS and 34 children without CMS were included in the review. Among children with CMS, 53% experienced mutism for less than 4 weeks; ataxia persisted beyond 4 weeks for more than 88% of the children and was still present in 71% 1 year after diagnosis. Clinical characteristics did not differ between the case and control groups. Discussion: CMS symptoms interfere with the child's quality of life and ongoing development. Study findings inform nurses providing anticipatory guidance and support to patients experiencing CMS and their families.

Sex differences in myelin content of white matter tracts in adolescents with depression.

Depression is a chronic and debilitating condition that often emerges during adolescence, a period of significant brain maturation. Few studies, however, have examined how mechanisms of neuroplasticity, including myelination, are affected by adolescent-onset depression. Here, we used multimodal MR imaging to characterize myelin, indexed by R1, in white matter tracts previously associated with depression and compare 48 adolescents with lifetime depression (45 with current depression, 3 remitted) and 35 healthy controls in R1. Compared to healthy controls, R1 was higher in adolescents with lifetime depression in the uncinate fasciculus and corpus callosum genu (all ßs > 0.42; all ps < 0.037). Sex significantly moderated the association between depression and R1 in the left uncinate fasciculus and corpus callosum genu (all ßs > 0.86; all ps < 0.02), such that depressed female adolescents had significantly higher R1 in these tracts than did healthy female adolescents (all ßs > 0.82; all ps < 0.0012). In contrast, depressed and non-depressed male adolescents did not differ in R1 in these tracts (all ps > 0.32). While fractional anisotropy (FA), a commonly examined measure of white matter organization based on diffusion-weighted MRI, in the left uncinate was positively associated with lifetime depression in our sample (ß = 0.56; p = 0.016), we found no evidence of sex-specific effects of depression in FA. Our results suggest that R1 is more sensitive to sex-specific effects of depression than FA, particularly in female adolescents. Given evidence that myelin inhibits synapse formation and reduces brain plasticity, our findings implicate experience-driven regional myelination as a mechanism underlying depression during periods of significant neural maturation such as adolescence.

A Randomized, Open-Label Comparison of Once-Weekly Insulin Icodec Titration Strategies Versus Once-Daily Insulin Glargine U100.

OBJECTIVE: Insulin icodec is a novel once-weekly basal insulin analog. This trial investigated the efficacy and safety of icodec using different once-weekly titration algorithms. RESEARCH DESIGN AND METHODS: This was a phase 2, randomized, open-label, 16-week, treat-to-target study. Insulin-naive adults (n = 205) with type 2 diabetes and HbA1c 7-10% while treated with oral glucose-lowering medications initiated once-weekly icodec titrations A (prebreakfast self-measured blood glucose target 80-130 mg/dL; adjustment ±21 units/week; n = 51), B (80-130 mg/dL; ±28 units/week; n = 51), or C (70-108 mg/dL; ±28 units/week; n = 52), or once-daily insulin glargine 100 units/mL (IGlar U100) (80-130 mg/dL; ±4 units/day; n = 51), all titrated weekly. Percentage of time in range (TIR) (70-180 mg/dL) during weeks 15 and 16 was measured using continuous glucose monitoring. RESULTS: TIR improved from baseline (means: A, 57.0%; B, 55.2%; C, 51.0%; IGlar U100, 55.3%) to weeks 15 and 16 (estimated mean: A, 76.6%; B, 83.0%; C, 80.9%; IGlar U100, 75.9%). TIR was greater for titration B than for IGlar U100 (estimated treatment difference 7.08%-points; 95% CI 2.12 to 12.04; P = 0.005). No unexpected safety signals were observed. Level 2 hypoglycemia (<54 mg/dL) was low in all groups (0.05, 0.15, 0.38, 0.00 events per patient-year of exposure for icodec titrations A, B, and C and IGlar U100, respectively), with no episodes of severe hypoglycemia. CONCLUSIONS: Once-weekly icodec was efficacious and well tolerated across all three titration algorithms investigated. The results for icodec titration A (80-130 mg/dL; ±21 units/week) displayed the best balance between glycemic control and risk of hypoglycemia.

Associations between stress exposure and new mothers' brain responses to infant cry sounds.

Exposure to severe stress has been linked to negative postpartum outcomes among new mothers including mood disorders and harsh parenting. Non-human animal studies show that stress exposure disrupts the normative adaptation of the maternal brain, thus identifying a neurobiological mechanism by which stress can lead to negative maternal outcomes. However, little is known about the impact of stress exposure on the maternal brain response to infant cues in human mothers. We examined the association of stress exposure with brain response to infant cries and maternal behaviors, in a socioeconomically diverse (low- and middle-income) sample of first-time mothers (N=53). Exposure to stress across socioeconomic, environmental, and psychosocial domains was associated with reduced brain response to infant cry sounds in several regions, including the right insula/inferior frontal gyrus and superior temporal gyrus. Reduced activation in these regions was further associated with lower maternal sensitivity observed during a mother-infant interaction. The findings demonstrate that higher levels of stress exposure may be associated with reduced brain response to an infant's cry in regions that are important for emotional and social information processing, and that reduced brain responses may further be associated with increased difficulties in developing positive mother-infant relationships.

Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment.

BACKGROUND: It is thought that a reduction in the frequency of basal insulin injections might facilitate treatment acceptance and adherence among patients with type 2 diabetes. Insulin icodec is a basal insulin analogue designed for once-weekly administration that is in development for the treatment of diabetes. METHODS: We conducted a 26-week, randomized, double-blind, double-dummy, phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose type 2 diabetes was inadequately controlled (glycated hemoglobin level, 7.0 to 9.5%) while taking metformin with or without a dipeptidyl peptidase 4 inhibitor. The primary end point was the change in glycated hemoglobin level from baseline to week 26. Safety end points, including episodes of hypoglycemia and insulin-related adverse events, were also evaluated. RESULTS: A total of 247 participants were randomly assigned (1:1) to receive icodec or glargine. Baseline characteristics were similar in the two groups; the mean baseline glycated hemoglobin level was 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change from baseline in the glycated hemoglobin level was -1.33 percentage points in the icodec group and -1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively, at week 26; the estimated between-group difference in the change from baseline was -0.18 percentage points (95% CI, -0.38 to 0.02, P = 0.08). The observed rates of hypoglycemia with severity of level 2 (blood glucose level, <54 mg per deciliter) or level 3 (severe cognitive impairment) were low (icodec group, 0.53 events per patient-year; glargine group, 0.46 events per patient-year; estimated rate ratio, 1.09; 95% CI, 0.45 to 2.65). There was no between-group difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low. Most adverse events were mild, and no serious events were deemed to be related to the trial medications. CONCLUSIONS: Once-weekly treatment with insulin icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily insulin glargine U100 in patients with type 2 diabetes. (Funded by Novo Nordisk; NN1436-4383 ClinicalTrials.gov number, NCT03751657.).

Effects of proactive and rescue enteral tube feedings on weight change in children undergoing treatment for high-grade CNS tumors.

BACKGROUND: Children with high-grade CNS cancers frequently experience malnutrition during treatment. We assessed the effects of proactive enteral tube (ET) placement/enteral tube feedings (ETF) on weight in infants/children with high-grade CNS tumors treated with aggressive chemotherapy. METHODS: We conducted a retrospective study of patients age 0 to 19 years treated for new high-grade CNS tumors between 2002 and 2017 at a tertiary pediatric hospital system. Patients underwent placement of proactive ET (≤ 31 days postdiagnosis; n = 45), rescue ET (> 31 days, due to weight loss; n = 9), or no ET (n = 18). Most received surgically placed ET (98%), with percutaneous endoscopic gastrojejunostomy or gastrojejunostomy tubes favored to allow jejunal feeding. The majority of patients with ET used ETF (91%). Using mixed-effects regression models, we examined differences in mean weights between ET/ETF groups across the first year of treatment. We also evaluated observed weight changes. RESULTS: All infants (n = 22, median age, 1.5 years) had proactive ET placed and 21 of 22 used proactive ETF. Infants showed an initial increase in mean percentage weight change that eventually leveled off, for an estimated increase of 10.4% over the year. For the pediatric cohort (n = 50, median, 8.1 years), those receiving proactive ETF experienced weight increases (+9.9%), those with rescue ETF experienced an initial decline and eventually rebounded for no net change (0.0%), and those with no ETF demonstrated an initial decline that persisted (-11.9%; P interaction < .001). Analysis of observed weights revealed nearly identical patterns. CONCLUSIONS: Proactive ETF was effective at maintaining weight and/or facilitating weight gain over the first year of treatment and was acceptable to patients/families.

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

AIMS/HYPOTHESIS: A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin. METHODS: This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0-5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period. RESULTS: Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300. CONCLUSIONS/INTERPRETATION: There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300. TRIAL REGISTRATION: ClinicalTrials.gov NCT03078478 FUNDING: This trial was funded by Novo Nordisk (Bagsvaerd, Denmark).

Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100: Results from SWITCH 2.

AIM: This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). METHODS: In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16-week maintenance periods. RESULTS: For individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1-40) vs 15 (1-54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively. CONCLUSION: Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7).

AIMS: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. MATERIALS AND METHODS: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). RESULTS: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. CONCLUSIONS: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Interventions to address burden among family caregivers of persons aging with TBI: A scoping review.

PURPOSE: To capture the scope of literature exploring interventions for caregivers of aging persons with TBI. METHODS: A scoping review of peer reviewed literature was conducted in two phases. Phase I: Searching seven databases, two independent raters screened articles using a set of predetermined criteria. Included articles were reviewed, and categorized according to common themes. Phase II: Five stakeholders were engaged in a consultation. A content analysis was performed by extracting statements from each interview using an inductive strategy, and organizing each into themes. FINDINGS: A total of 11 articles were included in the final analysis. Inter-rater reliability was assessed at both the title and abstract search [98.8% agreement; k = 0.3425 (95% CI, .246 to .439), p < .05]; and the full-text review [83% agreement; k = 0.542 (95% CI, 0.340 to 0.745), p < .05] phases. Seven articles identified potential interventions, and four identified and evaluated an intervention. Interventions targeted subjective burden (n = 4) and objective burden (n = 4), with caregiver knowledge and skill development (n = 3) classified as a sub-category of objective burden. Stakeholders overwhelmingly emphasized the need for interventions to reduce objective burden. IMPLICATIONS: Included articles were primarily composed of levels six and seven evidence, suggesting that this literature is in an early stage of development. Future research should emphasize the development and evaluation of interventions to reduce objective burden.

Cognitive Contributors to Multiple Errands Test (MET) Performance.

OBJECTIVE: The Multiple Errands Test (MET) was designed to measure the effect of executive dysfunction on everyday life activities, but little is known about the cognitive requirements for successful performance. This study's objective was to investigate cognitive functions associated with successful MET performance, specifically, the Baycrest-MET. METHOD: Correlation analysis examined relationships between Baycrest-MET performance and neuropsychological functioning in participants with acquired brain injury (ABI; N = 27). RESULTS: The association of tasks omitted with executive function (EF) accounted for 15.2%-42.3% of the variance; the association of tasks omitted with attention and processing speed, for 16.8%-24.0%; and the association of tasks omitted and total rule breaks with visuospatial memory, for 18.5%-31.4%. CONCLUSION: Poor performance on the Baycrest-MET in people with ABI is associated with impairments of EF, attention, memory, and processing speed. Different patterns of performance may arise from different constellations of impairments.

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications.

The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.

An adverse drug event manager facilitates spontaneous reporting of adverse drug reactions.

INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assists healthcare professionals in reporting suspected ADRs to the Danish Health Authority. The aim of this retrospective observational study was to quantify and describe ADRs reported via the ADEM in 2014. METHODS: All ADR reports handled by the ADEM in 2014 were recorded anonymously and analysed descriptively. RESULTS: A total of 484 ADRs were reported through the ADEM in 2014 (the median number of reports per month was 37; range: 17-78). The majority of the reports came from departments of internal medicine (61%), psychiatry (14%) and dermatology, ophthalmology or otorhinolaryngology (11%). The drugs most frequently reported were lisdexamphetamine (n = 40), rivaroxaban (n = 16) and warfarin (n = 15) (vaccines excluded). In 13 out of 484 reports, the ADR was associated with a fatal outcome. CONCLUSION: The findings of this study indicate that an ADEM promotes and facilitates spontaneous ADR reporting and helps raise awareness about ADRs, including how and why they should be reported. Hopefully, this will assist national and European spontaneous reporting systems in their work to increase patient safety nationally and abroad. FUNDING: none. TRIAL REGISTRATION: not relevant. .

Effect of Melatonin on Sleep in the Perioperative Period after Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial.

STUDY OBJECTIVES: To investigate whether administration of an oral dose of 6 mg melatonin before bedtime perioperatively in breast cancer surgery could change sleep outcomes measured by actigraphy. METHODS: This paper reports secondary outcomes from a double-blind, placebo-controlled, randomized clinical trial where patients received 6 mg melatonin (n = 27) or placebo (n = 21) approximately 60 minutes before bedtime 3 nights preoperatively until at least one week postoperatively. Participants were monitored in the entire period with actigraphy, and were instructed to complete visual analogue scale (VAS) for sleep, and the Karolinska Sleepiness Scale (KSS) each morning. RESULTS: Administration of 6 mg oral melatonin approximately 1 hour before bedtime resulted in significantly increased sleep efficiency and reduced wake after sleep onset for the entire 2-week postoperative period. No other significant differences for actigraphy determined sleep outcomes or subjective outcome parameters in the perioperative period were found between the groups. Overall, the patients sleep outcomes were within normal ranges and no participants had pathological sleep disturbances. CONCLUSIONS: Melatonin significantly changed sleep efficiency and wake after sleep onset after surgery, but had no effects on other objective sleep outcomes or on subjective sleep quality (VAS and KSS).