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.).

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).

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.

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.

Melatonin for pre- and postoperative anxiety in adults.

BACKGROUND: Anxiety in relation to surgery is a well-known problem. Melatonin offers an atoxic alternative to benzodiazepines in ameliorating this condition in the pre- and postoperative period. OBJECTIVES: To assess the effect of melatonin on pre- and postoperative anxiety in adults when comparing melatonin with placebo or when comparing melatonin with benzodiazepines. SEARCH METHODS: The following databases were searched on 19 April 2013: CENTRAL, MEDLINE, EMBASE, CINAHL and Web of Science. For ongoing trials and protocols we searched clinicaltrials.gov, Current Controlled Trials and the World Health Organization (WHO) International Clinical Trials Registry Platform. We reran the search in October 2014. We will deal with any studies of interest when we update the review. SELECTION CRITERIA: Randomized, placebo-controlled or standard treatment-controlled, or both, studies that evaluated the effect of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both genders (15 to 90 years of age) undergoing any kind of surgical procedure in which it was necessary to use general, regional or topical anaesthesia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two review authors. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimen, preoperative anxiety outcome measures and postoperative anxiety outcome measures. MAIN RESULTS: This systematic review identified 12 randomized controlled trials (RCTs) including 774 patients that assessed melatonin for treating preoperative anxiety, postoperative anxiety or both. Four of the 12 studies compared melatonin, placebo and midazolam, whereas the remaining eight studies compared melatonin and placebo only.The quality of the evidence for our primary outcome (melatonin versus placebo for preoperative anxiety) was high. More than half of the included studies had a low risk of selection bias and at least 75% of the included studies had a low risk of attrition, performance and detection bias. Most of the included studies had an unclear risk of reporting bias.Eight out the 10 studies that assessed the effect of melatonin on preoperative anxiety using a visual analogue scale (VAS) (ranging from 0 to 100 mm, higher scores indicate greater anxiety) showed a reduction compared to placebo. The reported estimate of effect (relative effect -13.36, 95% confidence interval (CI) -16.13 to -10.58; high quality evidence) was based on a meta-analysis of seven studies. Two studies did not show any difference between melatonin and placebo. Two studies comparing melatonin with midazolam using a VAS found no evidence of a difference in preoperative anxiety between the two groups (relative effect -1.18, 95% CI -2.59 to 0.23; low quality evidence).Eight studies assessed the effect of melatonin on postoperative anxiety. Four of these studies measuring postoperative anxiety 90 minutes postoperatively using a VAS did not find any evidence of a difference between melatonin and placebo (relative effect -3.71, 95% CI -9.26 to 1.84). Conversely, two studies showed a reduction of postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) when comparing melatonin with placebo (relative effect -5.31, 95% CI -8.78 to -1.84; moderate quality evidence). Two studies comparing melatonin with midazolam using a VAS did not find any evidence of a difference between the two groups in postoperative anxiety (relative effect -2.02, 95% CI -5.82 to 1.78). AUTHORS' CONCLUSIONS: When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults (measured 50 to 100 minutes after administration). The effect of melatonin on postoperative anxiety (measured 90 minutes and 6 hours after surgery) in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.

Using Prescription Drug Monitoring Programs to Address Drug Abuse.

(1) Forty-nine states have established prescription drug monitoring programs (PDMPs) to address misuse and abuse of controlled substances. (2) Pilot programs have shown that connecting prescribers' PDMPs using health information technology results in improved patient care. (3) Legislators can access up-to-date information about their state PDMP at the Prescription Drug Monitoring Program Training and Technical Assistance Center.

Ceramides mediate cigarette smoke-induced metabolic disruption in mice.

Cigarette smoke exposure increases lung ceramide biosynthesis and alters metabolic function. We hypothesized that ceramides are released from the lung during cigarette smoke exposure and result in elevated skeletal muscle ceramide levels, resulting in insulin resistance and altered mitochondrial respiration. Employing cell and animal models, we explored the effect of cigarette smoke on muscle cell insulin signaling and mitochondrial respiration. Muscle cells were treated with conditioned medium from cigarette smoke extract (CSE)-exposed lung cells, followed by analysis of ceramides and assessment of insulin signaling and mitochondrial function. Mice were exposed to daily cigarette smoke and a high-fat, high-sugar (HFHS) diet with myriocin injections to inhibit ceramide synthesis. Comparisons were conducted between these mice and control animals on standard diets in the absence of smoke exposure and myriocin injections. Muscle cells treated with CSE-exposed conditioned medium were completely unresponsive to insulin stimulation, and mitochondrial respiration was severely blunted. These effects were mitigated when lung cells were treated with the ceramide inhibitor myriocin prior to and during CSE exposure. In mice, daily cigarette smoke exposure and HFHS diet resulted in insulin resistance, which correlated with elevated ceramides. Although myriocin injection was protective against insulin resistance with either smoke or HFHS, it was insufficient to prevent insulin resistance with combined CS and HFHS. However, myriocin injection restored muscle mitochondrial respiration in all treatments. Ceramide inhibition prevents metabolic disruption in muscle cells with smoke exposure and may explain whole body insulin resistance and mitochondrial dysfunction in vivo.

Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial.

Depression, anxiety and sleep disturbances are known problems in patients with breast cancer. The effect of melatonin as an antidepressant in humans with cancer has not been investigated. We investigated whether melatonin could lower the risk of depressive symptoms in women with breast cancer in a three-month period after surgery and assessed the effect of melatonin on subjective parameters: anxiety, sleep, general well-being, fatigue, pain and sleepiness. Randomized, double-blind, placebo-controlled trial undertaken from July 2011 to December 2012 at a department of breast surgery in Copenhagen, Denmark. Women, 30-75 years, undergoing surgery for breast cancer and without signs of depression on Major Depression Inventory (MDI) were included 1 week before surgery and received 6 mg oral melatonin or placebo for 3 months. The primary outcome was the incidence of depressive symptoms measured by MDI. The secondary outcomes were area under the curve (AUC) for the subjective parameters. 54 patients were randomized to melatonin (n = 28) or placebo (n = 26) and 11 withdrew from the study (10 placebo group and 1 melatonin group, P = 0.002). The risk of developing depressive symptoms was significantly lower with melatonin than with placebo (3 [11 %] of 27 vs. 9 [45 %] of 20; relative risk 0.25 [95 % CI 0.077-0.80]), giving a NNT of 3.0 [95 % CI 1.7-11.0]. No significant differences were found between AUC for the subjective parameters. No differences in side effects were found (P = 0.78). Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery.

Two rooms, two representations? Episodic-like memory in toddlers and preschoolers.

Episodic memory involves binding together what-where-when associations. In three experiments, we tested the development of memory for such contextual associations in a naturalistic setting. Children searched for toys in two rooms with two different experimenters; each room contained two identical sets of four containers, but arranged differently. A distinct toy was hidden in a distinct container in each room. In Experiment 1, which involved children between 15 and 26 months who were prompted with a very explicit cue (a part of the hidden toy), we found a marked shift in performance with age: while 15- to 20-month-olds concentrated their searches on the two containers that sometimes contained toys, they did not distinguish between them according to context, but 21-26-month-olds did. However, surprisingly, without toy cues, even the youngest children showed a fragile ability to disambiguate the two containers by room context. In Experiment 2, we tested 34- to 40-month-olds and 64- to 72-month-olds without toy cues. The 5-year-olds were nearly perfect, and the 3-year-olds showed a significant preference for the correct container given only the context. In Experiment 3, we filled in the age range, and also investigated the effects of the use of labels (i.e. names of experimenters and rooms) and of familiarization time, in groups of 34- to 40-month-olds, 42- to 48-month-olds, and 50- to 56-month-olds. Neither labels nor familiarization time had an effect. Across experiments, there was regular age-related improvement in context-based memory. Overall, the results suggest that children's episodic memory may undergo an early qualitative change, yet to be precisely characterized, and that continuing increments in the use of contextual cues occur throughout the preschool period. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=DkwEFw0UEz4&list=PLwxXcOKHPC0llAPVcJyW4EtzlA934A2Rz&index=1.

Methadone and prescription drug overdose.

(1) Methadone accounted for 2 percent of painkiller prescriptions and more than 30 percent of prescription painkiller deaths in 2009. (2) Data suggest that the rise in deaths from methadone overdose is not related to its use in treating drug abuse but, rather, to its use for pain management. (3) Preferred drug lists in most Medicaid programs identify methadone as a preferred drug for managing chronic pain, but most experts do no recommend it as a first choice.

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 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.

Lack of circadian variation and reduction of heart rate variability in women with breast cancer undergoing lumpectomy: a descriptive study.

Changes in the autonomic nervous system with increased sympathetic tone may be a cause of postoperative short-, and long-term cardiovascular complications. Heart rate variability (HRV) is assessed by Holter monitoring as a measure of autonomic tone and has not been investigated in patients with breast cancer undergoing surgery. We aimed to investigate evening- and night-time HRV after lumpectomy. Twelve patients were included in this descriptive study. HRV was measured the night before surgery (PREOP), the night after surgery (PO1) and 14 days after surgery (PO14) from 1900 to 0700 h. For calculation of HRV, time domain parameters (SDNN-standard deviation of all normal-to-normal (NN) intervals around the mean NN for the period of measurement, pNN50-percentage of beats where the change from one beat to the next is more than 50 ms, rMSSD-root mean square of successive differences) were used. We analyzed the variation of the overall time period and the circadian variation between evening and night (sympathetic vs. parasympathetic tonus). Mean heart rate increased from PREOP to PO1 (p < 0.001) and also increased between PREOP and PO14 (p < 0.05). SDNN (p < 0.001) and PNN50 (p < 0.001) decreased from PREOP to PO1. There was also a significant decrease between PREOP and PO14 for both parameters (p < 0.005 and p = 0.05 respectively). SDNN increased from PO1 to PO14 (p < 0.005). rMSSD decreased from PREOP to PO1 (p < 0.001). A circadian variation was found in the mean heart rate for all three monitoring periods (p < 0.005). Circadian variation was also present on PREOP for pNN50 (p ≤ 0.05) and rMSSD (p < 0.05). This variation was missing for both PO1 and PO14. Patients had a shift of autonomic tone with reduced parasympathetic activity and lack of circadian variation 14 days after lumpectomy.

Pharmacological treatment of depression in women with breast cancer: a systematic review.

The objective of this study is to review the literature on pharmacological treatment of depression in women with breast cancer. According to the PRISMA guidelines, we conducted a systematic review of randomized, controlled clinical trials and open label prospective studies on antidepressants effects on depression in women with breast cancer up to January 14, 2013. In this analysis, a total of 213 studies were identified, and six studies met the inclusion criteria. Of the six studies, three were placebo-controlled randomized controlled clinical trials with fluoxetine, a selective serotonin reuptake inhibitor; and Mianserin­a noradrenergic and specific serotonergic antidepressant. Both studies found that fluoxetine and mianserin significantly improved depressive symptoms and quality of life (QOL) compared with placebo. Conversely, desipramine, a tricyclic antidepressant, and the SSRI, paroxetine, showed no significant effects on depression compared with placebo. A double-blind, parallel group study comparing a tricyclic antidepressant, amitriptyline, and paroxetine showed a significant and comparable improvement in depression and QOL. Two open label, prospective studies found that escitalopram and the norepinephrine reuptake inhibitor, reboxetine, significantly improved depression and QOL compared with baseline values. In conclusion, depression is a clinical problem in patients with breast cancer. Pharmacological treatment with antidepressants may improve depression and QOL. However, the evidence is limited, and the studies are too heterogeneous to recommend one regimen or drug over another. Further antidepressant studies are needed to guide depression treatment in patients with breast cancer.