This study analyses the current literature to evaluate the effectiveness of dabrafenib and trametinib in the multi-modal treatment of anaplastic thyroid cancer (ATC).

A systematic review and meta-analysis of the literature were undertaken. The primary endpoint measured was overall response rate (ORR) defined by the RECIST v1.1 guidelines. Secondary endpoints were 12-month overall survival (OS), median OS and progression-free survival (PFS).

Of 656 identified reports, 8 studies were included which featured 95 patients (median age 68.5 years, 46 per cent male). Median follow-up period was 11.8 months with a 12-month OS of 51 per cent. Median OS was 10.4 months. Progression-free survival (PFS) was 6.5 months. The ORR was 71 per cent. A total of 65 patients exhibited a partial or complete response in radiological tumour size. Side effects compared favourably to other kinase inhibitors.

Dabrafenib and trametinib exhibit a promising tumour response with a tolerable side profile. BRAF/MEK inhibitors continue to provide robust responses in BRAF-mutated ATC. The heterogeneity and lack of controls in included studies limits the confidence in the conclusions drawn.

One in eight children experience early life stress (ELS), which increases risk for psychopathology. ELS, particularly neglect, has been associated with reduced responsivity to reward. However, little work has investigated the computational specifics of this disrupted reward response – particularly with respect to the neural response to Reward Prediction Errors (RPE) – a critical signal for successful instrumental learning – and the extent to which they are augmented to novel stimuli. The goal of the current study was to investigate the associations of abuse and neglect, and neural representation of RPE to novel and non-novel stimuli.

One hundred and seventy-eight participants (aged 10–18, M = 14.9, s.d. = 2.38) engaged in the Novelty task while undergoing functional magnetic resonance imaging. In this task, participants learn to choose novel or non-novel stimuli to win monetary rewards varying from $0 to $0.30 per trial. Levels of abuse and neglect were measured using the Childhood Trauma Questionnaire.

Adolescents exposed to high levels of neglect showed reduced RPE-modulated blood oxygenation level dependent response within medial and lateral frontal cortices particularly when exploring novel stimuli (p < 0.05, corrected for multiple comparisons) relative to adolescents exposed to lower levels of neglect.

These data expand on previous work by indicating that neglect, but not abuse, is associated with impairments in neural RPE representation within medial and lateral frontal cortices. However, there was no association between neglect and behavioral impairments on the Novelty task, suggesting that these neural differences do not necessarily translate into behavioral differences within the context of the Novelty task.

Adolescent substance use, externalizing and attention problems, and early life stress (ELS) commonly co-occur. These psychopathologies show overlapping neural dysfunction in the form of reduced recruitment of reward processing neuro-circuitries. However, it is unclear to what extent these psychopathologies show common v. different neural dysfunctions as a function of symptom profiles, as no studies have directly compared neural dysfunctions associated with each of these psychopathologies to each other.

In study 1, a latent profile analysis (LPA) was conducted in a sample of 266 adolescents (aged 13–18, 41.7% female, 58.3% male) from a residential youth care facility and the surrounding community to investigate substance use, externalizing and attention problems, and ELS psychopathologies and their co-presentation. In study 2, we examined a subsample of 174 participants who completed the Passive Avoidance learning task during functional magnetic resonance imaging to examine differential and/or common reward processing neuro-circuitry dysfunctions associated with symptom profiles based on these co-presentations.

In study 1, LPA identified profiles of substance use plus rule-breaking behaviors, attention-deficit hyperactivity disorder, and ELS. In study 2, the substance use/rule-breaking profile was associated with reduced recruitment of reward processing and attentional neuro-circuitries during the Passive Avoidance task (p < 0.05, corrected for multiple comparisons).

Findings indicate that there is reduced responsivity of striato-cortical regions when receiving outcomes on an instrumental learning task within a profile of adolescents with substance use and rule-breaking behaviors. Mitigating reward processing dysfunction specifically may represent a potential intervention target for substance-use psychopathologies accompanied by rule-breaking behaviors.

Obstructive sleep apnea (OSA) is a sleep disorder that is highly comorbid with psychiatric disorders, including depression and anxiety. Excessive daytime sleepiness (EDS) is common in psychiatric disorders and OSA. In participants with OSA, EDS can persist despite use of positive airway pressure (PAP) therapy. This analysis of real-world data aimed to describe EDS and its relationship with PAP use in participants with and without depression.

US residents (≥18 years of age, self-reported physician diagnosis of OSA [from 1/1/2015 to 3/31/2020]) completed a survey in Evidation Health’s Achievement app assessing subjective levels of sleepiness (Epworth Sleepiness Scale [ESS]) and self-reported PAP usage, categorized as nonuse (no PAP use), nonadherent (<4 h/night or <5 d/wk), intermediate (4-6 h/night, ≥5 d/wk), or highly adherent (≥6 h/night, ≥5 d/wk). ESS score >10 defined EDS. A linear model assessed relationships between PAP use and ESS score. P-values are uncontrolled for multiplicity (nominal).

In total, 2289 participants (EDS, n=972; no EDS, n=1317) completed the survey (50.3% female; 82.5% White; mean±standard deviation [SD] age, 44.8 ± 11.1 years). Anxiety and depression were the most common comorbidities and were more common in participants with EDS (49% and 49%, respectively) than those without EDS (41% and 37%, respectively). Overall, EDS was more common among participants with comorbid depression (49%) than those without (38%), even among highly adherent PAP users (46% vs 30%, respectively). In a linear model (PAP users only), an additional 1 h/night of PAP use was associated with lower ESS scores in the subgroup of participants without depression (n=928; estimate [SE], −0.42 [0.09]; P<0.05), but not in the subgroup with depression (n=661; estimate [SE], −0.15 [0.10]; P>0.05). In a sensitivity analysis that excluded participants using medications that cause sleepiness, PAP use was associated with lower ESS scores regardless of depression status; however, EDS remained more common in participants with comorbid depression (46%) than in those without (36%).

In this real-world population of participants with OSA, those with EDS were more likely to have comorbid anxiety or depression. EDS was more common in participants with comorbid depression than those without, even with highly adherent PAP use. PAP use was associated with lower ESS scores in participants without comorbid depression, but not in those with comorbid depression; the use of medications that cause sleepiness may contribute to but does not fully explain this phenomenon.

Axsome Therapeutics and Jazz Pharmaceuticals

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is often associated with numerous medical and psychiatric comorbidities. Patients with OSA experience a variety of symptoms that can be burdensome and affect their quality of life and satisfaction with care. Excessive daytime sleepiness (EDS) is a common symptom of OSA, and can persist despite primary airway therapy (e.g., positive airway pressure [PAP]). This analysis aimed to characterize common comorbidities, as well as symptoms present at OSA diagnosis and their burden in a real-world population of participants with OSA.

US residents (≥18 years of age, self-reported clinician diagnosis of OSA [from 1/1/2015 to 3/31/2020]) completed a survey in Evidation Health’s Achievement app that assessed self-reported sleepiness (Epworth Sleepiness Scale [ESS]), self-reported PAP usage, self-reported physician-diagnosed comorbidities, and information on their symptoms at time of OSA diagnosis. Self-reported PAP use was categorized as nonuse (no PAP use), nonadherent (<4 h/night or <5 d/wk), intermediate (4–6 h/night, ≥5 d/wk), or highly adherent (≥6 h/night, ≥5 d/wk). EDS was defined as ESS score >10. All data were summarized descriptively.

In total, 2289 participants completed the survey (50.3% female; 82.5% White; mean ± standard deviation [SD] age, 44.8 ± 11.1 years; mean ± SD age at OSA diagnosis, 40.7 ± 11.4 years; mean ± SD body mass index, 35.4 ± 8.7 kg/m2); 42.5% had EDS. Among the total population, 30.6% were PAP non-users, 6.7% were nonadherent, 9.8% were intermediate adherent, and 52.9% were highly adherent. Across the study population, the most common self-reported physician-diagnosed comorbidities were anxiety (44%) and depression (42%) followed by hypertension (39%), dyslipidemia (26%), and asthma (21%). Among the symptoms participants reported having had at the time of OSA diagnosis, the most common were EDS (79%), fatigue (79%), snoring (75%), and awakening with a dry mouth or sore throat (63%). Concentration/Memory problems (48%) and mood changes (46%) were also common. In the overall population, the symptoms present at the time of OSA diagnosis that were most likely to be highly burdensome were fatigue (53%), EDS (46%), snoring (35%), difficulty concentrating/memory issues (31%), and mood changes (25%).

These real-world survey data identify anxiety and depression as the most frequently reported comorbidities in a population of participants with OSA, each affecting over 40% of participants. In addition to classic OSA symptoms (e.g., EDS, fatigue, snoring, and awakening with dry mouth/sore throat), concentration/memory problems and mood changes were also common at the time of OSA diagnosis and were among the presenting symptoms most frequently reported as highly burdensome, along with fatigue, EDS, and snoring.

Axsome Therapeutics and Jazz Pharmaceuticals

Conduct disorder (CD) has been associated with dysfunction in reinforcement-based decision-making. Two forms of affective traits that reflect the components of CD severity are callous-unemotional (CU; reduced guilt/empathy) traits and irritability. The form of the reinforcement-based decision-making dysfunction with respect to CD and CU traits remains debated and has not been examined with respect to irritability in cases with CD. The goals of the current study were to determine the extent of dysfunction in differential (reward v. punishment) responsiveness in CD, and CU traits and irritability in participants with CD.

The study involved 178 adolescents [typically developing (TD; N = 77) and cases with CD (N = 101)]. Participants were scanned with fMRI during a passive avoidance task that required participants to learn to respond to (i.e. approach) stimuli that engender reward and refrain from responding to (i.e. passively avoid) stimuli that engender punishment.

Adolescents with CD showed reduced differential reward-punishment responsiveness within the striatum relative to TD adolescents. CU traits, but not irritability, were associated with reduced differential reward-punishment responsiveness within the striatum, rostromedial, and lateral frontal cortices.

The results suggest CD is associated with reduced differential reward-punishment responsiveness and the extent of this dysfunction in participants with CD is associated with the severity of CU traits but not irritability.

The degree to which suicide risk aggregates in US families is unknown. The authors aimed to determine the familial risk of suicide in Utah, and tested whether familial risk varies based on the characteristics of the suicides and their relatives.

A population-based sample of 12 160 suicides from 1904 to 2014 were identified from the Utah Population Database and matched 1:5 to controls based on sex and age using at-risk sampling. All first through third- and fifth-degree relatives of suicide probands and controls were identified (N = 13 480 122). The familial risk of suicide was estimated based on hazard ratios (HR) from an unsupervised Cox regression model in a unified framework. Moderation by sex of the proband or relative and age of the proband at time of suicide (<25 v. ⩾25 years) was examined.

Significantly elevated HRs were observed in first- (HR 3.45; 95% CI 3.12–3.82) through fifth-degree relatives (HR 1.07; 95% CI 1.02–1.12) of suicide probands. Among first-degree relatives of female suicide probands, the HR of suicide was 6.99 (95% CI 3.99–12.25) in mothers, 6.39 in sisters (95% CI 3.78–10.82), and 5.65 (95% CI 3.38–9.44) in daughters. The HR in first-degree relatives of suicide probands under 25 years at death was 4.29 (95% CI 3.49–5.26).

Elevated familial suicide risk in relatives of female and younger suicide probands suggests that there are unique risk groups to which prevention efforts should be directed – namely suicidal young adults and women with a strong family history of suicide.

A novel paediatric disease, multi-system inflammatory syndrome in children, has emerged during the 2019 coronavirus disease pandemic.

To describe the short-term evolution of cardiac complications and associated risk factors in patients with multi-system inflammatory syndrome in children.

Retrospective single-centre study of confirmed multi-system inflammatory syndrome in children treated from 29 March, 2020 to 1 September, 2020. Cardiac complications during the acute phase were defined as decreased systolic function, coronary artery abnormalities, pericardial effusion, or mitral and/or tricuspid valve regurgitation. Patients with or without cardiac complications were compared with chi-square, Fisher’s exact, and Wilcoxon rank sum.

Thirty-nine children with median (interquartile range) age 7.8 (3.6–12.7) years were included. Nineteen (49%) patients developed cardiac complications including systolic dysfunction (33%), valvular regurgitation (31%), coronary artery abnormalities (18%), and pericardial effusion (5%). At the time of the most recent follow-up, at a median (interquartile range) of 49 (26–61) days, cardiac complications resolved in 16/19 (84%) patients. Two patients had persistent mild systolic dysfunction and one patient had persistent coronary artery abnormality. Children with cardiac complications were more likely to have higher N-terminal B-type natriuretic peptide (p = 0.01), higher white blood cell count (p = 0.01), higher neutrophil count (p = 0.02), severe lymphopenia (p = 0.05), use of milrinone (p = 0.03), and intensive care requirement (p = 0.04).

Patients with multi-system inflammatory syndrome in children had a high rate of cardiac complications in the acute phase, with associated inflammatory markers. Although cardiac complications resolved in 84% of patients, further long-term studies are needed to assess if the cardiac abnormalities (transient or persistent) are associated with major cardiac events.