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Psychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom non-remission in first-episode psychosis.
Our development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 to 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 to 2009 from a further 11 English early intervention services. The one-year non-remission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for non-remission, which was externally validated.
The prediction model showed good discrimination (C-statistic of 0.74 (0.72, 0.76) and adequate calibration with intercept alpha of 0.13 (0.03, 0.23) and slope beta of 0.99 (0.87, 1.12). Our model improved the net-benefit by 16% at a risk threshold of 50%, equivalent to 16 more detected non-remitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases.
Once prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of non-remission at initial clinical contact.
According to the most recent cancer statistics, more than 870,000 new diagnosis of cancer are expected in the US female population in 2018, with the three most common cancers in women being breast, lung, and colorectal cancers .
Several improvements have been made in the early diagnosis and treatment of infant and adults cancer and these advances have resulted in greatly increased life expectancy and chances of survival. Nevertheless, some oncological treatments, although leading to cancer cure rates higher than 90%, have a detrimental effect in the reproductive potential of children and young women, resulting in a population at high-risk of developing premature ovarian insufficiency (POI) and therefore infertility .
In order to prevent the risk of facing this outcome, fertility preservation options are offered to these patients in order to protect their fertility potential prior to gonadotoxic treatment. Among the available options, ovarian tissue cryopreservation and transplantation is the only method suitable for prepubertal girls and adult women who require urgent treatment.
In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.
Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.
All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.
Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Chorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.
Patients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.
Of 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119  weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.
The type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.
Using data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.
Externalizing was heritable (h2 = 0.46, p = 1 × 10−6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = −0.412, p = 0.004), verbal reasoning (ρg = −0.485, p = 0.001), spatial reasoning (ρg = −0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10−4), verbal knowledge (ρg = −0.314, p = 0.002), and general cognitive ability (g)(ρg = −0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = −0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing.
Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.
Recent research points to a gender gap in journal-article authorship: women are underrepresented. Given that publishing a book remains central to many political scientists’ careers, this article explores the extent to which gender publication and citation gaps also exist for books. We find that although the gender publication gap for university-press books has narrowed over time, it remains larger than for journal articles. We also find that book-authorship patterns do not reflect the shift toward coauthorship observed for journal articles. Conversely, we find no gender citation gap for books written by one woman. However, books coauthored by coed teams or teams of women receive far fewer citations than books written by one man or one woman or by teams of men.
We present a diode-pumped, electro-optically Q-switched Tm:YAG laser with a cryogenically cooled laser crystal at 120 K. Output pulses of up to 2.55 mJ and 650 ns duration were demonstrated in an actively Q-switched configuration with a repetition rate of 1 Hz. By using cavity dumping the pulse duration was shortened to 18 ns with only a slightly lower output energy of 2.22 mJ. Furthermore, using a simplified rate equation model, we discuss design constraints on the pump fluence in a pulse pump approach for Tm:YAG to maximize the energy storage capability at a given pump power.
The ‘last mile’ is a transportation planning term that describes the movement of people and goods from a transportation hub to a final destination; a local place such as a home or a shop. This is the final step of the logistics process that unites the product with its new owner. We present and explain challenges of science-guided adaptation at the local level, and how this is an equivalent ‘last mile’ challenge for climate adaptation.
The ‘last mile’ issue, a term used in transportation planning, describes the movement of people and goods from a transportation hub to a final destination, a local place such as a home or a shop. This is the critical final step of the logistics process that unites the product with its new owner, and the point of the value chain. This analogy aptly describes the last steps between presenting scientific evidence of climate change to decision-makers for use in local adaptation and planning. Climate change data (observational and model simulation data e.g. climate change projections and predictions) remain under-utilised, especially by local institutions and actors for which adaptation is a priority. The assumptions and assertions of the classical data–information–knowledge–wisdom are challenged, and a derivative form of the information hierarchy is proposed. Elements of the classical information hierarchy are offset by four balancing elements of access (to data); usability (of information); governance (of knowledge) and politics (of wisdom). These balancing elements and their relatedness coincide with newer models of innovation relating to the interaction between different stakeholders across the different levels of governance, the inclusion of stakeholder expectations, transparency and accountability.
Social media summary
Climate data to wise decision-making in the ‘last mile’: a novel perspective on science-guided local adaptation.
This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience.
We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression.
Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma.
These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.
It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.
In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).
As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement.
The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.
Patients with terminal illness are at high risk of developing delirium, in particular, those with multiple predisposing and precipitating risk factors. Delirium in palliative care is largely under-researched, and few studies have systematically assessed key aspects of delirium in elderly, palliative-care patients.
In this prospective, observational cohort study at a tertiary care center, 229 delirious palliative-care patients stratified by age: <65 (N = 105) and ≥65 years (N = 124), were analyzed with logistic regression models to identify associations with respect to predisposing and precipitating factors.
In 88% of the patients, the underlying diagnosis was cancer. Mortality rate and median time to death did not differ significantly between the two age groups. No inter-group differences were detected with respect to gender, care requirements, length of hospital stay, or medical costs. In patients ≥65 years, exclusively predisposing factors were relevant for delirium, including hearing impairment [odds ratio (OR) 3.64; confidence interval (CI) 1.90–6.99; P < 0.001], hypertonia (OR 3.57; CI 1.84–6.92; P < 0.001), and chronic kidney disease (OR 4.84; CI 1.19–19.72; P = 0.028). In contrast, in patients <65 years, only precipitating factors were relevant for delirium, including cerebral edema (OR 0.02; CI 0.01–0.43; P = 0.012).
Significance of results
The results of this study demonstrate that death in delirious palliative-care patients occurs irrespective of age. The multifactorial nature and adverse outcomes of delirium across all age in these patients require clinical recognition. Potentially reversible factors should be detected early to prevent or mitigate delirium and its poor survival outcomes.
Virus outbreaks such as the current SARS-CoV-2 pandemic are challenging for health care workers (HCWs), affecting their workload and their mental health. Since both, workload and HCW's well-being are related to the quality of care, continuous monitoring of working hours and indicators of mental health in HCWs is of relevance during the current pandemic. The existing investigations, however, have been limited to a single study period. We examined changes in working hours and mental health in Swiss HCWs at the height of the pandemic (T1) and again after its flattening (T2).
We conducted two cross-sectional online studies among Swiss HCWs assessing working hours, depression, anxiety, and burnout. From each study, 812 demographics-matched participants were included into the analysis. Working hours and mental health were compared between the two samples.
Compared to prior to the pandemic, the share of participants working less hours was the same in both samples, whereas the share of those working more hours was lower in the T2 sample. The level of depression did not differ between the samples. In the T2 sample, participants reported more anxiety, however, this difference was below the minimal clinically important difference. Levels of burnout were slightly higher in the T2 sample.
Two weeks after the health care system started to transition back to normal operations, HCWs' working hours still differed from their regular hours in non-pandemic times. Overall anxiety and depression among HCWs did not change substantially over the course of the current SARS-CoV-2 pandemic.
Infants with CHD requiring positive pressure ventilation via tracheostomy are especially vulnerable to malnutrition following cardiac surgery. Current post-operative feeding recommendations may overestimate the caloric needs.
We retrospectively studied infants requiring tracheostomy after cardiac surgery. Anthropometric and nutritional data were collected, including caloric goals, weight-for-age z score, length-for-age z score, and weight-for-length z score. Changes in anthropometrics over time were compared to ascertain the impact of nutritional interventions. Data were shown as mean ± standard deviation.
Nineteen infants with CHD required tracheostomy at 160 ± 109 days (7–364 days), 13 had reparative surgery, and 6 had palliative surgery for single ventricle. The indications for tracheostomy consisted of airway abnormality/obstruction (n = 13), chronic respiratory failure (n = 7), and/or vocal cord paresis (n = 2). Initial maintenance nutritional target was set at 100–130 cal/kg per day. Fourteen patients (73.7%) became obese (maximum weight-for-length z score: 2.59 ± 0.47) under tracheostomy and gastrostomy feeding, whereas five patients did not (weight-for-length z score: 0.2 ± 0.83). Eight obese patients (weight-for-length z score: 2.44 ± 0.85) showed effective reduction of obesity within 6 months (weight-for-length z score: 0.10 ± 0.20; p < 0.05 compared with pre-adjustment) after appropriate feeding adjustment (40–90 cal/kg per day). Overall mortality was high (31.6%) in this population.
Standard nutritional management resulted in overfeeding and obesity in young children with CHD requiring positive pressure ventilation via tracheostomy. Optimal nutritional management in this high-risk population requires close individualised management by multidisciplinary teams.
Nursing instruments have the potential for daily screening of delirium; however, they have not yet been evaluated. Therefore, after assessing the functional domains of the electronic Patient Assessment — Acute Care (ePA-AC), this study evaluates the cognitive and associated domains.
In this prospective cohort study in the intensive care unit, 277 patients were assessed and 118 patients were delirious. The impacts of delirium on the cognitive domains, consciousness and cognition, communication and interaction, in addition to respiration, pain, and wounds were determined with simple logistic regressions and their respective odds ratios (ORs).
Delirium was associated with substantial impairment throughout the evaluated domains. Delirious patients were somnolent (OR 6), their orientation (OR 8.2–10.6) and ability to acquire knowledge (OR 5.5–11.6) were substantially impaired, they lost the competence to manage daily routines (OR 8.2–22.4), and their attention was compromised (OR 12.8). In addition, these patients received psychotropics (OR 3.8), were visually impaired (OR 1.8), unable to communicate their needs (OR 5.6–7.6), displayed reduced self-initiated activities (OR 6.5–6.9) and challenging behaviors (OR 6.2), as well as sleep–wake disturbances (OR 2.2–5), Furthermore, delirium was associated with mechanical ventilation, abdominal/thoracic injuries or operations (OR 4.2–4.4), and sensory perception impairment (OR 3.9–5.8).
Significance of results
Delirium caused substantial impairment in cognitive and associated domains. In addition to the previously described functional impairments, these findings will aid the implementation of nursing instruments in delirium screening.
Conventional wisdom holds that landed elites oppose democratization. Whether they fear rising wages, labor mobility or land redistribution, landowners have historically repressed agricultural workers and sustained autocracy. What might change landowning elites’ preferences for dictatorship and reduce their opposition to democracy? Change requires reducing landowners’ need to maintain political control over labor. This transition occurs when mechanization reduces the demand for agricultural workers, eliminating the need for labor-repressive policies. We explain how the adoption of labor-saving technology in agriculture alters landowners’ political preferences for different regimes, so that the more mechanized the agricultural sector, the more likely is democracy to emerge and survive. Our theoretical argument offers a parsimonious revision to Moore’s thesis that applies to the global transformation of agriculture since his Social Origins first appeared, and results from our cross-national statistical analyses strongly suggest that a positive relationship between agricultural mechanization and democracy does in fact exist.
There is evidence that depression can be prevented; however, traditional approaches face significant scalability issues. Digital technologies provide a potential solution, although this has not been adequately tested. The aim of this study was to evaluate the effectiveness of a new smartphone app designed to reduce depression symptoms and subsequent incident depression amongst a large group of Australian workers.
A randomized controlled trial was conducted with follow-up assessments at 5 weeks and 3 and 12 months post-baseline. Participants were employed Australians reporting no clinically significant depression. The intervention group (N = 1128) was allocated to use HeadGear, a smartphone app which included a 30-day behavioural activation and mindfulness intervention. The attention-control group (N = 1143) used an app which included a 30-day mood monitoring component. The primary outcome was the level of depressive symptomatology (PHQ-9) at 3-month follow-up. Analyses were conducted within an intention-to-treat framework using mixed modelling.
Those assigned to the HeadGear arm had fewer depressive symptoms over the course of the trial compared to those assigned to the control (F3,734.7 = 2.98, p = 0.031). Prevalence of depression over the 12-month period was 8.0% and 3.5% for controls and HeadGear recipients, respectively, with odds of depression caseness amongst the intervention group of 0.43 (p = 0.001, 95% CI 0.26–0.70).
This trial demonstrates that a smartphone app can reduce depression symptoms and potentially prevent incident depression caseness and such interventions may have a role in improving working population mental health. Some caution in interpretation is needed regarding the clinical significance due to small effect size and trial attrition.
Trial Registration Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au/) ACTRN12617000548336
Isolated aortic regurgitation and myocardial infarction are a rare congenital defect among neonatal patients. We present a case of a neonate with an unusual aortic valve morphology causing both regurgitation and obstruction of the left coronary artery ostium. Despite both non-invasive and invasive imaging modalities, accurate diagnosis of the valve morphology was only determined by direct visualisation at the time of surgical repair. To the knowledge of authors, this particular aortic valve morphology in neonatal population has not been previously reported in the literature.