Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Cognitive behavioural therapy and third-wave approaches for anxiety and related disorders in older people.

BACKGROUND: Cognitive behavioural therapy (CBT) is the most researched psychological therapy for anxiety disorders in adults, and known to be effective in this population. However, it remains unclear whether these results apply to older adults, as most studies include participants between 18 and 55 years of age. This systematic review aims to provide a comprehensive and up-to-date synthesis of the available evidence on CBT and third wave approaches for older adults with anxiety and related disorders. OBJECTIVES: To assess the effects of Cognitive Behavioural Therapy (CT, BT, CBT and third-wave CBT interventions) on severity of anxiety symptoms compared with minimal management (not providing therapy) for anxiety and related disorders in older adults, aged 55 years or over. To assess the effects of CBT and related therapies on severity of anxiety symptoms compared with other psychological therapies for anxiety and related disorders in older adults, aged 55 years or over. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled studies Register (CCMDCTR), CENTRAL, Ovid MEDLINE, Ovid Embase and Ovid PsycINFO to 21 July 2022. These searches were updated on 2 February 2024. We also searched the international studies registries, including Clinicalstudies.gov and the WHO International Clinical Trials Registry Platform (ICTRP), to identify additional ongoing and unpublished studies. These sources were manually searched for studies up to 12 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in older adults (≥ 55 years) with an anxiety disorder, or a related disorder, including obsessive compulsive disorder (OCD), acute stress disorder and post-traumatic stress disorder (PTSD), that compared CBT to either minimal management or an active (non-CBT) psychological therapy. Eligible studies had to have an anxiety-related outcome. DATA COLLECTION AND ANALYSIS: Several authors independently screened all titles identified by the searches. All full texts were screened for eligibility according to our prespecified selection criteria. Data were extracted and the risk of bias was assessed using the Cochrane tool for RCTs. The certainty of evidence was evaluated using GRADE. Meta-analyses were performed for outcomes with quantitative data from more than one study. MAIN RESULTS: We included 21 RCTs on 1234 older people allocated to either CBT or control conditions. Ten studies focused on generalised anxiety disorder; others mostly included a mix of clinical diagnoses. Nineteen studies focused on the comparison between CBT and minimal management. Key issues relating to risk of bias were lack of blinding of participants and personnel, and participants dropping out of studies, potentially due to treatment preference and allocation. CBT may result in a small-to-moderate reduction of anxiety post-treatment (SMD -0.51, 95% CI -0.66 to -0.36, low-certainty evidence). However, compared to this benefit with CBT immediately after treatment, at three to six months post-treatment, there was little to no difference between CBT and minimal management (SMD -0.29, 95% CI -0.59 to 0.01, low-certainty evidence). CBT may have little or no effect on clinical recovery/ improvement post-treatment compared to minimal management, but the evidence is very uncertain (RR 1.56, 95% CI 1.20 to 2.03, very low-certainty evidence). Results indicate that five people would need to receive treatment for one additional person to benefit (NNTB = 5). Compared to minimal management, CBT may result in a reduction of comorbid depression symptoms post-treatment (SMD -0.57, 95% CI -0.74 to -0.40, low-certainty evidence). There was no difference in dropout rates post-treatment, although the certainty of the evidence was low (RR 1.19, 95% CI 0.80 to 1.78). Two studies reported adverse events, both of which related to medication in the control groups (very low-certainty evidence, no quantitative estimate). Only two studies compared CBT to other psychological therapies, both of which only included participants with post-traumatic stress disorder. Low-certainty evidence showed no difference in anxiety severity post-treatment and at four to six months post-treatment, symptoms of depression post-treatment, and dropout rates post-treatment. Other outcomes and time points are reported in the results section of the manuscript. AUTHORS' CONCLUSIONS: CBT may be more effective than minimal management in reducing anxiety and symptoms of worry and depression post-treatment in older adults with anxiety disorders. The evidence is less certain longer-term and for other outcomes including clinical recovery/improvement. There is not enough evidence to determine whether CBT is more effective than alternative psychological therapies for anxiety in older adults.

Depressive symptomatology in older adults treated with behavioral activation: A network perspective.

BACKGROUND: Late-life depression is a serious mental health problem. Behavioral Activation (BA) is an effective, accessible psychotherapeutic treatment for older adults. However, little is known about which symptoms decrease and how associations between depressive symptoms change during BA treatment. METHODS: Using data from a cluster-randomized trial for older adults with late-life depression, we estimated a partial correlation network and a relative importance network of depressive symptoms before and after 8 weeks of BA treatment in primary care (n = 96). Networks were examined with measures of network structure, connectivity, centrality as well as stability. RESULTS: The most central symptoms at baseline and post-treatment were anhedonia, fatigue, and feeling depressed. In contrast, sleeping problems had the lowest centrality. The post-treatment network was significantly more interconnected than at baseline. Moreover, all symptoms were significantly more central at post-treatment. CONCLUSION: Our findings highlight the utility of the network approach to better understand symptom networks of depressed older adults before and after BA treatment. Results show that network connectivity and centrality of all symptoms increased after treatment. Future studies should investigate longitudinal idiographic networks to explore symptom dynamics within individuals over time.

Dynamics of miRNA accumulation during C. elegans larval development.

Temporally and spatially controlled accumulation underlies the functions of microRNAs (miRNAs) in various developmental processes. In Caenorhabditis elegans, this is exemplified by the temporal patterning miRNAs lin-4 and let-7, but for most miRNAs, developmental expression patterns remain poorly resolved. Indeed, experimentally observed long half-lives may constrain possible dynamics. Here, we profile miRNA expression throughout C. elegans postembryonic development at high temporal resolution, which identifies dynamically expressed miRNAs. We use mathematical models to explore the underlying mechanisms. For let-7, we can explain, and experimentally confirm, a striking stepwise accumulation pattern through a combination of rhythmic transcription and stage-specific regulation of precursor processing by the RNA-binding protein LIN-28. By contrast, the dynamics of several other miRNAs cannot be explained by regulation of production rates alone. Specifically, we show that a combination of oscillatory transcription and rhythmic decay drive rhythmic accumulation of miR-235, orthologous to miR-92 in other animals. We demonstrate that decay of miR-235 and additional miRNAs depends on EBAX-1, previously implicated in target-directed miRNA degradation (TDMD). Taken together, our results provide insight into dynamic miRNA decay and establish a resource to studying both the developmental functions of, and the regulatory mechanisms acting on, miRNAs.

Cost-effectiveness of behavioral activation compared to treatment as usual for depressed older adults in primary care: A cluster randomized controlled trial.

INTRODUCTION: Depression in older adults is associated with decreased quality of life and increased utilization of healthcare services. Behavioral activation (BA) is an effective treatment for late-life depression, but the cost-effectiveness compared to treatment as usual (TAU) is unknown. METHODS: An economic evaluation was performed alongside a cluster randomized controlled multicenter trial including 161 older adults (≥65 years) with moderate to severe depressive symptoms (PHQ-9 ≥ 10). Outcome measures were depression (response on the QIDS-SR), quality-adjusted life-years (QALYs) and societal costs. Missing data were imputed using multiple imputation. Cost and effect differences were estimated using bivariate linear regression models, and statistical uncertainty was estimated with bootstrapping. Cost-effectiveness acceptability curves showed the probability of cost-effectiveness at different ceiling ratios. RESULTS: Societal costs were statistically non-significantly lower in BA compared to TAU (mean difference (MD) -€485, 95 % CI -3861 to 2792). There were no significant differences in response on the QIDS-SR (MD 0.085, 95 % CI -0.015 to 0.19), and QALYs (MD 0.026, 95 % CI -0.0037 to 0.055). On average, BA was dominant over TAU (i.e., more effective and less expensive), although the probability of dominance was only 0.60 from the societal perspective and 0.85 from the health care perspective for both QIDS-SR response and QALYs. DISCUSSION: Although the results suggest that BA is dominant over TAU, there was considerable uncertainty surrounding the cost-effectiveness estimates which precludes firm conclusions.

Age related differences in symptom networks of overall psychological functioning in a sample of patients diagnosed with anxiety, obsessive compulsive disorder, or posttraumatic stress disorder.

Anxiety disorders, obsessive compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are among the most prevalent mental disorders across the lifespan. Yet, it has been suggested that there are phenomenological differences and differences in treatment outcomes between younger and older adults. There is, however, no consensus about the age that differentiates younger adults from older adults. As such, studies use different cut-off ages that are not well founded theoretically nor empirically. Network tree analysis was used to identify at what age adults differed in their symptom network of psychological functioning in a sample of Dutch patients diagnosed with anxiety disorders, OCD, or PTSD (N = 27,386). The networktree algorithm found a first optimal split at age 30 and a second split at age 50. Results suggest that differences in symptom networks emerge around 30 and 50 years of age, but that the core symptoms related to anxiety remain stable across age. If our results will be replicated in future studies, our study may suggest using the age split of 30 or 50 years in studies that aim to investigate differences across the lifespan. In addition, our study may suggest that age-related central symptoms are an important focus during treatment monitoring.

Functional improvement by behavioural activation for depressed older adults.

BACKGROUND: Recovery in mental health care comprises more than symptomatic improvement, but preliminary evidence suggests that only collaborative care may improve functioning of depressed older adults. This study therefore evaluates the effectiveness of behavioural activation (BA) on functional limitations in depressed older adults in primary care. METHODS: This study uses data from a multicentre cluster randomised controlled trial in which 59 primary care centres (PCCs) were randomised to BA and treatment as usual (TAU), and 161 consenting older (≥65 years) adults with clinically relevant symptoms of depression participated. Interventions were an eight-week individual BA programme by a mental health nurse (MHN) and unrestricted TAU. The outcome was self-reported functional limitations (WHODAS 2.0) at post-treatment (9 weeks) and at 12-month follow-up. RESULTS: At the end of treatment, the BA participants reported significantly fewer functional limitations than TAU participants (WHODAS 2.0 difference -3.62, p = 0.01, between-group effect size = 0.39; 95% CI = 0.09-0.69). This medium effect size decreases during follow-up resulting in a small and non-significant effect at the 12-month follow-up (WHODAS 2.0 difference = -2.22, p = 0.14, between-group effect size = 0.24; 95% CI = -0.08-0.56). MoCA score moderated these results, indicating that the between-group differences were merely driven by those with no cognitive impairment. CONCLUSIONS: Compared to TAU, BA leads to a faster improvement of functional limitations in depressed older adults with no signs of cognitive decline. Replication of these findings in confirmatory research is needed.

Association Between Personality Traits and Functional Limitations in Older Adults with Affective Disorders: A Cross Sectional Study.

OBJECTIVES: Personality traits and affective disorders are both related to functional limitations. It is unknown whether personality traits have an additional effect on functioning in older adults with affective disorders. We studied the association between personality traits and functioning within this group. METHODS: We performed a cross-sectional study of 180 older patients referred to outpatient specialized geriatric mental health care centers with a depressive, anxiety and/or somatic symptom disorder according to DSM-criteria. We studied the association between the Big Five personality traits and functional limitations assessed with the WHO-DAS II, adjusting for potential confounders, including the severity of various affective disorders. RESULTS: The 180 patients (57.1% female, mean age 69.2 years) had an average WHO-DAS II score of 31.3 (SD 15.1). Lower scores on Conscientiousness were associated with more overall functional limitations (p = .001), particularly limitations in self-care (p = .001) and household activities (p = .001). Lower Extraversion scores were associated with more limitations in getting along with others (p = .001). CONCLUSIONS: Personality traits are related to functional limitations independent of the severity of affective disorders in older adults. CLINICAL IMPLICATIONS: Personality traits may be used as predictive factors for functioning in older adults with affective disorders.

Behavioural Activation versus Treatment as Usual for Depressed Older Adults in Primary Care: A Pragmatic Cluster-Randomised Controlled Trial.

INTRODUCTION: Effective non-pharmacological treatment options for depression in older adults are lacking. OBJECTIVE: The effectiveness of behavioural activation (BA) by mental health nurses (MHNs) for depressed older adults in primary care compared with treatment as usual (TAU) was evaluated. METHODS: In this multicentre cluster-randomised controlled trial, 59 primary care centres (PCCs) were randomised to BA and TAU. Consenting older (≥65 years) adults (n = 161) with clinically relevant symptoms of depression (PHQ-9 ≥ 10) participated. Interventions were an 8-week individual MHN-led BA programme and unrestricted TAU in which general practitioners followed national guidelines. The primary outcome was self-reported depression (QIDS-SR16) at 9 weeks and 3, 6, 9, and 12-month follow-up. RESULTS: Data of 96 participants from 21 PCCs in BA and 65 participants from 16 PCCs in TAU, recruited between July 4, 2016, and September 21, 2020, were included in the intention-to-treat analyses. At post-treatment, BA participants reported significantly lower severity of depressive symptoms than TAU participants (QIDS-SR16 difference = -2.77, 95% CI = -4.19 to -1.35), p < 0.001; between-group effect size = 0.90; 95% CI = 0.42-1.38). This difference persisted up to the 3-month follow-up (QIDS-SR16 difference = -1.53, 95% CI = -2.81 to -0.26, p = 0.02; between-group effect size = 0.50; 95% CI = 0.07-0.92) but not up to the 12-month follow-up [QIDS-SR16 difference = -0.89 (-2.49 to 0.71)], p = 0.28; between-group effect size = 0.29 (95% CI = -0.82 to 0.24). CONCLUSIONS: BA led to a greater symptom reduction of depressive symptoms in older adults, compared to TAU in primary care, at post-treatment and 3-month follow-up, but not at 6- to 12-month follow-up.

Molecular spikes: a gold standard for single-cell RNA counting.

Single-cell sequencing methods rely on molecule-counting strategies to account for amplification biases, yet no experimental strategy to evaluate counting performance exists. Here, we introduce molecular spikes-RNA spike-ins containing built-in unique molecular identifiers (UMIs) that we use to identify critical experimental and computational conditions for accurate RNA counting in single-cell RNA-sequencing (scRNA-seq). Using molecular spikes, we uncovered impaired RNA counting in methods that were not informative for cellular RNA abundances due to inflated UMI counts. We further leverage molecular spikes to improve estimates of total endogenous RNA amounts in cells, and introduce a strategy to correct experiments with impaired RNA counting. The molecular spikes and the accompanying R package UMIcountR ( https://github.com/cziegenhain/UMIcountR ) will improve the validation of new methods, better estimate and adjust for cellular mRNA amounts and enable more indepth characterization of RNA counting in scRNA-seq.

Transcriptional kinetics and molecular functions of long noncoding RNAs.

An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene's transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.

The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial.

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus-pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.

Development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP): Facilitating the early detection of patients in need of highly specialized care.

BACKGROUND: Early identification of patients with an anxiety disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD) in need of highly specialized care could facilitate the selection of the optimal initial treatment in these patients. This paper describes the development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP), which aims to aid clinicians in the early identification of patients with an anxiety disorder, OCD, or PTSD in need of highly specialized mental healthcare. METHODS: A systematic literature review and a concept mapping procedure were carried out to inform the development of the DTAOP. To evaluate the psychometric properties of the DTAOP, a cross-sectional study in 454 patients with a DSM-IV-TR anxiety disorder was carried out. Feasibility was evaluated by the completion time and the content clarity of the DTAOP. Inter-rater reliability was assessed in a subsample of 87 patients. Spearman's rank correlation coefficients between the DTAOP and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were computed to examine the convergent validity. Criterion validity was assessed against independent clinical judgments made by clinicians. RESULTS: The average time required to complete the eight-item DTAOP was 4.6 min and the total DTAOP was evaluated as clear in the majority (93%) of the evaluations. Krippendorff's alpha estimates ranged from 0.427 to 0.839. Based on the qualitative feedback, item wording and instructions were improved. As hypothesized, the DTAOP correlated negatively with EQ-5D-5L scores. The area under the curve was 0.826 and the cut-off score of ≥4 optimized sensitivity (70%) and specificity (71%). CONCLUSIONS: The DTAOP demonstrated excellent feasibility and good validity, but weak inter-rater reliability. Based on the qualitative feedback and reliability estimates, revisions and refinements of the wording and instructions were made, resulting in the final version of the DTAOP.

Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance.

Transcriptional bursts render substantial biological noise in cellular transcriptomes. Here, we investigated the theoretical extent of allelic expression resulting from transcriptional bursting and how it compared to the amount biallelic, monoallelic and allele-biased expression observed in single-cell RNA-sequencing (scRNA-seq) data. We found that transcriptional bursting can explain the allelic expression patterns observed in single cells, including the frequent observations of autosomal monoallelic gene expression. Importantly, we identified that the burst frequency largely determined the fraction of cells with monoallelic expression, whereas the burst size had little effect on monoallelic observations. The high consistency between the bursting model predictions and scRNA-seq observations made it possible to assess the heterogeneity of a group of cells as their deviation in allelic observations from the expected. Finally, both burst frequency and size contributed to allelic imbalance observations and reinforced that studies of allelic imbalance can be confounded from the inherent noise in transcriptional bursting. Altogether, we demonstrate that allele-level transcriptional bursting renders widespread, although predictable, amounts of monoallelic and biallelic expression in single cells and cell populations.

MX2 mediates establishment of interferon response profile, regulates XAF1, and can sensitize melanoma cells to targeted therapy.

MX2 is an interferon inducible gene that is mostly known for its antiviral activity. We have previously demonstrated that MX2 is also associated with the tumorigenesis process in melanoma. However, it remains unknown which molecular mechanisms are regulated by MX2 in response to interferon signaling in this disease. Here, we report that MX2 is necessary for the establishment of an interferon-induced transcriptional profile partially through regulation of STAT1 phosphorylation and other interferon-related downstream factors, including proapoptotic tumor suppressor XAF1. MX2 and XAF1 expression tightly correlate in both cultured melanoma cell lines and in patient-derived primary and metastatic tumors, where they also are significantly related with survival. MX2 mediates IFN growth-inhibitory signals in both XAF1 dependent and independent ways and in a cell type and context-dependent manner. Higher MX2 expression renders melanoma cells more sensitive to targeted therapy drugs such as vemurafenib and trametinib; however, this effect is XAF1 independent. In summary, we uncovered a new mechanism in the complex regulation of interferon signaling in melanoma that can influence both survival and response to therapy.

How Does Behavioural Activation Work? A Systematic Review of the Evidence on Potential Mediators.

INTRODUCTION: Behavioural activation is an effective treatment for depression, but little is known about its working mechanisms. Theoretically, its effect is thought to rely on an interplay between activation and environmental reward. OBJECTIVE: The present systematic review examines the mediators of behavioural activation for depression. METHODS: A systematic literature search without time restrictions in Medline, EMBASE, PsycINFO, The Cochrane Library, and CINAHL resulted in 14 relevant controlled and uncontrolled prospective treatment studies that also performed formal mediation analyses to investigate their working mechanisms. After categorising the mediators investigated, we systematically compared the studies' methodological quality and performed a narrative synthesis of the findings. RESULTS: Most studies focused on activation or environmental reward, with 21 different mediators being investigated using questionnaires that focused on psychological processes or beliefs. The evidence for both activation and environmental reward as mediators was weak. CONCLUSIONS: Non-significant results, poor methodological quality of some of the studies, and differences in questionnaires employed precluded any firm conclusions as to the significance of any of the mediators. Future research should exploit knowledge from fundamental research, such as reward motivation from neurobiology. Furthermore, the use of experience sampling methods and idiographic analyses in bigger samples is recommended to investigate potential causal pathways in individual patients.

Stepped-care versus treatment as usual in panic disorder: A randomized controlled trial.

Stepped-care (SC) models for anxiety disorders are implemented on a large scale and are assumed to be as effective for the greater majority of patients as more intensive treatment schemes. To compare the outcomes of SC and international guideline-based treatment (Treatment as Usual: TAU) for panic disorder, a total of 128 patients were randomized to either SC or TAU (ratio 2: 1, respectively) using a computer generated algorithm. They were treated in four mental health care centres in the Netherlands after therapists had been trained in SC by a senior expert therapist. SC comprised 10-week guided self-help (pen-and-paper version) followed, if indicated, by 13-week manualized face-to-face cognitive behavioural therapy (CBT), with medication- if prescribed- kept constant. TAU consisted of 23-week regular face-to-face CBT (RCBT) with medication -when prescribed- also kept constant. The means of the attended sessions in the SC condition was 5.9 (SD = 4.8) for ITT and 9.6 (SD = 9.6) for the RCBT condition. The difference in the number of attended sessions between the conditions was significant (t(126) = -3.87, p < .001). Remission rates between treatment conditions did not differ significantly (SC: 44.5%; RCBT: 53.3%) and symptom reduction was similar. Stepping up SC treatment to face-to-face CBT showed a minimal additional effect. Importantly, drop-out rates differed significantly for the two conditions (SC: 48.2%; RCBT: 26.7%). SC was effective in the treatment of panic disorder in terms of symptom reduction and remission rate, but dropout rates were twice as high as those seen in RCBT, with the second phase of SC not substantially improving treatment response. However, SC required significantly less therapist contact time compared to RCBT, and more research is needed to explore predictors of success for guided self-help interventions to allow treatment intensity to be tailored to patients' needs and preferences.

Developmental function and state transitions of a gene expression oscillator in Caenorhabditis elegans.

Gene expression oscillators can structure biological events temporally and spatially. Different biological functions benefit from distinct oscillator properties. Thus, finite developmental processes rely on oscillators that start and stop at specific times, a poorly understood behavior. Here, we have characterized a massive gene expression oscillator comprising > 3,700 genes in Caenorhabditis elegans larvae. We report that oscillations initiate in embryos, arrest transiently after hatching and in response to perturbation, and cease in adults. Experimental observation of the transitions between oscillatory and non-oscillatory states at high temporal resolution reveals an oscillator operating near a Saddle Node on Invariant Cycle (SNIC) bifurcation. These findings constrain the architecture and mathematical models that can represent this oscillator. They also reveal that oscillator arrests occur reproducibly in a specific phase. Since we find oscillations to be coupled to developmental processes, including molting, this characteristic of SNIC bifurcations endows the oscillator with the potential to halt larval development at defined intervals, and thereby execute a developmental checkpoint function.

Single-cell RNA counting at allele and isoform resolution using Smart-seq3.

Large-scale sequencing of RNA from individual cells can reveal patterns of gene, isoform and allelic expression across cell types and states1. However, current short-read single-cell RNA-sequencing methods have limited ability to count RNAs at allele and isoform resolution, and long-read sequencing techniques lack the depth required for large-scale applications across cells2,3. Here we introduce Smart-seq3, which combines full-length transcriptome coverage with a 5' unique molecular identifier RNA counting strategy that enables in silico reconstruction of thousands of RNA molecules per cell. Of the counted and reconstructed molecules, 60% could be directly assigned to allelic origin and 30-50% to specific isoforms, and we identified substantial differences in isoform usage in different mouse strains and human cell types. Smart-seq3 greatly increased sensitivity compared to Smart-seq2, typically detecting thousands more transcripts per cell. We expect that Smart-seq3 will enable large-scale characterization of cell types and states across tissues and organisms.

The Impact of Personality Pathology on Treatment Outcome in Late-life Panic Disorder.

BACKGROUND: Comorbid personality disorders are assumed to negatively interfere with the treatment outcome of affective disorders. Data on late-life panic disorder remain unknown. We examined the association of personality pathology and treatment outcome related to age and treatment modality. METHODS: An observational study on the effectiveness of cognitive-behavioral therapy (CBT) for panic disorder with agoraphobia among patients 18 to 74 years of age and randomized controlled comparison of paroxetine and CBT in older patients (60 y of age or older) were performed. The diagnosis of panic disorder was confirmed by the Anxiety Disorder Interview Schedule-Revised (ADIS-IV) and personality features were assessed with the Personality Diagnostic Questionnaire. The impact of personality features on either agoraphobic cognitions (Agoraphobic Cognitions Questionnaire) or avoidance behavior (Mobility Inventory Avoidance Scale) was examined by multiple linear regression analyses adjusted for sex, level of education, duration of illness, comorbid psychopathology, and baseline severity. The interaction between personality and age was examined among those treated with CBT (n=90); the interaction between personality and treatment modality was examined among the older subgroup (n=34). RESULTS: Cluster B personality pathology (evaluated on the basis of either Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria depending on the date of assessment) was negatively associated with outcomes of CBT in both younger and older adults with panic disorder and agoraphobia. Older adults with a higher number of features of any personality pathology or cluster A pathology had worse treatment outcomes when treated with paroxetine compared with CBT. CONCLUSIONS: Cluster B pathology had a detrimental effect on CBT treatment outcome for panic disorder in both age groups. In late-life panic disorder with comorbid personality pathology, CBT may be preferred over treatment with paroxetine.