Systematic review and meta-analysis: The association between child and adolescent depression and later educational attainment

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordObjective: The association between depression and educational attainment in young people is unclear. This systematic review and meta-analysis examines the longitudinal association between depression and subsequent attainment, and its potential effect modifiers and mediators. Method: We searched Embase, PsycINFO, PubMed, ERIC and British Education Index from inception to 23 October 2019, conducted citation searching, and contacted authors for articles. Eligible studies reported on the longitudinal association between depression in children and adolescents age 4-18 years and later educational attainment. Two reviewers independently conducted screening, data extraction, and risk of bias assessment. Correlation coefficients were pooled in meta-analysis, and effect modifiers were explored using metaregression and stratification. Other evidence on confounders, modifiers and mediators was narratively synthesized. PROSPERO record: CRD42019123068. Results: Thirty-one studies were included, of which 22 were pooled in meta-analysis. There was a small but statistically significant association between depression and lower subsequent attainment (pooled Fisher’s z=-0.19, 95% CI=-0.22 to -0.16, I 2=62.9%). Fifteen studies also reported an enduring effect after adjusting for various confounders. No statistically significant effect modifiers were identified. Social and school problems may mediate between depression and low attainment. Conclusion: Depression was associated with lower educational attainment, but further research is needed to establish mechanisms. Nonetheless, there is a clear need for mental health and educational support among children and adolescents with depression.NIHRMQ Data Science AwardPsychiatry Research TrustUniversity of ExeterMedical Research Council (MRC)Janssen, GSK and TakedaPsychiatry Research Trus

The association between depression and later educational attainment in children and adolescents: a systematic review protocol.

This is the final version. Available from BMJ Open via the DOI in this record. INTRODUCTION: Depression represents a major public health concern for children and adolescents, and is thought to negatively impact subsequent educational attainment. However, the extent to which depression and educational attainment are directly associated, and whether other factors play a role, is uncertain. Therefore, we aim to systematically review the literature to provide an up-to-date estimate on the strength of this association, and to summarise potential mediators and moderators on the pathway between the two. METHODS AND ANALYSIS: To identify relevant studies, we will systematically search Embase, PsycINFO, PubMed, Education Resources Information Centre and British Education Index, manually search reference lists and contact experts in the field. Studies will be included if they investigate and report on the association between major depression diagnosis or depressive symptoms in children and adolescents aged 4-18 years (exposure) and later educational attainment (outcome). Two independent reviewers will screen titles, abstracts and full texts according to eligibility criteria, perform data extraction and assess study quality according to a modified version of the Newcastle-Ottawa Scale. If sufficiently homogeneous studies are identified, summary effect estimates will be pooled in meta-analysis, with further tests for study heterogeneity, publication bias and the effects of moderators using meta-regression. ETHICS AND DISSEMINATION: Because this review will make use of already published data, ethical approval will not be sought. The review will be submitted for publication in a peer-reviewed journal, presented at practitioner-facing conferences, and a lay summary will be written for non-scientific audiences such as parents, young people and teachers. The work will inform upcoming investigations on the association between child and adolescent mental health and educational attainment.NIHRMedical Research Counci

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations

Preoperative Plasma Club (Clara) Cell Secretory Protein Levels Are Associated With Primary Graft Dysfunction After Lung Transplantation

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC‐16, sRAGE, ICAM‐1, IL‐8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC‐16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p < 0.001). CC‐16 was associated with PGD in nonidiopathic pulmonary fibrosis (non‐IPF) subjects (OR for highest quartile of CC‐16: 2.87, 95% CI: 1.37, 6.00, p = 0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p = 0.59). After adjustment, preoperative CC‐16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p = 0.013) in non‐IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients. The authors demonstrate a relationship between perioperative CC‐16 blood levels and an increased risk of primary lung allograft dysfunction, particularly in those without idiopathic pulmonary fibrosis as a pretransplant diagnosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102697/1/ajt12541.pd

Drivers of HIV self-testing among female sex workers: Findings from a multi-state study in Malaysia

BackgroundAlthough research on HIV self-testing (HIVST) has rapidly increased, few studies have explored HIVST uptake in female sex workers (FSW), and none in Malaysia. Therefore, we endeavored to assess the willingness to use HIVST in this at-risk, vulnerable population.MethodsA cross-sectional survey study was conducted among 113 HIV-negative Malaysian FSW in 2017. Participants were recruited using advertisements on social media, flyers, and direct referrals from community-based organizations. Data were collected using self-administered surveys. Multivariable logistic regression was used to identify correlates of willingness to use HIVST.ResultsNearly a third of participants (30.1%) reported they would be willing to use HIVST. Multivariable analyses adjusting for Malay ethnicity, stable housing, living in Kuala Lumpur (KL), years in sex work, age of first sex work, childhood sexual assault, history of HIV testing, and previously in prison indicated that living in KL [adjusted odds ratio (aOR) = 5.214, p = 0.0137] was associated with a greater willingness to use HIVST. In contrast, having stable housing (aOR = 0.100, p = 0.0064) was negatively associated with willingness to use HIVST.ConclusionsOur results indicate that HIVST may potentially enhance the uptake of HIV testing among FSWs living in an urban environment and experiencing unstable housing, but an overall willingness to use HIVST is low. These findings highlight the need for efforts to increase awareness of HIVST among FSWs and additional research on the effective implementation of HIVST for FSW

Input-specific control of reward and aversion in the ventral tegmental area

Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.National Institutes of Health (U.S.) (Grant NIH NS069375)JPB FoundationNational Institute of Mental Health (U.S.

Genetic dissection of an amygdala microcircuit that gates conditioned fear

The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ^+ neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ^− neurons in CEl. Electrical silencing of PKC-δ^+ neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called Cel_(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing

Efficient preparation of internally modified single-molecule constructs using nicking enzymes

Investigations of enzymes involved in DNA metabolism have strongly benefited from the establishment of single molecule techniques. These experiments frequently require elaborate DNA substrates, which carry chemical labels or nucleic acid tertiary structures. Preparing such constructs often represents a technical challenge: long modified DNA molecules are usually produced via multi-step processes, involving low efficiency intermolecular ligations of several fragments. Here, we show how long stretches of DNA (>50 bp) can be modified using nicking enzymes to produce complex DNA constructs. Multiple different chemical and structural modifications can be placed internally along DNA, in a specific and precise manner. Furthermore, the nicks created can be resealed efficiently yielding intact molecules, whose mechanical properties are preserved. Additionally, the same strategy is applied to obtain long single-strand overhangs subsequently used for efficient ligation of ss- to dsDNA molecules. This technique offers promise for a wide range of applications, in particular single-molecule experiments, where frequently multiple internal DNA modifications are required

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies