Self-harm and suicide in adolescents Hawton, Keith, Prof; Saunders, Kate EA, MRCPsych; O'Connor, Rory C, Prof
The Lancet (British edition),
06/2012, Letnik:
379, Številka:
9834
Journal Article
Recenzirano
Self-harm and suicide are major public health problems in adolescents, with rates of self-harm being high in the teenage years and suicide being the second most common cause of death in young people ...worldwide. Important contributors to self-harm and suicide include genetic vulnerability and psychiatric, psychological, familial, social, and cultural factors. The effects of media and contagion are also important, with the internet having an important contemporary role. Prevention of self-harm and suicide needs both universal measures aimed at young people in general and targeted initiatives focused on high-risk groups. There is little evidence of effectiveness of either psychosocial or pharmacological treatment, with particular controversy surrounding the usefulness of antidepressants. Restriction of access to means for suicide is important. Major challenges include the development of greater understanding of the factors that contribute to self-harm and suicide in young people, especially mechanisms underlying contagion and the effect of new media. The identification of successful prevention initiatives aimed at young people and those at especially high risk, and the establishment of effective treatments for those who self-harm, are paramount needs.
The availability of mobile technologies has enabled the efficient collection of prospective longitudinal, ecologically valid self-reported clinical questionnaires from people with psychiatric ...diagnoses. These data streams have potential for improving the efficiency and accuracy of psychiatric diagnosis as well predicting future mood states enabling earlier intervention. However, missing responses are common in such datasets and there is little consensus as to how these should be dealt with in practice. In this study, the missing-response-incorporated log-signature method achieves roughly 74.8% correct diagnosis, with f1 scores for three diagnostic groups 66% (bipolar disorder), 83% (healthy control) and 75% (borderline personality disorder) respectively. This was superior to the naive model which excluded missing data and advanced models which implemented different imputation approaches, namely, k-nearest neighbours (KNN), probabilistic principal components analysis (PPCA) and random forest-based multiple imputation by chained equations (rfMICE). The log-signature method provided an effective approach to the analysis of prospectively collected mood data where missing data was common and should be considered as an approach in other similar datasets. Because of treating missing responses as a signal, its superiority also highlights that missing data conveys valuable clinical information.
We generalize Newton-type methods for minimizing smooth functions to handle a sum of two convex functions: a smooth function and a nonsmooth function with a simple proximal mapping. We show that the ...resulting proximal Newton-type methods inherit the desirable convergence behavior of Newton-type methods for minimizing smooth functions, even when search directions are computed inexactly. Many popular methods tailored to problems arising in bioinformatics, signal processing, and statistical learning are special cases of proximal Newton-type methods, and our analysis yields new convergence results for some of these methods. PUBLICATION ABSTRACT
Existing therapeutic options are insufficient to tackle the disease burden of depression, and new treatments are sorely needed. Defining new psychotherapeutic targets is challenging given the paucity ...of coherent mechanistic explanations for depression.
To assess whether mood homeostasis (ie, the stabilization of one's mood by engaging in mood-modifying activities) is a possible new therapeutic target by testing the hypothesis that people with low (vs high) mean mood and people with (vs without) a history of depression have impaired mood homeostasis.
The quantitative association between mood and daily activities was computed in 2 large case-control studies based on the 58sec data set (collected from December 1, 2012, to May 31, 2014, and analyzed from April 1 to 30, 2019), and the World Health Organization Study on Global Aging and Adult Health (WHO SAGE) data set (collected from January 1, 2007, to December 31, 2010, and analyzed from June 1 to 30, 2019). The 58sec data set consists of self-enrolled participants from high-income countries. The WHO SAGE data set consists of nationally representative participants in low- and middle-income countries recruited via cluster sampling.
The main outcome (defined before data analysis) was the difference in mood homeostasis between people with high vs low mean mood (58sec data) and between people with vs without a history of depression (WHO SAGE data).
A total of 28 212 participants from the 58sec data set (65.8% female; mean SD age, 28.1 9.0 years) and 30 116 from the WHO SAGE data set (57.0% female; mean SD age, 57.8 14.7 years) were included, for an overall study population of 58 328 participants. Mood homeostasis was significantly lower in people with low (vs high) mean mood (0.63 95% CI, 0.45 to 0.79 vs 0.96 95% CI, 0.96 to 0.98; P < .001) and in people with (vs without) a history of depression (0.03 95% CI, -0.26 to 0.24 vs 0.68 95% CI, 0.55 to 0.75; P < .001). In dynamic simulations, lower mood homeostasis led to more depressive episodes (11.8% vs 3.8% yearly risk; P < .001) that lasted longer (4.19 vs 2.90 weeks; P = .006).
In this study, mood homeostasis appeared to have been impaired in people with low mood and in those with a history of depression. Mood homeostasis may therefore provide new insights to guide the development of treatments for depression.
Structural variation of the genome involves kilobase- to megabase-sized deletions, duplications, insertions, inversions, and complex combinations of rearrangements. We introduce high-throughput and ...massive paired-end mapping (PEM), a large-scale genome-sequencing method to identify structural variants (SVs) ~3 kilobases (kb) or larger that combines the rescue and capture of paired ends of 3-kb fragments, massive 454 sequencing, and a computational approach to map DNA reads onto a reference genome. PEM was used to map SVs in an African and in a putatively European individual and identified shared and divergent SVs relative to the reference genome. Overall, we fine-mapped more than 1000 SVs and documented that the number of SVs among humans is much larger than initially hypothesized; many of the SVs potentially affect gene function. The breakpoint junction sequences of more than 200 SVs were determined with a novel pooling strategy and computational analysis. Our analysis provided insights into the mechanisms of SV formation in humans.
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded ...proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.
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•The endoplasmic reticulum co-chaperone ERdj4 selectively represses IRE1 signaling•ERdj4 associates with the IRE1 luminal domain and recruits the Hsp70 BiP•Recruited BiP hydrolyzes ATP to disrupt the active IRE1 luminal domain dimer•Unfolded proteins compete for the repressive machinery to restore IRE1 dimers
Molecular basis for the regulation of the unfolded protein response by chaperones and misfolded proteins.
Congenital heart disease is an important subset of all cardiovascular disease in dogs and cats that is present at birth and most often detected in young animals but can be diagnosed in adulthood. The ...range of abnormalities that can occur during development of the heart is vast incorporating simple and complex defects, varying degrees of severity and clinical presentations that include heart failure and cyanosis. While some defects do not result in morbidity in an individual animal, others cause severe clinical signs and death at a young age. Advances in imaging and expanding treatment options offer increasingly more possibilities in the diagnosis and management of congenital heart disease which is the focus of this review. The objective is to provide a broad overview of current practice and highlight key aspects to guide practitioners in their approach to congenital heart disease diagnosis and knowledge of available treatment options.
MicroRNAs (miRNAs) function as endogenous translational repressors of protein-coding genes in animals by binding to target sites in the 3' UTRs of mRNAs. Because a single nucleotide change in the ...sequence of a target site can affect miRNA regulation, naturally occurring SNPs in target sites are candidates for functional variation that may be of interest for biomedical applications and evolutionary studies. However, little is known to date about variation among humans at miRNAs and their target sites. In this study, we analyzed publicly available SNP data in context with miRNAs and their target sites throughout the human genome, and we found a relatively low level of variation in functional regions of miRNAs, but an appreciable level of variation at target sites. Approximately 400 SNPs were found at experimentally verified target sites or predicted target sites that are otherwise evolutionarily conserved across mammals. Moreover, almost equal to250 SNPs potentially create novel target sites for miRNAs in humans. If some variants have functional effects, they might confer phenotypic differences among humans. Although the majority of these SNPs appear to be evolving under neutrality, interestingly, some of these SNPs are found at relatively high population frequencies even in experimentally verified targets, and a few variants are associated with atypically long-range haplotypes that may have been subject to recent positive selection.
Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase ...inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety.
In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-positive, APOE ε4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE ε4 homozygotes, and the full intent-to-treat population.
No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR).
No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
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