Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit?

BACKGROUND: Many young people with major depression fail first-line treatments. Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication. In young people, cognitive behavioral therapy (CBT) is the recommended first-line intervention, thus the definition of treatment resistance should be expanded. Therefore, our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression, broadly defined, in children and adolescents and to investigate the effectiveness of CBT in this context. METHODS: We used Cochrane Collaboration methodology, with electronic searches of Medline, PsycINFO, Embase, and the Cochrane Depression Anxiety and Neurosis Group trials registers. Only randomized controlled trials were included, and were assessed for risk of bias. Meta- analysis was undertaken where possible and appropriate. RESULTS: Of 953 articles retrieved, four trials were eligible for inclusion. For one study, only the trial registration document was available, because the study was never completed. All other studies were well conducted with a low risk of bias, although one study had a high dropout rate. Two studies assessed the effect of adding CBT to medication. While an assertive trial of antidepressants does appear to lead to benefit, when compared with placebo, there was no significant advantage, in either study, or in a meta-analysis of data from these trials, that clearly demonstrated an additional benefit of CBT. The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission. CONCLUSION: Few randomized controlled trials have investigated interventions for treatment-resistant depression in young people, and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT. Overall, there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence-based interventions for depression. Research in this area is urgently required

Interventions to reduce suicides at suicide hotspots: a systematic review

BACKGROUND: 'Suicide hotspots' include tall structures (for example, bridges and cliffs), railway tracks, and isolated locations (for example, rural car parks) which offer direct means for suicide or seclusion that prevents intervention. METHODS: We searched Medline for studies that could inform the following question: 'What interventions are available to reduce suicides at hotspots, and are they effective?' RESULTS: There are four main approaches: (a) restricting access to means (through installation of physical barriers); (b) encouraging help-seeking (by placement of signs and telephones); (c) increasing the likelihood of intervention by a third party (through surveillance and staff training); and (d) encouraging responsible media reporting of suicide (through guidelines for journalists). There is relatively strong evidence that reducing access to means can avert suicides at hotspots without substitution effects. The evidence is weaker for the other approaches, although they show promise. CONCLUSIONS: More well-designed intervention studies are needed to strengthen this evidence base.Australian Government Department of Health and AgeingUK National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for the Southwest Peninsul

Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche

SummaryTumor cell metastasis is facilitated by “premetastatic niches” formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease

Characterisation of the effect of day length, and associated differences in dietary intake, on the gut microbiota of Soay sheep.

Differences in the rumen bacterial community have been previously reported for Soay sheep housed under different day length conditions. This study extends this previous investigation to other organs of the digestive tract, as well as the analysis of ciliated protozoa and anaerobic fungi. The detectable concentrations of ciliated protozoa and anaerobic fungi decreased with increased day length in both the rumen and large colon, unlike those of bacteria where no effect was observed. Conversely, bacterial community composition was affected by day length in both the rumen and large colon, but the community composition of the detectable ciliated protozoa and anaerobic fungi was not affected. Day length associated differences in the bacterial community composition extended to all of the organs examined, with the exception of the duodenum and the jejunum. It is proposed that differences in rumen fill and ruminal ‘by-pass’ nutrients together with endocrinological changes cause the observed effects of day length on the different gut microbial communities

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis,independent of RANK ligand, which disrupts normal bone homeostasisleading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications

Women’s experiences of medical treatment for endometriosis and its impact on PRE-EMPT trial participation: a qualitative study

Due to the sensitive nature of the data generated and the possibility of identification of individuals, datasets are not generally available. The anonymised datasets used and/or analysed during the current qualitative study are available from the corresponding author on reasonable request. This study formed part of the HTA Project: 11/114/01 - PRE-EMPT: Preventing Recurrence of Endometriosis by Means of long acting Progestogen Therapy.Peer reviewedPublisher PD

The status of the world's land and marine mammals: diversity, threat, and knowledge

Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year