Proof-of-concept of a data-driven approach to estimate the associations of comorbid mental and physical disorders with global health-related disability

Objective: The standard method of generating disorder-specific disability scores has lay raters make rankings between pairs of disorders based on brief disorder vignettes. This method introduces bias due to differential rater knowledge of disorders and inability to disentangle the disability due to disorders from the disability due to comorbidities. Methods: We propose an alternative, data-driven, method of generating disorder-specific disability scores that assesses disorders in a sample of individuals either from population medical registry data or population survey self-reports and uses Generalized Random Forests(GRF) to predict global (rather than disorder-specific) disability assessed by clinician ratings or by survey respondent self-reports. This method also provides a principled basis for studying patterns and predictors of heterogeneity in disorder-specific disability. We illustrate this method by analyzing data for 16 disorders assessed in the World Mental Health Surveys(n=53,645).Results: Adjustments for comorbidity decreased estimates of disorder-specific disability substantially. Estimates were generally somewhat higher with GRF than conventional multivariable regression models. Heterogeneity was nonsignificant. Conclusions: The results show clearly that the proposed approach is practical, and that adjustment is needed for comorbidities to obtain accurate estimates of disorder-specific disability. Expansion to a wider range of disorders would likely find more evidence for heterogeneity

Progression of vertebral fractures in patients with adrenocortical carcinoma undergoing mitotane therapy

Context: patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long-time period. The drug exerts an adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone. Objectives: to explore whether mitotane plus/minus chemotherapy is associated with an increased proportion of morphometric vertebral fractures (VFs) in ACC patients. Secondary objectives were: proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; predictive factors of VF progression and prognostic role of VF progression. Design and setting: multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, recruited from January 2010 to January 2020 in two reference centers in Italy and France. Results: a significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, p: 0.04) and French (17.8% vs 35.6%, p 0.04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival. Conclusions: the administration of mitotane plus/minus chemotherapy in ACC patients impairs bone health independently from cortisol supplementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients

Proof-of-concept of a data-driven approach to estimate the associations of comorbid mental and physical disorders with global health-related disability

Objective: The standard method of generating disorder-specific disability scores has lay raters make rankings between pairs of disorders based on brief disorder vignettes. This method introduces bias due to differential rater knowledge of disorders and inability to disentangle the disability due to disorders from the disability due to comorbidities. Methods: We propose an alternative, data-driven, method of generating disorder-specific disability scores that assesses disorders in a sample of individuals either from population medical registry data or population survey self-reports and uses Generalized Random Forests (GRF) to predict global (rather than disorder-specific) disability assessed by clinician ratings or by survey respondent self-reports. This method also provides a principled basis for studying patterns and predictors of heterogeneity in disorder-specific disability. We illustrate this method by analyzing data for 16 disorders assessed in the World Mental Health Surveys (n = 53,645). Results: Adjustments for comorbidity decreased estimates of disorder-specific disability substantially. Estimates were generally somewhat higher with GRF than conventional multivariable regression models. Heterogeneity was nonsignificant. Conclusions: The results show clearly that the proposed approach is practical, and that adjustment is needed for comorbidities to obtain accurate estimates of disorder-specific disability. Expansion to a wider range of disorders would likely find more evidence for heterogeneity.</p

The piRNA Pathway Guards the Germline Genome Against Transposable Elements

Transposable elements (TEs) have the capacity to replicate and insert into new genomic locations. This contributs significantly to evolution of genomes, but can also result in DNA breaks and illegitimate recombination, and therefore poses a significant threat to genomic integrity. Excess damage to the germ cell genome results in sterility. A specific RNA silencing pathway, termed the piRNA pathway operates in germ cells of animals to control TE activity. At the core of the piRNA pathway is a ribonucleoprotein complex consisting of a small RNA, called piRNA, and a protein from the PIWI subfamily of Argonaute nucleases. The piRNA pathway relies on the specificity provided by the piRNA sequence to recognize complementary TE targets, while effector functions are provided by the PIWI protein. PIWI-piRNA complexes silence TEs both at the transcriptional level – by attracting repressive chromatin modifications to genomic targets – and at the posttranscriptional level – by cleaving TE transcripts in the cytoplasm. Impairment of the piRNA pathway leads to overexpression of TEs, significantly compromised genome structure and, invariably, germ cell death and sterility. The piRNA pathway is best understood in the fruit fly, Drosophila melanogaster, and in mouse. This Chapter gives an overview of current knowledge on piRNA biogenesis, and mechanistic details of both transcriptional and posttranscriptional TE silencing by the piRNA pathway. It further focuses on the importance of post-translational modifications and subcellular localization of the piRNA machinery. Finally, it provides a brief description of analogous pathways in other systems