The Depression Conundrum and the advantages of uncertainty

According to the WHO (2012), the prevalence of unipolar depressive disorders is rising, even in those places where mental health treatments are widely available. The WHO predicts that these disorders will be the leading contributor to the global burden of disease by 2030. This sobering projection fits poorly with how psychological treatments for depression are presented in the mainstream scientific literature: as highly effective therapies, based upon a sound understanding of the causes of distress. There is a clear discrepancy between the rising prevalence figures on the one hand, and the confident claims of this effectiveness research on the other. This discrepancy prompts a set of complex interlinked questions, which we have called 'The Depression Conundrum.' In search of a partial answer, the aim of our study was to critically analyze five meta-analytic studies investigating the effectiveness of psychological EBTs for depression, all of which had been published in high impact factor journals. Our examination established a number of methodological and statistical shortcomings in every study. Furthermore, we argue that the meta-analytic technique is founded upon problematic assumptions. The implications of our analysis are clear: decades of quantitative research might not allow us to conclude that psychological EBTs for depression are effective. The uncertainty and questions raised by our findings might act as a catalyst to broaden the way in which depression and associated therapies are researched. In addition, it might contribute toward a more vigorous and interdisciplinary debate about how to tackle this soon-to-be global public health priority number one

Market views of monetary policy and reactions to M1 announcements

Monetary policy

Compound heterozygous SCN5A mutations in severe sodium channelopathy with Brugada syndrome : a case report

Aims:Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in theSCN5Agene, encoding the main cardiac sodium Na(v)1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused bySCN5Acompound heterozygous mutations. We performed a genetic analysis ofSCN5Ain a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Methods and Results:Next-generation sequencing allowed the detection of twoSCN5Avariants intrans: c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and thede novooccurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the beta(1)-subunit. Compared to theSCN5Awild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide alpha-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. Conclusion:This is the first report providing support for the pathogenicity of the p.Phe1571LeuSCN5Avariant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2

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Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome

\ua9 The Author(s) 2024.Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Bond Covenants and Delegated Monitoring.

This paper examines alternative contracting arrangements available to a firm seeking to finance an investment project. The authors consider the choice between loan contracts with covenants bas ed on noisy indicators of the firm's financial health and loan contra cts enforced by a monitoring specialist. In one interpretation, the s pecialist is a financial intermediary. The firm's choice is shown to depend upon the firm's credit rating, the accuracy of financial indic ators of the firm's condition, the loss from premature liquidation of the firm's project, and the cost of monitoring. Copyright 1988 by American Finance Association.

Perceived mattering in stepfamilies: A social relations model analysis

The current study examined the respective role of step- family members' individual characteristics and their dyadic relationships in stepfamily members' percep- tions of mattering to one another. Parents, stepparents, and adolescents from 86 stepfamilies participated. Applying social relations model analyses, several trends emerged regarding the relative importance of individ- ual and dyadic factors. Parents' and adolescents' reports of mattering to one another were mainly driven by individual factors, whereas relational factors were important to understand the reports of mattering in which the stepparent was one of the dyad members. These findings contribute to stepfamily research by highlighting that stepfamily members' sense of belong- ing is at least partly a function of the interpersonal adaptation between the stepparent and other family members