Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia-Schizophrenia Increases Developmental Vulnerability to TNFα.

Schizophrenia (SZ) is a neurodevelopmental genetic disorder in which maternal immune activation (MIA) and increased tumor necrosis factor-α (TNF-α) may contribute. Previous studies using iPSC-derived cerebral organoids and neuronal cells demonstrated developmental malformation and transcriptional dysregulations, including TNF receptors and their signaling genes, common to SZ patients with diverse genetic backgrounds. In the present study, we examined the significance of the common TNF receptor dysregulations by transiently exposing cerebral organoids from embryonic stem cells (ESC) and from representative control and SZ patient iPSCs to TNF. In control iPSC organoids, TNF produced malformations qualitatively similar in, but generally less pronounced than, the malformations of the SZ iPSC-derived organoids. TNF and SZ alone disrupted subcortical rosettes and dispersed proliferating Ki67+ neural progenitor cells (NPC) from the organoid ventricular zone (VZ) into the cortical zone (CZ). In the CZ, the absence of large ramified pan-Neu+ neurons coincided with loss of myelinated neurites despite increased cortical accumulation of O4+ oligodendrocytes. The number of calretinin+ interneurons increased; however, they lacked the preferential parallel orientation to the organoid surface. SZ and SZ+TNF affected fine cortical and subcortical organoid structure by replacing cells with extracellular matrix (ECM)-like fibers The SZ condition increased developmental vulnerability to TNF, leading to more pronounced changes in NPC, pan-Neu+ neurons, and interneurons. Both SZ- and TNF-induced malformations were associated with the loss of nuclear (n)FGFR1 form in the CZ and its upregulation in deep IZ regions, while in earlier studies blocking nFGFR1 reproduced cortical malformations observed in SZ. Computational analysis of ChiPseq and RNAseq datasets shows that nFGFR1 directly targets neurogenic, oligodendrogenic, cell migration, and ECM genes, and that the FGFR1-targeted TNF receptor and signaling genes are overexpressed in SZ NPC. Through these changes, the developing brain with the inherited SZ genome dysregulation may suffer increased vulnerability to TNF and thus, MIA.

Weighting regressions by propensity scores.

Regressions can be weighted by propensity scores in order to reduce bias. However, weighting is likely to increase random error in the estimates, and to bias the estimated standard errors downward, even when selection mechanisms are well understood. Moreover, in some cases, weighting will increase the bias in estimated causal parameters. If investigators have a good causal model, it seems better just to fit the model without weights. If the causal model is improperly specified, there can be significant problems in retrieving the situation by weighting, although weighting may help under some circumstances.

Statistical models for causation: what inferential leverage do they provide?

Experiments offer more reliable evidence on causation than observational studies, which is not to gainsay the contribution to knowledge from observation. Experiments should be analyzed as experiments, not as observational studies. A simple comparison of rates might be just the right tool, with little value added by "sophisticated" models. This article discusses current models for causation, as applied to experimental and observational data. The intention-to-treat principle and the effect of treatment on the treated will also be discussed. Flaws in per-protocol and treatment-received estimates will be demonstrated.

Graphical models for causation, and the identification problem.

This article (which is mainly expository) sets up graphical models for causation, having a bit less than the usual complement of hypothetical counterfactuals. Assuming the invariance of error distributions may be essential for causal inference, but the errors themselves need not be invariant. Graphs can be interpreted using conditional distributions, so that we can better address connections between the mathematical framework and causality in the world. The identification problem is posed in terms of conditionals. As will be seen, causal relationships cannot be inferred from a data set by running regressions unless there is substantial prior knowledge about the mechanisms that generated the data. There are few successful applications of graphical models, mainly because few causal pathways can be excluded on a priori grounds. The invariance conditions themselves remain to be assessed.

On the efficacy of screening for breast cancer.

BACKGROUND: 'Mammography' (screening for breast cancer by X-ray examination) came to be widely-although not universally-accepted in the 1980s when a number of clinical trials demonstrated a substantial reduction in risk. Early detection, before the disease spread, permitted therapy that was simultaneously less invasive and more effective. Questions that remained were largely about efficacy for younger women and optimal frequency for older women. The consensus was challenged in a series of papers by two researchers at the Nordic branch of the Cochrane collaboration, Gøtzsche and Olsen, who concluded that mammography does not save lives: instead, it exposes women to unnecessary surgical procedures. METHODS: Qualitative review. RESULTS: The basis for the Gøtzsche-Olsen critique turns out to be simple. Studies that found a benefit from mammography were discounted as being of poor quality; remaining negative studies were combined by meta-analysis. The critique therefore rests on judgements of study quality, but these judgements are based on misreadings of the data and the literature. CONCLUSION: The prior consensus on mammography was correct.

Psicoanálisis y desviaciones sexuales

Se ha realizado para este libro una cuidadosa selección de importantes estudios de psicoanalisatas y psicólogos sobre la homosexualidad en el hombre y en la mujer, la impotencia, la frigidez, el exhibicionismo, el fetichismo y el transvestismo