Introducing longitudinal modified treatment policies: a unified framework for studying complex exposures

This tutorial discusses a recently developed methodology for causal inference based on longitudinal modified treatment policies (LMTPs). LMTPs generalize many commonly used parameters for causal inference including average treatment effects, and facilitate the mathematical formalization, identification, and estimation of many novel parameters. LMTPs apply to a wide variety of exposures, including binary, multivariate, and continuous, as well as interventions that result in violations of the positivity assumption. LMTPs can accommodate time-varying treatments and confounders, competing risks, loss-to-follow-up, as well as survival, binary, or continuous outcomes. This tutorial aims to illustrate several practical uses of the LMTP framework, including describing different estimation strategies and their corresponding advantages and disadvantages. We provide numerous examples of types of research questions which can be answered within the proposed framework. We go into more depth with one of these examples -- specifically, estimating the effect of delaying intubation on critically ill COVID-19 patients' mortality. We demonstrate the use of the open source R package lmtp to estimate the effects, and we provide code on https://github.com/kathoffman/lmtp-tutorial

Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures

Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development

Regulatory T Cells and the Risk of CMV End-Organ Disease in Patients With AIDS

Cytomegalovirus (CMV)-specific T-cell effectors (CMV-Teff) protect against CMV end-organ disease (EOD). In HIV-infected individuals, their numbers and function vary with CD4+ cell numbers and HIV load. The role of regulatory T cells (Treg) in CMV-EOD has not been extensively studied. We investigated the contribution of Treg and Teff towards CMV-EOD in HIV-infected individuals independently of CD4+ cell numbers and HIV load and controlling for CMV reactivations

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum