A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype

<p>Abstract</p> <p>Background</p> <p>The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood.</p> <p>Results</p> <p>To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-<it>tau-lacZ </it>reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs), but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as <it>reeler</it>. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the <it>Emx2 </it>gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development.</p> <p>Conclusions</p> <p>These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the mouse brain, identifying mutant phenotypes at multiple steps of the pathway, and revealing a new aspect of the <it>Emx2 </it>mutant. The phenotypes highlight vulnerable choice points and latent tendencies of TCAs, and will lead to a refined understanding of the elements and interactions required to form the thalamocortical system.</p> <p>See Commentary: <url>http://www.biomedcentral.com/1741-7007/9/1</url></p

Feature Selection for Support Vector Regression Using a Genetic Algorithm

Support vector regression (SVR) is particularly beneficial when the outcome and predictors are nonlinearly related. However, when many covariates are available, the method\u27s flexibility can lead to overfitting and an overall loss in predictive accuracy. To overcome this drawback, we develop a feature selection method for SVR based on a genetic algorithm that iteratively searches across potential subsets of covariates to find those that yield the best performance according to a user-defined fitness function. We evaluate the performance of our feature selection method for SVR, comparing it to alternate methods including LASSO and random forest, in a simulation study. We find that our method yields higher predictive accuracy than SVR without feature selection. Our method outperforms LASSO when the relationship between covariates and outcome is nonlinear. Random forest performs equivalently to our method in some scenarios, but more poorly when covariates are correlated. We apply our method to predict donor kidney function 1 year after transplant using data from the United Network for Organ Sharing national registry

A pragmatic, stepped-wedge, hybrid type II trial of interoperable clinical decision support to improve venous thromboembolism prophylaxis for patients with traumatic brain injury.

BACKGROUND: Venous thromboembolism (VTE) is a preventable medical condition which has substantial impact on patient morbidity, mortality, and disability. Unfortunately, adherence to the published best practices for VTE prevention, based on patient centered outcomes research (PCOR), is highly variable across U.S. hospitals, which represents a gap between current evidence and clinical practice leading to adverse patient outcomes. This gap is especially large in the case of traumatic brain injury (TBI), where reluctance to initiate VTE prevention due to concerns for potentially increasing the rates of intracranial bleeding drives poor rates of VTE prophylaxis. This is despite research which has shown early initiation of VTE prophylaxis to be safe in TBI without increased risk of delayed neurosurgical intervention or death. Clinical decision support (CDS) is an indispensable solution to close this practice gap; however, design and implementation barriers hinder CDS adoption and successful scaling across health systems. Clinical practice guidelines (CPGs) informed by PCOR evidence can be deployed using CDS systems to improve the evidence to practice gap. In the Scaling AcceptabLE cDs (SCALED) study, we will implement a VTE prevention CPG within an interoperable CDS system and evaluate both CPG effectiveness (improved clinical outcomes) and CDS implementation. METHODS: The SCALED trial is a hybrid type 2 randomized stepped wedge effectiveness-implementation trial to scale the CDS across 4 heterogeneous healthcare systems. Trial outcomes will be assessed using the RE2-AIM planning and evaluation framework. Efforts will be made to ensure implementation consistency. Nonetheless, it is expected that CDS adoption will vary across each site. To assess these differences, we will evaluate implementation processes across trial sites using the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework (a determinant framework) using mixed-methods. Finally, it is critical that PCOR CPGs are maintained as evidence evolves. To date, an accepted process for evidence maintenance does not exist. We will pilot a Living Guideline process model for the VTE prevention CDS system. DISCUSSION: The stepped wedge hybrid type 2 trial will provide evidence regarding the effectiveness of CDS based on the Berne-Norwood criteria for VTE prevention in patients with TBI. Additionally, it will provide evidence regarding a successful strategy to scale interoperable CDS systems across U.S. healthcare systems, advancing both the fields of implementation science and health informatics. TRIAL REGISTRATION: Clinicaltrials.gov - NCT05628207. Prospectively registered 11/28/2022, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05628207

Blood absolute lymphocyte count and trajectory are important in understanding severe COVID-19

BACKGROUND: Low blood absolute lymphocyte count (ALC) may predict severe COVID-19 outcomes. Knowledge gaps remain regarding the relationship of ALC trajectory with clinical outcomes and factors associated with lymphopenia.METHODS: Our post hoc analysis of the Therapeutics for Inpatients with COVID-19 platform trial utilized proportional hazards models to assess relationships between Day (D) 0 lymphopenia (ALC &lt; 0.9 cells/uL), D0 severe lymphopenia (ALC &lt; 0.5 cells/uL) or lymphopenia trajectory between D0 and D5 with mortality and secondary infections, and with sustained recovery using Fine-Gray models. Logistic regression was used to assess relationships between clinical variables and D0 lymphopenia or lymphopenia trajectory.RESULTS: D0 lymphopenia (1426/2579) and severe lymphopenia (636/2579) were associated with increased mortality (aHR 1.48; 1.08, 2.05, p = 0.016 and aHR 1.60; 1.20, 2.14, p = 0.001) and decreased recovery (aRRR 0.90; 0.82, 0.99, p = 0.033 and aRRR 0.78; 0.70, 0.87, p &lt; 0.001 respectively). Trial participants with persistent D5 lymphopenia had increased mortality, and increased secondary infections, and participants with persistent or new lymphopenia had impaired recovery, as compared to participants with no lymphopenia. Persistent and new lymphopenia were associated with older age, male sex; prior immunosuppression, heart failure, aspirin use, and normal body mass index; biomarkers of organ damage (renal and lung), and ineffective immune response (elevated IL-6 and viral nucleocapsid antigen levels). Similar results were observed with severe lymphopenia.CONCLUSIONS: Lymphopenia was predictive of severe COVID-19 outcomes, particularly when persistent or new during hospitalization. A better understanding of the underlying risk factors for lymphopenia will help illuminate disease pathogenesis and guide management strategies.</p

ACTIV trials: Lessons learned in trial design in the setting of an emergent pandemic

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies

Machine Learning Identifies Sexual Behavior Subgroups Among Men Who Have Sex with Men in Switzerland

Sexual behavior is heterogeneous and dynamic. Characterization of such complexity constitutes evidence for public health authorities and caregivers concerned with the framing of sexual health messages aimed at specific subgroups. We developed a machine-learning-based methodology for inference and characterization of such subgroups from longitudinal data on men who have sex with men (MSM) attending individual sexual health counseling sessions. Because longitudinal data take time to record, we assessed the ability of first visit data to predict subgroups’ membership. Our methodology comprised two main steps: (1) Hierarchical clustering to group 2349 HIV-negative MSM based on their self-reported longitudinal sexual behavior during visits to Swiss sexual health counseling centers between November 2016 and April 2019; and (2) Random forest-based classification to predict subgroup membership from first visit data. We found six subgroups with significant differences in behavioral trends, most of which sharply deviated from the overall trends. Two subgroups, which contained 37% of the study population, accounted for over 70% of the overall increases in condomless anal intercourse with non-steady partners, group sex, and having more than five anal intercourse partners. Subgroup-specific trends in online-dating and group sex were heterogeneous with opposing trends across subgroups. Data from first visits predicted trends of sexual behavior with accuracy ranging from 64 to 86%. This study evidenced specific sexual behavioral subgroups that might benefit from customized sexual health messages, demonstrated that first visit registries could predict subgroups, and contributes an algorithmic alternative for establishing subgroups relevant to inform customized sexual health messages that capture sexual behavioral diversity