High Level Mobility Training in Ambulatory Patients with Acquired Non-Progressive Central Neurological Injury: a Feasibility Study.

The purpose of this study was to test the feasibility and safety of High-Level Mobility (HLM) training on adults with Acquired Brain Injury (ABI). Our hypotheses were that HLM training would be feasible and safe. This study was a pilot randomized control trial with a Simple Skill Group (SSG) and a Complex Skill Group (CSG). Both groups received 12 sessions over 8 weeks and completed 4 testing sessions over 16 weeks. The SSG focused on locomotion, while CSG focused on the acquisition of running. Feasibility was assessed in terms of process, resources, management, and scientific metrics, including safety. Among the 41 participants meeting inclusion criteria, 28 consented (CSG, n = 13, SSG, n = 15), 20 completed the assigned protocol and 8 withdrew (CSG n = 4, SSG n = 4). Adherence rate to assigned protocol was 100%. There were two Adverse Events (AEs), 1 over 142 SSG sessions and 1 over 120 CSG sessions. The AE Odd Ratio (OR) (CSG:SSG) was 1.18 (95% CI: 0.07, 19.15). The data support our hypotheses that HLM training is feasible and safe on ambulatory adults with ABI.

Intracranial infection caused by Mycobacterium rhodesiae with specific imaging findings and good response to medication: a case report and literature review.

Nontuberculous mycobacteria (NTM) are exceedingly rare etiological agents of intracranial infections. Among them, Mycobacterium rhodesiae stands out as an even less common pathogen. In this paper, we report the first documented case of a central nervous system (CNS) infection in humans caused by Mycobacterium rhodesiae, which has specific imaging findings and good response to the therapy by using Linezolid, Clarithromycin, and Minocycline. The diagnosis was facilitated by a comprehensive multimodal approach, incorporating multisite imaging, cerebrospinal fluid analysis via next-generation sequencing (NGS), and targeted genetic testing. Furthermore, this paper provides a derivation of the clinical characteristics observed in other documented instances of CNS infections attributable to NTM and based on a review of the current literature. Our experience contributes to the evidence that is needed to understand the full spectrum of NTM-related CNS pathologies and underscores the importance of a multidisciplinary diagnostic process in atypical presentations of intracranial infections.

Exercise intolerance associated with impaired oxygen extraction in patients with long COVID.

OBJECTIVE: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. RESULTS: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

A Single Index Model for Longitudinal Outcomes to Optimize Individual Treatment Decision Rules.

A pressing challenge in medical research is to identify optimal treatments for individual patients. This is particularly challenging in mental health settings where mean responses are often similar across multiple treatments. For example, the mean longitudinal trajectories for patients treated with an active drug and placebo may be very similar but different treatments may exhibit distinctly different individual trajectory shapes. Most precision medicine approaches using longitudinal data often ignore information from the longitudinal data structure. This paper investigates a powerful precision medicine approach by examining the impact of baseline covariates on longitudinal outcome trajectories to guide treatment decisions instead of traditional scalar outcome measures derived from longitudinal data, such as a change score. We introduce a method of estimating "biosignatures" defined as linear combinations of baseline characteristics (i.e., a single index) that optimally separate longitudinal trajectories among different treatment groups. The criterion used is to maximize the Kullback-Leibler Divergence between different treatment outcome distributions. The approach is illustrated via simulation studies and a depression clinical trial. The approach is also contrasted with more traditional methods and compares performance in the presence of missing data.

Assessment of the individual and compounding effects of marginalization factors on injury severity, discharge location, recovery, and employment outcomes at 1 year after traumatic brain injury.

Objective: The aim of this study is to examine the effect of eight distinct marginalized group memberships and explore their compounding effect on injury severity, recovery, discharge location, and employment outcomes 1-year after traumatic brain injury (TBI). Methods: Individuals with medically confirmed, complicated mild-severe TBI (N = 300) requiring inpatient rehabilitation care between the ages of 18 and 65 were recruited at two urban (public and private) health systems between 2013 and 2019. Data were collected from self-report and medical record abstraction. Marginalized group membership (MGM) includes racial and ethnic minority status, less than a high school diploma/GED, limited English proficiency, substance abuse, homelessness, psychiatric hospitalizations, psychiatric disorders, and incarceration history. Membership in four or more of these groups signifies high MGM. In addition, these factors were explored individually. Unadjusted and adjusted linear and logistic regressions and Kruskal-Wallis tests were used to assess the associations of interest in RStudio. Results: After adjusting for age, sex, and cause of injury, compared to TBI patients with low MGM, those with high MGM experience significantly longer post-traumatic amnesia (95% CI = 2.70, 16.50; p = 0.007) and are significantly more likely to have a severe TBI (per the Glasgow-Coma Scale) (95% CI = 1.70, 6.10; p ≤ 0.001) than a complicated mild-moderate injury. Individuals with high MGM also are significantly less likely to be engaged in competitive paid employment 1 year after injury (95% CI = 2.40, 23.40; p = 0.001). Patients with high MGM are less likely to be discharged to the community compared to patients with low MGM, but this association was not significant (95% CI = 0.36, 1.16; p = 0.141). However, when assessing MGMs in isolation, certain associations were not significant in unadjusted or adjusted models. Conclusion: This exploratory study's findings reveal that when four or more marginalization factors intersect, there is a compounding negative association with TBI severity, recovery, and employment outcomes. No significant association was found between high MGM and discharge location. When studied separately, individual MGMs had varying effects. Studying marginalization factors affecting individuals with TBI has critical clinical and social implications. These findings underline the importance of addressing multidimensional factors concurrent with TBI recovery, as the long-term effects of TBI can place additional burdens on individuals and their economic stability.

Properties and pitfalls of weighting as an alternative to multilevel multiple imputation in cluster randomized trials with missing binary outcomes under covariate-dependent missingness.

The generalized estimating equation (GEE) approach can be used to analyze cluster randomized trial data to obtain population-averaged intervention effects. However, most cluster randomized trials have some missing outcome data and a GEE analysis of available data may be biased when outcome data are not missing completely at random. Although multilevel multiple imputation for GEE (MMI-GEE) has been widely used, alternative approaches such as weighted GEE are less common in practice. Using both simulations and a real data example, we evaluate the performance of inverse probability weighted GEE vs. MMI-GEE for binary outcomes. Simulated data are generated assuming a covariate-dependent missing data pattern across a range of missingness clustering (from none to high), where all covariates are measured at baseline and are fully observed (i.e. a type of missing-at-random mechanism). Two types of weights are estimated and used in the weighted GEE: (1) assuming no clustering of missingness (W-GEE) and (2) accounting for such clustering (CW-GEE). Results show that, even in settings with high missingness clustering, CW-GEE can lead to more bias and lower coverage than W-GEE, whereas W-GEE and MMI-GEE provide comparable results. W-GEE should be considered a viable strategy to account for missing outcomes in cluster randomized trials.

Engineering Escherichia coli to bind to cyanobacteria.

We engineered Escherichia coli cells to bind to cyanobacteria by heterologously producing and displaying lectins of the target cyanobacteria on their surface. To prove the efficacy of our approach, we tested this design on Microcystis aeruginosa with microvirin (Mvn), the lectin endogenously produced by this cyanobacterium. The coding sequence of Mvn was C-terminally fused to the ice nucleation protein NC (INPNC) gene and expressed in E. coli. Results showed that E. coli cells expressing the INPNC::Mvn fusion protein were able to bind to M. aeruginosa and the average number of E. coli cells bound to each cyanobacterial cell was enhanced 8-fold. Finally, a computational model was developed to simulate the binding reaction and help reconstruct the binding parameters. To our best knowledge, this is the first report on the binding of two organisms in liquid culture mediated by the surface display of lectins and it may serve as a novel approach to mediate microbial adhesion.