Advancing the scale of synthetic biology via cross-species transfer of cellular functions enabled by iModulon engraftment.

Machine learning applied to large compendia of transcriptomic data has enabled the decomposition of bacterial transcriptomes to identify independently modulated sets of genes, such iModulons represent specific cellular functions. The identification of iModulons enables accurate identification of genes necessary and sufficient for cross-species transfer of cellular functions. We demonstrate cross-species transfer of: 1) the biotransformation of vanillate to protocatechuate, 2) a malonate catabolic pathway, 3) a catabolic pathway for 2,3-butanediol, and 4) an antimicrobial resistance to ampicillin found in multiple Pseudomonas species to Escherichia coli. iModulon-based engineering is a transformative strategy as it includes all genes comprising the transferred cellular function, including genes without functional annotation. Adaptive laboratory evolution was deployed to optimize the cellular function transferred, revealing mutations in the host. Combining big data analytics and laboratory evolution thus enhances the level of understanding of systems biology, and synthetic biology for strain design and development.

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma.

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Chronic shedding of a SARS-CoV-2 Alpha variant in wastewater.

BACKGROUND: Central Michigan University (CMU) participated in a state-wide SARS-CoV-2 wastewater monitoring program since 2021. Wastewater samples were collected from on-campus sites and nine off-campus wastewater treatment plants servicing small metropolitan and rural communities. SARS-CoV-2 genome copies were quantified using droplet digital PCR and results were reported to the health department. RESULTS: One rural, off-campus site consistently produced higher concentrations of SARS-CoV-2 genome copies. Samples from this site were sequenced and contained predominately a derivative of Alpha variant lineage B.1.1.7, detected from fall 2021 through summer 2023. Mutational analysis of reconstructed genes revealed divergence from the Alpha variant lineage sequence over time, including numerous mutations  in the Spike RBD and NTD. CONCLUSIONS: We discuss the possibility that a chronic SARS-CoV-2 infection accumulated adaptive mutations that promoted long-term infection. This study reveals that small wastewater treatment plants can enhance resolution of rare events and facilitate reconstruction of viral genomes due to the relative lack of contaminating sequences.

Getting patients to the right level of trauma center after motorcycle crashes in a rural trauma system.

PURPOSE: After a motorcycle crash (MCC), emergency medical services (EMS) responders must balance trauma center proximity with clinical needs of patients, which is especially challenging in rural states. The study purpose was to determine if MCC patients treated at lower-level trauma centers (LLTC) experienced higher mortality when compared to patients transported directly to the highest level of trauma care available in the state at Level II trauma centers. PROCEDURES: A retrospective study was conducted on MCC patients transported by EMS to Montana hospitals and met registry inclusion criteria in 2020-2021. The first study group included patients initially transported to state-designated trauma centers (equivalent to Level III-V) or non-designated hospitals (LLTC), and the second group included patients transported directly to American College of Surgeon verified Level II trauma centers (L2TC). Secondary transfer was defined as initial transport to a LLTC and subsequent transfer to a L2TC. Primary study outcome was mortality at the L2TC. Chi-square tests and Wilcoxon rank sum tests were used for analysis. FINDINGS: In the study period, 337 MCC patients were transported by EMS; 186 (55%) patients were transported to a LLTC while 151 patients (45%) were transported to a L2TC. There were no statistically significant differences in mortality (12% vs 8%, p = 0.30) when comparing secondary transfer patients to patients transported directly to a L2TC. CONCLUSIONS: Nearly half of patients initially evaluated at a LLTC required transfer to a higher-level of care. Secondary transfer was not associated with increased mortality.

Leveraging Clinical Informatics to Address the Quintuple Aim for End-of-Life Care.

As the population of older adults grows at an unprecedented rate, there is a large gap to provide culturally tailored end-of-life care. This study describes a payor-led, informatics-based approach to identify Medicare members who may benefit from a Compassionate CareSM Program (CCP), which was designed to provide specialized care management services and support to members who have end-stage and/or life-limiting illnesses by addressing the quintuple aim. Potential participants are identified through machine learning models whereby nurse care managers then provide tailored outreach via telephone. A retrospective, observational cohort analysis of propensity-weighted Medicare members was performed to compare decedents who did or did not participate in the CCP. This program enhanced the end-of-life care experience while providing equitable outcomes regardless of age, gender, and geography and decreased inpatient (-37%) admissions with concomitant reduced (-59%) medical spend when compared to decedents that did not utilize the end-of-life care management program.