Evaluation of the Use of Phenobarbital and Benzodiazepines in the Management of Alcohol Withdrawal Syndrome in Patients Requiring Neurological/Neurosurgical Critical Care: A Propensity-Matched Analysis.

Objective There is growing interest in the use of phenobarbital for alcohol withdrawal syndrome in critically ill patients, though experience in neurologically injured patients is limited. The purpose of this study was to compare the safety and effectiveness of phenobarbital-containing alcohol withdrawal regimens versus benzodiazepine monotherapy in the neurocritical care unit. Methods We conducted a retrospective cohort study of adult patients admitted to the neurocritical care unit from January 2014 through November 2021 who received pharmacologic treatment for alcohol withdrawal. Treatment groups were defined as benzodiazepine monotherapy versus phenobarbital alone or in combination with benzodiazepines. The primary outcome was the percentage of patients requiring intubation after receiving alcohol withdrawal treatment. Secondary outcomes included all-cause, in-hospital mortality, intensive care unit length of stay, discharge disposition, change in Glasgow Coma Scale (GCS) score, and the use of adjunctive agents. Results We analyzed data from 156 patients, with 77 (49%) in the benzodiazepine group and 79 (51%) in the phenobarbital combination group. The groups were well-balanced for baseline characteristics, though more males (67, 85%) were in the phenobarbital group. Only three (1.9%) patients received phenobarbital monotherapy, and the rest (153, 98.1%) received combination therapy. The percentage of patients requiring mechanical ventilation was significantly higher in the phenobarbital combination group compared to benzodiazepine monotherapy (39% (n=31) versus 13% (n=10); OR: 4.33, 95% CI: 1.94-9.66; p<0.001). The use of adjunctive propofol and dexmedetomidine was higher in the phenobarbital group (propofol 35% (n= 28) versus 9% (n=7) and dexmedetomidine 30% (n=24) versus 5% (n=4), respectively). Patients in the phenobarbital group also had lower GCS scores and higher Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scores during their intensive care unit admission, possibly suggesting more severe alcohol withdrawal. There was no difference in intensive care unit length of stay, all-cause, in-hospital mortality, discharge disposition, or therapeutic adjuncts. Conclusions Combination therapy of phenobarbital plus benzodiazepines was associated with higher odds of requiring mechanical ventilation. Few patients received phenobarbital monotherapy. Additional studies are needed to better compare the effects of phenobarbital monotherapy versus benzodiazepines in neurocritical patients.

Fungal Cell Wall-Associated Effectors: Sensing, Integration, Suppression, and Protection.

The cell wall (CW) of plant-interacting fungi, as the direct interface with host plants, plays a crucial role in fungal development. A number of secreted proteins are directly associated with the fungal CW, either through covalent or non-covalent interactions, and serve a range of important functions. In the context of plant-fungal interactions many are important for fungal development in the host environment and may therefore be considered fungal CW-associated effectors (CWAEs). Key CWAE functions include integrating chemical/physical signals to direct hyphal growth, interfering with plant immunity, and providing protection against plant defenses. In recent years, a diverse range of mechanisms have been reported that underpin their roles, with some CWAEs harboring conserved motifs or functional domains, while others are reported to have novel features. As such, the current understanding regarding fungal CWAEs is systematically presented here from the perspective of their biological functions in plant-fungal interactions. An overview of the fungal CW architecture and the mechanisms by which proteins are secreted, modified, and incorporated into the CW is first presented to provide context for their biological roles. Some CWAE functions are reported across a broad range of pathosystems or symbiotic/mutualistic associations. Prominent are the chitin interacting-effectors that facilitate fungal CW modification, protection, or suppression of host immune responses. However, several alternative functions are now reported and are presented and discussed. CWAEs can play diverse roles, some possibly unique to fungal lineages and others conserved across a broad range of plant-interacting fungi. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Ustilago maydis PR-1-like protein has evolved two distinct domains for dual virulence activities.

The diversification of effector function, driven by a co-evolutionary arms race, enables pathogens to establish compatible interactions with hosts. Structurally conserved plant pathogenesis-related PR-1 and PR-1-like (PR-1L) proteins are involved in plant defense and fungal virulence, respectively. It is unclear how fungal PR-1L counters plant defense. Here, we show that Ustilago maydis UmPR-1La and yeast ScPRY1, with conserved phenolic resistance functions, are Ser/Thr-rich region mediated cell-surface localization proteins. However, UmPR-1La has gained specialized activity in sensing phenolics and eliciting hyphal-like formation to guide fungal growth in plants. Additionally, U. maydis hijacks maize cathepsin B-like 3 (CatB3) to release functional CAPE-like peptides by cleaving UmPR-1La's conserved CNYD motif, subverting plant CAPE-primed immunity and promoting fungal virulence. Surprisingly, CatB3 avoids cleavage of plant PR-1s, despite the presence of the same conserved CNYD motif. Our work highlights that UmPR-1La has acquired additional dual roles to suppress plant defense and sustain the infection process of fungal pathogens.

A Novel Core Effector Vp1 Promotes Fungal Colonization and Virulence of Ustilago maydis.

The biotrophic fungus Ustilago maydis secretes a plethora of uncharacterized effector proteins and causes smut disease in maize. Among the effector genes that are up-regulated during the biotrophic growth in maize, we identified vp1 (virulence promoting 1), which has an expression that was up-regulated and maintained at a high level throughout the life cycle of the fungus. We characterized Vp1 by applying in silico analysis, reverse genetics, phenotypic assessment, microscopy, and protein localization and provided a fundamental understanding of the Vp1 protein in U. maydis. The reduction in fungal virulence and colonization in the vp1 mutant suggests the virulence-promoting function of Vp1. The deletion studies on the NLS (nuclear localization signal) sequence and the protein localization study revealed that the C-terminus of Vp1 is processed after secretion in plant apoplast and could localize to the plant nucleus. The Ustilago hordei ortholog UhVp1 lacks NLS localized in the plant cytoplasm, suggesting that the orthologs might have a distinct subcellular localization. Further complementation studies of the Vp1 orthologs in related smut fungi revealed that none of them could complement the virulence function of U. maydis Vp1, suggesting that UmVp1 could acquire a specialized function via sequence divergence.