Treating Helicobacter pylori and Recurrent Clostridioides difficile Coinfection: A Delicate Balance in Management and a Need for Guidelines.

Treating Helicobacter pylori and Clostridioides difficile coinfection presents a challenging clinical dilemma. Treating H. pylori may increase the risk of C. difficile, and antibiotics generally have been shown to increase the risk of C. difficile infection/recurrence. While it may be reasonable to delay H. pylori treatment, this is especially challenging when there is an acute indication to treat H. pylori such as peptic ulceration or bleeding. There are no guidelines on the management of H. pylori and C. difficile coinfection. We report a patient who had H. pylori and recurrent C. difficile coinfection and suggest a management algorithm based on literature review and our institutional experience. Our patient received quadruple therapy for H. pylori along with vancomycin prophylaxis, taper, and a dose of bezlotoxumab and experienced good outcomes with resolution of his gastrointestinal bleeding and diarrhea.

Acute myeloid leukemia: An unusual manifestation of the trachea.

Objectives: Hematologic malignancy involving the trachea is rare. It is even less common for tracheal involvement to be the initial manifestation of this disease. We present a case report highlighting an unusual diagnosis of acute myeloid leukemia (AML) that first presented with prominent tracheal manifestations. There have been only three other published case reports of extramedullary AML with involvement of the trachea. Methods: We discuss direct laryngoscopy and bronchoscopy findings, including pinkish-white irregular lesions, which were similar to findings described in the available literature for tracheal AML. Results: Laboratory findings from our case are reported, including peripheral smear demonstrating 57% blasts and bone marrow biopsy confirming the diagnosis of AML, and the relevance of these findings is discussed. Conclusion: In patients with unusual airway lesions, laboratory testing and a comprehensive airway evaluation including biopsy are necessary to narrow the differential diagnosis. Level of Evidence: 5.

Nonendemic rhinoscleroma: An unusual manifestation of the trachea.

Objectives: Rhinoscleroma is classically described as a chronic granulomatous disease caused by Klebsiella rhinoscleromatis which primarily affects the nose and nasopharynx. When present, tracheal manifestations will be seen late in the disease course rather than on initial presentation. We describe a rare case of nonendemic rhinoscleroma that presented with tracheal lesions as an initial manifestation of disease. Methods: Case report and literature review. Results: An 88-year-old male presented with longstanding dysphonia. Flexible laryngoscopy demonstrated a septal perforation and diffuse glottic lesions. CT neck demonstrated a nonobstructive polypoid tracheal lesion and mucosal thickening of the paranasal sinuses. Biopsy confirmed an atypical lympho-histiocytic proliferation and microorganisms within macrophages on Grocott methenamine silver and Steiner stains consistent with rhinoscleroma. He was referred for rheumatology and pulmonology consultation. Conclusion: Systemic diseases rarely affect the trachea, and even less frequently is a tracheal lesion identified as the initial manifestation of disease. The most common systemic diseases that affect the trachea include relapsing polychondritis, granulomatosis with polyangiitis, amyloidosis, and inflammatory bowel disease. The literature surrounding nasolaryngotracheal rhinoscleroma is limited, especially in nonendemic areas. It is necessary to include unusual etiologies of airway lesions in the differential diagnosis, which warrants comprehensive airway evaluation including biopsy. Level of Evidence: 4.

Evaluating antibiotic therapy for ventilator-associated pneumonia caused by gram-negative bacilli.

Introduction: Ventilator-associated pneumonias (VAPs) are a complication of mechanical ventilation in the intensive care unit (ICU) that increase length of stay, morbidity, and mortality. While identifying and treating infections early is paramount to improving patient outcomes, more and more data demonstrate limited courses of antibiotics improve outcomes. Prolonged (10-14 day) courses of antibiotics have remained the standard of care for pneumonia due to gram-negative bacilli (GNR). We aimed to review our GNR VAPs to assess risk factors for recurrent GNR infections. Methods: We reviewed trauma patients who developed VAP from 02/2019 through 05/2022. Demographics, injury characteristics, and outcomes were reviewed with a focus on pneumonia details including the cultured pathogen(s), antibiotic(s) used, treatment duration, and presence of recurrent infections. We then compared single episode VAPs to multiple episode VAPs among patients infected by GNRs. Results: Eleven of the fifty trauma patients admitted to the ICU suffered a VAP caused by a GNR. Of these eleven patients, six experienced a recurrent infection, four of which were caused by Pseudomonas aeruginosa and two of which were caused by Enterobacter aerogenes. Among the patients who received ten days of antibiotic treatment, half suffered a recurrence. Although, there was no difference in the microbiology or antibiotic duration between the recurrences and single episodes. Conclusion: Despite prolonged use of antibiotics, we found that the risk of recurrent or persistent infections was high among patients with VAP due to GNB. Further study is needed to determine optimal treatment to minimize the risk of these recurrences. Key message: Ventilator-associated pneumonia due to gram-negative bacilli is a rare but high morbidity complication in intensive care units. Despite prolonged duration of therapy, these infections still appear to account for many recurrent infections and further study into optimal therapy is warranted.

Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells.

IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) alpha subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R-deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A-secreting CD4(+) T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4(+) T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.

An Expanded Framework for Situation Control.

There is an extensive body of literature on the topic of estimating situational states, in applications ranging from cyber-defense to military operations to traffic situations and autonomous cars. In the military/defense/intelligence literature, situation assessment seems to be the sine qua non for any research on surveillance and reconnaissance, command and control, and intelligence analysis. Virtually all of this work focuses on assessing the situation-at-the-moment; many if not most of the estimation techniques are based on Data and Information Fusion (DIF) approaches, with some recent schemes employing Artificial Intelligence (AI) and Machine Learning (ML) methods. But estimating and recognizing situational conditions is most often couched in a decision-making, action-taking context, implying that actions may be needed so that certain goal situations will be reached as a result of such actions, or at least that progress toward such goal states will be made. This context thus frames the estimation of situational states in the larger context of a control-loop, with a need to understand the temporal evolution of situational states, not just a snapshot at a given time. Estimating situational dynamics requires the important functions of situation recognition, situation prediction, and situation understanding that are also central to such an integrated estimation + action-taking architecture. The varied processes for all of these combined capabilities lie in a closed-loop "situation control" framework, where the core operations of a stochastic control process involve situation recognition-learning-prediction-situation "error" assessment-and action taking to move the situation to a goal state. We propose several additional functionalities for this closed-loop control process in relation to some prior work on this topic, to include remarks on the integration of control-theoretic principles. Expanded remarks are also made on the state of the art of the schemas and computational technologies for situation recognition, prediction and understanding, as well as the roles for human intelligence in this larger framework.

Situational Understanding in the Human and the Machine.

The Air Force research programs envision developing AI technologies that will ensure battlespace dominance, by radical increases in the speed of battlespace understanding and decision-making. In the last half century, advances in AI have been concentrated in the area of machine learning. Recent experimental findings and insights in systems neuroscience, the biophysics of cognition, and other disciplines provide converging results that set the stage for technologies of machine understanding and machine-augmented Situational Understanding. This paper will review some of the key ideas and results in the literature, and outline new suggestions. We define situational understanding and the distinctions between understanding and awareness, consider examples of how understanding-or lack of it-manifest in performance, and review hypotheses concerning the underlying neuronal mechanisms. Suggestions for further R&D are motivated by these hypotheses and are centered on the notions of Active Inference and Virtual Associative Networks.

The nuclear receptor HNF4 drives a brush border gene program conserved across murine intestine, kidney, and embryonic yolk sac.

The brush border is comprised of microvilli surface protrusions on the apical surface of epithelia. This specialized structure greatly increases absorptive surface area and plays crucial roles in human health. However, transcriptional regulatory networks controlling brush border genes are not fully understood. Here, we identify that hepatocyte nuclear factor 4 (HNF4) transcription factor is a conserved and important regulator of brush border gene program in multiple organs, such as intestine, kidney and yolk sac. Compromised brush border gene signatures and impaired transport were observed in these tissues upon HNF4 loss. By ChIP-seq, we find HNF4 binds and activates brush border genes in the intestine and kidney. H3K4me3 HiChIP-seq identifies that HNF4 loss results in impaired chromatin looping between enhancers and promoters at gene loci of brush border genes, and instead enhanced chromatin looping at gene loci of stress fiber genes in the intestine. This study provides comprehensive transcriptional regulatory mechanisms and a functional demonstration of a critical role for HNF4 in brush border gene regulation across multiple murine epithelial tissues.