Citations

Background: Piperacillin-Tazobactam (PTZ) is often used to treat community-acquired intra-abdominal infections (CA-IAIs) despite common causative pathogens being susceptible to more narrow-spectrum agents. However, susceptibility to PTZ among these predominant pathogens has been declining. Antibiotic de-escalation to non-antipseudomonal beta-lactams whenever possible is an important strategy to prevent the development of resistance to PTZ. Objective: The purpose of this study is to assess PTZ length of therapy in patients with CA-IAI, by comparing patients who received a pharmacist-led intervention involving the de-escalation of PTZ to narrow-spectrum regimens with those who did not receive the intervention. Methods: A retrospective analysis was conducted among patients >18 years old and admitted with CA-IAI empirically placed on PTZ between January 1, 2022, through June 30, 2022 (pre-intervention group), and January 1, 2024, through June 30, 2024 (post-intervention group). A total of 246 patients were included in the pre-intervention group and 129 patients in the post-intervention group. The utilization of PTZ, hospital length of stay (LOS), and treatment-associated complications were assessed using linear and logistic regression model, respectively. Results: Compared with patients in the pre-intervention group, those in the post-intervention group had a mean 1.2-day reduction in PTZ length of therapy (2.3 vs 1.2 days, P < 0.001). There was no difference in LOS, (β = 0.001, 98% confidence interval [CI] −1.29 to 1.29; P = 0.477), hospital readmission within 30 days due to IAI (odds ratio [OR] = 0.85, 98% CI = 0.51 to 1.44; P = 0.56), treatment-associated complications during current hospitalization (OR = 0.77, 98% CI = 0.45 to 1.32; P = 0.35), development of Clostridium difficile -associated diarrhea (OR = 3.29, 98% CI = 0.77 to 22.4; P = 0.14), or medication toxicity (OR = 2.07, 98% CI = 0.79 to 6.08; P = 0.15). Conclusion and relevance: The use of narrow-spectrum antibiotics for the empiric treatment of CA-IAI-reduced PTZ length of therapy and did not result in adverse clinical outcomes.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Abstract Description Cellular immune responses are critical for protection from environmental and genetic insults, including pathogens and cancer. However, immunity can also drive pathogenic responses that damage organs and drive pathogenesis. Immune response quality is influenced by several factors including genetics, age, sex and the environment. Environmental influences including everyday activities and lifestyle have been shown to modulate the immune system but are often difficult to monitor. We have developed a system of serial monitoring of peripheral blood mononuclear cells that coincided with wearable device activity monitoring to further understand how biometric data correlates with the composition of blood derived immune cells. Using a 31-marker CyTOF phenotyping panel we monitored blood derived immune cell composition over a 14-week period in an individual volunteer while biometric data was collected via wearable technology. To determine whether interventions can be introduced that change peripheral blood immune cell phenotypes our volunteer introduced lifestyle changes at specific intervals in this period of monitoring. These included intermittent fasting and the introduction of regular exercise. In addition, the individual was immunized against COVID-19 during this time to provide an immune challenge that would perturb immune homeostasis. In this study, we find that lifestyle changes can promote alterations in immune cell phenotypes identified using high parameter mass cytometry. Topic Categories Translational and Interventional Immunology (TI)

Abstract Description This study dissects mechanisms of spontaneous tumor rejection leading to better understanding of successful immune responses to cancer. Cancers persist despite expression of tumor-specific neoantigens promoting ongoing anti-tumor immune responses. While some occult tumor cells likely are cleared by effective anti-tumor immune responses, the targeted antigens are not easily identifiable as those cells spontaneously disappear. Congenic mouse breast carcinoma models expressing a defined protein mimicking neoantigens were used to dissect the protective spontaneous immune response. BALB/c (MHC H-2d) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite demonstrated tumor immunogenicity, mimicking known patient responses to cancer. Meanwhile, H-2b positive BALB.B and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in an MHC-II dependent manner. CD4+ T-cells and B-cells or the rat-erbB2-specific antibodies they produce are crucial mediators of this protective response. Differences in the tumor microenvironments in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflect the differences between effective and ineffective anti-tumor immunity. Identifying the nature of the optimal MHC-II antigens, how they activate protective CD4+ T-cells, and the interactions that promote protective antibodies will better inform future cancer therapies. Funding Sources Bernie Fineman Research Fund Mayo Clinic Center for Biomedical Discovery Mayo Clinic Department of Immunology Mayo Clinic Graduate School of Biomedical Sciences NIH Traning Grant 5 R25 GM 55252 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Purpose: The purpose of this study was to compare the height of velopharyngeal (VP) closure in relation to the palatal plane between individuals with velopharyngeal insufficiency (VPI) with or without cleft palate and individuals without cleft palate and with normal speech, considering the effects of age and sex. Method: Magnetic resonance imaging was used to analyze the height of VP closure in the midsagittal view during phonation of /i/ and /s/ sounds among 105 individuals with VPI and 45 individuals without cleft palate and normal speech. Results: Independent-samples t tests demonstrated that individuals with VPI display a significantly lower mean height of VP closure (3.7 mm) compared to individuals without cleft palate and normal speech during phonation of /i/ and /s/ sounds ( p < .001). Analysis of variance was used to evaluate the impact of age and sex on the height of VP closure. Significant differences were observed between the height of VP closure in individuals with VPI and those without cleft palate and normal speech across the age span during the production of /i/ and /s/ sounds. However, nonsignificant differences were found between the height of VP closure in males and females of the VPI group and those without cleft palate and normal speech during the production of these sounds. Conclusions: The results revealed the variations of the height of VP closure in relation to the palatal plane. These findings provide insights into the presurgical planning for individuals with VPI undergoing palatal surgeries, especially the location of pharyngeal flap insertion.