Repurposing crizotinib to target RIPK1-dependent cell death.

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of Food and Drug Administration (FDA)-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death. Furthermore, crizotinib rescued TNF-α-induced death in mice with systemic inflammatory response syndrome. RIPK1 kinase activity was directly inhibited by crizotinib. These findings identify a new use for an established compound and are expected to accelerate drug development for RIPK1-spectrum disorders.

SIRS epidemics with individual heterogeneity of immunity waning.

In the current paper we analyse an extended SIRS epidemic model in which immunity at the individual level wanes gradually at exponential rate, but where the waning rate may differ between individuals, for instance as an effect of differences in immune systems. The model also includes vaccination schemes aimed to reach and maintain herd immunity. We consider both the informed situation where the individual waning parameters are known, thus allowing selection of vaccinees being based on both time since last vaccination as well as on the individual waning rate, and the more likely uninformed situation where individual waning parameters are unobserved, thus only allowing vaccination schemes to depend on time since last vaccination. The optimal vaccination policies for both the informed and uniformed heterogeneous situation are derived and compared with the homogeneous waning model (meaning all individuals have the same immunity waning rate), as well as to the classic SIRS model where immunity at the individual level drops from complete immunity to complete susceptibility in one leap. It is shown that the classic SIRS model requires least vaccines, followed by the SIRS with homogeneous gradual waning, followed by the informed situation for the model with heterogeneous gradual waning. The situation requiring most vaccines for herd immunity is the most likely scenario, that immunity wanes gradually with unobserved individual heterogeneity. For parameter values chosen to mimic COVID-19 and assuming perfect initial immunity and cumulative immunity of 12 months, the classic homogeneous SIRS epidemic suggests that vaccinating individuals every 15 months is sufficient to reach and maintain herd immunity, whereas the uninformed case for exponential waning with rate heterogeneity corresponding to a coefficient of variation being 0.5, requires that individuals instead need to be vaccinated every 4.4 months.

KC-like chemokine as a biomarker of sepsis in dogs with pyometra.

BACKGROUND: Sepsis, defined as a dysregulated inflammatory response to infection inducing organ dysfunction, is a common cause of mortality in both humans and animals. Early detection and treatment is essential for survival, but accurate diagnosis is challenging due to the lack of specific biomarkers for sepsis. This study explored the potential of the keratinocyte-derived chemokine (KC)-like protein in dogs as a biomarker of sepsis in dogs with bacterial uterine infection (pyometra). The aim was to compare KC-like concentrations in dogs with pyometra with or without sepsis and to assess associations between KC-like and clinical variables, including days of hospitalization as an outcome. RESULTS: A mouse KC ELISA was validated and used to determine the concentrations of KC-like in serum from 34 dogs with pyometra and 18 healthy controls. Dogs with pyometra were classified as having sepsis based on two different criteria for systemic inflammatory response syndrome (SIRS), resulting in 74% and 30% sepsis-positive, respectively. The concentration of KC-like protein was higher in pyometra dogs with sepsis than in pyometra dogs without sepsis (p < 0.05) and in healthy controls (p < 0.0001) when using either of the two SIRS criteria. Moreover, KC-like was slightly increased in dogs with pyometra without sepsis compared with healthy controls when using the more stringent SIRS criteria (p < 0.05). Analyses of all dogs showed that KC-like concentrations correlated positively with hospitalization days, C-reactive protein (CRP) concentrations, white blood cells, and percentage of band neutrophils; however, KC-like correlated negatively with hemoglobin and did not correlate with circulating creatinine. CONCLUSIONS: Our results suggest that circulating KC-like protein increases in dogs with sepsis in pyometra and that KC-like is associated with more severe clinical illness. These findings support a potential role of KC-like as a biomarker of sepsis; however, the true identity of KC-like in dogs has yet to be uncovered.

Clinical Application of CT Imaging Grading System in Upper Urinary Tract Calculi with Kidney Infection.

PURPOSE: This study aimed to establish a CT imaging grading system and explore its value in evaluating upper urinary tract calculi associated with kidney infections. METHODS: CT images of 126 patients with kidney infections caused by upper urinary tract calculi were retrospectively analyzed. The CT grading system was developed based on CT images. CT images were classified into 4 grades. General information, symptoms, and clinical findings of patients in different CT grades were analyzed. With the occurrence of systemic inflammatory response syndrome (SIRS) as the endpoint, univariate and multivariate analysis was conducted to analyze the risk factors of SIRS. RESULTS: Patients with fever or diabetes had higher CT grades, and the following examination data revealed significant differences across the various CT grades (P < 0.05): the white blood cell count, urine leucocytes count, CT1, CT2, maximum body temperature, duration of disease, the proportion of blood neutrophils, the size of stones, and levels of the C-reactive protein and procalcitonin. Only CT grading was statistically significant after multivariate analysis. According to the values of the partial regression coefficient (B), the higher the CT grade, the greater the risk of SIRS. The risk of SIRS was 4.472 times higher with each increment of the CT grade. CONCLUSIONS: The CT grade is directly associated with clinical symptoms and the risk of SIRS.

Urine oxygenation predicts COVID-19 risk.

Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government's basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed.

Prolonged Systemic Inflammatory Response Syndrome After Cardiac Surgery.

OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.

Development and validation of a machine learning-based model to assess probability of systemic inflammatory response syndrome in patients with severe multiple traumas.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a predictor of serious infectious complications, organ failure, and death in patients with severe polytrauma and is one of the reasons for delaying early total surgical treatment. To determine the risk of SIRS within 24 h after hospitalization, we developed six machine learning models. MATERIALS AND METHODS: Using retrospective data about the patient, the nature of the injury, the results of general and standard biochemical blood tests, and coagulation tests, six models were developed: decision tree, random forest, logistic regression, support vector and gradient boosting classifiers, logistic regressor, and neural network. The effectiveness of the models was assessed through internal and external validation. RESULTS: Among the 439 selected patients with severe polytrauma in 230 (52.4%), SIRS was diagnosed within the first 24 h of hospitalization. The SIRS group was more strongly associated with class II bleeding (39.5% vs. 60.5%; OR 1.81 [95% CI: 1.23-2.65]; P = 0.0023), long-term vasopressor use (68.4% vs. 31.6%; OR 5.51 [95% CI: 2.37-5.23]; P < 0.0001), risk of acute coagulopathy (67.8% vs. 32.2%; OR 2.4 [95% CI: 1.55-3.77]; P < 0.0001), and greater risk of pneumonia (59.5% vs. 40.5%; OR 1.74 [95% CI: 1.19-2.54]; P = 0.0042), longer ICU length of stay (5 ± 6.3 vs. 2.7 ± 4.3 days; P < 0.0001) and mortality rate (64.5% vs. 35.5%; OR 10.87 [95% CI: 6.3-19.89]; P = 0.0391). Of all the models, the random forest classifier showed the best predictive ability in the internal (AUROC 0.89; 95% CI: 0.83-0.96) and external validation (AUROC 0.83; 95% CI: 0.75-0.91) datasets. CONCLUSIONS: The developed model made it possible to accurately predict the risk of developing SIRS in the early period after injury, allowing clinical specialists to predict patient management tactics and calculate medication and staffing needs for the patient. LEVEL OF EVIDENCE: Level 3. TRIAL REGISTRATION: The study was retrospectively registered in the ClinicalTrials.gov database of the National Library of Medicine (NCT06323096).

Primary Infection Site as a Predictor of Sepsis Development in Emergency Department Patients.

BACKGROUND: Sepsis is a life-threatening condition but predicting its development and progression remains a challenge. OBJECTIVE: This study aimed to assess the impact of infection site on sepsis development among emergency department (ED) patients. METHODS: Data were collected from a single-center ED between January 2016 and December 2019. Patient encounters with documented infections, as defined by the Systematized Nomenclature of Medicine-Clinical Terms for upper respiratory tract (URI), lower respiratory tract (LRI), urinary tract (UTI), or skin or soft-tissue infections were included. Primary outcome was the development of sepsis or septic shock, as defined by Sepsis-1/2 criteria. Secondary outcomes included hospital disposition and length of stay, blood and urine culture positivity, antibiotic administration, vasopressor use, in-hospital mortality, and 30-day mortality. Analysis of variance and various different logistic regression approaches were used for analysis with URI used as the reference variable. RESULTS: LRI was most associated with sepsis (relative risk ratio [RRR] 5.63; 95% CI 5.07-6.24) and septic shock (RRR 21.2; 95% CI 17.99-24.98) development, as well as hospital admission rates (odds ratio [OR] 8.23; 95% CI 7.41-9.14), intensive care unit admission (OR 4.27; 95% CI 3.84-4.74), in-hospital mortality (OR 6.93; 95% CI 5.60-8.57), and 30-day mortality (OR 7.34; 95% CI 5.86-9.19). UTIs were also associated with sepsis and septic shock development, but to a lesser degree than LRI. CONCLUSIONS: Primary infection sites including LRI and UTI were significantly associated with sepsis development, hospitalization, length of stay, and mortality among patients presenting with infections in the ED.

Prevalence of anterior uveitis in cases of systemic inflammatory response syndrome in dogs and cats.

OBJECTIVE: To determine the prevalence of anterior uveitis in dogs and cats hospitalized with a diagnosis of systemic inflammatory response syndrome (SIRS). ANIMALS STUDIED: Dogs and cats hospitalized between May 2020 and January 2021 were prospectively included. PROCEDURES: Patients were categorized into two different groups: The first group included patients diagnosed with SIRS, and the second group included patients hospitalized without SIRS as a control group. Daily physical and ophthalmological examinations were conducted during hospitalization. Diagnosis of anterior uveitis was made based on the presence of aqueous flare, low intraocular pressure, and other associated ocular signs such as episcleral injection and miosis. A multinomial logistic regression analysis was conducted to investigate factors associated with SIRS and anterior uveitis development. RESULTS: The study comprised 42 patients with SIRS and 26 patients without SIRS. Among those with SIRS, 38% developed anterior uveitis, whereas only 7.7% of patients without SIRS showed signs of anterior uveitis. The prevalence of uveitis was significantly higher in animals with SIRS compared to those without SIRS (p < .05). CONCLUSION: Anterior uveitis is more prevalent in patients with SIRS than patients without SIRS. Therefore, complete ophthalmic examination is recommended in all patients presenting with this syndrome.

Prevalence of SIRS with primary epiploic appendagitis.

PURPOSE: Primary epiploic appendagitis (PEA) is not an uncommon cause of abdominal pain. The systemic inflammatory response syndrome (SIRS) criteria have high sensitivity for early detection of inflammation and infection. To date, there is limited data about the association between SIRS and PEA. The aims of this retrospective study were to evaluate the prevalence of SIRS response and its clinical relevance in patients diagnosed with PEA within a large tertiary hospital network. METHODS: A retrospective study was performed on all consecutive adult patients who presented to four major emergency departments with CT-confirmed PEA from 01 January 2022 to 27 March 2023. The fulfilment of SIRS criteria, hospital admission rate and treatments provided were analysed for these patients. RESULTS: Seventy-three patients had CT-confirmed PEA. Seventeen patients (23.2%) with PEA were SIRS positive. The hospital admission rate in the SIRS group trended higher than the non-SIRS group (odds ratio of 2.51, 95% CI (0.75, 8.39)). The odds of having an associated radiological comorbidity unrelated to PEA were 18.7 times higher in the SIRS positive group. Fifty-seven (78%) patients were discharged home, and 16 (22%) patients were admitted into hospital. Nearly all patients were treated conservatively (98.6%). CONCLUSION: PEA patients with SIRS response trend towards a higher hospital admission rate and are significantly more likely to have other radiological comorbidities than non-SIRS patients. It is important to look for other pathological conditions in a SIRS positive patient with a CT-diagnosis of PEA.