1,2,3-Triazole-Containing Azamacrocycles from Chiral Triazolopeptoids: Synthesis and Solid-State Studies.

Two new chiral 1,2,3-triazole-containing macrocyclic oligoamides (i. e.: triazolopeptoid 4 and 5) were obtained through solid-phase synthesis of linear precursors followed by high dilution macrocyclization reaction. Theoretical (DFT) and spectroscopic (NMR) studies revealed the intricate interplay between the Nα-chiral side chains and their conformational attitudes. BH3-mediated reduction of the tertiary amide groups of known 1-3 and newly synthesized 4 gave novel azamacrocycles 6-9. Detection of borane complexes of azamacrocycles 6 and 9 (i. e.: 10 and 11), corroborated by X-ray diffraction studies, demonstrated the peculiar properties of 1,2,3-triazole-containing macrorings.

Circulating Cancer-Associated Macrophage-like Cells as a Blood-Based Biomarker of Response to Immune Checkpoint Inhibitors.

Evidence has been provided that circulating cancer-associated macrophage-like cell (CAM-L) numbers increase in response to chemotherapy, with an inverse trend compared to circulating tumor cells (CTCs). In the era of evolving cancer immunotherapy, whether CAM-Ls might have a potential role as predictive biomarkers of response has been unexplored. We evaluated whether a serial blood evaluation of CTC to CAM-L ratio might predict response to immune checkpoint inhibitors in a cohort of non-small-cell lung cancer patients. At baseline, CTCs, CAM-Ls, and the CTC/CAM-L ratio significantly correlate with both progression-free survival (PFS) and overall survival (OS). The baseline CTC/CAM-L ratio was significantly different in early progressors (4.28 ± 3.21) compared to long responders (0.42 ± 0.47) (p = 0.001). In patients treated with immune checkpoint inhibitors, a CTC/CAM-L ratio ≤ 0.25 at baseline is associated with better PFS and OS. A baseline CTC/CAM-L ratio ≤ 0.25 is statistically significant to discriminate early progressions from durable response. The results of the present pilot study suggest that CAM-Ls together with CTCs could play an important role in evaluating patients treated with cancer immunotherapy.

Relevance of obesity-related organ damage and metabolic syndrome classification in cardiovascular and renal risk stratification in patients with essential hypertension.

Introduction: Hypertension is a relevant cardiovascular comorbidity. Adipose tissue represents a metabolically active tissue involved in the regulation of blood pressure and metabolic alterations. In recent decades, several classifications for the metabolic syndrome (MS) have been proposed. Recently, a new syndrome called the "Cardiovascular-kidney-metabolic" (CKM) syndrome was identified, to determine patients at high cardiovascular and metabolic risk. The aim of the study was to compare different classifications in a large population of hypertensive patients. Materials and methods: Between September 2022 and August 2023, we consecutively enrolled 772 hypertensive patients (407 men; 365 women; mean age 52.2 ± 15.1 years), evaluating anthropometric, biochemical, and instrumental parameters (transthoracic echocardiogram, carotid echo-Doppler, 24-h ambulatory blood pressure monitoring, fundus oculi). Results: Using different classifications we found MS prevalence: Adult Treatment Panel III (ATP-III) 28.8%, International Diabetes Federation (IDF) 31.5%, CKM 40.7%. CKM Classes 3 and 4 showed higher body mass index and waist circumference compared with other groups. Compared with ATP-III and IDF, CKM Class 4 showed higher 24-h systolic blood pressure, lower percentage of controlled hypertension, increased interventricular septum and posterior wall, reduced ejection fraction, and greater prevalence of hypertensive arterial retinal damage. Discussion: Visceral obesity and MS are frequent conditions with healthy impact, becoming an important trigger for the development of cardiovascular and metabolic complications. The different MS classifications allow the early identification of patients at high risk of cardiometabolic complications. The new CKM syndrome proves useful to identify individuals at high risk for CKM morbidity and mortality.

Clinical impact of transient lymphopenia.

Transient or persistent immunosuppression is a known risk factor for morbidity and mortality in critically ill patients. Aim of the present study is to evaluate the lymphopenia in patients admitted to the Emergency Unit of AOU Policlinico Umberto I, to investigate its prevalence at admission and the persistence during hospitalization until discharge. Possible correlations were evaluated between lymphopenia, diagnosis of admission, comorbidities and chronic treatments. In this study, 240 patients (142 men; 98 female; mean age 75.1 ± 15.1) were enrolled. Patients were divided into two groups according to the lymphocytes count at hospital admission, namely "Group A" with lymphopenia and "Group B" with values in the normal range. Moreover, the patients in group A were distinguished in relation to the regression or persistence of the lymphopenia assessed at the time of hospital discharge (Group A1: persistence; Group A2: normalization). Prevalence of lymphopenia at admission was 57%; Group A showed higher mean age and percentage of patients over 65 years of age; and none differences were observed regarding gender. Prevalence of lymphopenia at admission was 57%; Group A showed higher mean age and percentage of patients over 65 years of age; no differences were observed regarding gender. All subsets of the lymphocytes (CD4+, CD8+, NK) were equally reduced. Persistent lymphopenia was found in 19% of patients. Lymphopenia should be valued at the time of hospital admission as a factor influencing the prognosis, the management and the treatment of these patients.

Machine learning in the prediction and detection of new-onset atrial fibrillation in ICU: a systematic review.

Atrial fibrillation (AF) stands as the predominant arrhythmia observed in ICU patients. Nevertheless, the absence of a swift and precise method for prediction and detection poses a challenge. This study aims to provide a comprehensive literature review on the application of machine learning (ML) algorithms for predicting and detecting new-onset atrial fibrillation (NOAF) in ICU-treated patients. Following the PRISMA recommendations, this systematic review outlines ML models employed in the prediction and detection of NOAF in ICU patients and compares the ML-based approach with clinical-based methods. Inclusion criteria comprised randomized controlled trials (RCTs), observational studies, cohort studies, and case-control studies. A total of five articles published between November 2020 and April 2023 were identified and reviewed to extract the algorithms and performance metrics. Reviewed studies sourced 108,724 ICU admission records form databases, e.g., MIMIC. Eight prediction and detection methods were examined. Notably, CatBoost exhibited superior performance in NOAF prediction, while the support vector machine excelled in NOAF detection. Machine learning algorithms emerge as promising tools for predicting and detecting NOAF in ICU patients. The incorporation of these algorithms in clinical practice has the potential to enhance decision-making and the overall management of NOAF in ICU settings.

Early Detection of Disease Progression in Metastatic Cancers: Could CTCs Improve RECIST Criteria?

Early detection of disease progression is a crucial issue in the management of cancer patients, especially in metastatic settings. Currently, treatment selection mostly relies on criteria based on radiologic evaluations (RECIST). The aim of the present retrospective study is to evaluate the potential inclusion of circulating tumor cells (CTCs) in hybrid criteria. CTC counts from a total of 160 patients with different metastatic tumors were analyzed for this purpose. In our cohort, 73 patients were affected by breast cancer, 69 by colorectal cancer and 18 by prostate cancer. PFS and OS were evaluated according to the corresponding prediction of disease progression by CTCs and RECIST criteria. In breast cancer, CTC-I has an important impact on the progression-free survival (PFS) and overall survival (OS) values. When CTC-I predicted earlier than RECIST-I, the disease progression, the PFS and OS were shorter with respect to the opposite case. In particular, PFS was 11 (5-16) vs. 34 (23-45)-with p < 0.001-and OS was 80 (22-138) vs. 116 (43-189), p = 0.33. The results suggest a promising role of CTCs as complementary information which could significantly improve the clinical outcomes, and they encourage consideration of future trials to evaluate new hybrid criteria, particularly for patients with breast cancer.

The Role of Fecal Microbiota Transplantation in the Allogeneic Stem Cell Transplant Setting.

Microbiota changes during allogeneic hematopoietic stem cell transplantation has several known causes: conditioning chemotherapy and radiation, broad-spectrum antibiotic administration, modification in nutrition status and diet, and graft-versus-host disease. This article aims to review the current knowledge about the close link between microbiota and allogeneic stem cell transplantation setting. The PubMed search engine was used to perform this review. We analyzed data on microbiota dysbiosis related to the above-mentioned affecting factors. We also looked at treatments aimed at modifying gut dysbiosis and applications of fecal microbiota transplantation in the allogeneic stem cell transplant field, with particular interest in fecal microbiota transplantation for graft-versus-host disease (GvHD), multidrug-resistant and clostridium difficile infections, and microbiota restoration after chemotherapy and antibiotic therapy.

Pulmonary embolism post-Covid-19 infection: physiopathological mechanisms and vascular damage biomarkers.

Covid-19 infection is characterized by several acute complications, as well long-term sequelae, mostly sustained by endothelial dysfunction; several studies show that complications as pulmonary embolism (PE) are described both in the acute phase and after negativization. Aim of research was to evaluate anthropometric, bio-humoral, instrumental parameters in a group of patients affected by PE after recent Covid-19 infection compared to PE patients without previous Covid-19 infection. We enrolled 72 consecutive patients (35M, 37F) with acute PE, distinguished in relation to previous acute Covid-19 infection: 54 pts without previous acute Covid-19 infection and 18 pts with previous Covid-19 infection within negativity at least 2 months before PE diagnosis; 44 healthy subjects (21M, 23F) were recruited as control group. Patients who had previously developed Covid-19 needed hospitalization in high percentage (84%); this group showed significantly higher prevalence of diabetes mellitus than Covid-19-free PE patients, reduced serum levels of C-reactive protein, sST2 and PESI score. In post-Covid-19 PE group, we observed higher mean IMPROVE risk score, whereas in Covid-19-free group lower P/F ratio, higher radiological severity, and worse PESI score and severity index. Covid-19 infection affects not just the lung parenchyma but also other organs; endothelial damage plays pivotal role in long-term alterations; in high thrombotic risk group (recent hospitalization due to acute Covid-19 infection), we have described thrombotic complications characterized by persistent prothrombotic state after recovery, highlighted by well-known markers as PCR and D-Dimer as well as novel vascular marker (sST2).

Ventilation Targets for Patients Undergoing Mechanical Thrombectomy for Acute Ischemic Stroke: A Systematic Review.

Mechanical thrombectomy (MT) has become a standard treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Recent evidence suggests that general anesthesia (GA) and mechanical ventilation do not lead to inferior neurologic outcomes if compared to non-GA. However, the guidelines lack specific recommendations for ventilation targets during MT under GA. This systematic review aims to identify ventilation strategies correlating with better neurological outcomes in AIS patients undergoing MT, particularly focusing on oxygenation and carbon dioxide (CO2) targets. A systematic search of multiple databases was conducted to identify human studies reporting the correlation between ventilation strategies and neurological outcomes in MT for AIS. Eligible studies included clinical trials, observational studies, and case-control studies. Out of 157 studies assessed, 11 met the inclusion criteria. Five studies investigated oxygenation targets, while six studies explored CO2 targets. The published studies highlighted the controversial role of supplemental normobaric oxygen therapy and its potential association with worse outcomes. Regarding CO2 targets, the studies identified a potential association between end tidal CO2 levels and functional outcomes, with hypocapnia being unfavorable. This systematic review demonstrates that the current available evidence still lacks strength to suggest specific ventilation targets, but it highlights the potential risks of hyperoxia and hypocapnia in this specific cohort of patients.

Heart Rate Variability for Outcome Prediction in Intracerebral and Subarachnoid Hemorrhage: A Systematic Review.

This systematic review presents clinical evidence on the association of heart rate variability with outcome prediction in intracerebral and subarachnoid hemorrhages. The literature search led to the retrieval of 19 significant studies. Outcome prediction included functional outcome, cardiovascular complications, secondary brain injury, and mortality. Various aspects of heart rate recording and analysis, based on linear time and frequency domains and a non-linear entropy approach, are reviewed. Heart rate variability was consistently associated with poor functional outcome and mortality, while controversial results were found regarding the association between heart rate variability and secondary brain injury and cardiovascular complications.

Prognostic Role of Circulating Tumor Cell Trajectories in Metastatic Colorectal Cancer.

BACKGROUND: A large amount of evidence from clinical studies has demonstrated that circulating tumor cells are strong predictors of outcomes in many cancers. However, the clinical significance of CTC enumeration in metastatic colorectal cancer is still questioned. The aim of this study was to evaluate the clinical value of CTC dynamics in mCRC patients receiving first-line treatments. MATERIALS AND METHODS: Serial CTC data from 218 patients were used to identify CTC trajectory patterns during the course of treatment. CTCs were evaluated at baseline, at a first-time point check and at the radiological progression of the disease. CTC dynamics were correlated with clinical endpoints. RESULTS: Using a cut-off of ≥1 CTC/7.5 mL, four prognostic trajectories were outlined. The best prognosis was obtained for patients with no evidence of CTCs at any timepoints, with a significant difference compared to all other groups. Lower PFS and OS were recognized in group 4 (CTCs always positive) at 7 and 16 months, respectively. CONCLUSIONS: We confirmed the clinical value of CTC positivity, even with only one cell detected. CTC trajectories are better prognostic indicators than CTC enumeration at baseline. The reported prognostic groups might help to improve risk stratification, providing potential biomarkers to monitor first-line treatments.

Genomic landscape and survival analysis of ctDNA "neo-RAS wild-type" patients with originally RAS mutant metastatic colorectal cancer.

Background: The term "neo-RAS wild-type" refers to the switch to RAS wild-type disease in plasma circulating tumor DNA (ctDNA) from originally RAS mutant colorectal cancers. Consistently, the hypothesis to re-determine RAS mutational status in ctDNA at disease progression in RAS mutant mCRC opened to a new perspective for clinically-based selection of patients to be treated with EGFR inhibitors. Currently, the genomic landscape of "neo-RAS wild-type" is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with RAS mutation clearance in a large cohort of RAS mutant mCRC patients who converted to RAS wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of "true neo-RAS wild- type". Patients and methods: 70 patients with stage IV RAS mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. RAS/BRAF mutations in plasma were assessed by RT-PCR. In RAS/BRAF wild-type samples, ctDNA was used to generate libraries using a 17 genes panel whose alteration has clinical relevance. To investigate the prognostic significance of RAS mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test. Results: The most commonly detected actionable mutations in "neo-RAS wild-type" were: PIK3CA (35.7%); RET (11.9%); IDH1 (9.5%); KIT (7%); EGFR (7%); MET (4.7%); ERBB2 (4.7%); FGFR3 (4.7%). Both OS and post-progression survival were longer in patients with "neo-RAS wild-type" compared to those who remained RAS mutant (p<0.001 for both). Conclusions: De-novo-targetable mutations occured in a large percentage of "neo-RAS wild-type", being PIK3CA the most commonly detected. RAS mutation clearance in ctDNA is associated with long- term improvement of overall survival.

Assessment of sST2 Behaviors to Evaluate Severity/Clinical Impact of Acute Pulmonary Embolism.

Pulmonary embolism (PE) is a potentially life-threatening disorder. Beyond its usefulness in the prognostic stratification of heart failure, sST2 can represent a biomarker with high utility in several acute conditions. Our study was aimed to investigate whether sST2 can be used as a clinical marker of severity and prognostic outcome in acute PE. We enrolled 72 patients with documented PE and 38 healthy subjects; we measured the plasma concentrations of sST2 to evaluate the prognostic and severity performance of different levels of sST2 according to its association with the pulmonary embolism severity index (PESI) score and several parameters of respiratory function. PE patients had significantly higher levels of sST2 compared with healthy subjects (87.74 ± 17.1 vs. 17.1 ± 0.4 ng/mL, p < 0.001); we found higher PESI scores and serum lactate values in the group of patients with sST2 > 35 ng/mL compared with patients with sST2 < 35 ng/mL (138.7 ± 14.9 vs. 103.7 ± 15.1 and 2.43 ± 0.69 vs. 1.025 ± 0.05 mmol/L, respectively; p < 0.05). Patients with sST2 > 35 ng/mL showed higher radiological severity of PE compared with patients with sST2 < 35 ng/mL. Moreover, sST2 was the strongest parameter with a discriminative capacity for the development of acute respiratory failure and a PESI score >106 with respect to C reactive protein (CRP), creatinine, d-dimer, and serum lactate. We clearly demonstrated that sST2 significantly increased in PE and that its elevation was associated with disease severity. Therefore, sST2 may be used as a clinical marker in the evaluation of PE severity. However, further studies with larger patient populations are required to confirm these findings.

Obesity-Associated Hepatic Steatosis, Somatotropic Axis Impairment, and Ferritin Levels Are Strong Predictors of COVID-19 Severity.

The full spectrum of SARS-CoV-2-infected patients has not yet been defined. This study aimed to evaluate which parameters derived from CT, inflammatory, and hormonal markers could explain the clinical variability of COVID-19. We performed a retrospective study including SARS-CoV-2-infected patients hospitalized from March 2020 to May 2021 at the Umberto I Polyclinic of Rome. Patients were divided into four groups according to the degree of respiratory failure. Routine laboratory examinations, BMI, liver steatosis indices, liver CT attenuation, ferritin, and IGF-1 serum levels were assessed and correlated with severity. Analysis of variance between groups showed that patients with worse prognoses had higher BMI and ferritin levels, but lower liver density, albumin, GH, and IGF-1. ROC analysis confirmed the prognostic accuracy of IGF-1 in discriminating between patients who experienced death/severe respiratory failure and those who did not (AUC 0.688, CI: 0.587 to 0.789, p < 0.001). A multivariate analysis considering the degrees of severity of the disease as the dependent variable and ferritin, liver density, and the standard deviation score of IGF-1 as regressors showed that all three parameters were significant predictors. Ferritin, IGF-1, and liver steatosis account for the increased risk of poor prognosis in COVID-19 patients with obesity.

Interleukin 18 and IL-18 BP response to Sars-CoV-2 virus infection.

The immune response to the SARS-CoV-2 infection is crucial to the patient outcome. IL-18 is involved in the lymphocyte response to the disease and it is well established its important role in the complex developing of the host response to viral infection. This study aims at the analysis of the concentrations of IL-18, IL-18BP, INF-γ at the onset of the SARS-CoV-2 infection. The serum levels of measured interleukins were obtained through enzyme-linked immunosorbent assay. Furthermore, the free fraction of IL-18 was numerically evaluated. The enrolled patients were divided in two severity groups according to a threshold value of 300 for the ratio of arterial partial pressure of oxygen and fraction of inspired oxygen fraction and according to the parenchymal involvement as evaluated by computerized tomography at the admittance. In the group of patients with a more severe disease, a significant increase of the IL-18, INF-γ and IL-18BP levels have been observed, whereas the free IL-18 component values were almost constant. The results confirm that, at the onset of the disease, the host response keep the inflammatory cytokines in an equilibrium and support the hypothesis to adopt the IL-18BP modulation as a possible and effective therapeutic approach.

Prognostic Role of sST2 in Acute Heart Failure and COVID-19 Infection-A Narrative Review on Pathophysiology and Clinical Prospective.

The importance of cardiovascular biomarkers in clinical practice increased dramatically in the last years, and the interest extends from the diagnosis purpose to prognostic applications and response to specific treatment. Acute heart failure, ischemic heart failure, and COVID-19 infection represent different clinical settings that are challenging in terms of the proper prognostic establishment. The aim of the present review is to establish the useful role of sST2, the soluble form of the interleukin-1 receptor superfamily (ST2), physiologically involved in the signaling of interleukin-33 (IL-33)-ST2 axis, in the clinical setting of acute heart failure (HF), ischemic heart disease, and SARS-CoV-2 acute infection. Molecular mechanisms associated with the IL33/ST2 signaling pathways are discussed in view of the clinical usefulness of biomarkers to early diagnosis, evaluation therapy to response, and prediction of adverse outcomes in cardiovascular diseases.

Empirical Antimicrobial Therapy and QTc Interval Prolongation in Emergency Medicine.

BACKGROUND: QTc prolongation is common in dangerous clinical conditions, associated with an increased risk of life-threatening arrhythmia torsades de pointes. The goal of this short communication is to evaluate the principal causes of risk of QTc prolongation that are observed in an emergency department and discuss the differences between drug- and non-drug-associated factors. METHODS: The retrospective analysis was carried out on 130 patients that presented a QTc prolongation (>480 ms for man and >470 for female, respectively), admitted to the emergency department of a single Italian hospital. Patients with pace-maker (22) were excluded from this study. For each patient, a minimum of 3 ECGs (12 leads) were recorded. Attention was paid on electrolytes disturbances and to the pharmacotherapy, with a particular emphasis to the use of antibiotics. RESULTS: Mean age of the patients was 79.6 years (SD=11.3) and females and males were almost equally present (46.6% F, 53.7% M). The average QTc value was 492.2 ms (493.3 ms F, 492.8 M). The patients were divided in those with electrolytes disturbances (24.0%), antimicrobial therapy (35.2%), both antimicrobial therapy and electrolytes disturbances (24.1%), and other causes of QTc prolongation (16.7%). CONCLUSION: This analysis shows the relevance of the empirical therapy established at the admission, in particular for infective diseases, as an important risk factor for the prolongation of QTc. Other factors that can increase the risk are electrolytes alterations, advanced age, cardiovascular diseases, and drug-drug interaction.

Cardiac complications in a patient affected by systemic mastocytosis and primitive myelofibrosis: A case report.

Systemic mastocytosis with associated primitive myelofibrosis is a rare and complex disease with a difficult therapeutic management. The release of several inflammation mediators can trigger acute cardiovascular events.

An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes.

Ethyl- and propyl-prism[6]arenes are obtained in high yields and in short reaction times, independent of the nature and size of the solvent, in the cyclization of 2,6-dialkoxynaphthalene with paraformaldehyde. PrS[6]Et or PrS[6]nPr adopt, both in solution and in the solid state, a folded cuboid-shaped conformation, in which four inward oriented alkyl chains fill the cavity of the macrocycle. On these bases, we proposed that the cyclization of PrS[6]Et or PrS[6]nPr occurs through an intramolecular thermodynamic self-templating effect. In other words, the self-filling of the internal cavity of PrS[6]Et or PrS[6]nPr stabilizes their cuboid structure, driving the equilibrium toward their formation. Molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-fit mechanism. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer, PrS[5]. These results represent a rare example of a thermodynamically controlled cyclization process driven through an intramolecular self-template effect, which could be exploited in the synthesis of novel macrocycles.

Time to hospitalisation, CT pulmonary involvement and in-hospital death in COVID-19 patients in an Emergency Medicine Unit.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) are often treated at home given the limited healthcare resources. Many patients may have sudden clinical worsening and may be already compromised at hospitalisation. We investigated the burden of lung involvement according to the time to hospitalisation. METHODS: In this observational cohort study, 55 consecutive COVID-19-related pneumonia patients were admitted to the Emergency Medicine Unit. Groups of lung involvement at computed tomography were classified as follows: 0 (<5%), 1 (5%-25%), 2 (26%-50%), 3 (51%-75%) and 4 (>75%). We also investigated in-hospital death and the predictive value of Yan-XGBoost model and PREDI-CO scores for death. RESULTS: The median age was 74 years and 34 were men. Time to admission increased from 2 days in group 0 to 8.5-9 days in groups 3 and 4. A progressive increase in LDH, CRP and d-dimer was found across groups, while a decrease of lymphocytes paO2 /FiO2 ratio and SpO2 was found. Ten (18.2%) patients died during the in-hospital staying. Patients who died were older, with a trend to lower lymphocytes, a higher d-dimer, creatine phosphokinase and troponin T. The Yan-XGBoost model did not accurately predict in-hospital death with an AUC of 0.57 (95% confidence interval [CI] 0.37-0.76), which improved after the addition of the lung involvement groups (AUC 0.68, 95%CI 0.45-0.90). Conversely, a good predictive value was found for the original PREDI-CO score with an AUC of 0.76 (95% CI 0.58-0.93) which remained similar after the addition of the lung involvement (AUC 0.76, 95% CI 0.57-0.94). CONCLUSION: We found that delayed hospital admission is associated with higher lung involvement. Hence, our data suggest that patients at risk for more severe disease, such as those with high LDH, CRP and d-dimer, should be promptly referred to hospital care.