mRNA drugs are synthesized using cell-free systems without complex and stringent manufacturing processes, which makes their preparation simple, efficient, and economical. Over the past few years, mRNAs encoding antibodies have been one of the research frontiers of antibody drug development. In cancer immunotherapy, mRNAs encoding immune checkpoint antibodies may be advantageous regarding antibody persistence and durability of the anti-tumor immune response of patients. In our previous study, a candidate antibody—AET2010—targeting the novel immune checkpoint TIGIT was reported. Its anti-tumor activity was also investigated using adoptive transfer of NK-92MI cells in a xenograft mouse model, but the limitations of the model did not facilitate precise evaluation. In the present study, we further investigated the therapeutic potential of AET2010 for cancer in TIGIT-humanized BALB/c mice. Next, we explored the design, synthesis, and optimization of mRNAs encoding AET2010 and ultimately obtained a candidate mRNA (mRNA-BU) with favorable in vitro and in vivo expression levels of active AET2010. Particularly, lipid-nanoparticle-encapsulated mRNA-BU delivered to mice produced AET2010 with significantly higher peak concentration and expression duration than an equivalent dose of original AET2010. This study provides a sound basis for developing novel drugs targeting TIGIT.

In 2005 we reported for the first time on a chemical route aiming to synthesize stable magnetic carbon/graphite. By using the Nuclear Magnetic Resonance (NMR) technique we have verified that its magnetism is an intrinsic property of this synthesized material and not originated from ferromagnetic impurities of any kind. Through direct measurement of the local magnetic field using Carbon-13, we have concluded that its magnetism originated from defects in the structure. From its biocompatibility, we have been working on the use of magnetic carbon/graphite to deliver many compounds aiming to fight different diseases. Despite all the scientific and technological advances of the present day, cancer is a multifactorial and difficult-to-treat disease, killing hundreds of thousands of people a year worldwide. Therefore, the development of a new and efficient drug delivery system to fight cancer – among other diseases - is as important as the discovery of a novel active molecule. In this review of our own work, we show the drug delivery system named MAGUS® (an acronym for Magnetic Graphite Universal System) we have built based on nanostructured magnetic carbon/graphite. This is an innovative and promising system composed of a biocompatible nanostructured particle of magnetic carbon/graphite functionalized with different molecules and materials. MAGUS®, depending on what we link to its structure, is so versatile and can be used to detect a wide range of specimens, from tumors and cancers to chemical and biological agents used as non-conventional weapons. That is why we call it universal. In the present work, MAGUS® will be acting as a biosensor, where the magnetic carbon/graphite is functionalized with radioactive particles of Iodine-131 and antibodies of different types of cancer. Then, by focusing on both the antigen-antibody interaction and the spatial guiding through an external magnetic field we are providing our drug delivery system a double way to detect and reach just the target. Based on these strategies, the functionalized magnetic carbon/graphite will reach only the neoplasm and not the surrounding healthy cells around. In a general view, it means that we are giving specificity to the MAGUS® drug delivery system as a pioneering and effective way to detect and treat cancers. We are also working on this unprecedented and efficient drug delivery system using the principles of Boron Neutron Capture Therapy (BNCT) with Boron-10 instead of Iodine-131. BNCT technique uses neutrons as the external source and is frequently employed to treat specific tumors that are radio resistant or very difficult to kill using conventional radiation therapy. In summary, we show here for the first time that our Magnetic Graphite Universal System associated with nuclear techniques can be successfully used as a biosensor to detect and fight cancers and tumors with powerful features that conventional delivery drug systems and other treatments do not have at all.

The gold standard for advanced-stage ovarian cancer surgery entails exploration via a midline vertical laparotomy. Studies have shown that minimally invasive surgery (MIS) can be a safe and effective method for the surgical management of early ovarian cancer. In some cases, MIS can also be selectively used for cytoreductive surgery in cases with advanced-stage ovarian cancer. The robotic platform has the potential to provide similar outcomes to the laparotomy-based standard of care in advanced complex surgery while accelerating recovery, minimizing morbidity, and reducing perioperative complications. The primary objective of this study was to evaluate surgical and perioperative outcomes in patients with advanced ovarian carcinoma who underwent robotic-assisted cytoreduction. A chart review of a nonselected consecutive series of all patients undergoing surgical management of advanced ovarian cancer between 7/1/2017 and 12/31/2021 was conducted. All patients that were diagnosed with Stage III to IV ovarian cancer between the timeframe underwent robotic-assisted cytoreductive surgery at two urban community teaching hospitals in Los Angeles. Twenty-five patients were identified and included in this study. All surgeries were performed by a single surgeon. Optimal or complete CRS was achieved in 96% of the patients (24 of 25 cases). Seven (28%) underwent primary cytoreduction (PCRS) and 18 (72%) underwent interval cytoreduction (ICRS). The estimated median blood loss was 100 mL (25-500 mL), the median operative time was 5.9 hours (3.1-10.5 hours), and the conversion rate to open laparotomy was 0%. There were no intraoperative complications and the readmission rate within 30 days was 4% (1 patient) for ileus, which was managed conservatively. Currently, 64% of the patients in the case series remain alive. The median survival has not been reached. The median follow-up is 4.08 years. Results presented from this nonselected, consecutive case series illustrate how a minimally invasive robotic approach can be safely used in place of the standard exploratory laparotomy for ovarian cytoreduction.

Brain metastases in any gynecological cancer are a rare occurrence. Even more so, it is extremely rare for a gynecological malignancy to manifest itself with symptoms indicative of cerebral involvement. Literature regarding the association between MS and cancer is conflicting. We herein report a rare presentation of single metastasis of endometrial carcinoma in a 59-year-old woman affected by Primary Progressive Multiple Sclerosis (PPMS). A head CT scan was performed, which revealed the presence of an expansive lesion in the left parietal region. After careful assessment, a high-grade endometrial carcinoma was diagnosed and a decision was made to remove both the primary lesion and the brain metastasis in one sitting, through a conjoined surgery session involving neurosurgeons and gynecologists. The postoperative course was free from complications up until a few days after being transferred to a rehabilitation center, where she died following respiratory complications.

Cancer prognosis reflects a complex biological process measured by multiple types of omics data. Deep learning frameworks have been proposed to integrate multi-omics data and predict patient outcomes in different cancer types, potentially revolutionizing cancer prognosis with superior performance. This minireview summarizes the advances in the strategies for multi-omics data integration and the performance of different deep learning models in prognosis prediction of diverse cancer types using multi-omics data published in the past 18 months. The challenges and limitations of deep learning models for predicting cancer outcomes based on multi-omics data are discussed.

Aminonitriles are pharmacological-interest bioactive due to their promising antimicrobial and antitumor activity. Since cytotoxicity tests are inherent to the new drug development process, this work aimed to verify reports in the scientific literature on the cytotoxic effects of aminonitriles. The method adopted was an integrative review of works published in the last 10 years in the PubMed, Embase, Web of Science, and Virtual Health Library (VHL) databases. Three articles that matched the selection and eligibility criteria were included in this review. A total of 33 aminonitriles were used in the cytotoxicity experiments, and of the nine molecules based on pyridine, two exerted moderate cytotoxic activity, of the twelve synthesized from benzimidazole, none showed cytotoxic activity, and of the twelve derived from renieramycins, all showed considerable cytotoxic activities. The studies used in this research evaluated the cytotoxic effects of aminonitriles with evident anticancer and antimicrobial activity. The importance of evaluating the cytotoxicity of aminonitriles is emphasized, as well as the need for investigative research that explores other evaluation methods in pre-clinical tests that may corroborate the existing findings, with a view to the development of therapies against emerging health problems.

This is a literature review study focusing on the expression of p53 and WT1. Both the p53 and WT1 proteins are tumor suppressors, which means that they play a role in preventing the progression into cancerous ones. If these proteins are altered or deleted, they lose the ability to carry out their role, which might result in the development of cancer. The primary objectives of this study were to review the literature regarding the expression of both p53 and WT1 and to investigate their prognostic significance; and to discuss our new hypothesis regarding the ratios of expression of WT1/p53, as well as our model regarding acute myeloid leukemia. In brief, the objectives were to make the focus in the suggested hypothesis as well as collecting the supportive literature. According to the findings of the current research, the level of expression of WT1 and p53 can indicate either a favorable or unfavorable prognosis for cancer patients. Further, we demonstrated that the expression, not just as a quality variable but also as a quantity variable, may have a more substantial explanation in the progression of tumors than we had previously thought. According to the theory that was derived from this research, if the expression of WT1/p53 (the expression is given as a ratio) is somewhere around 4, then p53 acts as though it were wild type and offers protection against tumors. In order to verify this idea, we need to do additional study.

Genistein is an isoflavone glycoside that provides a variety of health advantages. The possibility of cancer chemopreventive drugs derived from natural sources, such as polyphenols, may constitute a novel, cost-effective strategy to reduce the rising burden of cancer throughout the world. A soy-rich diet was linked to cancer prevention in several epidemiological studies, which was explained by the presence of the phenolic component genistein in soy-based foods. Inhibiting metastasis and changing apoptosis, the cell cycle, and angiogenesis are the key ways that genistin fights various cancers. It acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. This study critically evaluates the literature that is currently available on the therapeutic benefits of genistin for various cancers.

Purpose: Stereotactic body radiation therapy (SBRT) has emerged as an alternative to surgery for patients with inoperable early-stage non-small cell lung cancer (NSCLC). The majority of inoperable NSCLC patients are elderly and frequently have comorbidities including cardiovascular diseases for which they frequently receive angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). The interactions of these medications with SBRT are not clear. The objective of the current study is to investigate the interaction of ARBs and ACEIs with SBRT for the outcomes of early-stage NSCLC. Methods and Materials: A retrospective chart review of patients treated with SBRT for Stage I and II NSCLC (AJCC 7th edition) at a single institution between 2006 and 2017 was conducted. Information on the use of ARBs, ACEIs, demographics, and tumor-related factors was collected. Kaplan-Meier and Cox proportional hazard analyses were performed to assess the impact of ARBs and ACEIs combined with SBRT respectively on the treatment outcomes of these patients. Results: In total, 116 patients were included in the study, among whom 38/116 (32.76%) received ACEIs, and 20/116 (17.24%) received ARBs. In the multivariable analysis, the use of ARBs, but not ACEIs, with SBRT, was significantly associated with the increased risk of dissemination (Hazard Ratio (HR): 2.97; CI: 1.40-6.27; p < 0.004) compared to SBRT without ARBs. The tumor size of > = 3 cm was associated with significantly decreased time to local failure and OS compared to tumor size <3cm. Conclusion: In the current retrospective study, the use of ARBs, in combination with SBRT, was associated with a significantly increased risk of disease dissemination in early-stage NSCLC compared to SBRT alone. The findings warrant further investigations on the concurrent use of ARBs, ACEIs, and other medicines used for chronic diseases with SBRT for early-stage NSCLC.

Cancer is a major public health issue and the main cause of death worldwide. Despite improvements in diagnostic techniques and treatment methods, cancer still seriously affects the quality of life of patients, which cause serious social and economic burdens. Therefore, there is an urgent need to identify potential biomarkers to improve diagnosis, treatment, and prognosis of cancer. BTG2 is a cell proliferation suppressor gene that serves as a tumor suppressor gene in the occurrence and development of various tumors. Many studies have shown that BTG2 can serve as a prognostic marker in various tumors. So, fully tap the potentials of BTG2 as a tumor prognostic marker will bring more possibilities to provide a new method or new diagnostic and therapeutic tool for treating cancer.

Daily high-fat diet (HFD) intake is generally associated with an increased risk of metabolic diseases, cancer, and neurological disorders, which represent a major global health burden with significant social and economic consequences. In the present study, mice were treated with HFD containing 40% lipids. Furthermore, HFD was supplemented with 0.5% or 1.0% acylated sterol-β-glucoside (ASG).After 55 days of rearing, body weight, epididymal fat weight, weight, and pH of cecum contents and intestinal microflora were compared with mice fed HFD or a low-fat diet (LFD) containing lipid at 7%. The results showed that body weight and epididymis fat weight on the last day of feeding were significantly higher in HFD, 0.5% ASG, and 1.0% ASG compared to LFD, but significantly lower in 0.5% ASG and 1.0% ASG compared to HFD. Cecum content weight was lower with HFD compared to LFD but increased to LFD levels with the addition of ASG. Cecum pH was significantly lower on the 1.0% ASG compared to the other groups.The gut microbiota was significantly elevated in the HFD compared to the LFD, with Bacilliota specific to obese mice. However, the addition of ASG to the HFD decreased the Bacilliota and increased the Bacteroidota. Clostridium cluster XI and Clostridium subcluster XIVa, intestinal bacteria involved in the production of carcinogenic secondary bile acids, were markedly increased by consumption of the HFD but were markedly decreased by ASG.Daily intake of ASG may inhibit the deterioration of gut bacteria caused by HFD and reduce the disease risk posed by HFD.

Introduction: In the present study we evaluated and compared RBC parameters, iron status, and ferritin for discriminating between patients with iron deficiency anemia and anemia of chronic disease. Anemia that accompanies infection, inflammation, and cancer, is commonly termed anemia of chronic disease (ACD). Methods: We compared the ability of serum ferritin concentration, using the microplate immunoenzymometric assay method with other, more traditional indicators of iron status like total iron binding capacity [TIBC], mean corpuscular volume [MCV], percent transferrin saturation [%TS], RBC distribution width [RDW], and serum iron concentration [SIC]. The ferritin concentration was determined in 80 serum samples selected from men and women above the age of 18 years. The patients were assigned to IDA and ACD groups based on serum ferritin concentration.Observation: By studying the ROC Curve for various red cell parameters for the diagnosis of IDA and ACD, we found that diagnostic accuracy of various indicators was as follows TIBC>TS%>MCV>MCH>SI>MCHC for anemia of chronic diseases, and TIBC>MCH>MCV>MCHC>TS%>SI for iron deficiency anemia. When both the value of AUCs (Area under Curve) of ROC were compared it is apparent that TIBC, TS%, MCV, and MCH are important discriminating factors between IDA and ACD. Conclusion: Conventional laboratory parameters play an important role in distinguishing overt causes of IDA and ACD. MCV, MCH, and TIBC were found to be (p -value < .05) significantly discriminated against IDA and ACD. Serum ferritin is an important diagnostic tool with reasonable accuracy for the detection and differentiation of iron deficiency anemia and anemia of chronic disease.

Background: Breast Cancer is the most common cancer in women and the quality of life of women with breast cancer is a significant healthcare issue specifically in developing and underdeveloped countries.Globally quality of Life (QoL) has become an important indicator to measure the outcomes of medical and nursing interventions. The QoL studies have an imperative role in healthcare especially in chronic disease as the latest diagnostic and treatment modalities have increased the survival rates and duration of cancer patients. Similarly, breast cancer itself and its treatment with Chemotherapy, in particular, has many complications and negative impacts on the QoL of cancer women. Aim: The aim of this study was to assess the QoL of Pakistani women with Breast Cancer patients undergoing chemotherapy and the relationship of QoL with socio-demographic variables.Methodology: A descriptive cross-sectional correlational study was conducted on 110 female breast cancer patients undergoing chemotherapy. FACIT-B questionnaire was used to assess the quality of life of these patients. Statistical analysis was done by using SPSS version 20 using the Pearson correlation coefficient, Chi-square test, and Spearman’s rho correlation coefficient. Results: The mean age of participants was (mean ± SD) 42.98 ± 8.98. A significant negative correlation was observed with age and QoL, r = -0.218, p - value 0.022. No significant association was observed between QoL and marital status; education status; and socioeconomic status.Conclusion: The majority of breast cancer women 59(53.6%) had moderate QoL and Chemotherapy also showed moderate impacts on different domains: physical, functional emotional, social, and sexual well-being of the women.

A critical component of the radiation regimen for treating cancer patients is the precise dose delivery to the treatment organ while minimizing the dose to the healthy tissue. This study aims to evaluate in-field organ dose and dose distribution outside the target organs to estimate the excess lifetime risk of second cancer. The study was carried out with a male Alderson Rando Phantom. 20 sets of thermoluminescence dosimeters (MTS-100) were used in this study. The in-field organs absorbed dose was measured by inserting TLDs at different geometrical depths of the left lung, right lung, and stomach, and for peripheral organs skin dose TLDs were placed at the surface of the corresponding organs. Target organs were irradiated at 100 cGy and 200 cGy by a 60Co teletherapy unit, and irradiated TLDs were read out by a RE-2000 TLD reader. For precise dose delivery to the cancerous organs by 60Co teletherapy, the depth dose correction factor for lung cancer treatment is 0.8667 ± 0.01, and for the stomach is 0.7856 ± 0.017. In the case of the treatment for the lung and stomach, the closest organs received significant doses compared to the other distant organs. Thus, the risk of second cancer due to the peripheral dose is obtained. The stomach is at the highest risk when the lung is the target and the liver is at the highest risk when the stomach is the targeted organ.

During this period of time, mushroom experience changes in functional aspects and consumption areas. Due to its magnificent role in promoting health, it was considered one of the most healthy sources of food. Agaricus spp., Marcrolepoita spp., Auricularia spp, Armillaria spp, Pholoita, Hericium, Grifola spp, Flammulina, and Hypsizygus spp. are some most commonly consumed mushrooms in the world. They provide inexpensive means of nutritious and tasty food worldwide. However, ancient people are also very much aware of their holistic function towards health and that was why they used mushrooms for medicinal purposes in the past onwards. Mushroom plays an important role in the treatment of some lethal diseases like cancer, inflammation, autoimmune disorders, allergy, hypertension, arthritis, hyperglycemia, atherosclerosis, and many more. Meanwhile, researchers still focus on other functions of mushrooms in health science and also explore their anticancerous activity. However, many findings are left to be found in the future. This review paper throws light on the various important mushrooms and their functions related to human health, and also ongoing research towards treating some critical diseases.

Brf1 (TFIIB-related factor 1) is a transcription factor, which specifically modulates the transcription of RNA polymerase III-dependent genes (RNA Pol III genes), such as tRNAs and 5S rRNA. The products of tRNAs and 5S rRNA transcription will be changed with the alteration of Brf1 expression. Whereas deregulation of Brf1 and RNA Pol III genes are tightly associated with cell proliferation and transformation, and tumorigenesis. In recent years, emerging studies indicate that Brf1 expression is increased in patients with cancers. In this review, we summarize the progress of the abnormal expression of Brf1 in different human cancers to explore an underlying mechanism and its clinical implication, as well as to prompt its application prospect. With the depth of the Brf1 study and the progress of biotechnology, the status of Brf1 expression may be used as a universal indicator of the early detection and prognosis observation of human cancers.

Background: Postoperative Pulmonary Complications (PPCs) escalate mortality, hospitalization, and costs. This study aimed to predict PPCs after curative digestive cancer surgery using thickness fraction (TFdi) determined by ultrasonography. Methods: A prospective study was conducted over a period of 9 months. Diaphragmatic ultrasound was performed pre-surgery and repeated postoperatively (within 24 hours of ICU admission, then day 3). Right and left hemidiaphragm thickness at end-expiration (TEE) and peak-inspiration (TPI) were measured using ultrasonography. The maximal diaphragm thickening fraction during inspiration (TFdi,max) was calculated: TFdi,max = (TPI–TEE)/TEE. Patients were classified into No-PPCs and PPCs groups. Results: 159 patients participated, 55 (34.6%) developed PPCs. ICU stay was longer in PPCs patients with more deaths. TFdi,max decreased postoperatively and remained lower in PPCs patients [44.83% ± 11.07 vs. 31.54% ± 8.45; p < 0.001]. The receiver operating characteristic curve yielded an area under the curve of 0.83 [95% IC: 0.754 – 0.887]. TFdi,max < 37% had 72.7% sensitivity (95% IC: 59.0% – 83.8%) and 80.8% specificity (95% IC: 71.8% – 87.8%), Positive and negative Likelihood Ratios were 3.7 (95% IC: 2.4 – 5.7) and 0.3 (95% IC:0.2 – 0.5), respectively. In multiple logistic regression, preoperative risk factors for PPCs included TFdi,max < 37% [OR: 7.10; 95% CI: 1.71 – 18.60; p < 0.001] and supramesocolic surgery [OR: 9.94; 95% CI: 3.62 – 27.29; p < 0.001]. Epidural administration was protective [OR: 0.21; 95% CI: 0.052 – 0.87; p = 0.031]. Conclusion: A low preoperative TFdi,max identifies high-risk PPCs patients after digestive cancer surgery, aiding targeted preventive strategies like inspiratory muscle preoperative training.

Background and aim: Preclinical in vitro and in vivo experiments suggest that radiation-induced tumour cell death can be enhanced 10- to 40-fold when combined with focused-ultrasound (FUS)-stimulated microbubbles (MB). The acoustic exposure of MB in the tumour volume causes vasculature perturbation, activation of the acid sphingomyelinase (ASMase) ceramide pathway, and resultant endothelial cell apoptosis. When the tumour is subsequently treated with radiation, there is increased endothelial cell death and anoxic tumour killing. Here we describe a first-in-human experience treating patients with magnetic resonance (MR)-guided FUS-stimulated MB (MRgFUS+MB) radiation enhancement.Case presentation: A head and neck cancer patient with recurrent disease underwent radiotherapy for 5 separate sites of locoregional disease followed by systemic therapy. The first consisted of a course of 45 Gy in 5 fractions alone, the second of 30 Gy in 5 fractions with hyperthermia, and the three others of 20-30 Gy in 5 fractions along with MRgFUS+MB treatment. The treatment methodology used an MR-coupled FUS-device operating at 500 KHz and 540 kPa peak negative pressure with an insonification time of 750 ms spread over 5 minutes to stimulate intravenously administered MB within tumour target. All sites treated with stimulated MB had a complete radiological response, and subsequently, the patient’s other cutaneous metastatic disease disappeared. The patient has been under surveillance for over two years without active treatment or disease progression.Discussion: MRgFUS+MB was well-tolerated with no reported treatment-related adverse events, which can be attributed to the capability of FUS to selectively stimulate MB within the tumour volume while sparing the surrounding normal tissue. Sustained local control at all target sites aligns with earlier preclinical findings suggesting the radiation enhancement potential of FUS+MB.Conclusion: MRgFUS+MB represents a novel and promising therapy for enhancing radiation efficacy and improving therapeutic index with potential improvements in disease control.

Recently, many studies on the molecular activity of compounds have been carried out using simulations through computer programs or in silico simulations. Anthocyanins are one of the compounds that are often used as food coloring agents and can function as antioxidants to prevent blockage of blood vessels, as an anti-cancer that can prevent the development of cancer cells and tumors and have anti-inflammatory effects. The purpose of the research is to determine the stability of anthocyanins using molecular simulations and determine the best mixing sequence of ingredients to produce the most stable anthocyanin mixture. Based on the results of the simulations carried out, it can be proven that the final 3 sets (the modeled compound belonging to namely AP and AZ followed by a number based on the simulation order) selected are AP17, AP18, and AZ17. The AP17 set had the lowest potential energy at the end of molecular dynamics simulations, but molecular visualization showed structural instability indicated by the formation of gaps in the molecular conformation. The AP18 set had the second lowest potential energy at the end of molecular dynamics simulations and molecular visualization showed molecular conformation that tended to be stable during molecular simulations with no change in structure. The AZ17 set had the highest potential energy of the final 3 sets selected and molecular visualization showed a gap in the conformation at the beginning of the simulation, but over time the gap became denser, indicating that the molecule became more stable over time. Based on the research results, the AP18 set was chosen because it has relatively low potential energy and it can be proven that the structure visualization of this set tends to be more stable over time during molecular dynamics simulations.

As the introduction of immune checkpoint inhibitors in the treatment of various cancers is now proven to be already acquired knowledge, so does a new challenge arise for clinicians; the understanding, diagnosis, and management of the rarest adverse effects of immunotherapy. We present a case of type-1 diabetes Mellitus (T1DM) in a patient with non-small cell lung carcinoma (NSCLC) treated with pembrolizumab. Following ten cycles of treatment, our patient was diagnosed with T1DM after being admitted for diabetic ketoacidosis and stayed hospitalized in the ICU. Later, they continued treatment with insulin, having shown disease response to pembrolizumab, and resumed immunotherapy while on insulin. Immunotherapy-induced T1DM can sometimes occur with PD1/PD-L1 blockage therapies. It has a rapid onset, is characterized by insulin deficiency due to the autoimmune destruction of beta-cells, and usually presents itself with diabetic ketoacidosis. Unlike most of the other adverse effects of immunotherapy, glucocorticoids don’t seem to be of therapeutic value, and insulin substitution is required. Regular glucose monitoring can be key to early diagnosis and prevention of hospitalization.