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Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future.

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Introduction Fluid resuscitation is a crucial intervention for the management of critically ill patients. However, after initial volume expansion, the advantages of fluid bolus administration remain controversial. Our aim was to investigate the probabilistic reasoning against fluid bolus administration in critically ill patients after initial volume expansion. We then applied this reasoning to two hypothetical case studies that evaluated the benefits and risks associated with a fluid bolus for each patient. Methods We analyzed data from 12 previously published studies, totaling 334 patients, on fluid responsiveness in critically ill patients. Owing to differences in these studies, we used a Monte Carlo simulation based on their parameters to improve our Bayesian prior, generate strong estimates, and address uncertainty. Using the established Bayesian prior for volume responsiveness, we scrutinized two hypothetical case studies employing Bayesian mathematical notation to assess the pre-test probability, posterior probability, and likelihood ratios in patients with septic shock. Results The Monte Carlo simulation yielded a mean response rate of 0.54 (SD = 0.026), suggesting that only approximately 54% of patients were responsive to fluid bolus administration. These results had an effective sample size of 17,204 and an R-hat value of 1, demonstrating the reliability of our results. In our Bayesian case studies, we demonstrate the low probabilities of volume and VO2 responsiveness over time using common bedside testing. Conclusion Our analysis shows that the pretest and posttest probabilities for volume responsiveness following initial fluid resuscitation are low. Additional bedside testing should be pursued before administering additional volume. This approach emphasizes the importance of evidence-based decision-making in the management of critically ill patients to optimize patient outcomes and minimize potential risks.

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Vancomycin, a potent glycopeptide antibiotic renowned for its efficacy against methicillin-resistant Staphylococcus aureus, also harbors the potential for adverse reactions. While its use is often associated with infusion-related events and nephrotoxicity, ototoxicity has emerged as a noteworthy but rare concern. This adverse effect, characterized by a spectrum of transient to permanent hearing loss or damage, typically surfaces in patients receiving excessive doses, those undergoing concomitant therapy with other ototoxic agents such as aminoglycosides, or individuals with baseline hearing impairment or renal dysfunction. This report highlights the possibility of ototoxicity in the setting of normal renal function and therapeutic dosing. We report a case of a 58-year-old male patient with a complex medical history, who presented with sepsis, respiratory failure, and a constellation of underlying conditions. His treatment regimen encompassed intravenous vancomycin administration, which led to an unexpected development-severe-to-profound bilateral conductive and sensorineural hearing loss after three doses. The absence of concurrent ototoxic agents and Bayesian dosing software predicting an acceptable AUC/MIC ratio complicates the understanding of this adverse event. Amid this complex scenario, the case underscores the evolving landscape of vancomycin-induced ototoxicity, encouraging heightened vigilance, thorough audiometric monitoring, and an in-depth exploration of potential mechanisms underlying this adverse reaction. Early audiometric testing and referral to otolaryngology may allow for early intervention with high-dose steroids to mitigate the ototoxicity.

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: Une infection sévère constitue une situation préoccupante, car elle s'accompagne d'un taux élevé mortalité dans le monde. L'objectif de cette étude était de déterminer les facteurs pronostiques des infections sévères vues dans le service Accueil­triage­Urgence (ATU) du Centre Hospitalier Universitaire (CHU) Mahavoky Atsimo. Méthodes : Il s'agit d'une étude rétrospective et analytique réalisée dans le service ATU du CHU Mahavoky Atsimo durant 24 mois (Janvier 2020-Décembre 2021). Nous avons inclus tous les patients avec une infection sévère, âgés de 15 et plus ayant un score qSOFA≥2. Résultats : la prévalence d'infection sévère était de 9,8% dont 68,3% de sepsis et 31,7% de choc septique. Les principales étiologies étaient la pneumopathie (26,8%), le paludisme (22%), les méningites (14,6%). Le taux de létalité était de 43,9%. L'âge moyen des patients était de 48,34ans ±2,46 avec une majorité masculine (61%). Les facteurs prédictifs d'un mauvais pronostic étaient : l'HTA (p=0,009), la présence de cardiopathie (p=0,001), l'antécédent d'infection urinaire (p=0,000), le score de Glasgow (p=0,006), le score qSOFA (p=0,010), l'extrémité froide (p=0,000), la présence des signes de lutte (p = 0,005), les râle s crépitants (p = 0,005), la VS élevée (p=0,002), l'élévation de la procalcitonine (p<0,0005), le traitement par quinolone (p=0,048), l'utilisation d'amine Vasopressive (p=0,040), la durée longue de perfusion de catécholamines (p=0,039), l'oxygénothérapie (p= 0,014) et l'utilisation de canule oropharyngée (p=0,003). Conclusions: L'infection sévère est une situation difficile à maîtriser. Le pronostic reste dépendant à la fois de la rapidité du diagnostic et de l'instauration rapide d'un traitement adapté au germe en cause

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Sepsis is a potentially dangerous infection that requires prompt identification and treatment. Emergency medicine physicians must grasp the clinical signs and laboratory results of direct and indirect organ failure, the source of infection management, and the criteria for treating sepsis and septic shock. The pathogenesis of sepsis is connected to inflammation and an excess of reactive oxygen and nitrogen species, which activate the pathogen-associated molecular pattern (PAMP)-pattern recognition receptor (PRR) and damage-associated molecular pattern (DAMP)-PRR signaling pathways. The development of rapid, sensitive, and precise techniques for sepsis diagnosis might be aided by nanotechnology, a part of nanomedicine. Nanoparticles (NPs) such as magnetic NPs, gold NPs, fluorescent (silica and quantum dots), and lipid-based NPs have all been discussed to contribute to the detection of sepsis-related microbial infections. Because of the intrinsic and unique features of these nano-sized systems, researchers are evaluating nanotechnology-based alternatives for sepsis control. Recent advances in nanotechnology-based technologies for sepsis detection and management are discussed in this study. Databases (PubMed, Medline, PMC, Google Scholar) were used to source various studies that were carried out on sepsis in terms of assessment, types, diagnosis, and treatment controversies, with more attention being given with a focus on the most recent data, principles, and management guidelines. Priority was also given to studies published within the last 11 years, using keywords such as "sepsis guidelines," "sepsis clinical," "septic risk factors," "sepsis and nano technology," "nano particles," "sepsis controversies," and "nano diagnostic" in the search. After a filtration process, the eight most relevant studies were selected to be included in this review. The filtration process included the use of both inclusion and exclusion criteria. The excluded studies were pediatric populations, obstetrical populations, and nanotechnology advancements dealing with other fields not relating to sepsis. The selected studies were also undertaken through a quality appraisal process using corresponding assessment tools. The selected articles were all highly informative about sepsis and the processes of diagnosis and treatment that are currently in use as well as those that are still being developed or implemented. Furthermore, we look at how nanomedicine in the application of nanomaterials can be employed to efficiently manage sepsis.

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BACKGROUND: Although sepsis accounts for 1 in 5 deaths globally, few molecular therapies exist for this condition. The development of effective biomarkers and treatments for sepsis requires a more complete understanding of host responses and pathogenic mechanisms at early stages of disease to minimize host-driven pathology. METHODS: An alternative to the current symptom-based approach used to diagnose sepsis is a precise assessment of blood proteomic changes during the onset and progression of Salmonella Typhimurium (ST) murine sepsis. FINDINGS: A distinct pattern of coagulation factor protein abundance was identified in the pre-septic state- prior to overt disease symptoms or bacteremia- that was predictive of the dysregulation of fibrinolytic and anti-coagulant activities and resultant consumptive coagulopathy during ST murine sepsis. Moreover, the changes in protein abundance observed generally have the same directionality (increased or decreased abundance) reported for human sepsis. Significant overlap of ST coagulopathic activities was observed in Gram-negative Escherichia coli- but not in Gram-positive staphylococcal or pneumococcal murine sepsis models. Treatment with matrix metalloprotease inhibitors prevented aberrant inflammatory and coagulopathic activities post-ST infection and increased survival. Antibiotic treatment regimens initiated after specific changes arise in the plasma proteome post-ST infection were predictive of an increase in disease relapse and death after cessation of antibiotic treatment. INTERPRETATION: Altered blood proteomics provides a platform to develop rapid and easy-to-perform tests to predict sepsis for early intervention via biomarker incorporation into existing blood tests prompted by patient presentation with general malaise, and to stratify Gram-negative and Gram-positive infections for appropriate treatment. Antibiotics are less effective in microbial clearance when initiated after the onset of altered blood proteomics as evidenced by increased disease relapse and death after termination of antibiotic therapy. Treatment failure is potentially due to altered bacterial / host-responses and associated increased host-driven pathology, providing insight into why delays in antibiotic administration in human sepsis are associated with increased risk for death. Delayed treatment may thus require prolonged therapy for microbial clearance despite the prevailing notion of antibiotic de-escalation and shortened courses of antibiotics to improve drug stewardship. FUNDING: National Institutes of Health, U.S. Army.

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Sepsis is a complex, life-threatening hyperinflammatory syndrome associated with organ failure and high mortality due to lack of effective treatment options. Here we report a core-shell hydrogel nanoparticle with the core functionalized with telodendrimer (TD) nanotrap (NT) to control hyperinflammation in sepsis. The combination of multi-valent charged and hydrophobic moieties in TD enables effective binding with biomolecules in NT. The higher crosslinking in the shell structure of nanogel excludes the abundant large serum proteins and allows for size-selectivity in scavenging the medium-sized septic molecules (10-30 kDa), e.g., lipopolysaccharides (LPS, a potent endotoxin in sepsis), thus reducing cytokine production. At the same time, the core-shell TD NT nanogel captures the over-flowing proinflammatory cytokines effectively both in vitro and in vivo from biological fluids to further control hyperinflammation. Intraperitoneal injection of core-shell TD NT nanogel effectively attenuates NF-κB activation and cytokine production in LPS-induced septic mouse models. These results indicate the potential applications of the injectable TD NT core-shell nanogel to attenuate local or systemic inflammation.

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The number of annual total joint arthroplasties (TJA) is increasing. Periprosthetic joint infections (PJI) occur when there is infection involving the prosthesis and surrounding tissue, which has the potential to develop into sepsis if left untreated. Sepsis in patients who have undergone TJA is life threatening and requires urgent treatment. If sepsis is due to PJI, the focus should be on early intravenous antibiotics with aspiration as soon as possible to diagnose the infection. Patients who develop sepsis after surgery for PJI are particularly at high risk for mortality and need to be treated in the intensive care unit.

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A fresh metal-organic framework (MOF) based on the Zn ions as the metal ions has been prepared via the solvothermal method, and its chemical formula is [Zn(byia)(DMF)]·1.5DMF·7H2O (1, byia = â€¯5-(benzimidazol-2-yl) isophthalic acid). It is worth noting that the compound 1 has excellent water stability (which can be maintained in the water for at least a month). Most fascinating, in water, the compound 1 exhibits the strong blue luminescence, which can only be selectively quenched via the contaminant of the Cr2O7 2- ion. The selective luminescence quenching with low limits of detection and high values of K sv proved its better sensing property, which can be compared with the contemporary materials. To development new strategy for the sepsis treatment, the biological activity and mechanism of the compound was explored. Firstly, the ELIA detection was performed in this experiment to assess the inhibition of compound against inflammatory factor storm during sepsis. Then, the inflammatory response in the immune cells was assessed by real time RT-PCR.

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Capnocytophaga canimorsus is a gram-negative rod that is part of the commensal flora of dogs' mouths. Among splenectomized patients who maintain close contact with dogs, the bacteria can lead to infection and fulminant sepsis even without evidence of a skin breach. In this report, we describe the case of a 71-year-old woman who had undergone splenectomy 35 years ago. She came to our emergency department complaining of back pain, myalgia, asthenia, and a fever of 40.2ºC. No other symptoms were noted upon her admission. Blood workup revealed hyperlacticaemia, increased C-reactive protein, and lymphopenia. A urinalysis and chest radiography were ordered, with no abnormal findings, and the SARS-CoV-2 test was negative. The patient developed persistent hypotension and drowsiness that did not improve with intravenous fluids. Therefore, she was started on a norepinephrine infusion. Cultures were collected, and intravenous antibiotic therapy was started with amoxicillin/clavulanic acid 2.2 mg and azithromycin 500 mg. Besides all the diagnostic tests, no infectious cause was found. On the second day of hospitalization, she started to deteriorate, and antibiotic therapy was escalated to piperacillin/tazobactam 4.5 g, resulting in a good clinical response. On the third day after admission, thanks to a group discussion, we were able to identify C. canimorsus in the patient's blood cultures. A review of history revealed that the patient was in close contact with her pet dog. This case highlights the importance of a multidisciplinary discussion, including the microbiology team, in order to reach an uncommon diagnosis. When dealing with splenectomized individuals presenting with the septic shock of unclear origin, a history of close contact with dogs must lead clinicians to consider C. canimorsus as a causative agent.

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Machine learning (ML) has the potential to bring significant clinical benefits. However, there are patient safety challenges in introducing ML in complex healthcare settings and in assuring the technology to the satisfaction of the different regulators. The work presented in this paper tackles the urgent problem of proactively assuring ML in its clinical context as a step towards enabling the safe introduction of ML into clinical practice. In particular, the paper considers the use of deep Reinforcement Learning, a type of ML, for sepsis treatment. The methodology starts with the modelling of a clinical workflow that integrates the ML model for sepsis treatment recommendations. Then safety analysis is carried out based on the clinical workflow, identifying hazards and safety requirements for the ML model. In this paper the design of the ML model is enhanced to satisfy the safety requirements for mitigating a major clinical hazard: sudden change of vasopressor dose. A rigorous evaluation is conducted to show how these requirements are met. A safety case is presented, providing a basis for regulators to make a judgement on the acceptability of introducing the ML model into sepsis treatment in a healthcare setting. The overall argument is broad in considering the wider patient safety considerations, but the detailed rationale and supporting evidence presented relate to this specific hazard. Whilst there are no agreed regulatory approaches to introducing ML into healthcare, the work presented in this paper has shown a possible direction for overcoming this barrier and exploit the benefits of ML without compromising safety.

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Background Abdominal trauma and intra-abdominal sepsis are associated with significant morbidity and mortality. Microcirculation in the gut is disrupted in hemorrhagic and septic shock leading to tissue hypoxia, and the damaged gut acts as a reservoir rich in inflammatory mediators and provides a continual source of inflammation to the systemic circulation leading to sepsis. Sepsis is defined as the presence (probable or documented) of infection together with a systemic inflammatory response to infection. Blood culture is commonly considered to be the preferred approach for diagnosing sepsis, although it is time-consuming, that is, reports are normally available only after 12-48 hours. Procalcitonin levels (PCT) have recently emerged as a promising biomarker in the diagnosis of sepsis. The aim of the present study is to determine the diagnostic accuracy of PCT levels in predicting sepsis in critically ill trauma patients. Methodology This was designed as a validation study conducted in the Indoor Department of General Surgery, Liaquat National Hospital, Karachi. The sample size was calculated by taking the estimated frequency of sepsis in suspected patients at 62.13%, expected sensitivity of PCT at 70.83%, and specificity at 84.21% and the desired precision level of 12% for sensitivity; the calculated sample size was 96. The non-probability consecutive sampling method was used to recruit participants who were diagnosed with sepsis on clinical assessment. Blood culture samples were sent for the enrolled patients and a final diagnosis was made on the blood culture report. PCT levels were measured in these suspected patients on the same day of sending blood culture. Diagnostic accuracy of PCT size was measured using the receiver operating characteristic (ROC) curve. ROC curve was formulated for PCT levels against culture-proven sepsis to determine the ideal cut-off value of PCT levels. Two different cut-offs were determined to obtain the highest sensitivity and highest specificity accordingly. Results A total of 97 individuals met the inclusion criteria with a mean age of 34.89 ± 10.52 years. Mean PCT levels were 0.96 ± 0.59, with a gender predilection towards females (p < 0.001). No age difference was documented among gender (p = 0.655). The mean duration of intensive care unit stay was 11.73 ± 3.56 days. Culture-proven sepsis was identified in 67.0% of the study participants with a higher PCT level (p < 0.001). Among the 52.6% males included in the study, half were reported to have culture-positive sepsis, but among the 47.4% females culture was positive in 87% (p < 0.001). ROC revealed PCT was predictive for culture-positive sepsis at a cut-off value 0.47 ng/mL (p < 0.001), with a sensitivity of 92.3%, specificity of 68.7%, positive predictive value (PPV) of 85.7%, and negative predictive value (NPV) of 81.5%. By increasing the cut-off value to 0.90 ng/mL at area under the curve of 0.816, the specificity increased to 81.3% and sensitivity became 66.2%, with a PPV of 87.8% and NPV of 54.2%. Conclusion Our study determined two cut-values for PCT to predict sepsis, one with the highest sensitivity and the other with better specificity. Other than that, higher PCT levels were significant in female trauma patients. We conclude that PCT is a reliable marker for culture-proven diagnosis of sepsis and may aid physicians/surgeons to promptly manage patients accordingly.

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Introduction Fluid resuscitation is a critical aspect of the sepsis protocol with the usual initial dose being 30 mL per kilogram. Although this dose is well accepted in patients with normal cardiac function, there is some significant variation in clinical practice concerning the optimal fluid resuscitation in septic patients with underlying congestive heart failure (CHF). Many different approaches have been tried to best treat these patients by using lesser volumes of fluid. The purpose of this retrospective study is to attempt to better define optimal fluid resuscitation in congestive heart failure patients and whether standard fluid resuscitation exacerbates CHF in these cases. Methods This was a retrospective study involving patients admitted to the Emergency Department (ED) during the time period of September of 2016 through March of 2019 with a primary diagnosis of sepsis and pre-existing CHF. Data collected from the data warehouse and patient charts included demographics, total amount of fluid received in the ED and outcome data. Evidence of fluid overload (chest X-ray [CXR] evidence, rising B-type natriuretic peptide [BNP], or use of diuretics), was evaluated with respect to in-hospital mortality, white blood cell (WBC) count and comorbidities (chronic obstructive pulmonary disease [COPD], hypertension and coronary artery disease). Results There were 422 patients included in the cohort. Of the 422, 113 (26.8%) patients showed evidence of fluid overload on CXR during hospital stay and received diuretics and therefore considered in the CHF exacerbation group. The patients that experienced CHF exacerbation were significantly older (mean ± SD, 70.9 ± 11.8 years versus 67.4 ± 15.1 years, p=0.014). Patients with exacerbation also received more fluid (median and interquartile range, 3.0, 2:5.5 L versus 2.0, 1:4.3 L, p=0.017). The receiver operating characteristic curve analysis for fluid to predict exacerbation resulted in an area under the curve of 0.59 with a 95% confidence interval (CI) of 0.52 to 0.65, p=0.012. The Youden Index was used to determine an optimal cutoff value of 2.6 L. The percentage of patients in the exacerbation group above the threshold was significantly higher (57.3%) than those without exacerbation (43.3%), p=0.019. Following multivariate analysis, age greater than 60 (odds ratio [OR]: 2.5; CI: 1.4-4.6, p=0.003) and fluid cutoff of 2.6 L (OR: 1.9; CI: 1.2-3.1, p=0.007) were both found to be independent predictors of CHF exacerbation. There was no significant difference in mortality based on the total fluid received in the ED. Conclusion The findings of this study showed that septic patients with pre-existing CHF who received more than 2.6 L of fluid in the ED were 90% more likely to develop symptoms of CHF exacerbation with no evidence of lowering mortality compared to the group that received less than 2.6 L. Our data supports the practice of limiting total fluid resuscitation in CHF to 2.6 L and reconfirms the idea that fluid resuscitation for patients with CHF needs to be individualized.

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Systemic infections is one of the major causes of mortality worldwide, and a shortage of drug approaches applied for the rapid and necessary treatment contribute to increase the levels of death in affected patients. Several drug delivery systems based in nanotechnology such as metallic nanoparticles, liposomes, nanoemulsion, microemulsion, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, hydrogels and liquid crystals can contribute in the biological performance of active substances for the treatment of microbial diseases triggered by fungi, bacteria, virus and parasites. In the presentation of these statements, this review article present and demonstrate the effectiveness of these drug delivery systems for the treatment of systemic diseases caused by several microorganisms, through a review of studies on scientific literature worldwide that contributes to better information for the most diverse professionals from the areas of health sciences. The studies demonstrated that the drug delivery systems described can contribute to the therapeutic scenario of these diseases, being classified as safe, active platforms and with therapeutic versatility.

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Sepsis is a medical emergency and life-threatening condition due to a dysregulated host response to infection, which is time-dependent and associated with unacceptably high mortality. Thus, when treating suspicious or confirmed cases of sepsis, clinicians must initiate broad-spectrum antimicrobials within the first hour of diagnosis. Optimizing antibiotic use is essential to ensure successful outcomes and to reduce adverse antibiotic effects, as well as preventing drug resistance. All likely pathogens involved should be considered to provide an appropriate antibiotic coverage. Clinicians must investigate on the previous risk of multidrug-resistant (MDR) pathogens, and the principle of individualized dosing should replace the principle of standard dosing. The loading dose is an initial higher dose of an antibiotic for all patients, yet an individualized treatment approach for further doses should be implemented according to pharmacokinetics (PK)/pharmacodynamics (PD) and the presence of renal/liver dysfunction. Extended or continuous infusion of beta-lactams and therapeutic drug monitoring (TDM) can help to achieve therapeutic levels of antimicrobials. Reevaluation of duration and appropriateness of treatment at regular intervals are also necessary. De-escalation and shortened courses of antimicrobials must be considered for most patients, except in some justified circumstances. Leadership, teamwork, antimicrobial stewardship (AS) frameworks, guideline's recommendations on the optimal duration of treatments, de-escalation, and novel diagnostic stewardship approaches will help us to improve patients' quality of care.

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Sepsis and multiple organ dysfunction syndrome (MODS) is common in the surgical intensive care unit. Sepsis involves infection and the patient's immune response. Timely recognition of sepsis and swift application of evidence-based interventions is critical to the success of therapy. This article reviews the nature of the septic process, existing definitions of sepsis, and current evidence-based treatment strategies for sepsis and MODS. An improved understanding of the process of sepsis and its relation to MODS has resulted in clinical definitions and scoring systems that allow for the quantification of disease severity and guidelines for treatment.

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