Critical Care Unit Mortality Research Articles

LCN2 depletion aggravates sepsis-induced liver injury by regulating PTGS2-dependent ferroptosis.

Background: Sepsis-induced liver injury (SILI) is an independent risk factor for organ dysfunction and mortality in critical care units. Methods: In this study, the roles of lipocalin 2 (LCN2) in SILI were investigated because LCN2 expression was increased in liver tissues of the septic mice induced by caecal ligation and puncture (CLP), as well as in hepatocytes treated with lipopolysaccharide (LPS). To evaluate liver injury in mice, the levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were measured in both serum and liver tissues. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) in serum and liver samples. Additionally, ferroptosis was assessed by examining the expression of prostaglandin endoperoxide synthase 2 (PTGS2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in liver tissue. Results: The results demonstrated that LCN2 depletion significantly exacerbated SILI, oxidative stress, and ferroptosis. Moreover, in in vitro sepsis model, LCN2 overexpression notably ameliorated LPS-induced cell injury, oxidative stress, and ferroptosis by inhibiting PTGS2 expression. Conclusion: In conclusion, our study provides evidence that LCN2 depletion aggravates SILI by regulating PTGS2-mediated ferroptosis.

Outcomes among critically ill adults with influenza infection.

Influenza infection is a major cause of mortality in critical care units. ata on critically ill adult patients with influenza infection from 2014 to 2019 were retrospectively collected, including mortality and critical care resource utilization. Independent predictors of mortality were identified using Cox regression. ne hundred thirty patients with confirmed influenza infection had a mean age of 56 (SD 16) years; 72 (55%) were male. Mean Acute Physiology and Chronic Health Evaluation (APACHE II) score was 22 (SD 9). One hundred eight (83%) patients had influenza A (46% H1N1pdm09, 33% H3N2); 21 (16%) had influenza B. Fifty-five (42%) patients had bacterial co-infection. Only 5 (4%) had fungal co-infection. One hundred eight (83%) patients required mechanical ventilation; 94 (72%), vasopressor support; 26 (20%), continuous renal replacement therapy (CRRT); and 11 (9%), extracorporeal membrane oxygenation. One hundred twenty one (93%) patients received antiviral therapy (median 5 d). Thirty-day mortality was 23%. Patients who received antiviral treatment were more likely to survive with an adjusted hazard ratio (aHR) of 0.15 (95% CI 0.04 to 0.51, p = 0.003). Other independent predictors of mortality were the need for CRRT (aHR 2.48, 95% CI 1.14 to 5.43, p= 0.023), higher APACHE II score (aHR 1.08, 95% CI 1.02 to 1.14, p = 0.011), and influenza A (aHR 7.10, 95% CI 1.37 to 36.8, p = 0.020) compared with influenza B infection. mong critically ill influenza patients, antiviral therapy was independently associated with survival. CRRT, higher severity of illness, and influenza A infection were associated with mortality.

Mechanisms Underlying the Effects of Lianhua Qingwen on Sepsis-Induced Acute Lung Injury: A Network Pharmacology Approach.

Background and Purpose: Sepsis is a life-threatening condition associated with secondary multiple organ injury. Acute lung injury (ALI) caused by sepsis has high morbidity and mortality in critical care units. Lianhua Qingwen (LHQW) is a traditional Chinese medicine composing of 11 herbs and 2 medicinal minerals. LHQW exhibits anti-inflammatory activity and is effective in treating pneumonia. Our study aimed to evaluate the effect of LHQW on sepsis-induced ALI and its underlying mechanism. Materials and Methods: A network pharmacology approach was used to predict the bioactive components and effective targets of LHQW in treating ALI. We established ALI model C57/BL6 mice via an intraperitoneal injection of LPS and inhibited p53 expression by pifithrin-α, in order to validate the mechanism by which LHQW exerted protective role in ALI. Hematoxylin-eosin staining was conducted to assess the severity of lung injury. The severity of inflammation was evaluated based on MPO (myeloperoxidase) activity. TUNEL assay was employed to detect apoptotic cells. The levels of p53 and caspase-3 were tested by immunohistochemical staining and Western blotting. The expression levels of Bcl-2, Bax, cytochrome C and caspase-9 were detected by Western blotting. Results: A total of 80 genes were associated with LHQW in the treatment of ALI. After PPI network construction, four active components (quercetin, luteolin, kaempferol and wogonin) and 10 target genes (AKT1, TP53, IL6, VEGFA, TNF, JUN, STAT3, MAPK8, MAPK1, and EGF) were found to be essential for ALI treatment. GO and KEGG analyses indicated that apoptosis pathway was mainly involved in the LHQW-ALI network. Animal experiments showed that LHQW was able to attenuate LPS-induced ALI, and medium-dose LHQW exhibited the most prominent effect. LHQW could inhibit the overexpression of p53 induced by LPS and suppress p53-mediated intrinsic apoptotic pathways by decreasing the levels of Bax, caspase-3 and caspase-9, increasing the expression of Bcl-2, and attenuating the release of cytochrome C in ALI mice. Conclusion: This study reveals that LHQW may alleviate LPS-induced ALI via inhibiting p53-mediated intrinsic apoptosis pathways.

Vitamin D in Acute and Critically Sick Children with a Subgroup of Sepsis and Mortality: A Meta-Analysis

A meta-analysis study was performed to evaluate the relationship between vitamin D deficiency children and sepsis and acute and critically mortality. Through a systematic literature search up to December 2019, 23 studies with 4451 children, 2500 children with vitamin D deficiency were identified reporting relationships between vitamin D deficiency and sepsis and/or acute and critical care unit mortality (six sepsis only, four acute and critically mortality only and 13 both sepsis and acute and critically mortality). Odd ratio (OR) with 95% confidence intervals (CIs) was calculated comparing vitamin D deficiency children to normal vitamin D children on the bases of sepsis and mortality in acute and critical care units using the dichotomous method with a random effect model. No significant difference was found between males and females in pooled studies all together (OR, 0.72; 95% CI, 0.43–1.22). Vitamin D deficiency children (OR, 2.24; 95% CI, 1.42–3.53) had higher sepsis compared to normal vitamin D children. Also, vitamin D deficiency children (OR, 1.77; 95% CI, 1.26–2.49) had higher acute and critically mortality compared to normal vitamin D children but not as much as that in sepsis. The extent of increased sepsis was higher than that in acute and critically mortality. The impact of vitamin D deficiency in children was observed in all populations. Based on this meta-analysis, vitamin D deficiency in children may have an independent-relationship with up to 2.24 fold risk of sepsis and acute and critical care unit mortality. This relationship forces us to recommend checking vitamin D concentration in all critically ill children.

Admission patterns and survival from status epilepticus in critical care in the UK: an analysis of the Intensive Care National Audit and Research Centre Case Mix Programme database

Factors influencing the outcome after the critical care unit (CCU) for patients with status epilepticus (SE) are poorly understood. Survival for these patients was examined to establish (i) whether the risk of mortality has changed over time and (ii) whether admission to different unit types affects mortality risk over and above other risk factors. The Intensive Care National Audit and Research Centre database and the Case Mix Programme database (January 2001 to December 2016) were analysed. Units were defined as neuro-CCU (NCCU), general CCU with 24-h neurological support (GCCU-N) or general CCU with limited neurological support (GCCU-L). There were 35595 CCU cases of SE with a 3-fold increase over time (4739 in 2001-2004 to 14166 in 2013-2016). More recent admissions were older and were more often unsedated on admission. Mortality declined for all units although this was more marked for NCCUs (8.1% in 2001-2004 to 4.4% in 2013-2016 compared to 5.1% and 4.1% for GCCU-L). Acute hospital mortality was two to three times higher than CCU mortality although this has also declined with time. GCCU-L appeared to have lower mortality than NCCUs (odds ratio 0.84, 95% confidence interval 0.72, 0.98) but after post hoc adjustment for case mix there were no differences. Older age and markers of seriousness of morbidity were all associated with increased mortality risk. The number of patients admitted to a CCU for SE is rising but critical care and acute hospital mortality is decreasing. Patients treated in an NCCU have higher mortality but this is explicable by more severe underlying disease.

Incidence and Outcomes for Patients With Cirrhosis Admitted to the United Kingdom Critical Care Units.

To assess the epidemiology and outcome of patients with cirrhosis following critical care unit admission. Retrospective cohort study. Critical care units in England, Wales, and Northern Ireland participating in the U.K. Intensive Care National Audit and Research Centre Case Mix Programme. Thirty-one thousand three hundred sixty-three patients with cirrhosis identified of 1,168,650 total critical care unit admissions (2.7%) admitted to U.K. critical care units between 1998 and 2012. None. Ten thousand nine hundred thirty-six patients had alcohol-related liver disease (35%). In total, 1.6% of critical care unit admissions in 1998 had cirrhosis rising to 3.1% in 2012. The crude critical care unit mortality of patients with cirrhosis was 41% in 1998 falling to 31% in 2012 (p < 0.001). Crude hospital mortality fell from 58% to 46% over the study period (p < 0.001). Mean(SD) Acute Physiology and Chronic Health Evaluation II score in 1998 was 20.3 (8.5) and 19.5 (7.1) in 2012. Mean Acute Physiology and Chronic Health Evaluation II score for patients with alcohol-related liver disease in 2012 was 20.6 (7.0) and 19.0 (7.2) for non-alcohol-related liver disease (p < 0.001). In adjusted analysis, alcohol-related liver disease was associated with increased risk of death (odds ratio, 1.51 [95% CI, 1.42-1.62; p < 0.001]) with a year-on-year reduction in hospital mortality (adjusted odds ratio, 0.95/yr, [0.94-0.96, p < 0.001]). More patients with cirrhosis are being admitted to critical care units but with increasing survival rates. Patients with alcohol-related liver disease have reduced survival rates partly explained by higher levels of organ failure at admission. Patients with cirrhosis and organ failure warrant a trial of organ support and universal prognostic pessimism is not justified.

Total Coumarins from Hydrangea paniculata Show Renal Protective Effects in Lipopolysaccharide-Induced Acute Kidney Injury via Anti-inflammatory and Antioxidant Activities.

Background: Septic acute kidney injury (AKI) causes high mortality in critical care units, and no effective therapy exists in clinical treatment. In the current study, water and ethanol extracts of Hydrangea paniculata (HP), a traditional Chinese medicinal plant, were used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced murine model of septic AKI.Methods: C57BL/6 mice were orally pretreated with HP three times, and then intraperitoneal LPS injection was used to induce septic AKI. Blood from animals was collected for biochemical analysis and kidneys were obtained for pathological analysis. Kidney tissue homogenates were used to investigate the effect of HP on inflammation and oxidative stress. Immunohistochemistry was used to investigate tubular cell apoptosis. Flow cytometry was conducted to analyze leukocyte infiltration into the kidneys. Blood cell counts were used to analyze changes in peripheral leukocytes. In vitro studies with Ana1 and HK-2 cells stimulated by LPS were used to investigate the anti-inflammatory effects and inhibition of signaling pathways by HP.Results: HP significantly decreased blood urea nitrogen and plasma neutrophil gelatinase-associated lipocalin concentrations, as well as tubulointerstitium injuries in septic AKI mice. Moreover, HP administration improved animal survival following lethal LPS injections. HP ameliorated apoptosis of tubular cells by inhibiting the cleavage of caspase 3 and caspase 7. HP also showed pronounced antioxidant activity in AKI kidneys. HP showed anti-inflammatory effects by inhibiting the infiltration of neutrophils and macrophages into kidney tissues induced by LPS, as well as inhibiting the production of cytokines and chemokines. Possible molecular mechanisms included HP inhibition of NF-κB nuclear translocation in LPS-induced macrophages and tubular cells, and reduction of STAT3, STAT1, and ERK1/2 phosphorylation stimulated by LPS in vitro. Single acute toxicity tests confirmed that HP, even at 5 g/kg dosage, does not cause animal death. Pharmacokinetics also showed that coumarins from HP could be metabolized into two bioactive compounds, umbelliferone, and esculetin.Conclusions: HP extract may protect renal function in LPS-induced AKI by anti-inflammatory and antioxidant activities, and has potential in the critical care of AKI.

Daily bathing strategies and cross-transmission of multidrug-resistant organisms: Impact of chlorhexidine-impregnated wipes in a multidrug-resistant gram-negative bacteria endemic intensive care unit

Health-care associated infections are a major cause of morbidity and mortality in critical care units. The aim of this study is to evaluate the effectiveness of chlorhexidine gluconate (CHG)-impregnated wipes in the daily bathing of patients in an intensive care unit (ICU) to prevent cross-transmission and colonization by multidrug-resistant organisms (MDROs) METHODS: Prospective cohort study with an intervention of 11 months. The intervention consisted of using CHG-impregnated wipes for the daily bathing of patients on mechanical ventilation or colonized by MDROs. Monthly trends in the number of patients colonized by MDROs and the incidence of nosocomial infections were evaluated. A total of 1,675 patients were admitted to the unit during the intervention period, and 430 (25.7%) were bathed with chlorhexidine wipes. A significant decrease was observed in the incidence of colonization by MDROs over the months (β = -0.209; r2 = 0.549; P = .027), and in the number of patients colonized compared with the equivalent period of the previous year (22.0% vs 18.4%; P = .01). No significant decrease was observed in the incidence of nosocomial infection between the two periods (4.11% vs 4.57%; P = .355). No dermatologic problems were observed in the treated patients. The use of CHG-impregnated wipes reduces cross-transmission and colonization by MDROs in the ICUs in an endemic situation because of multidrug-resistant Enterobacteriaceae.

Prediction of in-hospital stroke mortality in critical care unit.

BackgroundCritical stroke causes high morbidity and mortality. We examined if variables in the early stage of critical stroke could predict in-hospital mortality.MethodsWe recruited 611 ischemic and 805 hemorrhagic stroke patients who were admitted within 24 h after the symptom onset. Data were analyzed with independent t test and Chi square test, and then with multivariate logistic regression analysis.ResultsIn ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score (OR 1.08; 95 % CI 1.06–1.11; P < 0.01), white blood cell count (OR 1.11; 95 % CI 1.05–1.18; P < 0.01), systolic blood pressure (BP) (OR 0.49; 95 % CI 0.26–0.90; P = 0.02) and age (OR 1.03; 95 % CI 1.00–1.05; P = 0.03) were associated with in-hospital mortality. In hemorrhagic stroke, NIHSS score (OR 1.12; 95 % CI 1.09–1.14; P < 0.01), systolic BP (OR 0.25; 95 % CI 0.15–0.41; P < 0.01), heart disease (OR 1.94; 95 % CI 1.11–3.39; P = 0.02) and creatinine (OR 1.16; 95 % CI 1.01–1.34; P = 0.04) were related to in-hospital mortality. Nomograms using these significant predictors were constructed for easy and quick evaluation of in-hospital mortality.ConclusionVariables in acute stroke can predict in-hospital mortality and help decision-making in clinical practice using nomogram.

A cross-sectional survey of critical care services in Sri Lanka: A lower middle-income country

PurposeTo describe the extent and variation of critical care services in Sri Lanka as a first step towards the development of a nationwide critical care unit (CCU) registry. Materials and MethodsA cross-sectional survey was conducted in all state CCUs by telephone or by visits to determine administration, infrastructure, equipment, staffing, and overall patient outcomes. ResultsThere were 99 CCUs with 2.5 CCU beds per 100000 population and 13 CCU beds per 1 000 hospital beds. The median number of beds per CCU was 5. The overall admissions were 194 per 100000 population per year. The overall bed turnover was 76.5 per unit per year, with CCU mortality being 17%.Most CCUs were headed by an anesthetist. There were a total of 790 doctors (1.6 per bed), 1 989 nurses (3.9 per bed), and 626 health care assistants (1.2 per bed). Majority (87.9%) had 1:1 nurse-to-patient ratio, although few (11.4%) nurses had received formal intensive care unit training. All CCUs had basic infrastructure (electricity, running water, piped oxygen) and basic equipment (such as electronic monitoring and infusion pumps). ConclusionSri Lanka, a lower middle-income country has an extensive network of critical care facilities but with inequalities in its distribution and facilities.

Outcomes for critically ill patients with haematological malignancies in specialist and non-specialist centres in the United Kingdom

Background: Patients with haematological malignancies admitted to critical care units have a high mortality. Specialist cancer centres may demonstrate better survival rates than non-specialist centres. We compared the outcomes of patients with haematological malignancies admitted to three different centres in the United Kingdom, and examined possible reasons for differences in outcomes. Methods: We compared the characteristics and outcomes of patients with haematological malignancies admitted to critical care units at the Christie, Royal Liverpool University and Glan Clwyd hospitals between 1st January 2007 and 1st July 2011. Differences between hospitals were compared using ANOVA or Chi-squared test, as appropriate. Factors associated with hospital mortality were analysed using logistic regression analysis. Results: 187 patients with haematological malignancies were identified. More patients with Hodgkin’s lymphoma were admitted to Glan Clwyd hospital (25%) compared to Royal Liverpool (5.8%) and the Christie (8.1%), p=0.0087. Patients admitted to the Christie had lower severity-of-illness scores compared to patients admitted to the other hospitals (p<0.001). Overall, 91 patients died before hospital discharge (48.7%). Unadjusted hospital mortality at the Christie was significantly lower (41.4%), compared to the Royal Liverpool (61.5%) and Glan Clwyd hospitals (54.2%), p=0.0240. On logistic regression analysis, the only factor associated with higher odds of hospital mortality was increasing APACHE II score (p=0.035, odds ratio 1.06 [95% CI 1.04-1.13] per point). Admission to a non-specialist centre was associated with higher odds of critical care unit mortality (p=0.036, odds ratio 2.17 [95% CI 1.05-4.46]), but was not associated with higher odds of hospital mortality (p=0.065). Conclusions: Admission to a specialist centre was not associated with lower hospital mortality compared to non-specialist centres for patients with haematological malignancies. However, admission to a specialist centre was associated with lower critical care unit mortality. Possible explanations for these differences in survival between centres could be the identified significant differences in casemix, or lower severity of illness at admission. In addition the severity of illness on admission to the critical care unit as indicated by the APACHE II score increased the odds of hospital mortality.

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial.

BackgroundAcute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.Methods/DesignPatients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1:1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.Trial registrationCurrent Controlled Trials ISRCTN88244364.

Effect of non-clinical inter-hospital critical care unit to unit transfer of critically ill patients: a propensity-matched cohort analysis

IntroductionNo matter how well resourced, individual hospitals cannot expect to meet all peaks in demand for adult general critical care. However, previous analyses suggest that patients transferred for non-clinical reasons have worse outcomes than those who are not transferred, but these studies were underpowered and hampered by residual case-mix differences. The aim of this study was to evaluate the effect of transferring adult general critical care patients to other hospitals for non-clinical reasons.MethodsWe carried out a propensity-matched cohort analysis comparing critical care patients who underwent a non-clinical critical care unit to unit transfer to another hospital with those who were not transferred. The primary outcome measure was mortality at ultimate discharge from acute hospital. Secondary outcomes were mortality at ultimate discharge from critical care, plus length of stay in both critical care and acute hospital.ResultsA total of 308,323 patients were admitted to one of 198 adult general critical care units in England and Wales between January 2008 and September 2011. This included 759 patients who underwent a non-clinical transfer within 48 hours of admission to the unit and 1,518 propensity-matched patients who were not transferred. The relative risk of ultimate acute hospital mortality was 1.01 (95% confidence interval = 0.87 to 1.16) for the non-clinical transfer group, compared with patients who were not transferred but had a similar propensity for transfer. There was no statistically significant difference in ultimate critical care unit mortality. Transferred patients received on average three additional days of critical care (P < 0.001) but the difference in length of acute hospital stay was of only borderline significance (P = 0.05).ConclusionIn our analysis the difference in mortality between non-clinical transferred and nontransferred patients was not statistically significant. Nevertheless, non-clinical transfers received, on average, an additional 3 days of critical care. This has potential ramifications in terms of distress, inconvenience and cost for patients, their families, and the National Health Service. We therefore need further evidence, including qualitative data from family members and cost-effective analyses, to better understand the broader effects of non-clinical transfer.

Outcome of adults with sickle cell disease admitted to critical care – experience of a single institution in the UK

Sickle cell disease (SCD) patients are perceived to have a high mortality when admitted to the Critical Care Unit (CCU). We performed a retrospective analysis of all adult sickle admissions to CCU at a single centre over an 8-year period (1 January 2000 to 31 December 2007). Thirty-eight patients (14 male) were admitted 46 times to CCU; the commonest reasons for admission were acute chest syndrome (14, 30%), multi-organ failure (8, 17%) and planned post-elective surgery (7, 15%). CCU mortality for SCD patients was 19.6%, comparable to a CCU-wide mortality of 17.6% during the study period in the same institution. Re-admission to CCU was high (16% over the 8-year period) but did not increase mortality risk.

Outcomes following oesophagectomy in patients with oesophageal cancer: a secondary analysis of the ICNARC Case Mix Programme Database

IntroductionThis report describes the case mix and outcomes of patients with oesophageal cancer admitted to adult critical care units following elective oesophageal surgery in England, Wales and Northern Ireland.MethodsAdmissions to critical care following elective oesophageal surgery for malignancy were identified using data from the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme Database. Information on admissions between December 1995 and September 2007 were extracted and the association between in-hospital mortality and patient characteristics on admission to critical care was assessed using multiple logistic regression analysis. The performance of three prognostic models (Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II and the ICNARC physiology score) was also evaluated.ResultsBetween 1995 and 2007, there were 7227 admissions to 181 critical care units following oesophageal surgery for malignancy. Overall mortality in critical care was 4.4% and in-hospital mortality was 11%, although both declined steadily over time. Eight hundred and seventy-three (12.2%) patients were readmitted to critical care, most commonly for respiratory complications (49%) and surgical complications (25%). Readmitted patients had a critical care unit mortality of 24.7% and in-hospital mortality of 33.9%. Overall in-hospital mortality was associated with patient age, and various physiological measurements on admission to critical care (partial pressure of arterial oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio, lowest arterial pH, mechanical ventilation, serum albumin, urea and creatinine). The three prognostic models evaluated performed poorly in measures of discrimination, calibration and goodness of fit.ConclusionsSurgery for oesophageal malignancy continues to be associated with significant morbidity and mortality. Age and organ dysfunction in the early postoperative period are associated with an increased risk of death. Postoperative serum albumin is confirmed as an additional prognostic factor. More work is required to determine how this knowledge may improve clinical management.