Lung ultrasound systematic review shows its prognostic and diagnostic role in acute viral bronchiolitis.

AIM: Lung ultrasound (LUS) has not been included in the current guidelines for the diagnosis of bronchiolitis so far, even though data concerning its effectiveness have been published. METHODS: A systematic literature review was carried out to determine the role of LUS scores in the diagnosis and prognosis of patients aged 0-2 years with bronchiolitis, using MEDLINE, Scopus and ScienceDirect databases from their inception to December 2021. RESULTS: A total of 18 studies matching our eligibility criteria were analysed for the purposes of this review and 1249 patients with bronchiolitis were included. The sonographic and radiological findings were comparable and chest radiography was found to have a higher sensitivity in ruling out severe complications such as concomitant pneumonia. The LUS scores were correlated to the clinical course of bronchiolitis and it was able to predict the need of admission in paediatric intensive care unit, the duration of hospitalisation and the need for respiratory support. CONCLUSION: This review suggests that LUS could have both a diagnostic and a prognostic role in bronchiolitis during first evaluation in the emergency department and hospitalisation. Physicians could adjust management according to sonographic findings as a useful adjunct to the clinical ones.

European Respiratory Society statement for defining respiratory exacerbations in children and adolescents with bronchiectasis for clinical trials.

Bronchiectasis is being diagnosed increasingly in children and adolescents. Recurrent respiratory exacerbations are common in children and adolescents with this chronic pulmonary disorder. Respiratory exacerbations are associated with an impaired quality of life, poorer long-term clinical outcomes, and substantial costs to the family and health systems. The 2021 European Respiratory Society (ERS) clinical practice guideline for the management of children and adolescents with bronchiectasis provided a definition of acute respiratory exacerbations for clinical use but to date there is no comparable universal definition for clinical research. Given the importance of exacerbations in the field, this ERS Task Force sought to obtain robust definitions of respiratory exacerbations for clinical research. The panel was a multidisciplinary team of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, methodology, patient advocacy, and parents of children and adolescents with bronchiectasis. We used a standardised process that included a systematic literature review, parent survey, and a Delphi approach involving 299 physicians (54 countries) caring for children and adolescents with bronchiectasis. Consensus was obtained for all four statements drafted by the panel as the disagreement rate was very low (range 3.6-7.2%). The panel unanimously endorsed the four consensus definitions for 1a) non-severe exacerbation and 1b) severe exacerbation as an outcome measure, 2) non-severe exacerbation for studies initiating treatment, and 3) resolution of a non-severe exacerbation for clinical trials involving children and adolescents with bronchiectasis. This ERS Task Force proposes using these internationally derived, consensus-based definitions of respiratory exacerbations for future clinical paediatric bronchiectasis research.

Takayasu arteritis in an adolescent with Crohn's disease.

Crohn's disease (CD) and Takayasu arteritis (TA) are two distinct clinical entities. Τhe likelihood of both diseases coexisting is low, and although CD co-occurs with all types of vasculitis, TA is the most common subtype. Herein, the case of a 15-year-old female, diagnosed with TA following an initial diagnosis of CD, is reported. A review of the literature, including a systemic review of the case reports and case series of children and adolescents up to the age of 21, with both CD and TA, follows the case description. In total, 28 cases of TA and CD were retrieved. The median age of patients was 14.8 years, they were mostly females (72%) and the median time between the two diagnoses was 3.7 years. In the majority of cases, CD was diagnosed first and TA followed. Computed tomography angiography and magnetic resonance angiography were the preferred imaging modalities to assist diagnosis.

European Respiratory Society guidelines for the management of children and adolescents with bronchiectasis.

There is increasing awareness of bronchiectasis in children and adolescents, a chronic pulmonary disorder associated with poor quality of life for the child/adolescent and their parents, recurrent exacerbations, and costs to the family and health systems. Optimal treatment improves clinical outcomes. Several national guidelines exist, but there are no international guidelines.The European Respiratory Society (ERS) Task Force for the management of paediatric bronchiectasis sought to identify evidence-based management (investigation and treatment) strategies. It used the ERS standardised methodology that included a systematic review of the literature and application of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to define the quality of the evidence and level of recommendations.A multidisciplinary team of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, immunology, methodology, patient advocacy and parents of children/adolescents with bronchiectasis considered the most relevant clinical questions (for both clinicians and patients) related to managing paediatric bronchiectasis. 14 key clinical questions (seven PICO (Patient, Intervention, Comparison, Outcome) and seven narrative) were generated. The outcomes for each PICO were decided by voting by the panel and parent/patient advisory group.This guideline addresses the definition, diagnostic approach and antibiotic treatment of exacerbations, pathogen eradication, long-term antibiotic therapy, asthma-type therapies (inhaled corticosteroids and bronchodilators), mucoactive drugs, airway clearance, investigation of underlying causes of bronchiectasis, disease monitoring, factors to consider before surgical treatment, and the reversibility and prevention of bronchiectasis in children/adolescents. Benchmarking quality of care for children/adolescents with bronchiectasis to improve clinical outcomes and evidence gaps for future research could be based on these recommendations.

Diagnostic accuracy of two-dimensional shear wave elastography in detecting hepatic fibrosis in children with autoimmune hepatitis, biliary atresia and other chronic liver diseases.

BACKGROUND: Although fibrosis is the main determinant of liver stiffness, other disease-related factors usually disregarded in studies on liver elastography, such as inflammation and cholestasis, may influence liver stiffness. OBJECTIVE: To evaluate the accuracy of two-dimensional (2-D) shear wave elastography in assessing liver fibrosis in children with chronic liver disease by controlling for the confounding role of several disease- and patient-related factors. MATERIALS AND METHODS: Three disease groups were studied: 1) various chronic liver diseases, 2) autoimmune hepatitis and 3) biliary atresia. The METAVIR (meta-analysis of histological data in viral hepatitis) score was used for fibrosis staging and grading of necroinflammatory activity. Multiple linear regression was used to evaluate the relationship between liver stiffness measurements and disease-related factors. The diagnostic accuracy of elastography for predicting fibrosis stages was assessed by calculating the area under the receiver operating characteristic curves. RESULTS: The various chronic liver diseases group (n=32; 7.1±4.9 [mean±standard deviation] years) showed liver stiffness of 8.9±5.0 (mean±standard deviation) kPa, the autoimmune hepatitis group (n=33; 8.1±4.4 years) of 7.1±2.7 kPa, and the biliary atresia group (n=19; 0.2±0.1 years) of 19.7±15.2 kPa. Liver stiffness measurements differed across METAVIR fibrosis categories in all disease groups. The highest values were found in biliary atresia, at fibrosis stages ≥F2 (F2: 12.4±1.6 kPa, F3: 17.8±2 kPa, F4: 41.5±12.4 kPa). Liver stiffness was strongly associated only with fibrosis (P<0.0001) in various chronic liver diseases, but with necroinflammatory activity (P<0.0001) and fibrosis (P=0.002) in autoimmune hepatitis, and with age (P<0.0001), fibrosis (P<0.0001) and cholestasis (P=0.009) in biliary atresia. Optimal cutoffs for detecting advanced fibrosis (≥F3) were 16 kPa (area under curve: 0.98; sensitivity: 87.5%; specificity: 96.7%) in biliary atresia and 8.7 kPa (area under curve: 0.98; sensitivity: 93.8%; specificity: 96.1%) in other chronic liver diseases. CONCLUSION: Two-dimensional shear wave elastography is reliable in assessing liver fibrosis in children with chronic liver diseases.

Operation of ultrasonography services in a dedicated paediatric hospital and a university hospital in Greece under the COVID-19 pandemic.

Ultrasonography (US) is one of the most common diagnostic imaging tests in children. During the coronavirus disease 2019 (COVID-19) pandemic, it is important to operate with a plan designed to protect health care workers, to prevent transmission of infection from child and parents to another child or an accompanying person in the US suite, and to save valuable protective material and resources. Measures during routine US in children can be challenging both in general hospitals with paediatric units and in dedicated paediatric hospitals. Special considerations include: a) cancellation or rescheduling of unnecessary imaging tests, b) a relevant questionnaire on the request form informing about patient and accompanying person's symptoms and likely exposure in addition to general triage, c) appropriate patient and parent protective measures, d) recruitment and selection of US machines in different protected areas depending on the possibility or certainty for the infection, e) regular personnel protective measures and personal hand hygiene, f) routine disinfection of probes and adjacent surfaces and g) machine/room deep disinfection, if required. Our purpose is to present the modified US services in children during the COVID-19 pandemic in two hospitals based on the instructions of the national organization of public health in Greece and what is known about the mode of transmission of the virus.

Thoracic imaging of coronavirus disease 2019 (COVID-19) in children: a series of 91 cases.

BACKGROUND: Pulmonary infection with SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2; COVID-19) has rapidly spread worldwide to become a global pandemic. OBJECTIVE: To collect paediatric COVID-19 cases worldwide and to summarize both clinical and imaging findings in children who tested positive on polymerase chain reaction testing for SARS-CoV-2. MATERIALS AND METHODS: Data were collected by completion of a standardised case report form submitted to the office of the European Society of Paediatric Radiology from March 12 to April 8, 2020. Chest imaging findings in children younger than 18 years old who tested positive on polymerase chain reaction testing for SARS-CoV-2 were included. Representative imaging studies were evaluated by multiple senior paediatric radiologists from this group with expertise in paediatric chest imaging. RESULTS: Ninety-one children were included (49 males; median age: 6.1 years, interquartile range: 1.0 to 13.0 years, range: 9 days-17 years). Most had mild symptoms, mostly fever and cough, and one-third had coexisting medical conditions. Eleven percent of children presented with severe symptoms and required intensive unit care. Chest radiographs were available in 89% of patients and 10% of them were normal. Abnormal chest radiographs showed mainly perihilar bronchial wall thickening (58%) and/or airspace consolidation (35%). Computed tomography (CT) scans were available in 26% of cases, with the most common abnormality being ground glass opacities (88%) and/or airspace consolidation (58%). Tree in bud opacities were seen in 6 of 24 CTs (25%). Lung ultrasound and chest magnetic resonance imaging were rarely utilized. CONCLUSION: It seems unnecessary to perform chest imaging in children to diagnose COVID-19. Chest radiography can be used in symptomatic children to assess airway infection or pneumonia. CT should be reserved for when there is clinical concern to assess for possible complications, especially in children with coexisting medical conditions.

ERS statement on tracheomalacia and bronchomalacia in children.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study.

Performance of two--dimensional ultrasound shear wave elastography: reference values of normal liver stiffness in children.

BACKGROUND: Two-dimensional (2-D) shear wave elastography is a new sonographic elastography method for noninvasive measurement of liver stiffness. OBJECTIVE: The aim of this study was to establish reference values of normal liver stiffness on 2-D shear wave elastography in children. MATERIALS AND METHODS: Two-dimensional shear wave elastography values were measured in 202 children with no liver disease from the neonatal period to puberty, who were divided into 4 age groups: newborns and infants, preschoolers, elementary school children and adolescents. We investigated the effects of age, depth of elastography measurement, transducer, number of measurements per child, liver size and Doppler parameters of hepatic blood flow on liver elasticity values. RESULTS: The mean normal liver elasticity value in the study population was: 4.29±0.59  kilopascals (kPa). In neonates and infants, mean liver elasticity value was 4.63 (± 0.6) kPa, in preschoolers and elementary school children, 4.05 (± 0.57) kPa and 4.15 (± 0.52) kPa, respectively, and in adolescents, 4.39 (± 0.55) kPa. Values in neonates and infants as well as adolescents were significantly higher than in preschoolers and elementary school children (Kruskal-Wallis, P<0.001; Mann-Whitney U tests, P<0.05). There was no significant association between liver elasticity values and size of the right lobe or Doppler parameters of hepatic blood flow. Different depths and the number of elastography measurements had no effect on liver elasticity values. CONCLUSION: Two-dimensional shear wave elastography is achievable in a wide range of age in children. We established the reference values of normal liver stiffness on 2-D shear wave elastography in children.

Lung Ultrasound as First-Line Examination for the Diagnosis of Community-Acquired Pneumonia in Children.

OBJECTIVES: The diagnosis of pediatric community-acquired pneumonia (CAP) is based on clinical criteria. Even though chest x-ray (CXR) is only recommended in severe cases, it is often requested from physicians in mild cases, thus increasing radiation exposure. Lung ultrasound (LUS) is not included in the diagnostic workup. The objective of this study was to evaluate the diagnostic performance of LUS against CXR. METHODS: Children who presented to the emergency department with clinical signs suggesting CAP and had already been evaluated with a CXR were included in the study. Availability of a pediatric sonographer expert in LUS was also considered a criterion for participation. Chest x-ray and LUS were considered positive for CAP in cases of alveolar or interstitial pattern of disease. The diagnostic criterion standard was the ex post diagnosis of pneumonia, made by an independent senior expert pediatrician, after evaluation of the complete medical chart. RESULTS: Sixty-nine children were enrolled in the study, with 66 of 69 positive for CAP. Receiver operating characteristic curve analysis results for CXR were 95.5% sensitivity and 100% specificity, whereas for LUS, sensitivity was reported 92.42% and specificity 100%. Comparison of the 2 receiver operating characteristic curves revealed no difference in the diagnostic value of the 2 methods for the diagnosis of pneumonia (P = 0.658). However, LUS classified more cases as alveolar disease compared with CXR. CONCLUSIONS: Lung ultrasound plays a significant role in the detection of CAP, not inferior to CXR. The aim of this study was to encourage the use of ultrasound as a first-line examination for CAP in children.

High-Resolution Computed Tomography Examinations for Chronic Suppurative Lung Disease in Early Childhood: Radiation Exposure and Image Quality Evaluations With Iterative Reconstruction Algorithm Use.

PURPOSE: High radiosensitivity of children undergoing repetitive computed tomography examinations necessitates the use of iterative reconstruction algorithms in order to achieve a significant radiation dose reduction. The goal of this study is to compare the iDose iterative reconstruction algorithm with filtered backprojection in terms of radiation exposure and image quality in 33 chest high-resolution computed tomography examinations performed in young children with chronic bronchitis. METHODS: Fourteen patients were scanned using the filtered backprojection protocol while 19 patients using the iDose protocol and reduced milliampere-seconds, both on a 64-detector row computed tomography scanner. The iDose group images were reconstructed with different iDose levels (2, 4, and 6). Radiation exposure quantities were estimated, while subjective and objective image qualities were evaluated. Unpaired t tests were used for data statistical analysis. RESULTS: The iDose application allowed significant effective dose reduction (about 80%). Subjective image quality evaluation showed satisfactory results even with iDose level 2, whereas it approached excellent image with iDose level 6. Subjective image noise was comparable between the 2 groups with the use of iDose level 4, while objective noise was comparable between filtered backprojection and iterative reconstruction level 6 images. CONCLUSIONS: The iDose algorithm use in pediatric chest high-resolution computed tomography reduces radiation exposure without compromising image quality. Further evaluation with iterative reconstruction algorithms is needed in order to establish high-resolution computed tomography as the gold standard low-dose method for children suffering from chronic lung diseases.

Fluoroscopy-guided infiltration for pain reduction in patients with Baastrup's disease: clinical experience and results.

OBJECTIVE: Baastrup disease refers to degenerative changes of adjacent spinous processes with resultant back pain. The purpose of this study is to assess the safety and efficacy of percutaneous, fluoroscopy-guided infiltrations in a consecutive series of patients suffering from Baastrup disease. MATERIALS AND METHODS: From January 2009 until December 2013, 55 patients suffering from Baastrup disease (diagnosed clinically and by imaging findings) underwent percutaneous, fluoroscopy-guided infiltration. The position of the needle (22-gauge spinal needle) was fluoroscopically verified at the level of interspinous ligament. Then a mixture of long-acting corticosteroid with local anesthetic (1.5/1 cc) was injected. A questionnaire with NVS scale helped in assessing pain relief degree, life quality, and mobility improvement. RESULTS: In the patients of our study, a total of 67 sessions was performed. In 12/55 patients (22%), a second infiltration was performed within 7-10 days apart from the first one. The end point was 1 year post-treatment. Patients were followed 1 week after the first injection for a subsequent treatment and then if asymptomatic re-controlled in 3-6 and 12 months. Comparing the pain scores prior (mean value, 8.18 ± 1.44 NVS units) and after (mean value, 0.62 ± 0.93 NVS units) there was a mean decrease of 7.56 ± 1.68 NVS units (p < 0.001) on terms of pain reduction, effect upon mobility and life quality. There were no clinically significant complications noted in our study. CONCLUSIONS: Fluoroscopy-guided infiltrations seem to be a feasible, efficacious, and safe approach for pain reduction and mobility improvement in patients with Baastrup disease.

Imaging of Acute Complications of Community-Acquired Pneumonia in the Paediatric Population-From Chest Radiography to MRI.

The most common acute infection and leading cause of death in children worldwide is pneumonia. Clinical and laboratory tests essentially diagnose community-acquired pneumonia (CAP). CAP can be caused by bacteria, viruses, or atypical microorganisms. Imaging is usually reserved for children who do not respond to treatment, need hospitalisation, or have hospital-acquired pneumonia. This review discusses the imaging findings for acute CAP complications and the diagnostic role of each imaging modality. Pleural effusion, empyema, necrotizing pneumonia, abscess, pneumatocele, pleural fistulas, and paediatric acute respiratory distress syndrome (PARDS) are acute CAP complications. When evaluating complicated CAP patients, chest radiography, lung ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) can be used, with each having their own pros and cons. Imaging is usually not needed for CAP diagnosis, but it is essential for complicated cases and follow-ups. Lung ultrasound can supplement chest radiography (CR), which starts the diagnostic algorithm. Contrast-enhanced computed tomography (CECT) is used for complex cases. Advances in MRI protocols make it a viable alternative for diagnosing CAP and its complications.

Plant testing with hemp and miscanthus to assess phytomanagement options including biostimulants and mycorrhizae on a metal-contaminated soil to provide biomass for sustainable biofuel production.

The need of biofuels from biomass, including sustainable aviation fuel, without using agricultural land dedicated to food crops, is in constant demand. Strategies to intensify biomass production using mycorrhizal fungi, biostimulants and their combinations could be solutions for improving the cultivation of lignocellulosic plants but still lack well-established validation on metal-contaminated soils. This study aimed to assess the yield of Miscanthus x giganteus J.M. Greef & Deuter and Cannabis sativa L. grown on a metal-contaminated agricultural soil (11 mg Cd, 536 mg Pb and 955 mg Zn kg-1) amended with biostimulants and/or arbuscular mycorrhizal fungi, and the shoot Cd, Pb and Zn uptake. A pot trial was carried out with soil collected from a field near a former Pb/Zn smelter in France and six treatments: control (C), protein hydrolysate (a mixture of peptides and amino acids, PH), humic/fulvic acids (HFA), arbuscular mycorrhizae fungi (AMF), PH combined with AMF (PHxAMF), and HFA combined with AMF (HFAxAMF). Metal concentrations in the soil pore water (SPW), pH and electrical conductivity were measured over time. Miscanthus and hemp shoots were harvested on day 90. Both PH and PHxAMF treatments increased SPW Cd, Pb, and Zn concentrations (e.g. by 26, 1.9, and 22.9 times for miscanthus and 9.7, 4.7, and 19.3 times for hemp in the PH and PHxAMF treatments as compared to the control one, respectively). This led to phytotoxicity and reduced shoot yield for miscanthus. Conversely, HFA and HFAxAMF treatments decreased SPW Cd and Zn concentrations, increasing shoot yields for hemp and miscanthus. Shoot Cd, Pb, and Zn uptakes peaked for PH and PHxAMF hemp plants (in µg plant-1, Cd: 310-334, Pb: 34-38, and Zn: 232-309 for PHxAMF and PH, respectively), while lowest values occurred for PH miscanthus plants mainly due to low shoot yield. Overall, this study suggested that humic/fulvic acids can be an effective biostimulant for increasing shoot biomass production in a metal-contaminated soil. These results warrant further investigations of the HFAxAMF in field trials.

A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.

Long term recurrence analysis post drug eluting bead (deb) chemoembolization for hepatocellular carcinoma (hcc).

UNLABELLED: BACKROUND-AIMS: To determine long term outcomes, regarding recurrence and survival, in patients with HCC that achieved complete response after initial treatment with drug eluting beads (DEB) using DC Bead loaded with doxorubicin (DEB-DOX). METHODOLOGY: Forty-five patients with HCC, not suitable for curative treatments that exhibited complete response (EASL criteria) to initial DEB-DOX treatment were retrospectively analyzed after a median follow up period of 63 months. Child-Pugh class was A/B (62.2/37.8%) and mean lesion diameter 5.36 ± 1.1 cm. Lesion morphology was one dominant ≤5cm (53.3%), one dominant >5cm (31.1%) and multifocal (15.6%). RESULTS: At 5 years, overall survival was 62.2% and recurrence-free survival 8.9%. All deaths that occurred were related to tumor progression (31.1%) or complications of underlying liver disease (28.9%). Median time of initial recurrence from baseline treatment was 18 months (range 8-52). When recurrence occurred, a mean time interval between additional DEB-DOX procedures less than 9 months was correlated to a poorer prognosis (p=0.025). Multivariate analysis identified Child-Pugh class at baseline (p=0.048), combined therapy of recurrences with local ablation (p=0.03) and number of DEB-DOX procedures (p=0.037) as significant prognostic factors of 5-year survival. Lesion morphology displayed significance for recurrence-free survival (p=0.014). Child-Pugh class at baseline, additional local ablation, pattern of initial recurrence and initial sum of recurrent tumor diameters all displayed statistical significance for post-recurrence survival (median 40 months), with the first two variables maintaining statistical significance in multivariate analysis (p=0.015 and p=0.014 respectively). CONCLUSION: Initial complete response to DEB-DOX ensures a favorable prognosis. However, management of recurrent tumors, which occur frequently mostly as new lesions, and preservation of underlying liver function appear to play a key role in prolonging survival.