Background Children with tracheostomies are at an increased risk of bacterial respiratory tract infections. Infections caused by multidrug-resistant organisms (MDROs) are more difficult to treat and can result in severe complications. We investigated the risk factors and sequelae of MDRO positivity in tracheostomy and chronic ventilator-dependent children. Methods We performed a retrospective chart review of 75 tracheostomy and chronic ventilator-dependent children at St. Louis Children’s Hospital. Data on demographics, respiratory cultures, hospitalizations, emergency department (ED) visits, and antibiotic usage were collected. We determined the frequency of MDRO positivity and compared the number of hospitalizations, number of ED visits, and antibiotic usage in patients with and without MDRO-positive cultures. Patient clinical variables were analyzed before and after MDRO acquisition. Results We found 75.7% (56/74) of our participants had an MDRO-positive culture, with methicillin-resistant Staphylococcus aureus (MRSA, n=36, 64%) and Pseudomonas aeruginosa (n=8, 14%) being the most commonly detected organisms. Patients with MDRO-positive cultures had a greater number of annual non-pulmonary admissions [OR=1.99, 95% CI (1.21-3.29), P= 0.008], inpatient antibiotic courses [OR=1.27, 95% CI (1.07-1.50), P=0.006], total antibiotic courses [OR=1.26, 95% CI (1.08-1.48), P= 0.004], and chronic antibiotic use [OR=2.31, 95% CI (1.12-4.74), P=0.03] compared to MDRO-negative participants. Patients that acquired MDROs during the study period subsequently required increased outpatient antibiotics [P= 0.006] but did not have increased pulmonary admissions or ED visits. Conclusion Frequent antibiotic usage and hospitalizations increase the risk of MDRO acquisition in children with tracheostomies and ventilator-dependence. Further antibiotic stewardship may help prevent resistant infections in technology-dependent children.

This study aimed to investigate epidemiological, clinical, and laboratory features of children with COVID-19 to identify predictors for pulmonary involvement. We conducted a retrospective, single-center study of pediatric COVID-19 at a tertiary care hospital in Turkey between December 2020 and June 2021. A total of 126 children (70 males, 55.6%) were examined during the study period. Their mean age was 74.73 ± 81.11 months (range, 1–216 months). The most frequent COVID-19 symptoms were fever (65.9%), cough (52.4%), and shortness of breath (18.3%). Ten patients required noninvasive mechanical ventilation. Sixty-nine patients (54.8%) had pneumonia. Longer duration of fever and the presence of cough were significantly associated with pulmonary involvement. In children with pneumonia, the C-reactive protein (CRP), procalcitonin levels, erythrocyte sedimentation rate (ESR), and viral load were significantly higher and lymphocyte and thrombocyte counts were significantly lower than in children without pneumonia. The cutoff viral load, CRP, and procalcitonin values for predicting pulmonary involvement were 26.5 cycle threshold (Ct; 95% confidence interval [CI], 0.54–0.74; sensitivity, 0.65; specificity, 0.56; area under curve [AUC]: 0.647, p = 0.005), 7.85 mg/L (95% CI, 0.56–0.75; sensitivity, 0.66; specificity, 0.64; AUC = 0.656; p = 0.003) and 0.105 ng/mL (95% CI, 0.52–0.72; sensitivity, 0.55; specificity, 0.58; AUC = 0.626; p = 0.02), respectively. High CRP, procalcitonin levels, ESR, and viral load and low lymphocyte and thrombocyte counts can predict pulmonary involvement in children with COVID-19, so better management may be provided for good prognosis.

Objective: To assess the quality of life (QoL) of Cystic fibrosis (CF) patients in West Bank, Palestine using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) form. Method: A cross-sectional study involving application of CFQ-R questionnaire in CF patients attending pediatric pulmonology clinic at Caritas Baby Hospital (CBH). Their health status was assessed by measuring different parameters including pulmonary function test (FEV1) and body mass index (BMI). Results: The sample consisted of 77 patients from 58 families: 46.75% were males. Mean age was 10.7 years. Patients were divided into three groups by age in years: group I (< 6), II (6-13), and III (≥ 14). The highest and lowest CFQ scores were for the eat domain in group III (55.56 ± 22.49) and the body domain in group II (14.48 ± 17.67), respectively. Illness severity as measured by FEV1 mean value 69.6. BMI mean value of 15.998. The overall mean age at time of diagnosis in our sample was 4.16 years (± 6.239). The study showed that 1.7% of families had four affected siblings and 21% had death cases related to CF. Finally, all parameters for CF patients in West Bank, Palestine appear to be noticeably lower than those reported in other countries. Conclusions: quality of life for patients with CF is poor relative to international standards, the medications used including hypertonic saline and Gentamycin IV form used as nebulizer solution are not first line therapies around the world. This study illustrates the need of new therapies for CF patients in Palestine.

Introduction Rhinoviruses (RV) and Enteroviruses (EV) are among the main causative etiologies of Lower Respiratory Tract Infection (LRTI) in children. The clinical spectrum of RV/EV infection is wide, which could be explained by diverse environmental, pathogen-, and host-related factors. Little is known about the nasopharyngeal microbiota as a risk factor or disease modifier for RV/EV infection in pediatric patients. This study describes distinct nasopharyngeal microbiota profiles according to RV/EV LRTI status in children. Methods Cross-sectional case-control study, conducted at Hospital Sant de Déu (Barcelona, Spain) from 2017 to 2020. Three groups of children <5 years were included: healthy controls without viral detection (Group A), mild or asymptomatic controls with RV/EV infection (Group B), and cases with severe RV/EV infection admitted to the pediatric intensive care unit (PICU) (Group C). Nasopharyngeal samples were collected from participants for viral DNA/RNA detection by multiplex-PCR and bacterial microbiota characterization by 16S rRNA gene sequencing. Results A total of 104 subjects were recruited (A=17, B=34, C=53). Children’s nasopharyngeal microbiota composition varied according to their RV/EV infection status. Richness and diversity were decreased among children with severe infection. Nasopharyngeal microbiota profiles enriched in genus Dolosigranulum were related to respiratory health, while genus Haemophiluswas specifically predominant in children with severe RV/EV LRTI. Children with mild or asymptomatic RV/EV infection showed an intermediate profile. Conclusions These results suggest a close relationship between the nasopharyngeal microbiota and different clinical presentations of RV/EV infection.

Interstitial Lung Disease in childhood (chILD) is rare and no longer solely a childhood issue. Many are surviving into adult life. Therefore, many affected with chILD need to transition from paediatric to adult healthcare services. Transition is a significant life event that has the potential to impact on physical and mental health outcomes and across Europe this is a haphazard process for chILD. This qualitative study explores how young people and parents in the United Kingdom experienced transition from paediatric to adult healthcare services for chILD. Participants (n = 7) were recruited from chILD patient organisations and online communities. We focused on the experience of transition and whether there were any information packs or support provided for the transition. The data was analysed by constructivist grounded theory. The study presents a lived experience of transition with themes of lack of transition preparation and planning, challenges of learning how to adapt to adult services and a changing healthcare scene. Due to the complexity of ChILD, parents discussed their need to remain, in part, as an advocate for the young person. Respondents provided recommendations for how transition could be improved along with tips for young people who are new to the transition process, which include educating oneself about the condition and learning medical terminology, being open if there are issues and reaching out for support.

Background Children with chronic lung disease (CLD) of prematurity who require invasive home mechanical ventilation (iHMV) are medically vulnerable and experience high caregiving and healthcare costs. Predictors for duration of iHMV remain unclear, which can make prognostication and decision-making challenging. Methods A retrospective cohort study of children with CLD of prematurity requiring invasive iHMV was conducted from an independent children’s hospital records (2005-2021). The primary outcome was iHMV duration, defined as time from initial discharge home on iHMV until cessation of positive pressure ventilation (day and night). Two new variables were included: corrected tracheostomy age (CTA) (chronological age at discharge minus age at tracheotomy) and level of ventilator support at discharge (minute ventilation per kg per day). Univariable Cox regression was performed with variables of interest compared to iHMV duration. Significant nonlinear factors (P<0.05) were included in the multivariable analysis. Results One-hundred-and-nineteen patients used iHMV primarily for CLD of prematurity. Patient median index hospitalization lasted 12 months (IQR 8.0,14.4). Once home, half of patients were weaned off iHMV by 36.0 months and 90% by 52.2 months. Being Hispanic/Lantix ethnicity (HR 0.14 (95% CI 0.04, 0.53), p<0.01) and having a higher CTA were associated with increased iHMV duration (HR 0.66 (CI 0.43, 0.98), p<0.05). Conclusions Disparity in iHMV duration exists among patients using iHMV after prematurity. Prospective multisite studies that further investigate new analytic variables, such as CTA and level of ventilator support, and address standardization of iHMV care are needed to create more equitable iHMV management strategies.

Background: eHealth CF-CBT is the first digital mental health intervention for depression/anxiety in adults with cystic fibrosis (awCF); an 8-session therapist-guided internet-delivered program that was developed in English and Dutch with stakeholder input and evaluation indicating high acceptability and usability. Methods: Dutch eHealth CF-CBT was piloted in awCF with mild-moderate symptoms of depression and/or anxiety. Feasibility, usability, acceptability, and preliminary efficacy were assessed, measuring pre-post changes in depression (PHQ-9), anxiety (GAD-7), perceived stress (PSS) and health-related quality of life (CFQ-R). Results: All participants (n=10, 7 female, mean age 29 (range 21-43), mean FEV1 71%pred (range 31-115)) completed all sessions. Patient-rated feasibility, usability and acceptability of eHealth CF-CBT was positive on validated scales, as were qualitative assessments of content and format. GAD-7 improved in 90% of participants; in 50% by ≥ the minimally important difference (MID) of 4 points. PHQ-9 improved in 90%; 40% by ≥ the MID of 5. PSS improved in 80%. CFQ-R improved in the domain Health Perceptions (70%). Conclusions: eHealth CF-CBT demonstrated feasibility, usability, acceptability and promising preliminary efficacy in this pilot trial with Dutch awCF with mild to moderate symptoms of depression and anxiety.

Asthma deaths were rare in children but attention should be paid to those with a severe exacerbation (requiring systemic steroids, an ED visit or hospitalization) in the past year, more than three beta-agonist refills in a year and poor adherence to controller medication.

In conclusion, we present this case in order to complement CFTR gene mutations data of Chinese children with cystic fibrosis and improve clinicians' understanding of this disease in China. Besides, with the development of molecular biology technology, gene detection was expected to play an important role in the early diagnosis, early treatment, and prognosis improvement of the disease.

Pathogenic variants in the Surfactant Protein C gene ( SFTPC) result in fibrotic childhood interstitial lung disease (chILD). We previously reported three children with SFTPC pathogenic variants with respiratory failure who were supported by chronic invasive ventilation via tracheostomy as an alternative to lung transplantation or comfort care [(1)](#ref-0001). We present two children with SFTPC pathogenic variants treated with non-invasive ventilation (NIV) (Figure 1).

Background: Globally, observational studies have demonstrated an association between high levels of air pollution and asthma attacks in children. It remains unclear whether and to what extent exposure may be associated with increased near fatal and fatal attacks. Objective: To systematically review the evidence for an association between ambient outdoor air pollution and fatal and/or near fatal asthma (NFA). Methods: Following Cochrane methodology, we searched MEDLINE, EMBASE, Web of Science, Scopus and Open Grey electronic databases for studies reporting the association of fatal/NFA and air pollution (Particulate Matter (PM), sulphur dioxide, nitrogen dioxide, black carbon and ozone) in children. NFA was defined as requiring intensive care (ICU) management. Results: Two reviewers independently screened 1,358 papers. 276 studies identified asthma attacks related to air pollution, 272 did not meet inclusion criteria after full text review. Four observational studies described fatal/NFA, of which 3 addressed NFA. PM2.5 and ozone (22ppb) were associated with NFA in one study (RR 1.26 CI (1.10-1.44)). PM10 was associated with ICU admission in the context of thunderstorm asthma. Elemental carbon was associated equally with NFA that did not require an ICU admission (p=0.67). Studies of fatal asthma including children did not demarcate age within analysis. Conclusions: Ozone and PM2.5 have been associated with NFA in children but synthesis is limited by the paucity of studies and methodological heterogeneity. Poor reporting of severities of asthma attack does not enable assessment of whether outdoor air pollution is associated with an increased number of NFA and fatal attacks in children.

Background: Foreign body (FB) aspiration is a typical emergency experienced by young children and associated with significant morbidity and mortality unless diagnosed early and treated adequately. Data on anesthetic management, applicability, complications and risk factors in the context of foreign body removal (FBR) is scarce, especially for flexible techniques, which are increasingly being used. Aim: To analyze the complication rate and risk factors as well as the anesthetic management of two different techniques (rigid versus flexible) for FBR in children. Method: This is a retrospective single center analysis of 160 cases who underwent bronchoscopy for suspected FB aspiration under general anesthesia between January 2014 and January 2022 at a tertiary hospital. Results: An FB was detected in 67 patients (median age 1.8 years). The preferred anesthesia regimes were total intravenous anesthesia (91.9%) and laryngeal mask (95%) for flexible bronchoscopy. Flexible bronchoscopy was used in 52.2%, rigid bronchoscopy in 31.3%, and both techniques were used in 16.4% of cases. The complication rate was 2.19 vs. 1.29/patient in rigid vs. flexible bronchoscopy, respectively. Independent risk factors for severe complications were rigid bronchoscopy (OR 11.6, p<0.01) and airway infections (OR 4.1, p<0.01). We observed flexible bronchoscopy being increasingly used for FBR during the observational period. Conclusion: FBR can result in serious complications that require experienced pediatric anesthetic management. In our series, the use of a rigid bronchoscope and preexisting airway infection were independent risk factors for severe complications. Flexible bronchoscopy was shown to be a safe, fast and successful tool for FBR with fewer adverse events compared to rigid bronchoscopy. Total intravenous anesthesia and a laryngeal mask airway for FBR are feasible and safe.

Objectives: To quantify and characterize systemic antibiotic prescribing among children with tracheostomies, and to identify predictors of higher prescribing. Study Design: This single-center retrospective cohort study included children with tracheostomies 2 months-18 years old cared for at a quaternary care pediatric institution between 2010-2018. Antibiotics prescribed for >1 day were recorded, classified by spectrum of activity, and stratified by setting and year. Presumptively prophylactic antibiotics were excluded. Child-level antibiotic prescribing was quantified using number of courses and days of therapy (DOT) per child per year. Group-level prescribing was summarized using total courses and DOT per 1000 person-days and analyzed by year over study course. Predictors of child-level prescribing were identified using backward elimination multivariable analyses within a generalized linear model. Results: The 548 children with tracheostomies were prescribed a median 4 antibiotic courses per child per year (IQR: 1.9-10.0) for a total median exposure of 33.8 DOT per child per year (IQR: 16.1-71.6). The group was prescribed 100.7 DOT per 1000 person-days. Most courses (72.7%) were broad-spectrum, with vancomycin, piperacillin-tazobactam, and ampicillin-sulbactam/ampicillin-clavulanate being the most frequently prescribed courses. Annual antibiotic prescribing decreased 30-33% between 2010 and 2018. Child ventilator use at baseline was associated with fewer DOT per child per year, while higher complexity and more ICU hospital days were risk factors for higher DOT. Conclusion: Children with tracheostomies have high systemic antibiotic use and are predominantly prescribed broad-spectrum antibiotics. Chronic ventilator use was associated with lower prescribing. This data may inform antimicrobial stewardship work.

Background: Exercise is an important part of a healthy lifestyle for people with cystic fibrosis (CF). Exercise testing is also recommended as part of a routine assessment to provide physical activity counseling/exercise prescription. Body composition assessment is also an important assessment to can also guide dietary counseling. Prior studies have found that exercise testing and exercise training programs are underutilized in CF care centers, and no one has assessed the prevalence of body composition assessment. Thus, the purpose of this study was to develop and validate a survey to explore the barriers and facilitators that obstruct or promote the use of exercise and body composition testing in the CF care centers. Methods: Seventy-nine individuals with expertise in exercise and CF were invited to participate in a Delphi study. They rated the importance and quality of a 106-item survey on exercise and body composting testing and exercise training and shared their feedback. Results: Thirteen subject matter experts (SMEs) agreed to participate in the study, which lasted 3 rounds, but only 6 of them were in the final round. Of the 106 original items, 46 were kept with revisions, 58 were revised, 2 items were dropped, and 8 items were added, resulting in a final survey of 114 items. Conclusions: This Delphi study validated a survey to be used in CF care centers to provide valuable information about the benefits and barriers to exercise testing, exercise training, and body composition assessment in people with CF in the CFTR-modulator era.

Background The approval of cystic fibrosis conductance regulator (CFTR) modulators including the triple modulator Elexacaftor/Tezacaftor/Ivacaftor (ETI) for people with cystic fibrosis (pwCF) have improved pulmonary function significantly. The effect on CF related bone disease (CFBD) and body composition remain unclear. Methods This is a retrospective real world study of adults pwCF. Bone density and body composition were obtained via dual-energy x-ray absorptiometry (DXA) 1.8 (SD0.7) years prior and 1.5 (SD0.4) years (postDXA1) and in a subgroup 3.5 (SD0.2) years (postDXA2) after ETI initiation. Clinical data were collected at time of DXA scan and ETI start. Results 74 pwCF were included of which 42% were female, with average age at ETI initiation of 38.9 (SD 9.3) years. 45.9% had cystic fibrosis related diabetes (CFRD) and 93.2% had exocrine pancreatic insufficiency. Bone density decreased at the spine (p= 0.0256), left hip (p< 0.001) and right hip (p< 0.001) from pre- to postDXA1, no change in bone density was seen in any of the sites when postDXA1 was compared to postDXA2. Body composition in the postDXA1 compared to preDXA showed increase in weight in female (p=0.011) and male (p=0.001), and in fat mass in female (p=0.003) and male (p=0.001), without a change in lean mass (p=0.4). Comparison of body composition in postDXA2 to postDXA1 failed to show significant change in body weight (woman p=0.38; men p=0.94) and in fat mass (woman p=77; men p=0.939). Conclusions Bone density decreased and body weight and fat mass increased early on after ETI initiation. This appears to stabilize with prolonged treatment.

Title page:Title: Beyond the Usual Suspects: Neonatal Fever and DesaturationAuthors: Karolína Doležalová¹, Jana Kodetová¹, Eva Klabusayová², Jana Svobodová ³, Karel Karmazín⁴, Pavel Tkadlec ⁵, Emília Kopecká ⁶, Jan Helešic ⁷Affiliation:₁ Clinic of Paediatrics of the First Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic₂ Department of paediatric anaesthesiology and intensive care medicine, University Hospital Brno and Faculty of medicine, Masaryk University, Brno, Czech Republic₃ Laboratory for mycobacteria, Ifcor- Clinical laboratories, Ltd., Brno, Czech Republic₄ Department of Pediatric Intensive Care, Thomayer University Hospital, Prague, Czech Republic₅ Department of Pulmology, Hospital Uherské Hradiště, Czech Republic₆ Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czech Republic₇ Department of children’s infectious diseases, The University Hospital BrnoCorresponding author: Karolína Doležalová, MD, PhD, Department of Paediatrics of the First Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic.Orcid: https://orcid.org/0000-0001-7786-8105 karolina.dolezalova@ftn.cz1 IntroductionA one-month-old infant presenting with fever, dyspnoea and desaturation poses a significant diagnostic challenge. The organism in question is notably fragile, exhibiting immature immune functions and the potential for as yet undetected developmental defects. The diagnostic challenge is further intensified in cases where the child is an immigrant, born as a result of an unmonitored pregnancy, born prematurely and with low birth weight. The attending physician must act quickly while carefully untangling the complicated web of different possible diagnoses.2 Case presentationOn the day of admission, the patient was a 31-day-old baby girl born to a Ukrainian mother from an unmonitored pregnancy with a birth weight of 2,350 g. Gestation age unknown. The infant was hospitalised for the first time in the third week of life, having been admitted to the local paediatric ward with a diagnosis of influenza A, which was confirmed by PCR testing of both the infant and her mother. Two weeks later, the infant was readmitted to hospital with a cough, dyspnoea and fever. The laboratory parameters of inflammation were elevated (CRP 188 mg/l, PCT 1,01 ug/l, WBC 26). The presence of bilaterally oriented opacities, suggestive of pneumonia, was evidenced on the chest X-ray. (Figure 1). Empirical antibiotic therapy with piperacillin/tazobactam (Tasocin) has been initiated. From a clinical perspective, the most prominent symptoms were tachypnoea (70 breaths per minute) and signs of increased respiratory effort. The patient experienced apnoeic episodes accompanied by cyanosis and bradycardia, prompting the initiation of high-flow nasal oxygen therapy (HFNO) and transfer to the intensive care unit. Despite ongoing ventilatory support, respiratory insufficiency progressed. Due to persistent tachypnoea, overall deterioration and signs of respiratory acidosis, endotracheal intubation and the initiation of mechanical ventilation were indicated.Figure 1: A: initial chest X ray and initial laboratory markersChallenge pointThe patient is an immature infant who is exhibiting symptoms of dyspnoea, fever and tachypnoea. These symptoms required urgent transfer to a resuscitation care facility and mechanical ventilation. It is evident that the patient exhibits elevated levels of inflammation, as indicated by the presence of significant parameters of inflammation, along with the observation of bilateral opacities on a chest scan. (Podcast 1)Learner reflectionWhat is most likely going on with this patient?What would you do next and why?

Objectives: To evaluate disparities in 1-year mortality in infants with congenital diaphragmatic hernia (CDH) by maternal race/ethnicity in a US population-based dataset, and to quantify mediation effects of socioeconomic status (SES) and maternal and neonatal medical factors. Study design: We identified infants with CDH from the US Natality Database (2014-2019) that links birth and death certificates to 1-year of age. Primary outcome was 1-year mortality. Primary predictor was maternal race/ethnicity. Candidate mediators [SES (defined by maternal education level and public insurance status) and neonatal and maternal factors] were assessed using structural equation modeling. Results: Among 2,589 infants with CDH, 1-year mortality was 28.4% (n=734). Infant mortality differed by maternal race/ethnicity: Non-Hispanic White 25.5%, Black 39.1%, Hispanic 31.2%. Mortality differences persisted in multivariate analysis. Mediation analyses showed that SES accounted for 54.1% (20.4–68.6%) of the disparity between infants of Non-Hispanic White and Hispanic mothers. In contrast, SES accounted for only 17.1% (3.6–37.4%) of the disparity between infants of Non-Hispanic White and Black mothers, while the unmeasured remaining effect of race/ethnicity contributed 75.9% (49.5–91.1%). Conclusions: In CDH, SES accounts for a large proportion of the mortality disparity for infants of Hispanic mothers while the remaining effect of race, aside from SES and neonatal factors, accounts for a large proportion of the mortality disparity for infants of Black mothers. The remaining effect of maternal race may be due to unmeasured aspects of SES, such as social determinants of health, and structural and systemic racism and bias.

Introduction: Pediatric asthma exacerbations sometimes require aggressive intervention including continuous albuterol, a cornerstone therapy for reversing airway obstruction. However, pediatric dosing typically follows adult guidelines, with limited evidence for specific dosing ranges. This study aimed to compare the clinical outcomes of a reduced initial dose (10 mg/hr) of continuous albuterol with a standard dose (15 mg/hr) in children hospitalized for critical asthma exacerbations. Methods: This retrospective cohort study was conducted at Riley Hospital for Children, analyzing pediatric patients (ages 2-18) admitted with critical asthma exacerbations between 2014 and 2022. Stabilized inverse probability weighting (SIPW) was used to adjust for confounding factors between groups. The primary outcome was the percentage change in the Pediatric Asthma Severity Score (PASS) at 24 hours, with secondary outcomes including the duration of continuous albuterol, PICU length of stay, and hospital length of stay. Results: Analysis of 1,486 encounters revealed no significant difference in percent PASS changes at 24 hours between the 10 mg/hr and 15 mg/hr groups (Additive Treatment Effect of 1.69, 95% CI: -0.93-4.31, p = 0.207). PICU and hospital lengths of stay were also similar. However, the 10 mg/hr group showed a significantly shorter duration of continuous albuterol therapy compared to the 15 mg/hr group (Multiplicative Treatment Effect of 1.29, 95% CI: 1.14-1.45, p < 0.001). Conclusions: Findings suggested that starting continuous albuterol at 10 mg/hr provides clinical outcomes comparable to 15 mg/hr in managing pediatric critical asthma exacerbations. A lower starting dose may optimize resource use and reduce treatment-related adverse effects.