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Introduction | lung cancer, Lung cancer, ILD, Interstitial lung abnormalities | LUNG CANCER, INTERSTITIAL LUNG DISEASE, LUNG CANCER | Interstitial lung abnormalities (ILA) are relatively common incidental findings in participants undergoing low-dose CT screening for lung cancer. Some ILA are transient and inconsequential, but others represent interstitial lung disease (ILD). Lung cancer screening therefore offers the opportunity of earlier diagnosis and treatment of ILD for some screening participants. | PMC10450038 |
Methods | LUNG | The prevalence of ILA in participants in the baseline screening round of the Yorkshire Lung Screening Trial is reported, along with the proportion referred to a regional ILD service, eventual diagnoses, outcomes and treatments. | PMC10450038 |
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Results | sarcoidosis, idiopathic non-specific interstitial pneumonia, asbestosis, respiratory bronchiolitis ILD | SARCOIDOSIS, HYPERSENSITIVITY PNEUMONITIS, ASBESTOSIS, IDIOPATHIC INTERSTITIAL PNEUMONIA, PLEUROPARENCHYMAL FIBROELASTOSIS, IDIOPATHIC PULMONARY FIBROSIS | Of 6650 participants undergoing screening, ILA were reported in 169 (2.5%) participants. Following review in a screening review meeting, 56 participants were referred to the ILD service for further evaluation (0.8% of all screening participants). 2 participants declined referral, 1 is currently awaiting review and the remaining 53 were confirmed as having ILD. Eventual diagnoses were idiopathic pulmonary fibrosis (n=14), respiratory bronchiolitis ILD (n=4), chronic hypersensitivity pneumonitis (n=2), connective tissue disease/rheumatoid arthritis-related ILD (n=4), asbestosis (n=1), idiopathic non-specific interstitial pneumonia (n=1), sarcoidosis (n=1) and pleuroparenchymal fibroelastosis (n=1). Twenty five patients had unclassifiable idiopathic interstitial pneumonia. Overall, 10 people received pharmacotherapy (7 antifibrotics and 3 prednisolone) representing 18% of those referred to the ILD service and 0.15% of those undergoing screening. 32 people remain under surveillance in the ILD service, some of whom may require treatment in future. | PMC10450038 |
Discussion | lung cancer, Lung cancer | LUNG CANCER, LUNG CANCER | Lung cancer screening detects clinically significant cases of ILD allowing early commencement of disease-modifying treatment in a proportion of participants. This is the largest screening cohort to report eventual diagnoses and treatments and provides an estimate of the level of clinical activity to be expected by ILD services as lung cancer screening is implemented. Further research is needed to clarify the optimal management of screen-detected ILD. | PMC10450038 |
WHAT IS ALREADY KNOWN ON THIS TOPIC | lung cancer, ILD, Interstitial lung abnormalities | LUNG CANCER, INTERSTITIAL LUNG DISEASE | Interstitial lung abnormalities are common findings on low-dose CT screening scans performed in lung cancer screening programmes, and in some cases may represent interstitial lung disease (ILD) for which effective pharmacotherapy is now available. | PMC10450038 |
WHAT THIS STUDY ADDS | lung cancer | LUNG CANCER | Few previous studies have reported the eventual diagnoses and treatments of cases of screen-detected ILD; here, we report the largest lung cancer screening cohort to include eventual ILD diagnoses and treatments. Overall, 0.8% of participants undergoing baseline screening were diagnosed with ILD and 0.15% have commenced treatment to date. | PMC10450038 |
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY | lung cancer | LUNG CANCER | This study shows that lung cancer screening detects clinically significant cases of ILD fulfilling criteria for pharmacotherapy. The proportions of participants needing referral to ILD services and requiring eventual treatment reported here will help capacity planning for services alongside future roll-out of lung cancer screening programmes. | PMC10450038 |
Introduction | lung cancer, interstitial lung abnormalities | LUNG CANCER, LUNG | Low-dose CT (LDCT) screening for lung cancer has been shown to reduce lung cancer-specific and all-cause mortality in the National Lung Screening Trial (NLST)The term interstitial lung abnormalities (ILA) refers to a variety of incidental radiological findings on CT imaging, some of which are transient and inconsequential,Many screening participants with ILA can simply be kept under radiological surveillance, usually as part of the ongoing screening programme. However, a proportion of participants will have more significant radiological abnormalities meriting referral to an ILD service for further evaluation and, if appropriate, pharmacotherapy. Although many studies have reported the diagnostic prevalence of ILA, | PMC10450038 |
Methods | PMC10450038 |
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YLST study design | The full protocol of YLST has been published previously. | PMC10450038 |
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Patient and public involvement (PPI) | Mesothelioma, Lung Cancer | EVENTS, MESOTHELIOMA, LUNG CANCER | Patients and members of the public were closely involved in the YLST design. A group of four PPI representatives met regularly during the study design period, providing feedback on the design and suggesting amendments which were incorporated. PPI feedback was presented to both the Research Ethics Committee and Confidentiality Advisory Group. In addition, separate PPI sessions were involved using a pre-existing patient support group, the Leeds Lung Cancer and Mesothelioma Patient Support Group comprising patients and family members. Four events were held during the trial design phase where plans were presented to the group for feedback and comment. | PMC10450038 |
Participant history and symptoms | exertional breathlessness, exhaled carbon monoxide, cough, bronchitis, dyspnoea, wheeze | RESPIRATORY DISEASE, BRONCHITIS | At the LHC, participants were asked about a history of respiratory disease, presence of respiratory symptoms (exertional breathlessness, chronic cough, regular sputum production, wheeze, frequent winter bronchitis), number of hospital admissions for chest problems, number of antibiotic courses in the last 12 months, modified Medical Research Council (mMRC) dyspnoea score (0–4), and WHO performance status (0–4). Smoking status was recorded and number of pack years calculated. Participants had exhaled carbon monoxide measured and performed routine spirometry up to the onset of the COVID-19 pandemic in March 2020; spirometry did not continue following recommencement of screening in July 2020. | PMC10450038 |
LDCT scan reporting and review | cancers, incidental abnormalities, Lung Cancer | CANCERS, TRACTION BRONCHIECTASIS, LUNG CANCER | LDCT scans for YLST are reported by a team of eight consultant radiologists with a subspecialty interest in thoracic imaging. Scans are reported using Veolity (MeVis AG), a bespoke software package for Lung Cancer screening including automated volumetry and computer-aided detection. In addition to protocolised reporting of nodules and possible cancers, free-text comments allow reporting of other incidental abnormalities with the option of a flag for clinically significant findings requiring clinical review. All scans with such a flag are reviewed at a screening review meeting (SRM) attended by a consultant thoracic radiologist and a consultant respiratory physician. At the SRM, electronic healthcare records and previous imaging performed outside of YLST are available for review. The radiologists who attend the SRMs also regularly contribute to ILD multidisciplinary team (MDT) meetings. Scans without a clinical flag are signed off by a respiratory physician, with the option of listing for SRM if further discussion is thought necessary.The YLST reporting radiologists were asked to mention ILA in their clinical report in all cases, and to mark the scan report as having a significant incidental finding if there were clinically significant ILA defined as evidence of traction bronchiectasis or >10% reticulation. Some cases that were not flagged but had comments regarding ILA were also discussed at the discretion of YLST physicians. Following discussion at an SRM, if a clinically significant previously undiagnosed ILD was thought possible, a telephone clinic appointment with a YLST clinician was arranged. At this review, further relevant history was obtained, participants were advised of the scan findings and onward referral to the regional ILD service was organised. A letter outlining the LDCT findings and any further management was sent to both the patient and general practitioner. | PMC10450038 |
Data collection | death, interstitial lung abnormality, ILD, respiratory bronchiolitis ILD, interstitial pneumonia, fibrosis, lung cancer | CRYPTOGENIC ORGANISING PNEUMONIA, DISEASE, FIBROSIS, LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS, DESQUAMATIVE INTERSTITIAL PNEUMONIA, BRONCHIOLITIS OBLITERANS ORGANISING PNEUMONIA | All participants with ILA discussed at an SRM were prospectively logged, including the outcome of the telephone consultation. In order to identify ILA that did not meet the predefined criteria for clinically significant disease, a search was performed on a dataset of all baseline LDCT scans for terms in the comments or SRM sections relating to ILA. Search terms included: interstitial, fibrosis, honeycombing, interstitial lung abnormality, ILD, idiopathic pulmonary fibrosis, usual interstitial pneumonia, non-specific interstitial pneumonia, cryptogenic organising pneumonia, bronchiolitis obliterans organising pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis ILD (RB-ILD) and acronyms thereof. Electronic healthcare records were then retrospectively reviewed for all cases and clinical outcomes recorded, including whether participants were referred to the regional ILD service, outcomes within the ILD service (specifically diagnosis from the ILD MDT, pulmonary function test monitoring, initiation of treatment for ILD, discharge from the service), lung cancer diagnosis, palliative care referral and death. | PMC10450038 |
Statistical analysis | Statistical analysis was performed using GraphPad Prism, with comparison between those with ILD (known and newly referred) and those without ILD using methodologically appropriate tests. YLST is registered with the ISRCTN (reference ISRCTN42704678). | PMC10450038 |
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Results | interstitial lung abnormality, cancer, fibrosis, IPF, emphysema, lung cancer, infection, pneumoconiosis, interstitial lung abnormalities, interstitial lung diseaseFEVTwo | CANCER, FIBROSIS, EMPHYSEMA, LUNG CANCER, INFECTION, PLEURAL FIBROSIS, PNEUMOCONIOSIS, IDIOPATHIC PULMONARY FIBROSIS, RESPIRATORY BRONCHIOLITIS INTERSTITIAL LUNG DISEASE, HEART FAILURE, NON-SPECIFIC INTERSTITIAL PNEUMONIA | Baseline LDCT screening scans were performed on 6650 participants during the prevalent round of screening between November 2018 and February 2021. ILA were reported in 169 cases (2.5%) of which 153 cases were discussed in the SRM, usually because these cases were flagged as clinically significant, but occasionally at the discretion of the respiratory physician signing off the case.Of the 153 patients discussed in the SRM, 10 were known to the ILD service and no further action was needed and 87 were deemed to be not clinically significant and not referred. Thus, 56 patients (0.8% of the population undergoing prevalence LDCT screening) were identified as needing referral to the ILD service for initial discussion in the MDT meeting and subsequent review in the outpatient clinic. Demographic and clinical information is shown in Demographic and clinical information regarding participants with and without interstitial lung diseaseFEVTwo patients refused referral to the ILD clinic, and one patient is awaiting clinic review and a final diagnosis under the ILD team. A total of 53 patients have therefore received a final diagnosis and a consort diagram of diagnoses and treatments is shown in Flowchart for eventual diagnosis and treatment for participants with interstitial lung abnormalities reported on low-dose screening CT scans. ILA, interstitial lung abnormality; IPF, idiopathic pulmonary fibrosis; LDCT, low-dose CT; NSIP, non-specific interstitial pneumonia; RB-ILD, respiratory bronchiolitis interstitial lung disease.Thus, of 53 patients seen by the ILD service with a final diagnosis, 10 received pharmacotherapy (7 patients with antifibrotics, 3 patients with prednisolone) comprising 18% of those referred and 0.15% of all those undergoing prevalence LDCT screening. A total of 32 patients remain under active monitoring in the service with ongoing surveillance of lung function, 9 patients have now been discharged from the service after a period of stability and 2 patients died of unrelated causes.The most common reason for non-referral of cases to the ILD service was the trivial or mild nature of the ILA, as assessed by either the initial reporting radiologist or the radiologist reviewing the case in the SRM (n=42). In 33 cases, review in the SRM concluded that the LDCT findings were due to alternative causes (inflammatory change, infection or heart failure) rather than true ILA. Two cases were thought to represent classic RB-ILD but were not referred, as the patients had already engaged with the smoking cessation team on the mobile unit. In other cases, the reported ILA were thought to represent postradiation fibrosis, pleural fibrosis, pneumoconiosis or predominant emphysema, and thus patients were not referred to the service.Considering lung cancer diagnoses in the screening programme to date, a higher proportion of participants with ILD have been diagnosed with cancer compared with those without ILD (7.5% vs 2.4%, respectively, OR 3.16, 95% CI 1.25 to 7.94, p=0.015). Of the 103 participants with ILA mentioned in their LDCT reports who were not referred to the ILD service, 5 (4.9%) were subsequently diagnosed with lung cancer, thus considering the whole cohort with ILA/ILD 10 out of 169 participants (5.9%) were diagnosed with lung cancer. | PMC10450038 |
Discussion | idiopathic interstitial pneumonia, ILD | IDIOPATHIC INTERSTITIAL PNEUMONIA | In this analysis of ILA reported in a prevalence LDCT screening round, 2.5% of cases had mention of ILA in their CT report and 0.8% of cases were deemed clinically significant needing referral to the ILD service. Of those cases referred, IPF was the most common specific diagnosis (14 cases comprising 26% of referred cases with a final diagnosis), with 25 patients having unclassifiable idiopathic interstitial pneumonia (comprising 47% of referred cases with a final diagnosis). In total, 10 patients received pharmacotherapy (7 with antifibrotics and 3 with prednisolone) comprising 18% of all referred cases and 0.15% of all screening participants.In our cohort, participants with ILD were older than those without ILD, in keeping with the previous reports.The prevalence of ILA reported in this series is lower than that reported elsewhere (2.5% here compared with 8%–10% in other screening seriesThe current study is the largest to date to report eventual ILD diagnoses and the subsequent clinical outcomes following assessment. Two smaller studies from the UK have reported very different prevalence rates for new diagnoses of ILD across two rounds of LDCT screening. Only 1 study noted 28 new ILD diagnoses from 1853 screening participants (1.5%) with 0.6% commenced on pharmacotherapy.Other studies that have assessed changes in ILA over a 2-year interval reported 33% improving, 47% remaining stable and 20% progressing. | PMC10450038 |
Strengths and limitations | decline in lung function | This is the largest study to date to describe downstream impacts of screen-detected ILA including the proportion of screening participants needing review in an ILD service and the proportion eventually receiving pharmacotherapy. The main limitation is that findings are only available from the baseline round of screening (the first incidence screening round is still underway). The proportions of participants needing review by the ILD service, and fulfilling criteria for pharmacotherapy will therefore increase with time—first as people already under surveillance with the ILD team experience a decline in lung function parameters and therefore cross treatment thresholds and second as incident screening rounds reveal new onset or progression of ILA compared with the baseline screen. | PMC10450038 |
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Data availability statement | All data relevant to the study are included in the article or uploaded as supplementary information. | PMC10450038 |
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Ethics statements | PMC10450038 |
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Patient consent for publication | Not applicable. | PMC10450038 |
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Ethics approval | WEST | This study involves human participants and was approved by the North West—Greater Manchester West Research Ethics Committee. REC reference:18/NW/0012. Participants gave informed consent to participate in the study before taking part. | PMC10450038 |
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References | PMC10450038 |
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1. Introduction | VLBW, Hyperglycemia | HYPERGLYCEMIA, VERY LOW BIRTH WEIGHT INFANT | Hyperglycemia (HG) is an independent risk factor of mortality and morbidity in very low birth weight newborns (VLBW). Achievement of high nutritional intakes in the first days of life (DoL) by parenteral nutrition (PN) increases the risk of HG. We aim to assess if a delayed achievement of the PN macronutrient target dose could reduce the occurrence of HG in VLBW. We enrolled 353 VLBW neonates in a randomized controlled clinical trial comparing two PN protocols that differed in the timing of energy and amino acid target dose achievement: (1) early target dose achievement (energy within 4–5 DoL; amino acids within 3–4 DoL) vs. (2) late target dose achievement (energy within 10–12 DoL; amino acids within 5–7 DoL). The primary outcome was the occurrence of HG during the first week of life. An additional endpoint was long-term body growth. We observed a significant difference in the rate of HG between the two groups (30.7% vs. 12.2%, Despite improvement in neonatal care, post-natal growth restriction (EUGR) associated with undernourishment remain a challenge for neonatologists. Thus, adequate nutritional support immediately after birth is essential for preterm newborns to limit EUGR. Over the last decade, an early enhanced nutrition strategy has been adopted routinely in NICU in order to ensure a neonatal growth as close as possible to that of a fetus of the same gestational age (GA). In particular, current guidelines recommend preterm newborns to receive high doses of amino acids (i.e., 1.5–3.5 g/kg/d) and energy (i.e., 90–120 kcal/kg/d) [However, the efficacy of this nutritional approach in terms of growth herein remains controversial [However, guidelines recommend administration of PN ensuring that it is advisable continuing to treat a child with PN being wary that it might become harmful for the child [We hypothesized that delaying the time needed to achieve the macronutrient target of supplemental PN beyond the critical window period (first week of life), even maintaining the same target value recommended, may reduce the occurrence of metabolic side effects in very low birth weight infants (VLBW). The effects of this kind of nutritional strategy on growth in VLBW infants still needs to be established. To test this hypothesis, we designed a controlled clinical trial aiming to investigate the efficacy and safety of two PN strategies, which were different for the time of target achievement: (1) Group 1: early target achievement of PN; (2) Group 2: delayed target achievement of PN. | PMC10005207 |
2. Materials and Methods | PMC10005207 |
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2.1. Standard Protocol Approval, Ethics and Patient Consent | The study is a single center prospective randomized controlled trial. The study was conducted in conformity with World Medical Association Declaration of Helsinki for medical research involving human subjects; it was approved by Ethics Committee of Policlinico Umberto I, University La Sapienza of Rome (number 5089). We obtained written informed consent from all parents. | PMC10005207 |
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2.2. Population and Randomization | death, congenital malformations | CONGENITAL INFECTIONS, BLIND, INBORN ERRORS OF METABOLISM | We included all newborns with a gestational age (GA) <32 weeks or body birth weight (BW) <1500 g, consecutively admitted to the NICU of Policlinico Umberto I, La Sapienza University of Rome over a 4-year period. We excluded from the analysis neonates with major congenital malformations, inborn errors of metabolism, congenital infections, loss of central lines, hospital discharge or transfer or death within 24 h of life.Consecutive eligible patients were randomly assigned (1:1) to either one of the two PN protocols characterized by early (Group 1) or delayed (Group 2) achievement of the macronutrient target intake.Target intake was defined by the sum of macronutrient intake received by parenteral plus enteral nutrition. In both groups, the enteral nutrition protocol was administered according to a unique protocol. The nutritional protocol followed by patients included in the two study groups were reported in Patients were allocated to each group according to a software generated randomization list. Concealment of group assignment was ensured by the use of a computerized randomization system. On the randomization list, each patient was associated with a code belonging to either one of the two treatment protocols. A neonatologist in charge of PN prescription had to insert the specific code in the software that opened up either one of the group treatments. Performing a double-blind study would not have been ethically feasible, physicians prescribing the supplemental PN proposed by the software were unaware of the study aims and we used the third-party blind observer method to assess efficacy. Outcome assessors and investigators who were not directly involved in NICU patient care were not informed of treatment allocation. | PMC10005207 |
2.3. Outcome | hyperglycemia | HYPERGLYCEMIA | The primary outcome measure was the rate reduction of patients experiencing severe hyperglycemia (HG) between Group 1 (HG 30%) and Group 2 (15%) during the first week of life. | PMC10005207 |
2.4. Nutritional Protocol | bradycardia, Human milk, emesis, apnea, abdominal distension, ileus | HEMODYNAMIC INSTABILITY, ILEUS | In both groups, PN was initiated within 24 h after admission into the NICU. The macronutrient dose varied according to group assignment (Neonatologists in charge prescribed PN on a daily basis to preterm neonates based upon each clinical condition, laboratory results and weight by using a specific software. The requirement of macro- and micronutrients administered through PN was calculated by deducting the amount of enteral nutrition from the total energy requirement. The PN was administered via central vascular access. The overall fluid intake administered by combined EN and PN started with 70–90 mL/kg/day and increased by 10–20 mL/kg/day until the achievement of 150–180 mL/kg/day. The enteral feeding scheme was the same for the 2 study groups. Minimal enteral feeding was commenced within 48 h after birth at 10–20 mL/kg/day. The amount was increased by 20–30 mL/kg/day if enteral nutrition (EN) was tolerated. We withheld enteral feeding in case of severe abdominal distension, emesis, ileus with visible intestinal loops, blood in the stools, apnea, bradycardia, inadequate perfusion and hemodynamic instability. Human milk (HM) of own mother without fortifications was given fresh as soon as possible after birth if available. The preterm formula (PF) was administered to the infants when HM was not available or sufficient. Preterm HM was assumed to contain 65 Kcal/100 mL (1.5 g of protein/100 mL, 3.5 g of fat/100 mL and 6.9 g of carbohydrate/100 mL). Macronutrient contents of formula (Pre-Nidina Nestlè 1, Milan, Italy) and of PN were calculated based on the published manufacturer’s labels and included proteins (TrophAmine1 6% Braun Medical Inc., Irvine, CA, USA), lipids (Smoflipd 1, Fresenius Kabi, Lake Zurich, IL, USA) and carbohydrates (Dextrose injection 10%, Fresenius Kabi, USA) expressed in g/kg/day. | PMC10005207 |
2.5. Data Collection | hypo-phosphoremia, NEC, ROP, prematurity, IVH) stage ≥ 2, periventricular leukomalacia, IVH, intraventricular hemorrhage, ’s stage ≥ 2,, BPD, sepsis, PVL | NECROTIZING ENTEROCOLITIS, BRONCHOPULMONARY DYSPLASIA (BPD), HYPONATREMIA, HYPERCALCEMIA, BLOOD, SEPSIS, COMPLICATIONS, RETINOPATHY OF PREMATURITY | All patient data were stored in a logged database that was closed 90 days after enrollment of the last patient. The HG was defined as two consecutive blood glucose levels greater than 180 mg/dL at least 3 h apart. Blood glucose levels were monitored by a validated micro-method from capillary blood and analyzed by point of care device Accu-Chek Inform II glucometer (Roche, Indianapolis, IN, USA) four to eight times per day from the first days of life and less frequently when the clinical conditions were stabilized [Investigators collecting reporting forms were blinded to the assigned group.Medical staff were blinded to the study aims but not to eligibility criteria. Researchers not involved in the clinical practice provided information to the parents and collected all data useful for statistical analysis. A third-party observer, not involved in the previous steps, was involved to collected data on the primary outcome. A blinded statistician performed data analysis. We prospectively recorded prenatal, perinatal, and postnatal data in a specific data form. Data on PN, EN and feeding tolerance were collected daily. Data on daily cumulative parenteral and enteral nutritional intake were reported in a specific data form. In order to study the occurrence of PN related complications, we collected data on glycemia, hypercalcemia, hypo-phosphoremia and hyponatremia. We also collected data on survival and morbidities of prematurity. Overall morbidity was defined as the presence of at least one of the major prematurity complications: necrotizing enterocolitis (NEC) Bell’s stage ≥ 2, intraventricular hemorrhage (IVH) stage ≥ 2, periventricular leukomalacia (PVL), culture proven sepsis, retinopathy of prematurity (ROP) stage ≥ 3 and bronchopulmonary dysplasia (BPD). Diagnosis of NEC, BPD, IVH, PVL, ROP and culture proven sepsis were performed according to standard criteria by physicians unaware of the study design and aims, as previously described [ | PMC10005207 |
2.6. Statistical Analysis | Statistical analysis performed using Statistical Package for Social Science Software for Microsoft Windows (SPSS Inc., Chicago, IL, USA), version 27.0. We checked for normality using a Shapiro–Wilk test. The mean and standard deviation or median summarized continuous variables. We used a chi-square test for categorical variable, We estimated the need of 177 participants in each group to obtain a power of 90% (type 1 error = 0.05, two tailed test, drop out 10%). | PMC10005207 |
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3. Results | hypoglycemia, BPD, ROP | HYPOGLYCEMIA, REGRESSION | A total of 321 patients underwent randomization and were included in the analysis, (At baseline, the characteristics of the patients were similar between the two groups, (Group 1 showed a significantly decreased duration of PN compared with Group 2 (13.43 DoL vs. 17.65 DoL; The rate of HG within 0–7 DoL is reported in The rate of hypoglycemia within 0–7 DoL was similar between the two groups (12.4 vs. 12; Data analyzed also per protocol showed similar results on the primary outcome. Despite the overall morbidity not being different among groups, we observed that the rate of BPD and ROP were significantly higher in Group 1 than Group 2 (The binary logistic regression analysis showed that group assignment did not influence the risk of BPD (In We found that group assignment (ß = 1.095, The rate of EUGR was lower in Group 1 compared with Group 2 (63.4 vs. 75.5, Unstandardized BW, length and CC were reduced in Group 1 compared with Group 2 at 12 months of life (Linear regression analysis showed that only actual energy intake in the first week of life through PN were positively related with weight at 12 months of life, ( | PMC10005207 |
4. Discussion | critically ill, ROP, Malnutrition, metabolic complications, hyperglycemia, BPD, sepsis | CRITICALLY ILL, MALNUTRITION, HYPERGLYCEMIA, REGRESSION, SEPSIS, COMPLICATIONS | Delayed target achievement of recommended nutritional intake reduces the risk of HG in preterm newborns. The occurrence of HG in the first week of life is an independent risk factor for mortality during hospitalization. Additionally, early target achievement reduces the risk of sepsis but is associated with an increased risk of ROP. Contrasting effects on brief- and long-term growth were observed comparing the two nutritional strategies adopted in the trial. If PN strategy characterized by early introduction of macronutrients was associated with an improvement in short-term growth, the analysis of long-term growth parameters revealed that delayed target achievement was advantageous for body weight and length as showed in multivariate model analysis.The drawbacks of an early target achievement seem to overcome the related advantages. We observed that the amino acid intake within the first week of life was similar between the two groups, whereas the amount of dextrose and lipids during the first week of life were significantly different between Group 1 and Group 2. Thus, it is plausible that the related effects of a nutritional strategy characterized by delayed target achievement may depend on the amount of nonprotein calories. Previous studies comparing PN strategies focused mainly on the effects of maximum macronutrient target intake but not on the modalities of advancement of macronutrient intake by PN. So far, in critically ill newborns, there is a dearth of adequately powered, randomized, controlled trials that address the effects of PN on clinical outcomes. Previous recommendations for the optimal amount and composition of PN were based on very few observational studies on infants in critical conditions, in which PN support was advised without focusing on the facts that critically ill infants face different clinical phases during NICU hospitalization [The PEPaNIC trial showed that starting PN after 1 week in critically ill children is clinically superior to providing early PN as soon as possible after hospitalization [Our results are in keeping with those of Stensvold et al. whereby, in a prospective cohort study comparing enhanced PN with standard PN, HG is an independent risk factor of mortality in preterm newborns [Our finding of greater morbidity in neonates receiving the early PN target is in keeping with previous evidence in critically ill adults, children and newborns, which has led to calls for the deimplementation of early PN in these groups [Despite our data disconfirm the relation between early PN intake and BPD occurrence, this aspect is still an ongoing debate. Several retrospective studies reported the association between low caloric intake and BPD development. Malnutrition seems to worsen BPD probably by compromising lung development and function; a recent study found that preterm infants who developed BPD received low caloric intake [The finding of increased sepsis in the delayed target group is out of keeping with the outcomes in children comparing early versus late PN [An early target achievement PN resulted in a reduction of EUGR occurrence. Previous studies have shown the association between early PN and improved short-term growth in preterm newborns [Despite interesting results, our study had some limitations. Parents of neonates included in the study and neonatologists were aware of the group assignment. Individualized PN solution adjusting is the milestone of our policy on PN in order to avoid deleterious consequences of PN-related complications. Despite being a potential information bias, we have preferred that neonatologists in charge knew the composition of PN in order to easily adjust the PN prescription in case of metabolic complications related to PN administration. To limit selection bias, physicians evaluating eligibility were blinded to the study aims and used objective inclusion criteria (such as GA and BW). To limit observer bias, outcome assessors were unaware of group assignment. We discussed and defined a protocol for the collection, measurement and interpretation of data before starting the study. Finally, a blinded statistician performed the data analysis.The overall morbidity and mortality were higher in Group 2, and it is very close to statistical significance. Further, Group 2 had a significantly higher risk for sepsis. However, we performed a multivariate analysis that identified hyperglycemia as independent risk factor for mortality in a model including sepsis. Additionally, we speculate that overcoming EUGR at 12 months of life could be explained by the increased morbidities, which in turn limit neonates’ growth. To verify this hypothesis, we performed a linear regression analysis showing that energy intake independently influences growth at 12 months of life.The trial was not designed for evaluating the difference in long-term growth; thus, the sample power of the study is insufficient to evaluate differences between study groups in body weight at 12 months of life. | PMC10005207 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10005207 |
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Author Contributions | Conceptualization, M.D.C. and G.T.; methodology M.D.C., E.T., G.L., R.P., C.S., G.B. and G.T.; validation M.D.C. and G.T.; formal analysis M.D.C. and G.T.; investigation, E.T., G.L., R.P., C.S., L.D., D.R., P.P., R.B., B.D.S. and G.B.; data curation, M.D.C. and G.T.; writing—original draft preparation, M.D.C. and G.T.; writing—review and editing, G.T. and M.D.C.; visualization, G.T.; supervision, G.T.; project administration, G.T. All authors have read and agreed to the published version of the manuscript. | PMC10005207 |
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Institutional Review Board Statement | The study was conducted in conformity with World Medical Association Declaration of Helsinki for medical research involving human subjects, and it was approved by Ethics Committee of Policlinico Umberto I, University La Sapienza of Rome (number 5089, 24 June 2020). | PMC10005207 |
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Informed Consent Statement | Written Informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. | PMC10005207 |
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Data Availability Statement | The datasets analyzed during the current study are available from the corresponding author on reasonable request. | PMC10005207 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10005207 |
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1. Introduction | cancer, death | CHRONIC ILLNESS, DISEASE, CANCER | Background: Hope is widely considered a subjective phenomenon able to bring beneficial consequences to human health and existence. Maintaining hope amid a life-threatening disease and during palliative care is critical. The study aims to examine the effectiveness of a psychosocial supportive Hope Promotion Program (HPP) in enhancing hope, comfort, and quality of life in Portuguese adult outpatients with advanced and progressive chronic illness. Method: Using a parallel Randomized Control Trial (RCT) with pre-post design, 56 cancer outpatients from two day hospitals. Participants were randomly assigned to either a control group (n = 28) or an intervention group (n = 28). The primary outcome measure was hope. Secondary measures included comfort and quality of life. Participants were assessed at baseline, day 15, and day 30 of follow-up. Results: Baseline characteristics were similar between the two groups. In the intervention group, there was a significant increase in the total hope scores after the HPP (day 15). Significant differences were still present after one month (Palliative care, as a medical speciality, has grown to occupy an essential area between the opposing emphases on prolonging life and hastening death [The promotion and inspiration of hope is closely linked to the effectiveness of nursing practice [Several studies have found that a range of psychosocial interventions can help palliative care patients feel more hopeful [The evaluation and promotion of hope is one of the standards of good clinical practice in palliative care [The overall aim of the present study was to evaluate the effectiveness of a psychosocial program to promote hope, comfort and QoL in Portuguese adult outpatients with advanced and progressive chronic illness. Understanding the effects of such programs will provide insights for other interventions focused on fostering hope in palliative care patients. | PMC9861685 |
2. Materials and Methods | PMC9861685 |
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2.1. Study Design | This was a two-group, parallel Randomized Control Trial (RCT), with a pre-test post-test control group design and repeated post-test measures. This RCT was retrospectively registered in the United States of America Clinical Trials Registry Platform (NCT02723799) according to the investigation protocol (see | PMC9861685 |
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2.2. Setting and Participants | DISEASE | Participants were recruited from the day hospitals of two medical institutions in the central region of Portugal. The services in both contexts are especially dedicated to providing healthcare to chronic patients at different stages of the disease, including the palliative phase, in a clinic with less than 24 h access and surveillance. After the main researcher (AQ) explained the study, each participant signed a written consent form before participating in the study. Consolidated Standards of Reporting Trials (CONSORT) guidelines were followed throughout the study [ | PMC9861685 |
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2.2.1. Eligibility Criteria | After agreeing to participate, participants were thoroughly screened for eligibility by the main researcher (palliative care and mental health nurse). Screening involved completion of the Mini-Mental State Examination (MMSE) [ | PMC9861685 |
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2.2.2. Random Assignment | The principal investigator (AQ) randomly allocated eligible participants to one of the two group using blocks of eight individuals, in a 1:1 distribution system, in order to guarantee an approximate number of individuals allocated to each group. Thus, for each block of eight individuals, a white ball/black ball system was used, using four balls of each colour for this purpose. | PMC9861685 |
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2.3. Intervention—Hope Promotion Program (HPP) | DISEASE, COMPLICATIONS | The intervention was designed based on the Narrative Communication Model of Hope Seeking Intervention [The participants randomly assigned to the intervention group were given the individual-based intervention (HPP) in three home visitation sessions conducted by a nurse. Each session lasted between 90 min and 2 h 30 min, depending on the patient’s need, capacity and will. The interval between sessions was scheduled to last two to three days, so that the full intervention occurred over 10 days. The possibility of adjusting session times according to the client’s conditions was considered whenever complications associated with the disease or treatments prevented the session. Participants were able to have a family member present whenever they wished, which happened in half of the situations. Each participant had an equal number of sessions with the same predetermined objectives.The first session, with the objective of awakening the self-perception of hope and expressing it verbally, was accompanied by viewing a Portuguese adaptation of the “Living with hope” video [The second session was focused on the expression of feelings and emotions related to the experience of the disease, and on working positively on the client’s capacities to carry out hope-promoting activities. An activity guide was provided to the patient and was explored during the session. Some hope-focused activities were proposed, such as gratitude exercises, therapeutic and forgiveness letters (writing someone a letter), a hope album (remembering memories of hope from the past), or stories of the present and a hope kit (collecting objects that are hopeful and significant) [The third session’s main objective was to facilitate the transcending of the suffering associated with the advanced disease through teaching and training relaxation using mental images [ | PMC9861685 |
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2.4. Sample Size | CHRONIC DISEASE | The sample size was calculated using power analysis based on four components: the level of significance or alpha (α), sample size, population effect size (ES), and power (1-β) [Given the inherent characteristics of individuals with advanced chronic disease, and the expected missing data and high attrition of the study, all subjects who met the initial selection and agreed to participate in the study were included in the randomization process. | PMC9861685 |
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2.5. Outcome Variables and Measurements | The primary outcome was hope, as measured using the Portuguese version of the Herth Hope Index (HHI) validated for chronic conditions [Secondary outcomes were:(a) Comfort, as measured by the Portuguese version of the Hospice Comfort Questionnaire (HCQ) [(b) QoL, as measured by the Portuguese version of McGill Quality of Life Questionnaire (MQoL) [ | PMC9861685 |
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2.6. Data Collection Procedure | depression, illness, fatigue, pain | BLIND | Data collection took place over an 8-month period. Participants completed baseline (T1) instruments upon enrolment. Follow-up instruments were collected immediately after the intervention (T2—15 days later), and one month after the program was completed (T3). Baseline data collected for all participants included: (1) demographics (gender, age, marital status and social status); (2) clinical characteristics (medical diagnosis, functional status, presence of medical symptoms, like pain, fatigue or depression); (3) the Herth Hope Index [HHI]; (4) the McGill Quality of Life Questionnaire [MQoL]; and (5) the Hospice Comfort Questionnaire [HCQ].The intervention group received the HPP, and the control group received a standard care and palliative care approach provided locally by a multidisciplinary healthcare team. After the intervention (T2 and T3), participants from the two groups completed the HHI, MQoL and HCQ through a face-to-face interview by a research assistant. As participants were suffering from a severe illness, we made every effort to simplify survey completion, including reading the survey over the phone or during home visits. Most follow-up contacts were made by home visitation and telephone, with the remainder occurring during normal clinic appointments. All of the participants, care providers, and the research assistant who assessed the participant’s outcomes were blind to the intervention. | PMC9861685 |
2.7. Analysis | A per-protocol analysis was done for all outcome variables and included only those patients who accomplished all assessments. Descriptive statistics were calculated to summarize patients’ characteristics and other baseline variables. The normality of distribution was checked using the Shapiro-Wilk test. Therefore, comparisons between the two study groups were analysed using the nonparametric Mann–Whitney test. The relationship between hope, comfort and QoL was tested using Spearman’s rho. Additionally, Wilcoxon tests were completed to compare pre-test and post-test scores between groups. Since data aren’t normally distributed, medians were preferred over means as pre- and post-test values. Due to the exploratory analysis and sample size, A | PMC9861685 |
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2.8. Ethical Issues | BLIND | The project received ethical clearance from the Ethics Committees for Health of the hospitals where the research was conducted, which is in line with the principles of the Helsinki Declaration and later amendments [All subjects provided informed consent prior to any evaluation during the enrolment phase. All participants were provided with written and verbal information about the study. Patients were informed that they had the option to withdraw from the study at any time without penalty or censure. All data collecting and management procedures took the participants’ privacy and confidentiality into account. The main researcher (AQ) was not blind for both the intervention and the control group. To ensure equity to access the Hope Intervention Program, the control group participants were offered the opportunity to enrol in the hope activities of the program after the study completion. | PMC9861685 |
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3. Results | PMC9861685 |
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3.1. Demographic and Clinical Characteristics | death, fatigue | A total of 165 eligible participants were assessed for potential enrolment. Of these, 72 individuals did not meet the inclusion criteria, 29 participants declined to participate mainly due to fatigue, five people had their clinical situation worsen, and three individuals died. A total of 56 patients consented to participate and were enrolled in the study. They were randomly assigned to either the intervention group [IG] (n = 28) or the control group [CG] (n = 28). Since the allocation to the follow-up, several participants dropped out mostly to clinical deterioration and death (see In a per-protocol analysis, the data are analysed only for patients who reach the study endpoint. Therefore, the characteristics of the participants who completed the protocol originally allocated are summarized in No statistically significant differences were identified between groups in baseline demographic and clinical variables. The equivalence between the two groups was also tested for the hope, comfort, and QoL variables. Groups were similar regarding QoL and comfort, but there were significant differences in hope indexes ( | PMC9861685 |
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3.2. Relationship between Hope, Comfort and QoL in the Sample | The resulting matrix shows positive, moderate and very significant relationships between hope, global comfort and total QoL. The highest correlation was found between hope and QoL (ρ = 0.605, | PMC9861685 |
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3.3. Effect of Intervention | The global median scores were graphically represented for each outcome, before and after the intervention in both groups (see | PMC9861685 |
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3.3.1. Primary Outcome | In the intervention group, there was a significant increase (+3.5; | PMC9861685 |
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3.3.2. Secondary Outcomes | There were no significant differences in comfort scores in either group between T1 and T2. However, there was a significant increase in global comfort median scores in the intervention group one month after the HPP (T1/T3) (+13.5; Regarding the state of ease, there was a statistically significant increase between baseline (T1) and post-intervention (T2) in the CG, but not in the IG. The group submitted to HPP evolved positively and significantly after 15 days (T2). In the CG, the median evolution was decreasing (−0.33) and significant (There was a significant increase in transcendence between T2 (Median = 5.57) and T3 (Median = 5.86; Regarding the context of comfort (HCQ), the difference between baseline (T1) and T2 was only significant for the IG in the psychospiritual context (Concerning the evolution of global QoL, no significant differences were identified for the IG between any of the three moments. Despite an increase in the median score in T2 (+0.25) and T3 (+0.19), the average after HPP decreased, corresponding to the lowest value of the three measurements. In the CG, the median evolution was negative between T1 and T2 (−2.01), and then rose significantly in T3 (+3.38). | PMC9861685 |
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4. Discussion | chronic illness, hope-promoting, illness, death | CHRONIC ILLNESSES, CHRONIC ILLNESS, DISEASE PROGRESSION | Comparison between the IG and CG suggests that the HPP had a positive effect on hope over time. The most expressive increases were in the levels of total hope and positive interior disposition and expectations, with significant differences in each period. Regarding temporality, trust and interconnection, differences were only significant one month after the intervention. This can be explained by the high level of hope before the HPP, making it difficult to detect large variations immediately after the intervention program. Even so, the increase was significant when compared to the CG (where levels of hope decreased), attesting to the effect of HPP upon the greater sense of temporality, trust and interconnection over time.These results support the active and effective role of nurses in promoting the hope of people with advanced chronic illness [This study was innovative in using a psychosocial supportive hope intervention that differed in terms of dose, composition and the possibility of individualizing the proposed activities. According to Chan et al. [The tested HPP’s design included a greater number of nurse visits in relation to the “Living with Hope Program” [The first HPP session, viewing the film “Living with hope”, may have been crucial in shaping the patients’ positive perception of hope. The use of the video has been an integral part of hope-promoting programs [Participants in the IG had a higher global and physical QoL than those of the CG immediately after the HPP. This difference between groups did not remain over time, although there was an increase in both groups. Disease progression and treatments may have prevented better results. However, considering that the instrument can detect changes in 48 h, these results may indicate the need to reinforce hope-promoting interventions and activities in order to obtain gains in QoL over time [One of the novelties of this study was the evaluation of the program’s ability to promote hope in comfort. So far, the developed programs have not included the relationship between these variables, although comfort is a major goal of care for people with advanced and progressive chronic illnesses in their end-of-life trajectory [In the HPP, the promotion of hope is associated with interventions and activities directed simultaneously toward comfort in the physical, psycho-spiritual, environmental and socio-cultural contexts. In addition to the proposed hope-focused activities, the program includes a relaxation exercise using guided imagery to reinforce the repertoire of coping strategies, self-control and self-confidence. This constitutes a non-pharmacological tool for symptom control using the ability to transcend the situation [The results indicate that HPP brings long-term gains in terms of overall comfort, relief, ease and transcendence, since the evolution was significant for all these states in the patients in the IG one month after the program. The increase in comfort can be partially explained by the increase in hope, as these variables were positively correlated in the study sample. The increase in comfort was most likely related to the relaxation activity using mental images, since this was performed by all participants. Guided imagination has been identified as a non-pharmacological strategy of symptom control capable of facilitating comfort in a hospital environment [Notably, there were significant differences between the experimental and control groups in the state of transcendence. This means that, despite the progression of the illness and the effects of their treatments, HPP enabled people to evolve in the discomfort-comfort continuum, increasing their ability to feel more competent and to plan, control their destiny and solve their problems. In the final phase of life, an increase in transcendental comfort can compensate for successive losses of autonomy and control associated with the experience of illness and the real possibility of death in the short term. The fact that patients were mostly Catholic may have influenced transcendence. Believing in life beyond death and giving meaning to suffering (compared with that of Jesus Christ and other models associated with religion) seems to have been decisive for the perception of hope and may also justify the significant gains in comfort in the psycho-spiritual context [The active involvement of patients in performing the hope-promoting activities proposed in the guide, which was only possible due to their good functional level, may have facilitated the state of greater harmony, satisfaction and calm necessary for efficient performance, leading to greater transcendental comfort [ | PMC9861685 |
4.1. Study Limitations | tiredness, ill | DISEASE, RECRUITMENT | Our study had several limitations. Firstly, only one nurse provided the intervention, which might have influenced the results. Secondly, the rapid deterioration in the health status of the participants implied a decrease in the number of patients in each group, which might impact the results. Indeed, participants’ numbers are lower than proposed in the planned power analysis due to recruitment challenges common to end-of-life studies. This reality is unavoidable and is often responsible for the low number of longitudinal studies carried out in this population. The effect of disease symptoms was the main factor behind the study’s dropout rate, with identical rates in both groups. In this study, the HPP was not responsible for patient exhaustion to the point of inducing them to give up due to tiredness. In the per-protocol analysis, data were examined only for those patients who completely adhere to the protocol, as this reduces the statistical power of the study, and the benefits of randomization are lost because the composition of the original groups has been disturbed. Despite the constraints motivated by the loss of subjects, the cases analysed guaranteed group homogeneity, which attests to the reliability of the results. Future studies with mixed methods should address these limitations with larger sample sizes and more diverse settings, including extended and more detailed follow-ups. The HPP should also be extended to include non-terminally ill patients, patients receiving palliative care, and patients with lower levels of functional status [Lastly, and while our clinical trial has not been prospectively registered, this study contains valuable information to improve palliative care and inform future clinical practice. | PMC9861685 |
4.2. Implications | This study can be a useful contribution to updating the International Classification for Nursing Practice (ICNP | PMC9861685 |
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5. Conclusions | ill | The HPP may be an effective intervention to increase hope and improve comfort and quality of life among palliative patients. This RCT suggests that is important to create training programs for nurses and nursing students within the scope of hope-promotion in order to promote the development of the personal and professional skills necessary to apply the HPP, both within the scope of palliative care and the context of acute hospitals. The intervention itself should also be developed by exploring other information and communication resources and technologies, namely the telephone, computer and the internet, since the population will tend to be more info-competent in the use of these technologies. The exploitation of these resources can promote empowerment and constitute a useful tool in the positive reinforcement of ill people’s skills and their own hope. | PMC9861685 |
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Author Contributions | Conceptualization, A.Q.; Methodology, A.Q.; Software, A.Q.; Validation, A.Q.; Formal analysis, A.Q.; Investigation, A.Q.; Resources, A.Q.; Data curation, A.Q.; Writing—original draft preparation, C.L. and A.Q.; Writing—review and editing, C.L. and A.Q.; Visualization, C.L. and A.Q.; Supervision, A.Q.; Project administration, A.Q.; Funding acquisition, A.Q. and C.L. All authors have read and agreed to the published version of the manuscript. | PMC9861685 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Boards (protocol approvals no. GIC/584; 942/C.A.). | PMC9861685 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9861685 |
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Data Availability Statement | The data are available upon reasonable request. | PMC9861685 |
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Conflicts of Interest | The authors declare that they have no conflict of interest. | PMC9861685 |
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References | SECONDARY | Participant flow through the phases of the RCT.Global median scores evolution of the primary and secondary outcome measures.Investigation protocol.* IG—Intervention Group; ** CG—Control Group.Participants’ baseline features.Differences in means and results of the Mann-Whitney tests to assess the equivalence between both groups in the variables of hope, comfort and QoL and its dimensions.HHI—Herth Hope Index; MQoL—McGill Quality of Life Questionnaire; HCQ—Hospice Comfort Questionnaire; SD—Standard Deviation.Evolution of the total hope, comfort, QoL and its dimensions, in both groups, comparing the three moments of assessment, using Wilcoxon tests.* T1 and T2 (n = 12); T3 (n = 11). † T1 and T2 (n = 14); T3 (n = 12). | PMC9861685 |
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1. Introduction | milk, ’ gastrointestinal tolerance, gastrointestinal (GI) disturbances, human milk or infant formula, weight gain | SECONDARY, DISEASES | Membership of the HASI Study Group is provided in the Acknowledgements.The evaluation of secondary parameters of a prospective, randomised, controlled, multicentre intervention trial aimed to analyse gastrointestinal tolerance of an infant formula manufactured from extensively hydrolysed whey protein (eHF) compared to intact cow’s milk protein (control formula, CF) in healthy term infants. Infants ≤ 25 days of age, who were exclusively formula-fed, were randomised to receive eHF or CF for at least three months up to 120 days of age. An exclusively breastfed reference group (BF) was included for descriptive comparison. Infants’ gastrointestinal tolerance was evaluated based on stool parameters, the Amsterdam Infant Stool Scale (AISS), the Infant Gastrointestinal Symptom Questionnaire (IGSQ), and sleeping patterns. Of 359 infants included, 297 randomised (eHF: Human milk is the gold standard for infant feeding, not only regarding nutritional needs of infants but also for providing bioactive components and ultimately reducing the risk of diseases later in life [Regardless of feeding with human milk or infant formula, a high incidence of gastrointestinal (GI) disturbances is observed in infants [Different types of infant formula have been developed in order to meet different needs; each is required to conform to the requirements set out by the European Food Safety Authority (EFSA). Most products are based on cow’s milk protein and are supplemented with nutrients or other bioactive components, such as long-chain unsaturated fatty acids, milk oligosaccharides, and probiotics, in order to best mimic human milk both in nutrient composition and GI tolerance. Studies have suggested that infant formula manufactured from hydrolysed protein may positively affect digestibility and GI symptoms during the first months of life due to the different molecular structures of proteins and peptides [The purpose of the analysis of the secondary outcome parameters of the “HA Safety in Infants” (HASI) Study was to evaluate the GI tolerance of an infant formula manufactured from extensively hydrolysed whey protein (eHF) compared to an infant formula manufactured from intact protein (control formula, CF) during the first 120 days of life using several well-validated parameters. Exclusively breastfed infants were included for descriptive purposes. Safety and suitability, i.e., weight gain and other growth parameters, of eHF for infant consumption have already been demonstrated within the HASI Study [ | PMC10647512 |
2. Methods and Materials | The study design and methods are described here briefly; they have been published in detail elsewhere [ | PMC10647512 |
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2.1. Study Design and Population | ICH, Breastfed | SECONDARY | The study was designed as a prospective, multicentre, randomised, double-blind, parallel-group, controlled, non-inferiority trial. It was carried out from March to October 2021 in 21 centres in four European countries (11 in Bulgaria, one in Germany, eight in Hungary, and one in the Czech Republic). The study was conducted in accordance with ICH Good Clinical Practice and the Declaration of Helsinki as well as with the local legal and regulatory requirements. It was approved by the corresponding ethics committees and registered at ClinicalTrials.gov (NCT04736082).Healthy term infants from singleton pregnancies whose mothers intended to exclusively feed either formula or human milk were eligible for participation. Further details on inclusion and exclusion criteria have been described elsewhere [Upon written informed consent of both parents or legal guardians (further referred to as “parents” only), eligible formula-fed infants were enrolled into the study and randomised to one of the two infant formula-fed (FF) groups (i.e., eHF or CF). Randomisation was carried out in a double-blinded dynamic manner using country and sex as stratification variables via a centralised randomisation management interface. Breastfed infants were assigned to a non-randomised breastfed reference group (BF).The presented evaluation of the secondary parameters representing GI tolerance includes the period from enrolment up to 120 days of age. After enrolment (≤25 days of age; V0), infants attended four study visits at 30 ± 3 (V1), 60 ± 3 (V2), 90 ± 3 (V3), and 120 ± 3 (V4) days of age. Exclusive infant formula feeding began no later than 26 days of age and was continued until at least V4. | PMC10647512 |
2.2. Study Product | The two infant formulae complied with the requirements defined in Art. 3 Del. Regulation (EU) 2016/127 [ | PMC10647512 |
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2.3. Safety Evaluation | In addition and as already published [ | PMC10647512 |
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2.4. Parameters of Gastrointestinal Tolerance | PMC10647512 |
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2.4.1. Stool Characteristics | GI tolerance was estimated using data from 3-day diaries completed prior to each visit. From these diaries, stool frequency as average daily number of stools (number of stools/day) and stool characteristics, using the Amsterdam infant stool scale (AISS) [ | PMC10647512 |
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2.4.2. Infant Gastrointestinal Symptom Questionnaire (IGSQ) | GI disturbances | Furthermore, the IGSQ was completed during each visit to assess GI disturbances [ | PMC10647512 |
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2.4.3. Sleeping Behaviour | Four adapted questions of the Sleep and Behaviour Questionnaire [ | PMC10647512 |
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2.5. Statistical Analysis | PMC10647512 |
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2.5.1. Stool Characteristics | REGRESSION | Stool characteristics were analysed using a mixed Poisson regression model for repeated measurements, with the visit (from V2 to V4), the infant formula group, the interaction between visit and infant formula group and the sex as fixed effects, and the subject and centre as random effects (with the total number of stools as offset). | PMC10647512 |
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2.5.2. IGSQ | The IGSQ total score at each visit was analysed using a linear mixed model for repeated measurements, with the visit (from V2 to V4), the infant formula group, the interaction between visit and infant formula group, and the sex as fixed effects, and the subject and centre as random effects. For the specific analysis of individual questions of the IGSQ at each visit, a mixed logistic ordinal model (for repeated measurements) with the same variables for fixed and random effects as the IGSQ total score analysis was used.Furthermore, a post-hoc analysis was performed in order to assess any effect of medications or products which may positively influence GI tolerance. In the subgroup of infants who did not receive such products, a mixed linear model (for repeated measurements) was used to compare eHF and CF with regard to IGSQ total score at each visit (the same model as for main statistical analyses). Additionally, to study the differences between the two subgroups (of infants who did or who did not receive medications or products intended to improve GI tolerance), a three-way interaction term with the infant formula group, the visit, and the subgroup was introduced in the previous mixed linear model. | PMC10647512 |
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2.5.3. Sleeping Behaviour | Sleeping behaviour was analysed using a linear mixed model (for repeated measurements) with the visit (from V2 to V4), the infant formula group, the interaction between visit and infant formula group, and sex as fixed effects, and the subject and centre as random effects. | PMC10647512 |
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2.5.4. Study Population | weight gain | The data analysis presented herein was performed using the full analysis set (FAS) and per protocol set (PPS). FAS contained all randomised infants in FF and all infants in BF, except those who turned out to be a screening failure, who did not participate in V1 or who did not receive the study product at least once (if in FF). PPS involved infants of FAS without major deviations to the protocol, which included visits outside the visit window, specified medications, or any complementary food and drinks up to V4. The results of GI tolerance are described here for PPS.The study product was intended to be the only source of nutrition, meaning no breastfeeding, no complementary food, no energy-containing liquids, no feedings of any other infant formula, and no energy-free drinks like water or unsweetened tea were to be consumed until the infant reached the age of 120 days. Infants, who received complementary liquids or foods before 120 days, were not included in the PPS analysis.The sample size calculation was based on the primary study outcome mean daily weight gain. Details are described elsewhere [BF was not randomised and therefore not included in the inferential statistical analyses. The presented results for BF and comparisons to FF are purely descriptive.Descriptive analyses were performed by group and by visit for all parameters. Data are presented as mean (SD) unless otherwise indicated.Inferential tests focused on an explorative two-sided 5% significance level. Statistical analyses were performed using the software SAS | PMC10647512 |
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3. Results | PMC10647512 |
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3.1. Study Participants and Population Characteristics | weight gain, birth [ | As reported previously [Birth characteristics, including gestational age, mode of birth, sex, and anthropometric parameters, as well as parental characteristics including maternal age, BMI, and weight gain during pregnancy, were comparable between eHF and CF, as previously reported in detail [Characteristics of BF were similar to FF, except for sex and mode of birth [ | PMC10647512 |
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3.2. Compliance | Study compliance was very high. Seven infants in eHF and nine infants in CF had major deviations in feeding instructions and were thus excluded from PPS; most of these deviations were related to the consumption of low amounts of water and non-sweetened tea. No complementary foods were given before V4. All infants in BF were fully compliant with the feeding instructions, i.e., exclusively breastfed [ | PMC10647512 |
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3.3. Safety Evaluation | Details on safety reporting are described in detail elsewhere [With regard to concomitant medications, approximately 30% of infants received a product which could potentially positively influence GI tolerance, such as simeticone, lactase, or aromatic oils ( | PMC10647512 |
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3.4. Gastrointestinal Tolerance | PMC10647512 |
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3.4.1. Stool Characteristics | ±, watery | Daily stool frequency varied strongly among individuals but did not differ between FF groups at any visit (While mean daily stool frequency in BF also decreased from V1 to V4, trending towards the levels of FF infants, it was higher at all visits compared to FF (4.0 ± 1.0 (range: 1.7–6.3) stools per day at V1 to 2.2 ± 0.6 (range: 1.3–4.3) stools per day at V4) (Although stool amount varied over time, no difference was observed between FF groups at any visit (Regarding stool consistency, no differences were observed between FF groups at any visit (Soft stool was also the predominant consistency in BF at all visits (ranging from 43.9 ± 22.6% of stools at V2 to 76.5 ± 19.8% at V4), followed by watery stool (ranging from 14.7 ± 15.9% of stools at V4 to 34.7 ± 22.0% at V2). In a descriptive comparison, BF had a higher prevalence of watery stools than FF and lower prevalence of formed and hard stools throughout the study period.Stool colour was largely comparable between FF groups, except for green stools, which were more common in eHF than CF (ranging from 7.6 ± 18.9% at V4 to 21.5 ± 26.4% at V2 in eHF and 4.3 ± 12.0% at V4 to 15.9 ± 19.9% at V2 in CF). This difference in stool colour was not significant in the PPS at any visit but reached significance at V3 only in the FAS (V3: eHF 16.9 ± 25.8% vs. CF 10.8 ± 16.1% stools with green colour over 3 days, Also in BF, the majority (>75%) of stools were yellow throughout the study period (V1: 84.9 ± 17.7%; V4: 83.9 ± 20.9%). Each of the other colours was observed in less than 12% of the stools reported at each visit ( | PMC10647512 |
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3.4.2. IGSQ | Mean IGSQ total score decreased from V1 to V4 in both FF groups and did not differ between FF groups at any visit (Similarly, in BF, mean IGSQ score decreased throughout the study period and showed a tendency to lower values compared to FF until V3. At V4, this trend was no longer visible (Consistent with IGSQ total scores, selected individual question scores did not differ between FF groups (The safety evaluation revealed that about one third of the infants preventively received products with a possible positive impact on GI tolerance ( | PMC10647512 |
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3.4.3. Sleeping Behaviour | There were no differences observed in any of the sleep parameters (24 h sleep, nocturnal sleep, interrupted nocturnal sleep, time to fall asleep) between eHF and CF throughout the study period. While 24 h sleep decreased from V1 to V4 by approximately 18% in both eHF and CF, the duration of nocturnal sleep increased in both groups by about 9% in eHF and 10% in CF (The mean duration of uninterrupted nocturnal sleep increased across all groups from approximately 4.0 ± 1.8 h per night at V1 to 6.2 ± 1.1 h per night at V4, while the time to fall asleep decreased from approximately 0.8 ± 0.4 h per day at V1 to a mean of 0.5 ± 0.2 h per day at V4 in all groups ( | PMC10647512 |
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4. Discussion | SECONDARY | In this secondary analysis of a multicentre, randomised, controlled, double-blind trial, the GI tolerance of eHF was compared to that of CF. No significant differences were observed during the first 120 days of life, as reflected by similar stool characteristics, IGSQ and sleeping patterns.The daily number of stools decreased over time, with no significant differences between FF groups as previously shown elsewhere [The most commonly reported stool consistency of FF infants was soft, which is in line with previous findings with infant formulae manufactured from hydrolysed or intact protein containing pre- and/or probiotics [Overall, stool colour was comparable between FF groups. A yellow stool colour was dominant, but orange, brown, green, meconium, and clay-coloured stools were also noted. This wide variety of stool colours is common in healthy infants [Throughout the study period, median IGSQ scores were highly comparable between FF groups and were below proposed norm-reference values [Furthermore, there were no differences in sleeping characteristics between FF groups, with decreasing 24 h sleep and fewer sleep interruptions during the night as age increased. Rivkees et al. described a progressive maturation of the circadian system in infants [No statistical comparison to the non-randomised BF reference group was performed; thus, the following discussion is based on descriptive statistics only. In accordance with previous studies, exclusively breastfed infants have more frequent and softer stools than exclusively formula-fed infants [In the present study, GI tolerance assessed by the IGSQ questionnaire was comparable between the BF and FF groups, which may have contributed to the similar feeding amounts between these two groups, as already published [Notably, in the current study, approximately one third of all infants (FF and BF) received a medication or preparation, usually preventatively, aiming to improve GI tolerance and thereby potentially preventing some symptoms of intolerance that may have otherwise occurred in the study cohort. For this reason, post-hoc statistical analyses were performed. These revealed no differences in IGSQ total score between eHF and CF in the subgroup of infants who did not receive such products. According to these results, it can be assumed that the intake of the recorded products intended to improve GI tolerance had no measurable effect in this cohort. Even so, the relatively prevalent intake of products intended to improve GI tolerance is a limitation in this study.Furthermore, due to the nature of the trial design as a safety study, no data on infant microbiome are available, which may have provided further insight into GI tolerance.The presented evaluation of secondary outcome parameters is further limited in that the sample size calculation was based on the primary objective. Nevertheless, the high compliance and low dropout rate in this study together with the use of several validated tools resulted in comprehensive data on GI tolerance, stool characteristics, and sleeping patterns at multiple time points. Furthermore, the inclusion of a reference breastfed group allowed the descriptive comparison of infant formula tolerance to human milk as the ideal and recommended nutrient source for infants. | PMC10647512 |
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5. Conclusions | The infant formula manufactured from extensively hydrolysed whey protein used in this study led to comparable results in various parameters of GI tolerance, including stool characteristics, IGSQ, and sleep behaviour, as the control infant formula manufactured from intact cow’s milk protein. Based on these findings, it can be concluded that the extensively hydrolysed whey protein-based infant formula is equally well-tolerated as the control infant formula in exclusively formula-fed infants during the first 4 months of life. Both formulae showed good GI tolerance. Nevertheless, future research should continue the effort in developing infant formula that results in stool consistency and GI symptoms in early infancy closer to those resulting from exclusive breastfeeding. | PMC10647512 |
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Supplementary Materials | The following supporting information can be downloaded at Click here for additional data file. | PMC10647512 |
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Author Contributions | Conceptualization: R.C., J.G., A.G. and F.J. Methodology: R.C., J.G., A.G. and F.J. Validation: R.C., J.G., A.G., F.J., A.N. and H.P. Resources: R.C., J.G., A.G. and F.J. Data Curation: R.C., J.G. and A.G. Writing—Original draft preparation: L.O., E.S. and A.N. Writing—Review & Editing: R.C., J.G., A.G., F.J., A.N., L.O. and E.S. Visualization: L.O. Supervision: R.C., J.G., A.G. and F.J. Project administration: A.G., R.C. and J.G. All authors have read and agreed to the published version of the manuscript. | PMC10647512 |
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Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the independent ethics committees in Germany (Ärztekammer Berlin; protocol version n. 1.1 approved on 11 January 2021), Bulgaria (Ethics Committee for Clinical Trials, Sofia; protocol version no. 1.1 approved on 26 Febrary 2021), Hungaria (ETT-KFEB, Budapest; protocol version no. 1.1 approved on 18 March 2021) and the local ethics committee of the Czech Republic (Etická komise Nemocnice, Strakonice) (protocol version no. 1.1 approved on 18 February 2021). | PMC10647512 |
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Informed Consent Statement | Informed consent was obtained from both parents/legal guardians involved in the study. | PMC10647512 |
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Data Availability Statement | The original contributions presented in the study are included in the article/ | PMC10647512 |
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Conflicts of Interest | L.O., E.S., H.P., A.N., F.J. are employed by the Evangelisches Waldkrankenhaus Spandau, a nonprofit hospital. The department does paid research for different companies in the field of infant nutrition. The employer and F.J. have received support for scientific and educational activities by companies that market food products for infants. F.J. is a member of the Nutritional Committee of the German Society of Pediatrics (Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ)), which tends to be biased towards breastfeeding, and advisor of the German Hospital Association (Deutsche Krankenhaus Gesellschaft (DKG)). R.C., J.G., and A.G. are employed by Hipp GmbH & Co. Vertrieb KG. | PMC10647512 |
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References | Flow chart of infant enrolment and distribution into formula-fed groups and the breastfed reference group (modified from Otten et al. [Mean daily stool frequency (daily number of stools; mean ± SD) from 3-day diary (PPS). Missing values in eHF: V4: Stool consistency from 3-day diary (% ± SD; PPS). Missing values in eHF: V1: Stool colour from 3-day diary (%; PPS). Missing values in eHF: V1: Receipt of products which may positively influence GI tolerance (PPS).Values presented as IGSQ 13-item total score (a.u., range 13–65) from 3-day diary (PPS).Missing values in eHF: V4: Mean 24 h sleep (hours/day) and duration of nocturnal sleep (hours/day) from 3-day diary (PPS).Values presented as mean (SD), (min; max). BF: breastfed reference group; CF: control formula; eHF: infant formula manufactured from extensively hydrolysed whey protein; | PMC10647512 |
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Background\Objectives | OUD, overdose | Concomitant with low rates of pharmacotherapy for incarcerated individuals with OUD, there is a high rate of opioid overdose following re-entry into the community. Our research objective was to develop a better understanding of the factors that influence health-related quality-of-life (HRQoL) among this population during the high-risk transition period from incarceration to community. Few studies have assessed health-related quality-of-life (HRQoL) among individuals with OUD who are involved with the criminal-legal system, let alone over the period directly surrounding release from incarceration. | PMC10210389 |
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Methods | anxiety/depression | REGRESSIONS | Secondary longitudinal analysis of data from a clinical trial where participants were randomized 1:1 to pre-release extended-release naltrexone (XR-NTX) + referral to community XR-NTX, vs. referral only. We conducted individual, multivariable regressions of EQ-5D domains (mobility, pain/discomfort, anxiety/depression; usual activities and self-care were excluded due to insufficient variation in scores), and the overall preference/utility score. HRQoL data were subset to timepoints immediately before release (baseline) and 12 weeks post-release; treatment groups were collapsed across condition. Multiple imputation by chained equations was conducted to handle missing 3-month data in the dependent variables and covariates, ad hoc. | PMC10210389 |
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