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Study design | This was a cohort study including both children from a trial and a parallel observational study. | PMC10664149 | ||
Overview of methods | cough | LRTI | Full details of all data-collection methods have been previously published.Acute LRTI was defined syndromically in several previous cohorts and trials as an acute cough as the predominant symptom, judged by the GP to be infective in origin, lasting <21 days (which will exclude children with protracted bacterial bronchi... | PMC10664149 |
Outcomes | PROGRESSION | Progression of illness, the focus of this article, was defined as illness requiring hospital assessment and/or admission within 1 month of the index consultation. It was documented from a medical record review. | PMC10664149 | |
Sample size | The standard rules used by statisticians suggest that the number of variables that can be assessed robustly in a prognostic model is one variable per ten cases — so, with 29 children experiencing adverse outcomes the three-variable model should be adequately powered. | PMC10664149 | ||
Statistical analysis | diarrhoea, illness, asthma, chest signs, vomiting, dry cough, chills | REGRESSION | Logistic regression models were used to assess the prediction of illness. The external validity of the STARWAVe score was assessed using the three STARWAVe classifications of low, normal, or high risk.As the performance of STARWAVe was limited in this population, the authors of the current study then developed a new mo... | PMC10664149 |
RESULTS | A total of 326 patients were recruited to the observational study (
In the observational cohort, 52/312 (16.7%) were recruited via accident and emergency (A&E)/paediatric assessment versus 260/312 via GP practices. In the trial, 5/432 (1.2%) were recruited via A&E/paediatric assessment versus 427/432 via GP practices. | PMC10664149 | ||
Clinical characteristics | illness | PROGRESSION | As expected, the number of children in the observational cohort with more severe clinical features (Baseline characteristics of observational participants and combined dataset
Progression of illness was recorded for 705 of 744 participants (94.8%). A total of 29 (4.1%) children in the cohort had illness progressi... | PMC10664149 |
DISCUSSION | PMC10664149 | |||
Summary | LRTI | A simple three-item prognostic score using clinical variables that are readily available in the consultation could be useful as a tool to identify children with acute LRTI who are at low risk of significant illness progression to guide clinical management. | PMC10664149 | |
Strengths and limitations | illness | The differences in clinical characteristics between the observational and the trial data participants was expected, but cannot be attributed just to clinical decision making in deciding who to recruit to the trial or the observational study as some observational patients came from less typical sites that were not able ... | PMC10664149 | |
Comparison with existing literature | Children given antibiotics in the observational study had much more severe clinical presentations than children not given antibiotics — matching the trends in STARWAVe.Some evidence of external validation is provided in that STARWAVe is able to distinguish different levels of prognostic risk in this dataset, albeit wit... | PMC10664149 | ||
Implications for practice | illness | LRTI | A simple, internally validated clinical score for use in more unwell children with uncomplicated acute LRTI uses variables that are easily documented in routine consultations, and shows promise in enabling clinicians to identify the minority of children whose illness is more likely to progress sufficiently to require h... | PMC10664149 |
Funding | This project is funded by
| PMC10664149 | ||
Ethical approval | WEST | The trial protocol was approved by the South West — Central Bristol Research Ethics Committee (reference: 15/SW/0300). | PMC10664149 | |
Data | De-identified participant data are available for further analyses. Request for data, with justification, should be made to the corresponding author. | PMC10664149 | ||
Provenance | Freely submitted; externally peer reviewed. | PMC10664149 | ||
Competing interests | Theo Verheij reports grants from the European Union and The Netherlands Organization of Health Research and Development during the conduct of the study; and grants from Abbott, Becton Dickinson, Bio-Merieux, and Janssen Pharmaceuticals outside the submitted work. The other authors have declared no competing interests (... | PMC10664149 | ||
Discuss this article | Contribute and read comments about this article: | PMC10664149 | ||
REFERENCES | PMC10664149 | |||
Abstract | PMC10176009 | |||
Introduction | We assess risks differently when they are explicitly described, compared to when we learn directly from experience, suggesting dissociable decision‐making systems. Our needs, such as hunger, could globally affect our risk preferences, but do they affect described and learned risks equally? On one hand, decision‐making ... | PMC10176009 | ||
Method | ± | Thirty‐two healthy participants (females: 20, mean age: 25.6 ± 6.5 years) with a normal weight (Body Mass Index: 22.9 ± 3.2 kg/m | PMC10176009 | |
Result | In agreement with previous studies, we found that rewarding contexts induced risk‐aversion when risks were explicitly described ( | PMC10176009 | ||
Conclusion | The results suggest that our metabolic state determines risk‐taking biases when we lack explicit descriptions.Our findings are the first account of how hunger differentially modulates decision‐making for experienced and described risks in the same individual. We complement existing results and provide a precise index o... | PMC10176009 | ||
INTRODUCTION | When we decide between options with uncertain outcomes, we factor risk into the decision. This is most commonly evaluated by asking people to decide between explicitly described, hypothetical choice scenarios (Allais, The effect of decision context is thought to be driven by anticipatory emotions (De Martino et al., Th... | PMC10176009 | ||
METHODS | PMC10176009 | |||
Participants | ±, psychiatric | Thirty‐two healthy volunteers (females: 20, mean age: 25.6 ± 6.5 years) were recruited for this study. All participants were healthy, had no history of psychiatric diagnoses, had no history of neurological or metabolic illnesses, and had not used recreational drugs in the past 3 months. All participants had a normal we... | PMC10176009 | |
Manipulation of metabolic state | Participants were tested in a within‐subjects counterbalanced, randomized crossover design for the effects of hunger on risk‐taking tasks (Figure Decisions by experience. (a) Participants were tested in a counterbalanced, randomized crossover design. Participants were tested on two separate days approximately 1 week ap... | PMC10176009 | ||
Experimental design | PMC10176009 | |||
Decisions by experience | We employed a modified version of a risk‐taking task developed by Moeller et al. (Each trial had the same structure. After a short intertrial interval (ITI) of 500–700 ms, the stimuli were presented on the screen. Responses were made by pressing on the left or right arrow key of the keyboard to choose the left or right... | PMC10176009 | ||
Decisions by description | Risk‐taking behavior from descriptions was probed using the probabilistic task described by Rogers and colleagues (Norbury et al., High‐ and low‐reward trials offered a choice between a certain win or loss (low‐risk option) and a 50:50 chance gamble (high‐risk option) with the Decisions by description. Decisions made f... | PMC10176009 | ||
Behavioral analyses | Risk was defined as the uncertainty in possible outcomes of a decision, expressed as the variance of the associated reward distribution (Rothschild & Stiglitz, For learned risks, the risk preference was averaged over the second half of the trials (72 trials) of each stimulus set (Figure S1A). Using only the second half... | PMC10176009 | ||
Computational model fitting | We used a reinforcement learning model to further assess the effects of hunger on experience‐based risk‐taking. The model itself is described in the results section. We used a hierarchical model‐fitting strategy that takes into account the likelihood of individual participant choices given the individual participant pa... | PMC10176009 | ||
RESULTS | As expected, participants rated their subjective feelings of hunger significantly higher after 14 h of fasting than after eating a full meal (Wilcoxon signed rank test: | PMC10176009 | ||
Hunger altered experiential risk‐taking in a context‐specific manner | hunger [ | REGRESSION | We first analyzed choice behavior in the low‐ and high‐reward context to evaluate experience‐based risk‐taking in a context‐specific manner (Figure Risk attitudes for learned and described risks. (a) For learned risks, participants were risk‐averse for low‐reward contexts and risk‐seeking for high‐reward contexts. Hung... | PMC10176009 |
Hunger did not affect risk‐taking from descriptions | To provide a comparable measure to the context effects in experience‐based risk‐taking, we also analyzed the risk preference for matched mean gambles in high‐ and low‐reward context in description‐based choices (Figure Participants chose the option with the highest expected value more often in mixed‐decision contexts, ... | PMC10176009 | ||
Modeling of risk‐sensitive choice behavior | PEIRS | The previous analyses showed that hunger only altered decision‐making when risks had to be learned. However, the behavioral analyses do not provide insight into what computational process was altered by hunger. Therefore, we employed a computational modeling strategy to account for the integration of a specific reward ... | PMC10176009 | |
Computational modeling captured risk preferences | PEIRS | To confirm that the PEIRS model described risk preferences, we compared it to a simplified model without Model fitting results with the Prediction Error Induced Risk‐Seeking (PEIRS) model. (a) Simulated choice behavior using estimated parameters for the fasted and sated condition. Simulated data showed a similar patter... | PMC10176009 | |
Subjective rating reflects learned utility | We also asked participants to indicate the reward distribution of each stimulus on a Visual Analogue Scale at the end of each block. We used these measures to examine whether people distinguished the stimuli based on the true mean and variance, or a scaled version of the objective values. We found that the subjectively... | PMC10176009 | ||
DISCUSSION | Using information about the current metabolic state to adapt to variable reward outcomes is critical for survival (Stephens, As postulated by the risk‐sensitive foraging theory (Stephens, “Optimal” choice scenarios for high‐ and low‐reward contexts. The circles denote the expected value of the high‐ and low‐risk option... | PMC10176009 | ||
PEER REVIEW | The peer review history for this article is available at | PMC10176009 | ||
Supporting information | Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.
Click here for additional data file. | PMC10176009 | ||
ACKNOWLEDGMENTS | This work was supported by Medical Research Council grants MC ST U16043, MC UU 12024/5, MC UU 00003/1, and MR/P00878/X and BBSRC grant BB/S006338/1. | PMC10176009 | ||
DATA AVAILABILITY STATEMENT | All data are openly available at | PMC10176009 | ||
REFERENCES | PMC10176009 | |||
Objectives | PERIODONTITIS | The aim of the present randomized clinical trial (RCT) with a parallel arm design was to evaluate the clinical and microbiological efficacy of repeated ICG-aPDT as an adjunct to full-mouth subgingival debridement in the treatment of periodontitis. | PMC10159973 | |
Materials and methods | periodontitis, PD | PERIODONTITIS | Twenty-four periodontitis patients were treated with full-mouth ultrasonic subgingival debridement (FMUD). Initial sites with probing depth (PD) > 4 mm were randomly assigned to receive the test (ICG-aPDT with an 810 nm diode laser) or the control treatment (off-mode aPDT) one and four weeks after FMUD. Clinical parame... | PMC10159973 |
Results | PD, PD reduction, bleeding | BLEEDING | Both treatment modalities resulted in significant clinical improvements at 3 and 6 months. The only significant differences in favour of the test group were found at 6 months for a higher PD reduction in initial deep pockets (PD ≥ 6 mm) and a higher percentage of closed pockets (PD ≤ 4 mm/no bleeding on probing). Limit... | PMC10159973 |
Conclusion | The combination of repeated ICG-aPDT and FMUD provided no benefits except for selective clinical and microbiological improvements compared to FMUD alone. | PMC10159973 | ||
Clinical relevance | Based on the obtained results, only limited adjunctive effects could be found for the combined use of ICG-aPDT and FMUD. Further, well-designed RCT with larger sample sizes are required to confirm these findings. | PMC10159973 | ||
Trial registration | PMC10159973 | |||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00784-023-04875-w. | PMC10159973 | ||
Keywords | Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. | PMC10159973 | ||
Introduction | Periodontitis | CELL INJURY, PERIODONTITIS, BACTERIAL RESISTANCE, DYSREGULATED HOST RESPONSE, PERIODONTITIS, INFLAMMATORY DISEASE | Periodontitis is a chronic multifactorial inflammatory disease initiated by a dysbiotic biofilm and mediated by a dysregulated host response. It is characterized by the progressive destruction of the supporting periodontal tissues [In this context, the use of lasers in combination with photosensitizer solutions, namely... | PMC10159973 |
Materials and methods | PMC10159973 | |||
Study design and general information | The study was designed as a 6-month, single-blinded, parallel group RCT with a 1:1 allocation ratio and was reported according to the CONSORT statement ( | PMC10159973 | ||
Sample size calculation | PD | Sample size calculation determined that 10 subjects per treatment group would provide an 80% power to detect a true difference of 1.0 mm between the test and control groups using probing depth (PD) reduction as the primary outcome variable. Assuming that the common standard deviation would be 0.8 mm and compensating fo... | PMC10159973 | |
Patient recruitment | bone loss | CHRONIC PERIODONTITIS, SYSTEMIC DISEASES, BONE LOSS | After a screening visit including a full-mouth periodontal and radiographic evaluation, all patients fulfilling the following criteria were asked to participate.The inclusion criteria were as follows:• Age between 18 and 80 years• Systemically healthy• Diagnosis of chronic periodontitis based on the presence of at leas... | PMC10159973 |
Outcome variables | Bleeding, PD, bleeding, tooth | BLEEDING, PLAQUE, ADVERSE EFFECTS, PLAQUE, BLEEDING | One blinded and calibrated examiner, different from the operator, performed all measurements. This examiner, before beginning the study, carried out a calibration session on five randomly selected patients, resulting in mean differences between repeated measurements of 0.5 mm for PD, with an intra-examiner reproducibil... | PMC10159973 |
Treatments | PD, ARC | FOX, PERIODONTAL ABSCESS, PLAQUE | Patients were randomly assigned to the test or control group according to a computer-generated list without any restriction. Allocation concealment was assured by opaque, sealed envelopes prepared and sequentially numbered by a person not otherwise involved in the study. Each patient enrolled in the study was instructe... | PMC10159973 |
Microbiological analysis | SUBGINGIVAL PLAQUE, PLAQUE | One site per quadrant with the deepest PD and BOP was selected for the microbiological analysis. Subgingival plaque samples were collected at baseline and 3 and 6 months after treatment. After removing the supragingival plaque, the selected sits were isolated from the saliva by cotton rolls and gently dried with air fl... | PMC10159973 | |
Genomic DNA extraction | LYSE | The phenol-chlorophorm method was used to extract the bacterial DNA from the samples. Briefly, bacteria were resuspended in Tris-HCl 50 mM pH 8.0, 0.25 M sucrose and 25 mg/ml lysozyme and incubated for 1 h at 37°C. Afterwards, a tungsten carbide bead in sample disruptor (Tissue Lyser, Qiagen, USA) followed addiction of... | PMC10159973 | |
Real-time PCR | Real-time PCR was used to assess the detection of the following periodontal pathogens within the subgingival samples: | PMC10159973 | ||
Statistical analysis | PD | The primary outcome variable was considered to be the change in PD. The percentage of closed pockets (PD < 4 mm and BOP-) was also calculated. PD was stratified in shallow to moderate (initial PD < 6 mm) and deep (initial PD ≥ 6 mm) pockets. Discrete variables (reported as percentages of all sites) were analysed by the... | PMC10159973 | |
Results | PD, controlNo | ADVERSE EVENTS | Fifty-five patients were consecutively screened, and 24 of them were enrolled, and 12 allocated to the test and 12 to the control group. All patients attended the 3- and 6-month follow-up visits. Figure CONSORT flow diagram of the studyThe characteristics of the included patients at baseline are listed in Table Charact... | PMC10159973 |
Discussion | periodontitis, PD | PERIODONTITIS | The recent EFP S3-level practice clinical guidelines for treatment of stage I–III periodontitis [In line with this recommendation, it was decided to carry out the present RCT. The findings obtained showed only a limited added clinical or microbiological benefit with the adjunctive use of ICG-aPDT, with a significant gr... | PMC10159973 |
Conclusions | PD | PERIODONTITIS | Taking into consideration the limitations found in the present study, it can be concluded that the adjunctive use of ICG-aPDT to FMUD in initial moderate-deep pockets indicated a limited clinical and microbiological added benefit at 3 and 6 months of follow-up. No significant differences between the groups were observe... | PMC10159973 |
Acknowledgements | The authors thank Sweden&Martina (Due Carrare, Padova, Italy) for providing the laser device and the photosensitizer solution used for the study and Dr. Mariella D’Ambrosio for helping in data collection. | PMC10159973 | ||
Author contribution | Marco Annunziata and Giovanna Donnarumma equally contributed to study design, data acquisition and interpretation, manuscript drafting and revision and share the first authorship. Agostino Guida contributed to data analysis and interpretation, manuscript drafting and revision. Livia Nastri contributed to data acquisiti... | PMC10159973 | ||
Funding | Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The present research did not receive external funding. | PMC10159973 | ||
Data availability | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10159973 | ||
Declarations | PMC10159973 | |||
Ethical approval | Institutional Review Board of the University of Campania “Luigi Vanvitelli” (Naples, Italy) approved the study protocol (Ref. n. 525/2014). | PMC10159973 | ||
Consent to participate | Written informed consent was obtained from all individual participants included in the study. | PMC10159973 | ||
Consent for publication | The authors confirm that they have obtained consent from the study participants to publish the data. | PMC10159973 | ||
Competing interests | The authors declare no competing interests. | PMC10159973 | ||
References | PMC10159973 | |||
Background | infection, CF, CF lung disease, inflammation | CYSTIC FIBROSIS, INFLAMMATION, GENETIC CONDITION, INFECTION, PATHOLOGICAL PROCESSES | Cystic Fibrosis (CF) is a genetic condition characterized by neutrophilic inflammation and recurrent infection of the airways. How these processes are initiated and perpetuated in CF remains largely unknown. We have demonstrated a link between the intestinal microbiota-related metabolites bile acids (BA) and inflammati... | PMC10262387 |
Results | cholestasis, lung damage, airway inflammation | CHOLESTASIS | Detection of BA in BALF was strongly associated with biomarkers of airway inflammation, more exacerbation episodes during the first year of life, increased use of oral antibiotics with prolonged treatment periods, a higher degree of structural lung damage, and distinct microbial profiles. Treatment with azithromycin, a... | PMC10262387 |
Conclusions | EVENTS | Detection of BA in BALF portend early pathological events in CF lung disease. Benefits early in life associated with azithromycin are not linked to its antimicrobial properties.
Video Abstract | PMC10262387 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s40168-023-01543-9. | PMC10262387 | ||
Keywords | PMC10262387 | |||
Background | OMIM 219700, CF | CYSTIC FIBROSIS, PATHOLOGICAL PROCESSES, GENETIC DISORDER | Cystic fibrosis (CF, OMIM 219700) is a genetic disorder caused by mutations in the In CF, genetic and environmental factors determine a distinct lung microenvironment characterized by mucus plugging [Current clinical practice does not prevent permanent damage to the bronchial tree, which is evident in most school-aged ... | PMC10262387 |
Results | PMC10262387 | |||
Study cohort | BALF specimens ( | PMC10262387 | ||
Detection of bile acids in BALF correlates with inflammation and clinical outcomes | lung disease, airway inflammation | LUNG DISEASE | We detected bile acids (BA) in 49/121 (40%) of the BALF specimens, with a concentration range of 0.003–1.095 µM (median 0.019 µM, IQR = 0.011–0.078 µM) (Table SDetection of bile acids in BALF associates with airway inflammation and clinical outcomes. Patients with BA detected in BALF demonstrated higher percentage of s... | PMC10262387 |
The microbial landscape of the lower airways in infants with CF | We profiled BALF-associated bacterial and fungal communities using amplicon-sequencing strategies. To monitor DNA contamination by laboratory reagents and clinical instrumentation, we processed and sequenced negative extraction controls and bronchoscope washes alongside the BALF specimens (see Methods section for a com... | PMC10262387 | ||
Detection of BA in BALF correlates with distinctive microbial profiles | Given the very young age of this cohort, we explored associations between BA detection and lung microbial profiles. BALF samples containing BA had higher bacterial burden (Log10(16S DNA copies), median [IQR], BA detected: 4.78 [4.23–5.13]; no BA detected: 4.12 [3.78–4.60]; WRST (Detection of BA in BALF links to distinc... | PMC10262387 | ||
Azithromycin therapy does not affect BA detection in BALF | reflux | EVENTS, REFLUX | Azithromycin has been demonstrated to facilitate gastric emptying and reduce reflux events [Azithromycin does not influence detection of BA in BALF. In our cohort BA detection was more prevalent in patients from Centres who do not use anti- | PMC10262387 |
Azithromycin does not alter the BALF microbiota in early CF | We evaluated how prophylactic antimicrobial therapies affect the composition of the BALF microbiota. Azithromycin was found not to alter bacterial load (median [IQR], azithromycin: 4.38 [4.03–4.93]; placebo: 4.44 [3.82–4.79]; WRST ( | PMC10262387 | ||
Discussion | gastrointestinal manifestations, CF, lung disease, exacerbations, bronchiectasis, inflammation, infections, worse disease, airway inflammation, neutrophilia, CF lung disease | DISEASE PROGRESSION, LUNG DISEASE, BRONCHIECTASIS, INFLAMMATION, DISEASE, INFECTIONS, PATHOPHYSIOLOGY, NEUTROPHILIA, INFLAMMATORY RESPONSE | In this observational study, we provide evidence supporting that detection of BAs in BALF constitutes an early predictor of both airway inflammation and clinical outcomes in CF. Specifically, we demonstrated neutrophilia and higher airway inflammation in asymptomatic infants with CF who have BAs in BALF. Our data linki... | PMC10262387 |
Conclusion | LUNG DISEASE | Collectively, our data implies that BA either contribute to or predict early pathomechanisms involved in establishing both the microbial and inflammatory landscapes in CF lungs early in life. Although the use of a potent prokinetic does not reduce BA levels in the lower airways, other strategies to modulate the lung ex... | PMC10262387 | |
Methods | PMC10262387 | |||
Clinical trial details | CF [, bronchiectasis | CYSTIC FIBROSIS, BRONCHIECTASIS | We used the BALF specimens from 12 months old infants with Cystic Fibrosis (CF) enrolled in the COMBAT-CF clinical trial. COMBAT-CF was a multi-centre, double-blinded, randomised, placebo-controlled study to evaluate the efficacy of azithromycin for the primary prevention of bronchiectasis in children with CF [ | PMC10262387 |
Isolation of microbial DNA from BALF, 16S and ITS2 metabarcoding, and sequencing of the amplicon pools | Microbial DNA was isolated from (1–2 mL) of BALF supernatant using our previously published protocol, which was specifically designed to improve the recovery of microbial DNA from low biomass BALF samples [To identify and characterize the fungal population associated with the BALF specimens, we carried out fungal DNA b... | PMC10262387 | ||
Processing pipeline of the sequencing data | Quality-based pre-processing and merging of paired-end reads for all the sequencing data files was as we described [For the 16S rRNA amplicon sequencing data, pre-processed joint reads were analysed following the SILVAngs pipeline [Processing and taxonomic assignment of the ITS2 reads was conducted in R (version 4.0.2)... | PMC10262387 | ||
Removal of the potential background contaminants determined by negative extraction controls | The susceptibility of contamination in low-biomass samples such as those used in this study, and the resulting implications for producing biologically meaningful datasets, have stimulated the development of guidelines and recommendations to mitigate the influence of contaminants in the interpretability of 16S-based mic... | PMC10262387 | ||
Quantitative analysis using TaqMan® assays | The protocol for qPCR using TaqMan® probes, as well as the assays for quantifying | PMC10262387 | ||
Bile acid profiling in BALF | acid-3α,12α-diol-2,2,4,4-d4 | Bile acids were profiled from the supernatants obtained after pelleting microbial cells for DNA extraction using high-speed centrifugation and blinded to the associated clinical data. Samples were spiked with 500 pmol of each internal standard and alkalinized with 0.1 volumes of 1 M NaOH solution. Extraction of bile ac... | PMC10262387 | |
Statistical analyses | Statistical analyses were done in R (Version 4.0.2). Normal distribution of the data was examined using the Shapiro–Wilk test. When the normality assumption was not met, we implemented non-parametric tests to compare groups. Linear models were fit with the R built-in function | PMC10262387 |
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