Neonatal Hypoglycemia and Neurocognitive Function at School Age: A Prospective Cohort Study.

OBJECTIVE: To determine the relationship between transient neonatal hypoglycemia in at-risk infants and neurocognitive function at 6-7 years of corrected age. STUDY DESIGN: The pre-hPOD Study involved children born with at least 1 risk factor for neonatal hypoglycemia. Hypoglycemia was defined as ≥1 consecutive blood glucose concentrations <47 mg/dl (2.6 mmol/L), severe as <36 mg/dl (2.0 mmol/L), mild as 36 to <47 mg/dL (2.0 to <2.6 mmol/L), brief as 1-2 episodes, and recurrent as ≥3 episodes. At 6-7 years children were assessed for cognitive and motor function (NIH-Toolbox), learning, visual perception and behavior. The primary outcome was neurocognitive impairment, defined as >1 SD below the normative mean in ≥1 Toolbox tests. The 8 secondary outcomes covered children's cognitive, motor, language, emotional-behavioral, and visual perceptual development. Primary and secondary outcomes were compared between children who did and did not experience neonatal hypoglycemia, adjusting for potential confounding by gestation, birthweight, sex and receipt of prophylactic dextrose gel (pre-hPOD intervention). Secondary analysis included assessment by severity and frequency of hypoglycemia. RESULTS: Of 392 eligible children, 315 (80%) were assessed at school age (primary outcome, n = 308); 47% experienced hypoglycemia. Neurocognitive impairment was similar between exposure groups (hypoglycemia 51% vs 50% no hypoglycemia; aRD -4%, 95% CI -15%, 7%). Children with severe or recurrent hypoglycemia had worse visual motion perception and increased risk of emotional-behavioral difficulty. CONCLUSION: Exposure to neonatal hypoglycemia was not associated with risk of neurocognitive impairment at school-age in at-risk infants, but severe and recurrent episodes may have adverse impacts. TRIAL REGISTRATION: Hypoglycemia Prevention in Newborns with Oral Dextrose: the Dosage Trial (pre-hPOD Study): ACTRN12613000322730.

Executive function and behaviour problems in school-age children born at risk of neonatal hypoglycaemia.

AIM: To examine the relationship between neonatal hypoglycaemia and specific areas of executive function and behaviour in mid-childhood. METHOD: Participants in a prospective cohort study of infants born late preterm or at term at risk of neonatal hypoglycaemia were assessed at 9 to 10 years. We assessed executive function using performance-based (Cambridge Neuropsychological Tests Automated Battery) and questionnaire-based (Behavior Rating Inventory of Executive Function) measures and behaviour problems with the Strengths and Difficulties Questionnaire. Data are reported as adjusted odds ratio (aOR) with 95% confidence intervals, and standardized regression coefficients. RESULTS: We assessed 480 (230 females, 250 males; mean age 9 years 5 months [SD 4 months, range 8 years 8 months-11 years 0 months]) of 587 eligible children (82%). There were no differences in performance-based executive function between children who did and did not experience neonatal hypoglycaemia (blood glucose <2.6 mmoL/L). However, children who experienced hypoglycaemia, especially if severe or recurrent, were at greater risk of parent-reported metacognition difficulties (aOR 2.37-3.71), parent-reported peer (aOR 1.62-1.89) and teacher-reported conduct (aOR 2.14 for severe hypoglycaemia) problems. Both performance- and questionnaire-based executive functions were associated with behaviour problems. INTERPRETATION: Neonatal hypoglycaemia may be associated with difficulties in specific aspects of parent-reported executive functions and behaviour problems in mid-childhood.

Experiences of parents whose children participated in a longitudinal follow-up study.

BACKGROUND: Long-term follow-up is necessary to understand the impact of perinatal interventions. Exploring parents' motives and experiences in consenting to their children taking part in longitudinal studies and understanding what outcomes are important to families may enhance participation and mitigate the loss to follow-up. As existing evidence is largely based on investigators' perspectives using Western samples, the present pilot study explored parents' perspectives in a multicultural New Zealand context. METHODS: Data were generated using semi-structured interviews with parents whose children had participated in a longitudinal study after neonatal recruitment. Parents' experiences of being part of the study were analysed thematically using an inductive approach. RESULTS: Parents (n = 16) were generally happy with the outcomes measured. Additionally, parents were interested in lifelong goals such as the impact of parental diabetes. We identified three themes: (1) Facilitators: Research participation was aided by motives and parent and research characteristics such as wishing to help others and straightforward recruitment; (2) Barriers: A hesitancy to participate was due to technical and clinical research aspects, participation burden and cultural barriers, such as complex wording, time commitment and nonindigenous research and (3) Benefits: Children and parents experienced advantages such as the opportunity for education. CONCLUSIONS: Parents reported positive experiences and described the unexpected benefit of increasing families' health knowledge through participation. Improvements for current follow-up studies were identified. Different ethnicities reported different experiences and perspectives, which warrants ongoing research, particularly with indigenous research participants. PATIENT OR PUBLIC CONTRIBUTION: No active partnership with parents of patients took place.

Association of Neonatal Hypoglycemia With Academic Performance in Mid-Childhood.

Importance: Neonatal hypoglycemia is associated with increased risk of poor executive and visual-motor function, but implications for later learning are uncertain. Objective: To test the hypothesis that neonatal hypoglycemia is associated with educational performance at age 9 to 10 years. Design, Setting, and Participants: Prospective cohort study of moderate to late preterm and term infants born at risk of hypoglycemia. Blood and masked interstitial sensor glucose concentrations were measured for up to 7 days. Infants with hypoglycemic episodes (blood glucose concentration <47 mg/dL [2.6 mmol/L]) were treated to maintain a blood glucose concentration of at least 47 mg/dL. Six hundred fourteen infants were recruited at Waikato Hospital, Hamilton, New Zealand, in 2006-2010; 480 were assessed at age 9 to 10 years in 2016-2020. Exposures: Hypoglycemia was defined as at least 1 hypoglycemic event, representing the sum of nonconcurrent hypoglycemic and interstitial episodes (sensor glucose concentration <47 mg/dL for ≥10 minutes) more than 20 minutes apart. Main Outcomes and Measures: The primary outcome was low educational achievement, defined as performing below or well below the normative curriculum level in standardized tests of reading comprehension or mathematics. There were 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health. Results: Of 587 eligible children (230 [48%] female), 480 (82%) were assessed at a mean age of 9.4 (SD, 0.3) years. Children who were and were not exposed to neonatal hypoglycemia did not significantly differ on rates of low educational achievement (138/304 [47%] vs 82/176 [48%], respectively; adjusted risk difference, -2% [95% CI, -11% to 8%]; adjusted relative risk, 0.95 [95% CI, 0.78-1.15]). Children who were exposed to neonatal hypoglycemia, compared with those not exposed, were significantly less likely to be rated by teachers as being below or well below the curriculum level for reading (68/281 [24%] vs 49/157 [31%], respectively; adjusted risk difference, -9% [95% CI, -17% to -1%]; adjusted relative risk, 0.72 [95% CI, 0.53-0.99; P = .04]). Groups were not significantly different for other secondary end points. Conclusions and Relevance: Among participants at risk of neonatal hypoglycemia who were screened and treated if needed, exposure to neonatal hypoglycemia compared with no such exposure was not significantly associated with lower educational achievement in mid-childhood.

The contributions of intelligence and executive function to behaviour problems in school-age children born very preterm.

AIM: To examine the contributions of specific neurocognitive skills to behaviour problems in children born very preterm. METHODS: We assessed children born <30 weeks' gestation or <1500 g at age 7 years using subtests of the Wechsler Intelligence Scale for Children Fourth Edition, performance and questionnaire-based measures of executive function, and Child Behavior Checklist and Teacher Rating Form. We evaluated the contributions of IQ and executive function to behaviour problems and the moderating effect of sex using multiple regression. RESULTS: The 129 children (mean age = 7.2 years) had lower IQ, inferior executive function and increased internalising problems compared with normative samples. Verbal comprehension skills and working memory were associated with total, internalising and externalising problems at school. Performance-based and questionnaire-based executive function were associated with total and externalising behaviour problems both at home and school. Sex moderated the relationships between information processing and parent-reported total problems, and between teacher-rated executive function and total problems. CONCLUSION: Both IQ and executive function are related to behaviour problems in children born very preterm, but the relationships are different in boys and girls. Executive function may be a useful target for intervention.

School readiness screening and educational achievement at 9-10 years of age.

AIM: To determine whether a multi-domain school readiness screening, the Before School Check (B4SC), identifies children at risk of low educational achievement and to compare the educational outcomes between those referred for intervention and those with B4SC concerns who were not referred. METHODS: In this longitudinal cohort study of children born at risk of neonatal hypoglycaemia (N 331), the B4SC was performed at 4.5 years of age and a standardised curriculum-based measure of educational achievement was completed at 9-10 years of age. Outcomes of school readiness screening were categorised into 'school readiness concern' or 'no school readiness concern' while 'below standard' and 'well below standard' ratings of educational achievement were combined into a single category of 'low educational achievement'. RESULTS: Overall, 52% of children had ≥1 school readiness concerns at the B4SC, predominantly about behaviour (46%). Having ≥1 school readiness concern was associated with a nearly twofold increase in the likelihood of low academic achievement (OR 1.85, 95% CI 1.14, 3.02), which was apparent only for behaviour concerns. Of the 128 children with behaviour concerns, only 10 (8%) were referred for further interventions. There was a statistically non-significant increase in the rates of low academic achievement among those referred than those non-referred (60% vs. 47%). CONCLUSION: Identification of behaviour concerns during B4SC is associated with a moderate increase in the likelihood of low academic achievement at 9-10 years. Further, research is needed to determine how academic achievement can be improved in children with behaviour concerns at school entry.

Systematic review of randomised controlled trials for interventions to treat injuries to the medial ligaments of the knee.

BACKGROUND: Optimal management of severe and complex injuries to the medial knee ligaments remains uncertain. This systematic review evaluates outcomes from randomised controlled trials investigating interventions for treating injuries of medial ligaments of the knee. METHODS: Randomised controlled clinical trials evaluating interventions for treating injuries of the medial knee ligaments were identified through searching EMBASE, Medline, Cochrane, WHO, and clinicaltrials.org. Comparisons were made between different non-operative interventions, surgical versus non-operative interventions, different surgical interventions, and different postoperative interventions. Primary outcome measures included patient reported outcome measures (PROM) of knee function, pain, and treatment failure. RESULTS: 412 trial records were identified; 259 were non-redundant and distinct studies, of which eight were included for analysis. No differences between operative and non-operative management strategies were found for either primary outcome: Lysholm and IKDC scores. Compared to non-operative interventions, operative interventions resulted in reduced quadriceps strength at eight weeks (mean difference (MD) 29 (% knee extension strength deficit compared with unaffected knee); 95%CI 3.89-54.11) and were associated with greater incidence of minor complications (relative risk (RR) 25; 95%CI: 1.51-421, and RR 25; 95%CI: 1.50-416.58, respectively). Quadriceps strength between 16 and 52 weeks was similar in non-operative and operative groups (MD 20; 95%CI -1.92-41.92). Functional rehabilitation was associated with reduced valgus laxity at six weeks compared to bracing ((MD) -1.40; 95%CI: -2.21-0.59). CONCLUSIONS: Non-operative interventions provided similar functional results to operative interventions for grade I-III injuries of the medial collateral ligaments. Non-operative intervention was associated with improved quadriceps strength during rehabilitation, and fewer complications, compared to operative interventions.

P-glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)-[11 C]verapamil PET.

OBJECTIVE: Overexpression of the drug transporter P-glycoprotein (P-gp) is thought to be involved in drug-resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P-gp substrate radiotracer (R)-[11 C]verapamil (VPM) together with the third-generation P-gp inhibitor tariquidar (TQD) to evaluate P-gp function in individuals with drug-resistant epileptogenic developmental lesions. METHODS: Twelve healthy controls (7 male, median age 45, range 35-55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM-PET scans before and 60 minutes after a 30-minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM-K1 , was estimated from the first 10 minutes of dynamic data using a single-tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls. RESULTS: At baseline, SPM voxel-based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P-gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002). SIGNIFICANCE: This study provides further evidence of P-gp overactivity in patients with drug-resistant epilepsy, irrespective of the type of lesion. Identifying P-gp overactivity as an underlying contributor to drug-resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P-gp overactivity.

Does connectedness to nature improve the eating behaviours of pre-schoolers? Emerging evidence from the Play&Grow randomised controlled trial in Hong Kong.

BACKGROUND: Nature-based interventions, which focus on outdoor play, mental health, and self-directed autonomous play, are becoming popular in promoting well-being. The objective of this study was to test whether connecting to nature would contribute to better feeding and eating habits in families with pre-schoolers. METHODS: 241 families with children aged two to five were randomly assigned to the Intervention (IG) and Control Groups (CG). IG received 10 sessions of a family-based programme, which included a novel Connectedness to Nature (CN) element. CG received only the government's health recommendations. The effectiveness of the intervention's primary outcomes (CN, eating/feeding behaviours) was analysed by a repeated measures structural equation model with intervention status as a causal predictor. RESULTS: 204 families (IG, n = 120; CG, n = 84) completed the measurements before and after the trial. The intervention had a medium effect on caregivers' CN (f2 = 0.16, (95%CI = 0.06, 0.30)) and a large effect on children's CN (f2 = 0.58, (95%CI = 0.36, 0.89)). In the IG, children's CN strongly predicted caregivers' feeding style (ß = 0.48 (p < .01, 95%CI = 0.14, 0.83)) and moderately, children's eating behaviours (ß = 0.21 (p = .16, 95%CI = -0.09, 0.52)). This produced a positive trend for greater vegetable consumption in the IG compared to the CG (ß = 0.20 (95%CI = 0.01, 0.39) vs. ß = -0.05, (95%CI = -0.18, 0.08)). Interestingly, the path values in the CG significantly reflected the traditional pattern, (e.g., parental feeding style strongly influenced children's eating behaviour (ß = 0.33, p = .001, 95%CI = 0.13, 0.54). CONCLUSIONS: The Play&Grow intervention positively increased caregivers' and children's CN. It also improved eating behaviors in children independent of their caregivers' feeding style. This may indicate a higher degree of autonomy in children's eating behaviour if they are exposed to nature. Further research should test the CN component in promotion of healthy eating in pre-schoolers.

Teacher rating versus measured academic achievement: Implications for paediatric research.

AIM: To determine whether teachers' reports of student academic performance can suffice for research purposes by comparing it with a curriculum-based standardised test. METHODS: In this longitudinal cohort study of children born at risk of neonatal hypoglycaemia, teachers' global assessment of student performance was compared with assessment tools for teaching and learning (asTTle) at 9-10 years. Performance on asTTLe was rated as being below, at or above that expected on the national curriculum for year and term of schooling. Teachers similarly rated the child's performance against the national curriculum. RESULTS: Of 125 children assessed, 104 had paired data for analysis. On asTTLe, 28% were rated below, 55% at and 17% above the expected curriculum level in reading and 24, 54 and 22%, respectively, in mathematics. Equivalent teacher ratings were 23, 58 and 19% in reading and 36, 55 and 9% in mathematics, respectively. However, there was limited agreement between asTTle and teacher rating of achievement in reading (κ = 0.23 (95% confidence interval 0.07-0.40)) and no significant agreement in mathematics (κ = 0.07 (95% confidence interval -0.09-0.22)). Only 45% of children performing below the curriculum level in reading and 52% in mathematics were correctly identified by teachers. CONCLUSION: In cohort studies, teacher ratings cannot substitute standardised educational testing.

Distinguishing prognostic and predictive biomarkers: an information theoretic approach.

Motivation: The identification of biomarkers to support decision-making is central to personalized medicine, in both clinical and research scenarios. The challenge can be seen in two halves: identifying predictive markers, which guide the development/use of tailored therapies; and identifying prognostic markers, which guide other aspects of care and clinical trial planning, i.e. prognostic markers can be considered as covariates for stratification. Mistakenly assuming a biomarker to be predictive, when it is in fact largely prognostic (and vice-versa) is highly undesirable, and can result in financial, ethical and personal consequences. We present a framework for data-driven ranking of biomarkers on their prognostic/predictive strength, using a novel information theoretic method. This approach provides a natural algebra to discuss and quantify the individual predictive and prognostic strength, in a self-consistent mathematical framework. Results: Our contribution is a novel procedure, INFO+, which naturally distinguishes the prognostic versus predictive role of each biomarker and handles higher order interactions. In a comprehensive empirical evaluation INFO+ outperforms more complex methods, most notably when noise factors dominate, and biomarkers are likely to be falsely identified as predictive, when in fact they are just strongly prognostic. Furthermore, we show that our methods can be 1-3 orders of magnitude faster than competitors, making it useful for biomarker discovery in 'big data' scenarios. Finally, we apply our methods to identify predictive biomarkers on two real clinical trials, and introduce a new graphical representation that provides greater insight into the prognostic and predictive strength of each biomarker. Availability and implementation: R implementations of the suggested methods are available at https://github.com/sechidis. Supplementary information: Supplementary data are available at Bioinformatics online.

Relationships between parenting practices and perceptions of child behaviour among Korean immigrant mothers and fathers.

This study examined parenting styles and culturally-specific parenting practices of Korean immigrant mothers (N = 128) and fathers (N = 79) of children (ages 6-10) in New Zealand and the parenting predictors of child behaviour. Participants completed questionnaires on parenting styles and practices, and parental perceptions of child behaviour. Both parents indicated a high degree of devotion (Mo jeong) and involvement in care and education of their child with fathers were more likely than mothers to utilise shaming/love withdrawal and modesty encouragement. Results of regression analyses showed that there were some differences between mothers and fathers in the parenting predictors of child internalising and externalising behaviour problems and prosocial behaviour. Across the whole sample, there were contrasting relationships for authoritative parenting styles, devoted/involved parenting and modesty encouragement/shaming/non-reasoning parenting practices with child behaviour problems. Results indicated a blend of Western and Korean parenting practices were being utilised after settling in New Zealand.

Detection of apoptosis by PET/CT with the diethyl ester of [¹8F]ML-10 and fluorescence imaging with a dansyl analogue.

The diethyl ester of [(18)F]ML-10 is a small molecule apoptotic PET probe for cancer studies. Here we report a novel multi-step synthesis of the diethyl ester of ML-10 in excellent yields via fluorination using Xtal-Fluor-E. In addition, a one-pot radiosynthesis of the diethyl ester of [(18)F]ML-10 from nucleophilic [(18)F]fluoride was completed in 23% radiochemical yield (decay corrected). The radiochemical purity of the product was ≥99%. The diethyl ester of [(18)F]ML-10 was used in vivo to detect apoptosis in the testes of mice. In parallel studies, the dansyl-ML-10 diethyl ester was prepared and used to detect apoptotic cells in an in vitro cell based assay.

The automated radiosynthesis and purification of the opioid receptor antagonist, [6-O-methyl-11C]diprenorphine on the GE TRACERlab FXFE radiochemistry module.

[6-O-Methyl-(11)C]diprenorphine ([(11)C]diprenorphine) is a positron emission tomography ligand used to probe the endogenous opioid system in vivo. Diprenorphine acts as an antagonist at all of the opioid receptor subtypes, that is, µ (mu), κ (kappa) and δ (delta). The radiosynthesis of [(11)C]diprenorphine using [(11)C]methyl iodide produced via the 'wet' method on a home-built automated radiosynthesis set-up has been described previously. Here, we describe a modified synthetic method to [(11)C]diprenorphine performed using [(11)C]methyl iodide produced via the gas phase method on a GE TRACERlab FXFE radiochemistry module. Also described is the use of [(11)C]methyl triflate as the carbon-11 methylating agent for the [(11)C]diprenorphine syntheses. [(11)C]Diprenorphine was produced to good manufacturing practice standards for use in a clinical setting. In comparison to previously reported [(11)C]diprenorphine radiosyntheisis, the method described herein gives a higher specific activity product which is advantageous for receptor occupancy studies. The radiochemical purity of [(11)C]diprenorphine is similar to what has been reported previously, although the radiochemical yield produced in the method described herein is reduced, an issue that is inherent in the gas phase radiosynthesis of [(11)C]methyl iodide. The yields of [(11)C]diprenorphine are nonetheless sufficient for clinical research applications. Other advantages of the method described herein are an improvement to both reproducibility and reliability of the production as well as simplification of the purification and formulation steps. We suggest that our automated radiochemistry route to [(11)C]diprenorphine should be the method of choice for routine [(11)C]diprenorphine productions for positron emission tomography studies, and the production process could easily be transferred to other radiochemistry modules such as the TRACERlab FX C pro.

Academic Success at Social Costs: An Exploratory Study on Social Networks of Chinese Students under Academic Streaming.

In universities that require students to reside in dormitories, there are two types of social networks-study/classroom-based and social/dorm room-based. The academic streaming system may disrupt study/classroom connections, but its impact on students' social networks is unknown. Using self-reported surveys, this study examines ego network measures of network sizes, turnover, multiplexity, and diversity among 382 students (44% female, 56% male). Surveys were administered before and after the university employed a first-semester grade-point average to demote or promote students into an honours college. Follow-up interviews were conducted with 11 honours students staying within their track and 11 students who were re-streamed to the non-honours track. Quantitative results showed that students in the non-honours college and who remained there had increasingly overlapping friendship circles between study and social environments, along with more diverse social connections, indicating stronger networks. In contrast, honours participants experienced fewer overlapping networks across domains and less dispersed social ties, especially after the academic replacement process. Qualitative results showed that the honours students faced a trade-off between academic success and social engagement in maintaining their elite status. Re-streamed students experienced otherness in social groups and decreased psychological wellbeing. This study contributes to the application of network analysis in education and provides insights into the unintended consequences of educational practice on students' social networks.

An assessment of nurses' perceived and actual household emergency preparedness.

Nurses' household preparedness is critical if they are to avoid role conflict and report for duty during an emergency. To date, the alignment between nurses' perceived and actual household preparedness remains under examined. Investigating one of these variables in isolation fails to consider that perceived and actual household preparedness must be high and aligned. If misaligned, vulnerabilities could surface during emergencies, like concerns about family safety, potentially impacting a nurse's commitment to duty during a crisis, or nurses may lack the actual preparedness to continue working long hours during an emergency. An online questionnaire was distributed to registered nurses in Ireland. The questionnaire was informed by a review of the literature and captured nurses' perceived and actual household preparedness, attitudes towards and exposure to a range of emergencies, and pertinent demographic characteristics. The results showed a relationship between how nurses view their household preparedness and their actual preparedness. Regression analyses indicate that while there is an overlap, the factors associated with how prepared nurses think they are and how prepared they are can differ. This means that strategies to boost actual preparedness may differ from those needed to boost perceived preparedness. This finding underscores the importance of psychosocial preparedness. Feeling prepared is crucial as it can influence how one responds in an emergency. Considering both the perceived and actual aspects of household preparedness can lead to a more effective response during emergencies.

Perspectives of adult offspring of participants recruited to a randomised trial in pregnancy: a qualitative study.

BACKGROUND: Routinely assessed outcomes in paediatric health studies may not reflect families' priorities. Increasing our understanding of childhood experiences of research participation may contribute to improving the quality of consent and better align study aims with the concerns of relevant communities. OBJECTIVE: To explore young adults' views on their participation in medical research during their childhood, specifically around the acceptability of consent and their priorities regarding health, development and well-being as potential trial outcomes. METHODS: A qualitative descriptive 20-year follow-up study of a medical trial which aimed to improve outcomes after preterm birth. Semistructured dialogue transcripts were analysed using inductive thematic analysis. SETTING AND PARTICIPANTS: Seventeen young adults whose parents consented to their participation in a clinical trial when they were fetuses, and in follow-up studies as preschoolers and school-age children. RESULTS: Overall, participants expressed comfort with their parents consenting to medical research on their behalf. However, autonomous child assent may not be attainable due to children's susceptibility to suggestions. Participants generally expressed satisfaction with the outcomes investigated in the follow-up studies, although some suggested other outcomes of interest such as mental health and learning disabilities. CONCLUSIONS: Current consent procedures were deemed acceptable as parents hold responsibility for making decisions on behalf of their children, and their commitment to their child's well-being ensures that they make appropriate choices. The outcomes assessed in this trial and health and developmental outcomes in the follow-up assessments aligned well with outcomes of interest to the young adult participants.

Multi-scale in vivo imaging of tumour development using a germline conditional triple-reporter system.

Imaging reporter genes are indispensable for visualising biological processes in living subjects, particularly in cancer research where they have been used to observe tumour development, cancer cell dissemination, and treatment response. Engineering reporter genes into the germline frequently involves single imaging modality reporters operating over limited spatial scales. To address these limitations, we developed an inducible triple-reporter mouse model (Rosa26LSL - NRL) that integrates reporters for complementary imaging modalities, flfluorescence, bioluminescence and positron emission tomography (PET), along with inducible Cre-lox functionality for precise spatiotemporal control of reporter expression. We demonstrated robust reporter inducibility across various tissues in the Rosa26LSL - NRL mouse, facilitating effective tracking and characterisation of tumours in liver and lung cancer mouse models. We precisely pinpointed tumour location using multimodal whole-body imaging which guided in situ lung microscopy to visualise cell-cell interactions within the tumour microenvironment. The triple-reporter system establishes a robust new platform technology for multi-scale investigation of biological processes within whole animals, enabling tissue-specific and sensitive cell tracking, spanning from the whole-body to cellular scales.

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging.

PURPOSE: The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression-based subtyping remain unknown. EXPERIMENTAL DESIGN: In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic). RESULTS: The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake. CONCLUSIONS: By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.