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BACKGROUND: We investigated the understudied influence of maternal diet quality, food timing, and their interactions during pregnancy on offspring metabolic health. METHODS: Maternal diet at 26-28 weeks' gestation was assessed using a 24-h recall and adherence to the modified-healthy-eating-index (HEI-SGP) reflects diet quality. Predominant night-eating (PNE) was defined as consuming >50% of total daily energy intake from 19:00 to 06:59. Outcomes were offspring composite metabolic syndrome score and its components measured at age 6 years. Multivariable linear regressions adjusted for relevant maternal and child covariates assessed associations of diet quality and PNE with these outcomes. RESULTS: Up to 758 mother-child pairs were included. The mean(SD) maternal HEI-SGP score was 52.3(13.7) points (theoretical range: 0-100) and 15% of the mothers demonstrated PNE. Maternal diet quality showed inverse relationship with offspring Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) [ß(95% CI): -0.08(-0.15, -0.02) per-10-point HEI-SGP increment; P = 0.012]. Maternal PNE was associated with a higher offspring HOMA-IR [0.28(0.06, 0.50); P = 0.012], with similar estimates after adjustment for children's BMI and diet quality; the association was stronger for boys (P-interaction<0.001) and among mothers with lower diet quality (

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Background: Physical activity (PA), sedentary behavior (SB), and sleep are collectively referred to as 24-h movement behaviors, which may be linked to cognitive development in children. However, most of the evidence was based on cross-sectional studies and/or solely relied on parent-reported information on children's behaviors, and it remains uncertain whether all domains/contexts of PA and SB are similarly associated with executive function and academic achievement. Objective: We investigated the prospective associations of accelerometer-measured 24 h-movement behaviors and domain-specific PA and SB with executive function and academic achievement among school-aged children in Singapore. Methods: The Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort used a wrist-worn accelerometer (Actigraph-GT3x+) to measure 24 h-movement behaviors data at ages 5.5 and 8 years. Executive function and academic achievement were assessed using NEuroPSYchology (NEPSY) and Wechsler Individual Achievement Tests at ages 8.5 and 9-years, respectively. Compositional data analyses were conducted to explore the associations of 24 h-movement behavior with outcomes, and multiple linear regression models to examine the associations of domain-specific PA and SB with outcomes (n = 432). Results: Among 432 children whose parents agreed to cognitive assessments (47% girls and 58% Chinese), the composition of 24 h-movement behaviors at ages 5.5 and 8 years was not associated with executive function and academic achievement. However, higher moderate-to-vigorous PA (MVPA) relative to remaining movement behaviors at age 5.5 years was associated with lower academic achievement [Mean difference (95% confidence interval): -0.367 (-0.726, -0.009) z-score], and reallocating MVPA time to sleep showed higher academic achievement scores [30 min from MVPA to sleep: 0.214 (0.023, 0.404) z-score]. Certain domains of PA and SB, notably organized PA/sports, outdoor play, and reading books were favorably associated with outcomes of interest, while indoor play and screen-viewing were unfavorably associated. Conclusion: The associations between movement behaviors and cognitive outcomes are multifaceted, influenced by specific domains of PA and SB. This study underscores the importance of participation in organized PA/sports, outdoor active play, and reading books, while ensuring adequate sleep and limiting screen viewing, to enhance cognitive outcomes. These findings underscore the need for further research into time-use trade-offs. Such studies could have major implications for revising current guidelines or strategies aimed at promoting healthier 24 h-movement behaviors in children. Study registration: https://clinicaltrials.gov/, NCT01174875.

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Background: While individuals who were separated from their biological family and placed into the care of the state during childhood (out-of-home care) are more prone to developing selected adverse health problems in adulthood, their risk of cardiovascular disease is uncertain. Our aim was to explore this association by pooling published and unpublished results from prospective cohort studies. Methods: We used two approaches to identifying relevant data on childhood care and adult cardiovascular disease (PROSPERO registration CRD42021254665). First, to locate published studies, we searched PubMed (Medline) until November 2023. Second, with the objective of identifying unpublished studies with the potential to address the present research question, we scrutinised retrieved reviews on childhood out-of-home care and other adult health outcomes. Included studies were required to satisfy three criteria: a cohort study in which the assessment of care was made prospectively pre-adulthood (in the avoidance of recall bias); data on an unexposed comparator group were available (for the computation of relative risk); and a diagnosis of adult cardiovascular disease events (coronary heart disease, stroke, or their combination) had been made (as opposed to risk factors only). Collaborating investigators provided study-specific estimates which were aggregated using random-effects meta-analysis. The Newcastle-Ottawa Scale was used to assess individual study quality. Findings: Twelve studies (2 published, 10 unpublished) met the inclusion criteria, and investigators from nine provided viable results, including updated analyses of the published studies. Studies comprised 611,601 individuals (301,129 women) from the US, UK, Sweden, Finland, and Australia. Five of the nine studies were judged to be of higher methodological quality. Relative to the unexposed, individuals with a care placement during childhood had a 51% greater risk of cardiovascular disease in adulthood (summary rate ratio after age- and sex-adjustment [95% confidence interval]: 1.51 [1.22, 1.86]; range of study-specific estimates: 1.07 to 2.06; I 2  = 69%, p = 0.001). This association was attenuated but persisted after adjustment for socioeconomic status in childhood (8 studies; 1.41 [1.15, 1.72]) and adulthood (9 studies, 1.29 [1.11, 1.51]). Interpretation: Our findings show that individuals with experience of out-of-home care in childhood have a moderately raised risk of cardiovascular disease in adulthood. Funding: Medical Research Council; National Institute on Aging; Wellcome Trust.

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BACKGROUND: Globally, one in ten babies is born preterm (<37 weeks), and 1-2% preterm at very low birth weight (VLBW, <1500 g). As adults, they are at increased risk for a plethora of health conditions, e.g., cardiometabolic disease, which may partly be mediated by epigenetic regulation. We compared blood DNA methylation between young adults born at VLBW and controls. METHODS: 157 subjects born at VLBW and 161 controls born at term, from the Helsinki Study of Very Low Birth Weight Adults, were assessed for peripheral venous blood DNA methylation levels at mean age of 22 years. Significant CpG-sites (5'-C-phosphate-G-3') were meta-analyzed against continuous birth weight in four independent cohorts (pooled n = 2235) with cohort mean ages varying from 0 to 31 years. RESULTS: In the discovery cohort, 66 CpG-sites were differentially methylated between VLBW adults and controls. Top hits were located in HIF3A, EBF4, and an intergenic region nearest to GLI2 (distance 57,533 bp). Five CpG-sites, all in proximity to GLI2, were hypermethylated in VLBW and associated with lower birth weight in the meta-analysis. CONCLUSION: We identified differentially methylated CpG-sites suggesting an epigenetic signature of preterm birth at VLBW present in adult life. IMPACT: Being born preterm at very low birth weight has major implications for later health and chronic disease risk factors. The mechanism linking preterm birth to later outcomes remains unknown. Our cohort study of 157 very low birth weight adults and 161 controls found 66 differentially methylated sites at mean age of 22 years. Our findings suggest an epigenetic mark of preterm birth present in adulthood, which opens up opportunities for mechanistic studies.

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INTRODUCTION: Few studies have investigated the association between frailty and subsequent body composition. METHODS: We performed separate linear mixed model analyses to study the associations between changes in the participant frailty status assessed by a frailty index (FI) and subsequent body mass index (BMI), lean mass index (LMI), fat mass index (FMI), and FMI to LMI ratio values assessed on three occasions over 17 years. The analyses were carried out among 996 participants spanning from age 57 to 84 years. RESULTS: With advancing age, LMI and BMI decreased, whereas FMI and FMI to LMI ratio increased. Participants with "stable frailty," followed by those with "increasing frailty" experienced faster decreases in LMI and faster increases in FMI and FMI to LMI ratio values from midlife into old age relative to those in the group "stable not frail." Contrastingly, those in the highest third of absolute annual increase in FMI and FMI to LMI ratio became more frail faster from midlife into old age relative to those in the lowest third. CONCLUSIONS: We found evidence of an adverse health outcome of frailty where lean indices declined faster and fat indices and fat-to-lean ratios increased faster from midlife into old age. The changes resembled those that occurred with aging, but at a faster pace. The relationship between body composition and frailty is likely bidirectional, where high or increasing levels of fat are associated with the risk of becoming more frail earlier, but where a longer duration of frailty may increase the risk of faster age-related changes to body composition.

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OBJECTIVE: To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. METHODS: This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. RESULTS: The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). CONCLUSIONS: Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

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Nanoscale hybrid inorganic-organic multilayers are attractive for accessing emergent phenomena and properties through superposition of nanomolecularly-induced interface effects for diverse applications. Here, we demonstrate the effects of interfacial molecular nanolayers (MNLs) of organo-diphosphonates on the growth and stability of titania nanolayers during the synthesis of titania/MNL multilayers by sequential atomic layer deposition and single-cycle molecular layer deposition. Interfacial organo-diphosphonate MNLs result in ∼20-40% slower growth of amorphous titania nanolayers and inhibit anatase nanocrystal formation from them when compared to amorphous titania grown without MNLs. Both these effects are more pronounced in multilayers with aliphatic backbone-MNLs and likely related to impurity incorporation and incomplete reduction of the titania precursor indicated by our spectroscopic analyses. In contrast, both MNLs result in two-fold higher titania nanolayer roughness, suggesting that roughening is primarily due to MNL bonding chemistry. Such MNL-induced effects on inorganic nanolayer growth rate, roughening, and stability are germane to realizing high-interface-fraction hybrid nanolaminate multilayers.

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DNA replication is a tightly coordinated event carried out by a multiprotein replication complex. An essential factor in the bacterial replication complex is the ring-shaped DNA sliding clamp, ß-clamp, ensuring processive DNA replication and DNA repair through tethering of polymerases and DNA repair proteins to DNA. ß -clamp is a hub protein with multiple interaction partners all binding through a conserved clamp binding sequence motif. Due to its central role as a DNA scaffold protein, ß-clamp is an interesting target for antimicrobial drugs, yet little effort has been put into understanding the functional interactions of ß-clamp. In this review, we scrutinize the ß-clamp structure and dynamics, examine how its interactions with a plethora of binding partners are regulated through short linear binding motifs and discuss how contexts play into selection. We describe the dynamic process of clamp loading onto DNA and cover the recent advances in drug development targeting ß-clamp. Despite decades of research in ß-clamps and recent landmark structural insight, much remains undisclosed fostering an increased focus on this very central protein.

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BACKGROUND: Ankle-brachial index (ABI) measurement is a widely used diagnostic test for lower extremity artery disease. Previously, a larger body surface area (BSA) has been associated with lower blood pressure and lower 2-h post-load glucose concentrations in the oral glucose tolerance test. Our aim was to evaluate whether BSA has an impact on ABI and the prevalence of lower ABI values. METHODS: ABI measurements were performed on 972 subjects aged 45 to 70 years at high cardiovascular disease (CVD) risk. Subjects with previously diagnosed kidney disease, CVD, and diabetes were excluded. Their BSA was calculated by the Mosteller formula. Study subjects were divided into five BSA levels corresponding to 12.5th, 25th, 25th, 25th, and 12.5th percentiles of the total distribution. Effect modification by BSA in ABI between sexes was derived from a four-knot restricted cubic splines regression model. RESULTS: After adjustments for age, sex, pulse pressure, glucose regulation, waist circumference, alcohol intake, smoking status, leisure-time physical activity and medication, BSA level had a positive linear relationship with ABI (p for linearity <0.001). When BSA was less than 2.0 m2, there was no difference between the sexes, but when BSA was higher than 2.0 m2, men had higher ABI. CONCLUSION: BSA shows a positive linear relationship with ABI in CVD risk subjects without manifested CVD. The difference in ABI between men and women is modified by BSA and is appreciable when BSA is larger than 2.0 m2.

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OBJECTIVES: Changes in socioeconomic status (SES) during life may impact health in old age. We investigated whether social mobility and childhood and adulthood SES are associated with trajectories of health-related quality of life (HrQoL) over a 17-year period. METHODS: We used data from the Helsinki Birth Cohort Study (n = 2003, 46% men, mean age 61.5 years). Social mobility was derived from childhood SES, obtained from healthcare records, and register-based adulthood SES. RESULTS: Logistic regression models showed that lower adulthood SES was associated with lower physical HrQoL trajectories. Among men low (OR 3.95, p < .001), middle (OR 2.20, p = .006), and declining lifetime SES (OR 2.41, p = .001) were associated with lower physical HrQoL trajectories compared to men with high SES. Socioeconomic status was not associated with mental HrQoL trajectories. DISCUSSION: Declining SES during life course may have negative health consequences, while improving SES is potentially as beneficial as high SES to later-life health among men.

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CONTEXT: Due to the essential role of carnitine as an intermediary in amino acid, carbohydrate and lipid metabolism, a detailed characterization of circulating and urinary carnitine concentrations will aid in elucidating the molecular basis of impaired maternal metabolic flexibility and facilitating timely intervention for expectant mothers. OBJECTIVE: To investigate the association of maternal plasma and urinary free carnitine and acylcarnitines with cardiometabolic risk factors. METHODS: LC-MS/MS-based quantification of free carnitine and acylcarnitines (C2-C18) was performed on 765 plasma and 702 urine samples collected at preconception, 26-28 weeks' pregnancy, and three months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. RESULTS: Plasma concentrations of free carnitine and acylcarnitines decreased coupled with increased renal clearance in pregnancy compared to preconception and postpartum. Renal clearance of carnitine increased with an increase in pre-pregnancy body mass index (ppBMI) and gestational weight gain. Plasma short-chain acylcarnitines were positively associated with ppBMI, irrespective of the physiological state, while medium- and long-chain acylcarnitines were negatively associated with ppBMI at preconception and postpartum but showed a positive association in pregnancy. Similarly, plasma short-chain acylcarnitines were positively associated with HOMA-IR whereas medium- and long-chain acylcarnitines were negatively associated with HOMA-IR at preconception and in pregnancy. Mothers who developed gestational diabetes mellitus during pregnancy had ∼10% higher plasma propionylcarnitine concentration and ∼18% higher urine tiglylcarnitine concentration compared to mothers with normal glucose metabolism at preconception. CONCLUSIONS: This study provides the metabolic and physiological basis of maternal carnitine homeostasis, which can be used in assessment of maternal cardiometabolic health at preconception to improve pregnancy outcomes.

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BACKGROUND: Few studies have examined longitudinal changes in lifestyle-related factors and frailty. METHODS: We examined the association between individual lifestyle factors (exercise, diet, sleep, alcohol, smoking and body composition), their sum at baseline, their change over the 17-year follow-up and the rate of change in frailty index values using linear mixed models in a cohort of 2,000 participants aged 57-69 years at baseline. RESULTS: A higher number of healthy lifestyle-related factors at baseline was associated with lower levels of frailty but not with its rate of change from late midlife into old age. Participants who stopped exercising regularly (adjusted ß × Time = 0.19, 95%CI = 0.10, 0.27) and who began experiencing sleeping difficulties (adjusted ß × Time = 0.20, 95%CI = 0.10, 0.31) experienced more rapid increases in frailty from late midlife into old age. Conversely, those whose sleep improved (adjusted ß × Time = -0.10, 95%CI = -0.23, -0.01) showed a slower increase in frailty from late midlife onwards. Participants letting go of lifestyle-related factors (decline by 3+ factors vs. no change) became more frail faster from late midlife into old age (adjusted ß × Time = 0.16, 95% CI = 0.01, 0.30). CONCLUSIONS: Lifestyle-related differences in frailty were already evident in late midlife and persisted into old age. Adopting one new healthy lifestyle-related factor had a small impact on a slightly less steeply increasing level of frailty. Maintaining regular exercise and sleeping habits may help prevent more rapid increases in frailty.

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Studies examining preconception eating behaviours with longitudinal dietary patterns from preconception to late pregnancy as well as gestational weight gain (GWG) are limited. We derived dietary pattern trajectories from preconception to late-pregnancy, and related preconception eating behaviours to these trajectories and GWG. Preconception eating behaviours were assessed using the Three-Factor Eating Questionnaire measuring cognitive restraint (CR) - conscious restriction of food intake, emotional eating (EE) - overeating in response to negative emotions, and uncontrolled eating (UE) - overeating with a feeling of lack of control. Dietary intakes were measured at preconception, 20-21 and 34-36 weeks' gestation with food frequency questionnaires. Dietary patterns were determined using factor analysis, and trajectories derived using group-based trajectory modelling. Inadequate and excessive GWG were defined according to Institute of Medicine guidelines based on weights at preconception and the last antenatal visit (median: 38 weeks' gestation). Two dietary patterns were derived: 'Fast Food, Fried Snacks and Desserts (FFD)' and 'Soup, Fish and Vegetables (SFV)'. Adherence trajectories from preconception to late-pregnancy were characterised as consistently high ("stable-high") and low ("stable-low"). Women with higher UE scores had higher odds of being in the "stable-high" trajectory (n = 34) of the FFD pattern [Odds Ratio (OR): 1.25, 95% Confidence Interval (CI): 1.03, 1.51], compared to "stable-low" (n = 260). Percentages of women with inadequate, adequate or excessive GWG were 21.7% (n = 70), 25.8% (n = 83), and 52.5% (n = 169), respectively; women with higher EE scores had a higher likelihood of excessive GWG [Relative Risk Ratio (RRR): 1.35, 95% CI: 1.02, 1.80], but this association was attenuated after adjusting for preconception body mass index. Eating behaviour interventions to improve dietary patterns among pregnant women may need to start as early as preconception, incorporating strategies to manage UE.

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Macrophage-based drug delivery systems are promising, but their development is still in its infancy, with many limitations remaining to be addressed. Our aim was to design a system harnessing microbial effectors to facilitate controlled drug cargo expulsion from macrophages to enable the use of more toxic drugs without adding to the risk of off-target detrimental effects. The pore forming and actin polymerizing Listeria monocytogenes effectors listeriolysin-O (LLO) and actin assembly-inducing protein (ActA) were synthesized using a novel green fluorescent protein (GFP)-linked heterologous expression system. These effectors were coated onto polystyrene beads to generate "synthetic cargo" before loading into primary M1 macrophages. Bead uptake and release from macrophages were evaluated by using high-throughput quantitative imaging flow cytometry and confocal microscopy. In vitro results confirmed appropriate activity of synthesized effectors. Coating of these effector proteins onto polystyrene beads (simulated drug cargo) resulted in changes in cellular morphology, bead content, and intracellular bead localization, which may support an interpretation of the induced release of these beads from the cells. This forms the basis for further investigation to fully elucidate any potential release mechanisms. Bacterial effectors ActA and LLO successfully effectuated actin polarization and protrusions from cell membranes similar to those seen in cells infected with Listeria spp., illustrating the potential of using these effectors and production methods for the development of an endogenous drug delivery system capable of low-risk, targeted release of high potency drugs.

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BACKGROUND: Parental practices and neighbourhood environmental factors may influence children's movement behaviours. We aimed to investigate the cross-sectional and prospective associations of parental practices and neighbourhood environmental factors with accelerometer-measured 24-hour movement behaviours (24 h-MBs) among school-aged children in Singapore. METHODS: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study collected information on dimensions of parental practices and neighbourhood environment at age 5.5 years. Confirmatory factor analyses were performed to generate latent variables and used to compute overall parental practices [involvement in PA + support for PA + control of screen viewing context] and environmental scores [facilities for active play + active mobility facilitators + barriers*-1]. Children wore an accelerometer on their non-dominant wrist for seven consecutive days at ages 5.5 and 8 years. The R-package GGIR 2.6 was used to derive moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), inactivity, and total-sleep (napping+night sleep) minutes per day. Associations were determined using compositional data analysis with multivariate linear regression models, taking into account potential confounders. RESULTS: Among 425 children (48% girls, 59% Chinese), higher parental involvement in PA, parental support for PA and overall parental practices were associated with 24 h-MBs at ages 5.5 and 8 years, specifically with greater time spent in MVPA and less time being inactive relative to the remaining movement behaviours. The corresponding mean changes in the overall 24 h-MB for increasing parental practices from lowest to highest scores (- 2 to + 2 z-scores) indicated potential increases of up to 15-minutes in MVPA, 20-minutes in LPA, 5-minutes in sleep duration, and a reduction of 40-minutes in inactivity at age 5.5 years. At age 8 years, this could translate to approximately 15-minutes more of MVPA, 20-minutes more of LPA, a 20-minute reduction in sleep duration, and a 20-minute reduction in inactivity. Parental control of screen viewing contexts and neighbourhood environmental factors were not associated with 24 h-MBs. CONCLUSIONS: Parental practices but not environmental factors were associated with higher MVPA and lower inactivity among Singaporean children, even at a later age. Further research may provide insights that support development of targeted public health strategies to promote healthier movement behaviours among children. STUDY REGISTRATION: This study was registered on 4th August 2010 and is available online at ClinicalTrials.gov: NCT01174875.

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Background: To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus. Methods: This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity. Results: Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes. Conclusion: hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.

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Mesoporous systems are ubiquitous in membrane science and applications due to their high internal surface area and tunable pore size. A new synthesis pathway of hydrolytic ionosilica films with mesopores formed by ionic liquid (IL) templating is proposed and compared with the traditional non-hydrolytic strategy. For both pathways, the multi-scale formation of pores has been studied as a function of IL content, combining the results of thermogravimetric analysis (TGA), nitrogen sorption, and small-angle X-ray scattering (SAXS). The combination of TGA and nitrogen sorption provides access to ionosilica and pore volume fractions, with contributions of meso- and macropores. We then elaborate an original and quantitative geometrical model to analyze the SAXS data based on small spheres (Rs = 1-2 nm) and cylinders (Lcyl = 10-20 nm) with radial polydispersity provided by the nitrogen sorption isotherms. As a result, we found that for a given incorporation of a templating IL, both synthesis pathways produce very similar pore geometries, but the better incorporation efficacy of the new hydrolytic films provides higher mesoporosity. Our combined study provides a coherent view of mesopore geometry, and thereby an optimization pathway of porous ionic membranes in terms of accessible mesoporosity contributing to the specific surface. Possible applications include electrolyte membranes with improved ionic properties, e.g., in fuel cells and batteries, as well as molecular storage.

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Background: Individuals who were separated from their biological family and placed into the care of the state during childhood (out-of-home care) are more prone to developing selected physical and mental health problems in adulthood, however, their risk of cardiovascular disease (CVD) is uncertain. Accordingly, we pooled published and unpublished results from cohort studies of childhood care and adult CVD. Methods: We used two approaches to identifying relevant data on childhood care and adult CVD (PROSPERO registration CRD42021254665). First, to locate published studies, we searched PubMed (Medline) until November 2023. Second, with the aim of identifying unpublished studies with the potential to address the present research question, we scrutinised retrieved reviews of the impact of childhood state care on related adult health outcomes. All included studies were required to have prospective measurement of state care in childhood and a follow-up of CVD events in adulthood as the primary outcome (incident coronary heart disease and/or stroke). Collaborating investigators provided study-specific estimates which were aggregated using random-effects meta-analysis. The Newcastle-Ottawa Scale was used to assess individual study quality. Findings: Thirteen studies (2 published, 11 unpublished) met the inclusion criteria, and investigators from nine provided viable results, including updated analyses of the published studies. Studies comprised 611,601 individuals (301,129 women) from the US, UK, Sweden, Finland, and Australia. Relative to the unexposed, individuals with a care placement during childhood had a 50% greater risk of CVD in adulthood (summary rate ratio after basic adjustment [95% confidence interval]: 1.50 [1.22, 1.84]); range of study-specific estimates: 1.28 to 2.06; I2 = 69%, p = 0.001). This association was attenuated but persisted after multivariable adjustment for socioeconomic status in childhood (8 studies; 1.41 [1.15, 1.72]) and adulthood (9 studies, 1.28 [1.10, 1.50]). There was a suggestion of a stronger state care-CVD association in women. Interpretation: Our findings show that individuals with experience of state care in childhood have a moderately raised risk of CVD in adulthood. For timely prevention, clinicians and policy makers should be aware that people with a care history may need additional attention in risk factor management.

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Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.

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Smoking, alcohol consumption, obesity, and physical inactivity are key lifestyle risk factors for cancer. Previously these have been mostly examined singly or combined as an index, assuming independent and equivalent effects to cancer risk. The aim of our study was to systematically examine the joint pairwise and interactive effects of these lifestyle factors on the risk of a first solid primary cancer in a multi-cohort prospective setting. We used pooled data from seven Finnish health survey studies during 1972-2015, with 197,551 participants diagnosed with 16,373 solid malignant primary tumors during follow-up. Incidence of any cancer was analyzed separately without and with lung cancers using Poisson regression with main and interaction effects of key lifestyle factors. When excluding lung cancer, the highest risk of any cancer in men was observed for smokers with a BMI of ≥25 kg/m2 (HR 1.36, 95 % CI 1.25-1.48) and in women for smokers consuming alcohol (HR 1.22, 1.14-1.30). No statistically significant interactions between any studied risk factor pairs were observed. When including lung cancer, the highest HRs among men were observed for smokers who consume alcohol (HR 1.72, 1.57-1.89) and among women for smokers who were physically inactive (HR 1.38, 1.27-1.49). Smoking combined with other lifestyle factors at any exposure level resulted in highest pairwise risks, both in men and women. These results highlight the importance of smoking prevention, but also the importance of preventing obesity and reducing alcohol consumption.