Efficacy, biodistribution and safety comparison of chemically modified antisense oligonucleotides in the retina.

Antisense oligonucleotides (AONs) are a versatile tool for treating inherited retinal diseases. However, little is known about how different chemical modifications of AONs can affect their biodistribution, toxicity, and uptake in the retina. Here, we addressed this question by comparing splice-switching AONs with three different chemical modifications commonly used in a clinical setting (2'O-methyl-phosphorothioate (2-OMe/PS), 2'O-methoxyethyl-phosphoriate (2-MOE/PS), and phosphorodiamidite morpholino oligomers (PMO)). These AONs targeted genes exclusively expressed in certain types of retinal cells. Overall, studies in vitro and in vivo in C57BL/6J wild-type mouse retinas showed that 2-OMe/PS and 2-MOE/PS AONs have comparable efficacy and safety profiles. In contrast, octa-guanidine-dendrimer-conjugated in vivo PMO-oligonucleotides (ivPMO) caused toxicity. This was evidenced by externally visible ocular phenotypes in 88.5% of all ivPMO-treated animals, accompanied by severe alterations at the morphological level. However, delivery of unmodified PMO-AONs did not cause any toxicity, although it clearly reduced the efficacy. We conducted the first systematic comparison of different chemical modifications of AONs in the retina. Our results showed that the same AON sequence with different chemical modifications displayed different splicing modulation efficacies, suggesting the 2'MOE/PS modification as the most efficacious in these conditions. Thereby, our work provides important insights for future clinical applications.

Proof-of-concept for multiple AON delivery by a single U7snRNA vector to restore splicing defects in ABCA4.

The high allelic heterogeneity in Stargardt disease (STGD1) complicates the design of intervention strategies. A significant proportion of pathogenic intronic ABCA4 variants alters the pre-mRNA splicing process. Antisense oligonucleotides (AONs) are an attractive yet mutation-specific therapeutic strategy to restore these splicing defects. In this study, we experimentally assessed the potential of a splicing modulation therapy to target multiple intronic ABCA4 variants. AONs were inserted into U7snRNA gene cassettes and tested in midigene-based splice assays. Five potent antisense sequences were selected to generate a multiple U7snRNA cassette construct, and this combination vector showed substantial rescue of all of the splicing defects. Therefore, the combination cassette was used for viral synthesis and assessment in patient-derived photoreceptor precursor cells (PPCs). Simultaneous delivery of several modified U7snRNAs through a single AAV, however, did not show substantial splicing correction, probably due to suboptimal transduction efficiency in PPCs and/or a heterogeneous viral population containing incomplete AAV genomes. Overall, these data demonstrate the potential of the U7snRNA system to rescue multiple splicing defects, but also suggest that AAV-associated challenges are still a limiting step, underscoring the need for further optimization before implementing this strategy as a potential treatment for STGD1.

Prevalence of Musculoskeletal and Metabolic Disorders in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis.

Introduction: Musculoskeletal disorders could be associated with metabolic disorders that are common after kidney transplantation, which could reduce the quality of life of patients. The aim of this study was to assess the prevalence of both musculoskeletal and metabolic disorders in kidney transplant patients. Methods: MEDLINE, CINAHL, Cochrane Library, EMBASE and Web of Science were searched from their inception up to June 2023. DerSimonian and Laird random-effects method was used to calculate pooled prevalence estimates and their 95% confidence intervals (CIs). Results: 21,879 kidney transplant recipients from 38 studies were analysed. The overall proportion of kidney transplant patients with musculoskeletal disorders was 27.2% (95% CI: 18.4-36.0), with low muscle strength (64.5%; 95% CI: 43.1-81.3) being the most common disorder. Otherwise, the overall proportion of kidney transplant patients with metabolic disorders was 37.6% (95% CI: 21.9-53.2), with hypovitaminosis D (81.8%; 95% CI: 67.2-90.8) being the most prevalent disorder. Conclusion: The most common musculoskeletal disorders were low muscle strength, femoral osteopenia, and low muscle mass. Hypovitaminosis D, hyperparathyroidism, and hyperuricemia were also the most common metabolic disorders. These disorders could be associated with poorer quality of life in kidney transplant recipients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42023449171].

Tuneable stimuli-responsive behaviour, spectroscopic signatures and redox properties of indolo[3,2-b]carbazole-based diradicals.

During the last decade, there has been an increasing interest in the rationalisation of how structural changes stabilise (or destabilise) diradical systems. Demonstrated herein is that indolocarbazole (ICz) diradicals, substituted with dicyanomethylene (DCM) groups, are useful motifs for dynamic covalent chemistry by self-assembling from isolated monomers to cyclophane structures. The comparison of ICz-based systems substituted with DCM groups in para- or meta-positions (p-ICz-CN and m-ICz-CN) and their short-chain carbazole analogues (p-Cz-CN and m-Cz-CN) may identify new potential design strategies for stimuli-responsive materials. The principal objectives of this investigation are the elucidation of (i) the connection between diradical character and the cyclophane stability, (ii) the spatial disposition of the cyclophane structures, (iii) the monomer/cyclophane interconversion both in solution and solid state in response to external stimuli and (iv) the impact that the different π-conjugation and electronic communication between the DCM terminals exerts on the electronic adsorption of the diradicals and their redox behavior. The spontaneous nature of the cyclophane structure is supported by the negative relative Gibbs free energies calculated at 298 K and experimentally by UV-Vis and Raman spectroscopy of the initial yellow solid powder. The conversion to monomeric species having diradical character was demonstrated by variable-temperature (VT) EPR, UV-Vis, Raman and IR measurements, resulting in appreciable chromic changes. In addition, electrochemical oxidation and reduction convert the cyclophane dimer (m-ICz-CN)2 to the monomer monocations and dianions, respectively. This research demonstrates how the chemical reactivity and physical properties of π-conjugated diradicals can be effectively tuned by subtle changes in their chemical structures.

Steps per day and health-related quality of life in schoolchildren: the mediator role of cardiorespiratory fitness.

To analyse the relationship between steps per day and health-related quality of life (HRQoL) and cardiorespiratory fitness (CRF) and to examine whether the relationship between steps per day and HRQoL is mediated by CRF in schoolchildren. This was a cross-sectional study including 501 schoolchildren (aged 9-12 years, 47% girls), from Cuenca, Spain. Steps per day were measured using the Xiaomi Mi Band 3 Smart Bracelet, HRQoL was estimated by the KIDSCREEN-27 questionnaire, and CRF was assessed using the 20-m shuttle run test. Analysis of covariance and multivariate analysis of covariance models showed that children with a higher mean number of steps per day (> 9000 steps/day) had better HRQoL (global score, and physical and psychological well-being) and higher CRF levels than their peers with a lower number of steps per day (p < 0.05); however, these differences were no longer significant when controlling for sex, age, mother's education level, and CRF (p > 0.05). Linear regression models estimated that each 1000-step increment was associated with better CRF (ß = 0.350; 95% CI, 0.192 to 0.508). In addition, the relationship between steps per day and HRQoL was mediated by CRF (p < 0.05).    Conclusion: Steps per day are a good metric to estimate daily physical activity because of its positive relationship with CRF. Moreover, those children taking more than 9000 steps per day are associated with higher levels of physical and psychological well-being. Finally, a substantial part of the improvement in HRQoL achieved through the increase in physical activity (steps per day) is mediated by CRF. What is Known: • Physical activity is known to have a positive impact on health-related quality of life in children. Steps per day are commonly used as a measure of physical activity. • Cardiorespiratory fitness is a recognized indicator of overall health in youth. What is New: • Increments of steps per day were associated with better CRF, with a nonlinear association after approximately 9000 steps/day. • Schoolchildren with > 9000 steps/ day showed better HRQoL.

Association of daily steps on lipid and glycaemic profiles in children: The mediator role of cardiorespiratory fitness.

AIM: To analyse, in schoolchildren, the relationship between daily steps with metabolic parameters; and to examine whether this association is mediated by cardiorespiratory-fitness (CRF). METHODS: A cross-sectional analysis of baseline data from a feasibility trial was performed in children from two primary schools in Cuenca, Spain. Daily steps were measured using the Xiaomi MI Band 3. Lipid and glycaemic profiles were analysed from blood samples. CRF was assessed using the 20-m shuttle run test. ANCOVA models were used to test the mean differences by daily steps quartiles. Mediation analyses were conducted to examine whether CRF mediates the association between daily steps and lipid and glycaemic parameters. RESULTS: A total of 159 schoolchildren (aged 9-12 years, 53% female) were included in the analysis. Schoolchildren in the highest daily steps quartiles (>10 000 steps) showed significantly lower triglycerides and insulin levels (p = 0.004 and 0.002, respectively). This association did not remain after controlling for CRF. In mediation analyses, a significant indirect effect was observed through CRF in the relationship between daily steps with triglycerides and insulin. CONCLUSION: Children who daily accumulate more than 10 000 steps have better lipid and metabolic profile, and CRF mediated their relationship in schoolchildren.

Effectiveness of eHealth Interventions Promoting Physical Activity in Children and Adolescents: Systematic Review and Meta-Analysis.

BACKGROUND: eHealth interventions have been postulated as a feasible, acceptable, and possibly effective tool to promote physical activity (PA) among children and adolescents; however, a comprehensive quantitative analysis of the effects of eHealth interventions promoting PA is lacking. OBJECTIVE: This study aims to conduct a systematic review and meta-analysis on experimental studies reporting the effects of eHealth interventions aimed at promoting PA on PA parameters and sedentary behavior parameters in children and adolescents. METHODS: The CENTRAL, MEDLINE, Embase, and Web of Science databases were searched from inception to February 2022 for randomized controlled trials that analyzed the effects of eHealth interventions aimed at promoting PA on PA and sedentary parameters in children and adolescents. The Hartung-Knapp-Sidik-Jonkman random effects method was used to determine the mean differences (MDs) with their respective 95% CIs. The risk of bias was assessed using the Risk of Bias 2 (RoB2; Cochrane) tool and its extension for cluster randomized controlled trials. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. RESULTS: A total of 20 trials reporting the effects of different eHealth interventions aimed at promoting PA were included. Results for each parameter were as follows: counts per minute (MD -16.11 counts, 95% CI -122.76 to 90.53; k=3; n=402; I2=69%; favoring control), steps per day (MD 593.46 steps, 95% CI -2102.27 to 3289.19; k=2; n=152; I2=0%; favoring intervention [FI]), moderate to vigorous PA (MD -1.99 min/d, 95% CI -8.95 to 4.96; k=14; n=2336; I2=86%; favoring control), light PA (MD 3.28 min/d, 95% CI -15.48 to 22.04; k=5; n=355; I2=67%; FI), screen time (MD -31.48 min/d, 95% CI -68.62 to 5.65; k=5; n=904; I2=0%; FI), and sedentary time (MD -33.12 min/d, 95% CI -57.27 to -8.97; k=8; n=819; I2=75%; FI). Our results should be interpreted cautiously because of important limitations such as the scarcity of evidence, overall risk of bias, and low to very low certainty of evidence. CONCLUSIONS: We did not find conclusive evidence regarding the impact of PA-targeted eHealth interventions on PA parameters, but the very low certainty of evidence suggests that eHealth interventions may reduce sedentary time in children and adolescents. Our results may have important scientific implications as they highlight that the rapid development of eHealth interventions to promote PA lacks robust supporting evidence. TRIAL REGISTRATION: PROSPERO CRD42020211020; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=211020.

Intelligence quotient-genotype association in dystrophinopathies: A systematic review and meta-analysis.

AIMS: Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are associated with intelligence quotients (IQs) lower than the normative values, and it is suggested that IQ is negatively correlated with the number of affected isoforms (i.e., Dp427, Dp140 and Dp71). Therefore, the objective of this meta-analysis was to estimate the IQ, and the IQ-genotype association according to the altered dystrophin isoforms, in the population with BMD or DMD. METHODS: A systematic search in Medline, Web of Science, Scopus and the Cochrane Library was conducted from inception to March 2023. Observational studies that determined the IQ and/or the IQ by genotype in the population with BMD or DMD were included. Meta-analyses of IQ, IQ by genotype and IQ-genotype association by comparing IQ according to the genotype were conducted. The results are shown as the mean/mean differences and 95% confidence intervals. RESULTS: Fifty-one studies were included. The IQ in BMD was 89.92 (85.84, 94.01) and in DMD was 84.61 (82.97, 86.26). Moreover, the IQ for Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71+ was 90.62 (86.72, 94.53) and 80.73 (67.49, 93.98) in BMD, while the IQ for Dp427-/Dp140+/Dp71+, Dp427-/Dp140-/Dp71+ and Dp427-/Dp140-/Dp71- was 93.05 (89.42, 96.67), 81.78 (77.23, 86.32) and 49.19 (40.47, 57.90) in DMD. Finally, in DMD, Dp427-/Dp140-/Dp71+ vs Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71- vs Dp427-/Dp140-/Dp71+ were associated with -10.73 (-14.66, -6.81) and -36.14 (-48.87, -23.41) points, respectively. CONCLUSIONS: The IQ in BMD and DMD was lower than the normative values. Moreover, in DMD, there is a synergistic association between the number of affected isoforms and IQ.

Association between severe hypoglycaemia and risk of dementia in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

The aim of this systematic review was to analyse whether there is an association between severe hypoglycaemia and the incidence of dementia in patients with type 2 diabetes mellitus. We systematically searched the MEDLINE, Scopus, and Cochrane databases from their inception until September 2022 for observational studies on the association between hypoglycaemia and the risk of dementia. The DerSimonian and Laird method was used to compute a pooled estimate of the risk for such association. Risk ratio (RR) and its respective 95% confidence interval (95% CI). Two analyses were performed to estimate the risk of dementia: (i) any hypoglycaemia versus no hypoglycaemia and (ii) a dose-response analysis for one, two, or more than three hypoglycemic events versus no hypoglycaemia. PROSPERO registration number CRD42020219200. Seven studies were included. The pooled RR for the association of severe hypoglycaemia and risk of dementia was 1.47 (95% CI: 1.24-1.74). When the dose-response trend was analysed, the pooled RR for the risk of dementia was increased according to the hypoglycaemia events as follows: 1.29 (95% CI: 1.15-1.44) for one hypoglycemic event; 1.68 (95% CI: 1.38-2.04) for two hypoglycemic events; and 1.99 (95% CI: 1.48-2.68) for three or more hypoglycemic events. Our study demonstrates a 54% higher risk of dementia among people who suffer a hypoglycaemia event compared to nonhypoglycaemia. Considering our results and the prevalence of people suffering from diabetes mellitus, health education for both newly diagnosed and already diagnosed people could be a useful tool for glycaemic control, thus avoiding hypoglycaemic events.

Comparative effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents: a systematic review and network meta-analysis.

OBJECTIVE: Arterial stiffness is an early and detectable marker of vascular changes leading to atherosclerotic cardiovascular disease (ACVD). Our objective was to compare the effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents. DESIGN: A systematic review and network meta-analysis (NMA) was conducted including experimental studies reporting the effects of exercise interventions on pulse wave velocity (PWV) in children and adolescents. DATA SOURCES: Cochrane Central Register of Controlled Trials, EMBASE (via Scopus), PubMed (via Medline) and Web of Science from database inception to 25 March 2022. ELIGIBILITY CRITERIA: Experimental studies reporting the effects of exercise interventions on PWV in children and adolescents. RESULTS: Fourteen studies were included in the NMA, all of them were randomised controlled trials except one quasi-experimental study, with an overall risk of bias of some concern. Regarding PWV reduction, all exercise modalities were more effective than control, with standardised mean difference ranging from -1.93 (95% CI: -2.84 to -1.02) and -1.11 (95% CI: -2.01 to -0.21) for aerobic exercise and high intensity interval training (HIIT), respectively, to -0.59 (95% CI: -1.39 to 0.22) for combined exercise. Only sensorimotor training was not superior to the control group 0.11 (95% CI: -1.10 to 1.32). CONCLUSION: Our results support that exercise interventions, especially aerobic exercise or HIIT, can improve arterial stiffness at early ages. The potential to address ACVD early and mitigate long-term consequences via exercise interventions in children and adolescents with higher arterial stiffness requires further investigation. PROSPERO REGISTRATION NUMBER: CRD42022322536.

Prognostic implications of systolic function in patients with cirrhosis.

INTRODUCTION: LV intrinsic systolic cardiac function in cirrhotic patients is conditioned by the degree of sympathetic activation and the use of non-selective beta-blockers (NSBBs). Systolic function can be non-invasively measured by ultrasound using Ejection Intraventricular Pressure Differences in the LV (EIVPD). We aimed to address the relationship between systolic function and long-term clinical outcomes using EIVPD. METHODS: We studied 45 Child-Pugh B or C patients (13 female, 24 on NSBBs) using echocardiography. The primary endpoint was the combination of any-cause mortality or liver transplantation. After a follow-up of 7 years (796 person-months) and a median period of 17 (10-42) months, 41 patients (91%) reached the primary endpoint: 13 (29%) died and 28 (62%) underwent transplantation. RESULTS: By univariable analysis the primary endpoint was related exclusively to MELD score. However, in a multivariable proportional-hazards analysis, adjusted for age, sex and MELD score, EIVPD was inversely related to the primary endpoint, showing interaction with NSBBs. In patients without NSBBs, EIVPD inversely predicted the primary endpoint, whereas in patients with NSBBs, EIVPD was unrelated to outcomes. These relationships were undetected by myocardial strain or conventional cardiac indices. CONCLUSIONS: LV intrinsic systolic function, as noninvasively measured by EIVPD is a predictor of long-term outcomes in patients with cirrhosis. The prognostic value of EIVPD is present along any degree of liver dysfunction but blunted by NSBBs. Because NSBBs have a deep effect on myocardial contractility, these drugs need to be considered when assessing the prognostic implications of cardiac function in these patients.

The role of daytime napping on salivary cortisol in children aged 0-5 years: a systematic review and meta-analysis.

Cortisol levels are implicated in emotional and cognitive development in children. However, it is not clear whether daytime napping influences cortisol levels in early childhood. This systematic review and meta-analysis aimed to synthesize the available evidence regarding the association between daytime napping and salivary cortisol in early childhood. The Medline, Embase, Web of Science, PsycINFO, and Cochrane Collaboration databases were searched for observational and experimental studies reporting data about napping behavior and salivary cortisol in children 0-5 years of age. Salivary cortisol levels were analyzed in three situations: CAR, cortisol awakening response from nap awakening; PRE-POST, before and after a daytime nap; and DIURNAL, from morning awakening to bedtime. Five studies showed a significant CAR after napping (mean difference, MD: 0.11µg/mL; 95% confidence interval, CI: 0.04, 0.18). In the PRE-POST analysis, a small decrease was observed for at-home naps (MD: -0.05 µg/mL; 95% CI: - 0.09, - 0.02) but not for at-childcare naps (MD: 0.04 µg/mL; 95% CI: - 0.01, 0.09). A similar pattern of DIURNAL salivary cortisol decrease was observed when children took a nap (MD: - 0.34 µg/mL; 95% CI: - 0.41, - 0.28) and when they did not sleep during the day (MD: - 0.28 µg/mL; 95% CI: - 0.38, - 0.19). CONCLUSIONS: Daytime napping plays a minor role in the fluctuation of salivary cortisol levels during the day. The conditions of the home or the childcare environment under which napping occurs might have a greater influence on cortisol levels than daytime napping itself in early childhood. PROSPERO Identifier: CRD42020212249. WHAT IS KNOWN: • The regulation of sleep involves circadian rhythmicity of cortisol secretion via activation of the HPA axis and a subsequent release of cortisol upon morning awakening followed by a decline throughout the day. WHAT IS NEW: • The available evidence supports the occurrence of a cortisol awakening response after a daytime nap. • A small decrease in cortisol after napping was observed when the nap occurred at home but not at childcare. • The conditions of the home or childcare environment under which the nap occurs and the activities before and after napping may have a greater influence on cortisol levels than napping itself.

Gal3 Plays a Deleterious Role in a Mouse Model of Endotoxemia.

Lipopolysaccharide (LPS)-induced endotoxemia induces an acute systemic inflammatory response that mimics some important features of sepsis, the disease with the highest mortality rate worldwide. In this work, we have analyzed a murine model of endotoxemia based on a single intraperitoneal injection of 5 mg/kg of LPS. We took advantage of galectin-3 (Gal3) knockout mice and found that the absence of Gal3 decreased the mortality rate oflethal endotoxemia in the first 80 h after the administration of LPS, along with a reduction in the tissular damage in several organs measured by electron microscopy. Using flow cytometry, we demonstrated that, in control conditions, peripheral immune cells, especially monocytes, exhibited high levels of Gal3, which were early depleted in response to LPS injection, thus suggesting Gal3 release under endotoxemia conditions. However, serum levels of Gal3 early decreased in response to LPS challenge (1 h), an indication that Gal3 may be extravasated to peripheral organs. Indeed, analysis of Gal3 in peripheral organs revealed a robust up-regulation of Gal3 36 h after LPS injection. Taken together, these results demonstrate the important role that Gal3 could play in the development of systemic inflammation, a well-established feature of sepsis, thus opening new and promising therapeutic options for these harmful conditions.

Molecular Tuning in Diaryl-Capped Pyrrolo[2,3-d:5,4-d']bisthiazoles: Effects of Terminal Aryl Unit and Comparison to Dithieno[3,2-b:2',3'-d]pyrrole Analogues.

A series of six conjugated oligomers consisting of a central pyrrolo[2,3-d:5,4-d']bisthiazole (PBTz) end-capped with either thienyl, furyl, or phenyl groups have been prepared from N-alkyl-and N-aryl-pyrrolo[2,3-d:5,4-d']bisthiazoles via Stille and Negishi cross-coupling. The full oligomeric series was thoroughly investigated via photophysical and electrochemical studies, in parallel with density functional theory (DFT) calculations, in order to correlate the cumulative effects of both aryl end-groups and N-functionalization on the resulting optical and electronic properties. Through comparison with the analogous dithieno[3,2-b:2',3'-d]pyrrole (DTP) materials, the effect of replacing DTP with PBTz on the material HOMO energy and visible light absorption is quantified.

Ultrasound-guided versus traditional method for peripheral venous access: an umbrella review.

BACKGROUND: Short peripheral catheters (SPC) insertion technique has a high failure rate, one of the reasons why the ultrasound (US)-guided method has been proposed as a valid alternative to traditional technique in SPC insertion. This umbrella review aims to synthesize the available evidence comparing the US-guided method with the traditional method on SPC insertion in terms of effectiveness, safety and patient satisfaction. METHODS: An umbrella review addressing the comparison between US-guided versus traditional method for SPC insertion in which only systematic reviews of all comparative study designs were eligible was carried out. Previous systematic reviews and meta-analyses were systematically searched in MEDLINE, EMBASE, Web of Science and Cochrane Library. Methodological quality was assessed with AMSTAR-2 tool. The quality of evidence per association was assessed using the GRADE criteria and was stablished as high, moderate, low and very low. RESULTS: Twelve systematic reviews with a range of 75-1860 patients were included. Moderate certainty evidence supports the positive effect of US-guided method on first-attempt success rate and number of attempts. There is moderate certainty evidence that US-guided method does not reduce the time spent in SPC insertion. Low certainty evidence supports that US-guided method improves both overall success rates and patient satisfaction. Emergency department was the main hospital department where these findings were reported. CONCLUSIONS: The best current evidence indicates that US-guided method for SPC insertion is postulated as a valid alternative for both adult and pediatric population, especially in patients with difficult venous access and in hospital departments where optimal vascular access in the shortest time possible is critical. TRIAL REGISTRATION: PROSPERO: CRD42021290824.

Cyclization-Promoted Ultralong Low-Temperature Phosphorescence via Boosting Intersystem Crossing.

Ultralong organic phosphorescence holds great promise as an important approach for optical materials and devices. Most of phosphorescent organic molecules with long lifetimes are substituted with heavy atoms or carbonyl groups to enhance the intersystem crossing (ISC), which requires complicated design and synthesis. Here, we report a cyclization-promoted phosphorescence phenomenon by boosting ISC. N-butyl carbazole exhibits a phosphorescence lifetime (τp) of only 1.45 ms and a low phosphorescence efficiency in the solution state at 77 K due to the lack of efficient ISC. In order to promote its phosphorescence behavior, we explored the influence of conjugation. By linear conjugation of four carbazole units, possible ISC channels are increased so that a longer τp of 2.24 s is observed. Moreover, by cyclization, the energy gap between the singlet and triplet states is dramatically decreased to 0.04 eV for excellent ISC efficiency accompanied by increased rigidification to synergistically suppress the nonradiative decay, resulting in satisfactory phosphorescence efficiency and a prolonged τp to 3.41 s in the absence of any heavy atom or carbonyl group, which may act as a strategy to prepare ultralong phosphorescent organic materials by enhancing the ISC and rigidification.

Dynamic Covalent Properties of a Novel Indolo[3,2-b]carbazole Diradical.

This work describes the synthesis and properties of a dicyanomethylene-substituted indolo[3,2-b]carbazole diradical ICz-CN. This quinoidal system dimerises almost completely to (ICz-CN)2 , which contains two long C(sp3 )-C(sp3 ) σ-bonds between the dicyanomethylene units. The minor open-shell ICz-CN component in the solid-state mixture was identified by EPR spectroscopy. Cyclic voltammetry and UV-visible spectroelectrochemical data, as well as comparison with reference monomer ICz-Br reveal that the nature of the one-electron oxidation of (ICz-CN)2 at ambient temperature and ICz-CN at elevated temperature is very similar in all these compounds due to the prevailing localization of their HOMO on the ICz backbone. The peculiar cathodic behaviour reflects the co-existence of (ICz-CN)2 and ICz-CN. The involvement of the dicyanomethylene groups stabilizes the close-lying LUMO and LUMO+1 of (ICz-CN)2 and especially ICz-CN compared to ICz-Br, resulting in a distinctive cathodic response at low overpotentials. Differently from neutral ICz-CN, its radical anion and dianion are remarkably stable under ambient conditions. The UV/Vis(-NIR) electronic transitions in parent (ICz-CN)2 and ICz-CN and their different redox forms have been assigned convincingly with the aid of TD-DFT calculations. The σ-bond in neutral (ICz-CN)2 is cleaved in solution and in the solid-state upon soft external stimuli (temperature, pressure), showing a strong chromism from light yellow to blue-green. Notably, in the solid state, the monomeric diradical species is predominantly formed under high hydrostatic pressure (>1 GPa).

Prevalence and trends of underweight in European children and adolescents: a systematic review and meta-analysis.

PURPOSE: This study aimed at providing prevalence trend estimates of underweight among children and adolescents in Europe from 2000 to 2017. METHODS: MEDLINE, Web of Science, Scopus and CINAHL were searched from their inception up to March 2020. Moreover, searches were conducted on health institutions' websites to identify studies not published in scientific journals. Underweight was defined according to the body mass index (BMI) cut-offs proposed by the International Obesity Task Force (IOTF) and the World Health Organization (WHO) definition criteria. The Mantel-Haenszel method was used to compute the pooled prevalence estimates whenever there was no evidence of heterogeneity; otherwise, the DerSimonian and Laird random-effects method was used. Subgroup analyses by sex, age range (2-13 and 14-18 years old), study year (2000-2006 and 2007-2017), country and European region were conducted. RESULTS: A total of 49 studies with data from 323,420 children and adolescents aged 2 to 18 years, from 26 countries were included. From 2000 to 2017, according to the IOTF criteria, the prevalence of underweight showed an increasing trend in Eastern, Northern and Southern Europe, where the underweight prevalence ranged from 9.1 to 12.0%, from 4.1 to 6.8%, and from 5.8 to 6.7%, respectively. In Western Europe, the prevalence of underweight tended to decrease, from 14.0 to 11.8%. No significant differences were found by sex or age range. CONCLUSION: The prevalence of underweight is considerable (overall, around 8-9%), particularly in Eastern Europe, and follows a slight upward trend during the past decade. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017056924.

Probing the nature of donor-acceptor effects in conjugated materials: a joint experimental and computational study of model conjugated oligomers.

A series of model oligomers consisting of combinations of a traditional strong donor unit (3,4-ethylenedioxythiophene), a traditional strong acceptor unit (benzo[c][1,2,5]thiadiazole), and the ambipolar unit thieno[3,4-b]pyrazine were synthesized via cross-coupling methods. The prepared oligomers include all six possible dimeric combinations in order to characterize the extent and nature of donor-acceptor effects commonly used in the design of conjugated materials, with particular focus on understanding how the inclusion of ambipolar units influences donor-acceptor frameworks. The full oligomeric series was thoroughly investigated via photophysical and electrochemical studies, in parallel with density functional theory (DFT) calculations, in order to correlate the nature and extent of donor-acceptor effects on both frontier orbital energies and the desired narrowing of the HOMO-LUMO energy gap. The corresponding relationships revealed should then provide a deeper understanding of donor-acceptor interactions and their application to conjugated materials.

Effect of retirement on cognitive function: a systematic review and meta-analysis.

The study aimed to determine the longitudinal association between retirement and cognitive function, including global cognition and memory-related skills. This is a systematic review of longitudinal studies on the association between retirement and cognitive function, using Medline (via PubMed), Scopus, Web of Science and PsycINFO databases from inception to April 2020 and longitudinal studies on the association between retirement and cognitive function. The Newcastle-Ottawa Scale was used to assess risk of bias of included studies. Effect size (ES) and 95% CI were calculated using Cohen's d index. Meta-regressions were calculated on the basis of sample characteristics: percentage of women, years of follow-up and age at baseline. A total of 23 longitudinal studies were included in this systematic review. The pooled ES for the association of retirement with global cognition and memory-related skills was -0.01 (95% CI -0.02 to 0.00; I2: 0.0%) and -0.09 (95% CI -0.16 to 0.01; I2: 93%), respectively. Meta-regression analyses showed that length of follow-up, percentage of women in the sample and mean age at baseline did not influence the longitudinal association between retirement and adults' memory-related skills. The results of this study indicate that retirement has no negative effects on adults' global cognition and slightly adversely influences memory-related skills. Moreover, this association does not seem to be influenced by some demographic and study characteristics.