Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance.

The accumulation of metabolic waste is a leading cause of numerous neurological disorders, yet we still have only limited knowledge of how the brain performs self-cleansing. Here we demonstrate that neural networks synchronize individual action potentials to create large-amplitude, rhythmic and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow1,2 through the brain parenchyma. Chemogenetic flattening of these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial optogenetic stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. Our study demonstrates that neurons serve as master organizers for brain clearance. This fundamental principle introduces a new theoretical framework for the functioning of macroscopic brain waves.

Evaluation of Support, a self-guided online type 1 diabetes self-management education and support web application-a mixed methods study.

Background: Type 1 diabetes requires making numerous daily decisions to maintain normoglycemia. Support is an evidence-based self-guided web application for type 1 diabetes diabetes self-management. Objective: Evaluate users' satisfaction with Support and investigate changes in self-reported frequency of-, fear of- hypoglycemia, and diabetes-related self-efficacy. Methods: Adults from a Quebec type 1 diabetes registry used Support. Data was collected through online surveys or extracted from the registry at 0, 6, and 12 months (number of episodes and fear of hypoglycemia). At 6 months, participants reported satisfaction with Support and diabetes-related self-efficacy. A sub-group of 16 users was interviewed about their experience. Transcripts were analyzed using inductive and deductive approaches. Results: In total, 207 accounts were created (35% men, 96% White, mean age and diabetes duration: 49.3 ± 13.8 and 25.2 ± 14.7 years). At 6 months, the median [Q1; Q3] satisfaction was 40/49 [35; 45] with a mean decrease in hypoglycemia frequency of 0.43 episodes over 3 days (95% CI: -0.86; 0.00, p = 0.051) and of -1.98 score for fear (95% CI: -3.76; -0.20, p = 0.030). Half of the participants reported increased diabetes-related self-efficacy. Conclusions: Participants reported a high level of satisfaction with Support. Its use has the potential to facilitate hypoglycemia management and increase diabetes-related self-efficacy. Trial registration: This study is registered on ClinicalTrials.gov NCT04233138.

The Morphological and Functional Effects of the Endoscope-Assisted One-Stage Approach for Crooked Nose.

BACKGROUND: A crooked nose is an external nose deformity predominantly caused by congenital aplasia or acquired secondary to trauma or surgery, often accompanied by a deviated nasal septum. Patients with crooked nose have dual needs to improve both esthetic and functional problems. METHODS: The clinical and photographic information of 48 patients diagnosed with a crooked nose and nasal septum deviation treated from January 2018 to January 2022 was acquired. The morphology and functional effects were investigated by evaluating the general condition of the operation, measuring the esthetic indexes of the nose, and subjectively scoring. RESULTS: For both morphology and function, endoscopy-assisted one-stage correction showed positive results in this study. The external nose deviation distance postoperatively measured 1.28 (0.85, 1.97) mm, which significantly decreased from the preoperative value of 3.96 (3.31, 5.29) mm. The scores of doctors and irrelevant medical students on nose morphology increased significantly from 4.75±1.88 and 3.84±0.76 to 6.48±1.21 and 7.21±0.67, respectively. The rhinoplasty outcome evaluation score and the "nasal obstruction symptom evaluation "score of patients were both significantly improved ( t = -7.508 and t =6.310, respectively, P < 0.001). CONCLUSION: Endoscope-assisted one-stage correction of the crooked nose can restore nasal morphology, improve the symptoms of nasal obstruction, and achieve patient satisfaction. It is a minimally invasive, safe, effective, and fast recovery approach for patients who need to solve both esthetic and functional problems.

Adaptation of an Adult Web Application for Type 1 Diabetes Self-management to Youth Using the Behavior Change Wheel to Tailor the Needs of Health Care Transition: Qualitative Interview Study.

BACKGROUND: Youth (aged 14-24 years) living with type 1 diabetes (T1D) encounter increased challenges in their diabetes self-management (DSM), especially during the transition to adult care. Although DSM education and support are imperative, there is insufficient information on how web-based digital tools tailored to their demands can be developed. OBJECTIVE: On the basis of the Behavior Change Wheel, this study aims to identify, among youth living with T1D, the needs and factors influencing their DSM in the context of health care transition and to inform the adaptation (content and features) of an adult self-guided web application (Support). METHODS: Internet-based semistructured individual interviews based on a phenomenological study design were conducted with 21 youths, and transcripts were analyzed using an inductive approach with concept mapping. RESULTS: Factors influencing T1D self-management were categorized into barriers and facilitators and then as external or internal. Features influencing the accessibility to information, increasing the sense of support, and use of the tool were positively accepted. Features unrelated to their expectations of digital tool use or difficulty navigating were viewed negatively. Participants expressed an interest in reliable, practical, and novel educational content. Although youth considered the information provided by medical professionals to be important, peer exchange was deemed necessary to obtain a practical perspective and real-life examples. CONCLUSIONS: Compared with the adult population, in addition to tailored content and a simplified information search process, when building a DSM education and support digital tool for youth, features should be selected to encourage supervised peer exchange.

Development of the Support self-guided, web application for adults living with type 1 diabetes in Canada by a multi-disciplinary team using a people-oriented approach based on the Behaviour Change Wheel.

Background: Diabetes self-management education and support (DSME/S) are central in type 1 diabetes (T1D) where individuals are responsible for 95% of care. In-person DSME/S programs have been proven clinically effective (e.g. optimizing glycemic management, improving diabetes-related behaviors) but are limited by a lack of accessibility and long-term follow-up. Self-guided digital tools such as web applications (web apps) can be an alternative for delivering DSME/S. Objective: This article describes the development of Support, a behavioral theory-based, self-guided, web application for adults living with T1D in the province of Quebec, Canada. Methods: A multi-disciplinary team developed Support. Patient partners first proposed its focus, learning topics, and expressed barriers to using digital tools for DSME/S. These barriers were analyzed based on the Behaviour Change Wheel. A group of healthcare professionals (HCPs) drafted the evidence-based learning content which was reviewed by external HCPs and by patient partners. Results: Support is a bilingual (English and French) web app accessible at any time via the Internet. It has four learning paths focusing on hypoglycemia and based on the user's method of diabetes treatment. Learning modules are divided into six categories with a maximum of three learning levels. It contains features such as a discussion forum, videos, and quizzes to ensure interactivity, provide social support, and maintain the motivation and long-term engagement of users. Conclusions: To the best of the authors' knowledge, Support is the first self-guided evidence-based web app for adults living with T1D. It is currently under study to evaluate its feasibility and clinical impacts.

Association of age at first birth and risk of non-alcoholic fatty liver disease in women: evidence from the NHANES.

BACKGROUND: Numerous studies have suggested that age at first birth (AFB) is inversely associated with metabolic diseases, but positively associated with liver cancer in women. Non-alcoholic fatty liver disease (NAFLD) is a canonical example of metabolic dysfunction and inflammation-based liver disease, while the association between AFB and the risk of NAFLD remains unclear. We aimed to investigate the association between AFB and the odds of NAFLD in women. METHODS: Women older than 20 years at the time of the survey were analyzed using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 in the US. AFB was obtained with self-administered questionnaires. NAFLD was diagnosed as fatty liver index (FLI) ≥ 60. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression models. RESULTS: Of the 12,188 women included in this study, 5670 (46.5%) had NAFLD. Compared to individuals with AFB of 30-32 years old (reference group), the fully adjusted ORs and 95% CI in women with AFB < 18, 18-20, 21-23, and 24-26 years were 1.52 (95% CI 1.14, 2.03), 1.60 (95% CI 1.21, 2.11), 1.40 (95% CI 1.06, 1.84), and 1.33 (95% CI 1.01-1.76), respectively. Yet there was no significant difference between AFB of 27-29, 33-35, or > 35 years compared to the reference group. CONCLUSIONS: Women with younger AFB have higher odds of NAFLD in later life. Policymakers should consider focusing on those with earlier AFB for screening and prevention of NAFLD.

Duration of Diabetes, Glycemic Control, and Risk of Heart Failure Among Adults With Diabetes: A Cohort Study.

CONTEXT: The influences of diabetes duration and glycemic control and their potential interplays on the risk of heart failure (HF) remain unclear. OBJECTIVE: This work aimed to investigate the association of diabetes duration and glycemic control with the risk of HF. METHODS: A total of 23 754 individuals with diabetes but without HF during the baseline recruitment of UK Biobank were included in this study. Duration of diabetes was self-reported, and the status of glycemic control was reflected by glycated hemoglobin A1c (HbA1c) levels. Their associations with incident HF were assessed using multivariate Cox models adjusting for traditional risk factors. RESULTS: Duration of diabetes and HbA1c levels both were positively associated with the risk of HF. The hazard ratios (HRs) (95% CI) for diabetes durations of 5 to less than 10, 10 to less than 15, and 15 years or more were 1.09 (0.97-1.23), 1.13 (0.97-1.30), and 1.32 (1.15-1.53), respectively (vs < 5 years); and the HRs for HbA1c of 53.0 to less than 58.5 mmol/mol (7.0% to < 7.5%), 58.5 to less than 63.9 mmol/mol (7.5% to < 8.0%), and 63.9 mmol/mol or greater (8.0%) were 1.15 (1.02-1.31), 1.07 (0.91-1.26), and 1.46 (1.30-1.65), respectively (vs < 53.0 mmol/mol [7.0%]). Individuals with the longest disease duration (≥ 15 years) and poorer glycemic control (HbA1c ≥ 63.9 mmol/mol [8.0%]) had a particularly higher risk of HF (P for interaction = .026). CONCLUSION: The risk of HF among individuals with diabetes increases with a longer duration of diabetes and increasing HbA1c levels. This finding may contribute to the individualized prevention of HF in patients with diabetes if being considered in clinical practices and policy-making.

Understanding Self-Guided Web-Based Educational Interventions for Patients With Chronic Health Conditions: Systematic Review of Intervention Features and Adherence.

BACKGROUND: Chronic diseases contribute to 71% of deaths worldwide every year, and an estimated 15 million people between the ages of 30 and 69 years die mainly because of cardiovascular disease, cancer, chronic respiratory diseases, or diabetes. Web-based educational interventions may facilitate disease management. These are also considered to be a flexible and low-cost method to deliver tailored information to patients. Previous studies concluded that the implementation of different features and the degree of adherence to the intervention are key factors in determining the success of the intervention. However, limited research has been conducted to understand the acceptability of specific features and user adherence to self-guided web interventions. OBJECTIVE: This systematic review aims to understand how web-based intervention features are evaluated, to investigate their acceptability, and to describe how adherence to web-based self-guided interventions is defined and measured. METHODS: Studies published on self-guided web-based educational interventions for people (≥14 years old) with chronic health conditions published between January 2005 and June 2020 were reviewed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement protocol. The search was performed using the PubMed, Cochrane Library, and EMBASE (Excerpta Medica dataBASE) databases; the reference lists of the selected articles were also reviewed. The comparison of the interventions and analysis of the features were based on the published content from the selected articles. RESULTS: A total of 20 studies were included. Seven principal features were identified, with goal setting, self-monitoring, and feedback being the most frequently used. The acceptability of the features was measured based on the comments collected from users, their association with clinical outcomes, or device adherence. The use of quizzes was positively reported by participants. Self-monitoring, goal setting, feedback, and discussion forums yielded mixed results. The negative acceptability was related to the choice of the discussion topic, lack of face-to-face contact, and technical issues. This review shows that the evaluation of adherence to educational interventions was inconsistent among the studies, limiting comparisons. A clear definition of adherence to an intervention is lacking. CONCLUSIONS: Although limited information was available, it appears that features related to interaction and personalization are important for improving clinical outcomes and users' experience. When designing web-based interventions, the selection of features should be based on the targeted population's needs, the balance between positive and negative impacts of having human involvement in the intervention, and the reduction of technical barriers. There is a lack of consensus on the method of evaluating adherence to an intervention. Both investigations of the acceptability features and adherence should be considered when designing and evaluating web-based interventions. A proof-of-concept or pilot study would be useful for establishing the required level of engagement needed to define adherence.

A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep.

How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states. VIDEO ABSTRACT.

The long-term impact of very preterm birth on adult bone mineral density.

INTRODUCTION: Preterm infants are at increased risk of osteopenia of prematurity due to insufficient bone mineral accretion. Data on long term effects of prematurity on bone health are conflicting. This study aimed to compare bone mineral density (BMD) in young adults born very preterm and full-term controls and to examine factors associated with long-term bone health. METHODS: This observational cross-sectional study enrolled 101 young adults (18-29 years) born <29 weeks of gestation and 95 sex- and age-matched full-term controls. Participants underwent dual-energy X-ray absorptiometry to measure areal BMD and body composition. Generalized estimated equations were used to compare groups adjusting for height Z-score, lean body mass and fat mass. RESULTS: Adults born preterm were shorter and lighter than full-term controls. Areal BMD was reduced at the lumbar spine, the femoral neck and whole body in the preterm versus full-term group, but after adjustment, areal BMD Z-score was only significantly lower at the femoral neck by -0.3 unit (95% confidence interval -0.6 to -0.0). Low BMD (Z-score ≤ -1 standard deviation) at any site was observed in 53% of adults born preterm versus 28% of full-term controls, but this was not statistically significantly different. We did not identify any neonatal factors associated with lower BMD within the preterm group. CONCLUSIONS: Very preterm birth is associated with lower areal BMD at the femoral neck in young adulthood, even after accounting for body size. Whether this will translate into higher risk of osteoporotic fractures later in life remains unknown.

Kidney Size, Renal Function, Ang (Angiotensin) Peptides, and Blood Pressure in Young Adults Born Preterm.

Preterm birth incurs a higher risk for adult cardiovascular diseases, including hypertension. Because preterm birth may impact nephrogenesis, study objectives were to assess renal size and function of adults born preterm versus full term and to examine their relationship with blood pressure (BP; 24-hour ambulatory BP monitoring) and circulating renin-Ang (angiotensin) system peptides. The study included 92 young adults born (1987-1997) preterm (≤29 weeks of gestation) and term (n=92) matched for age, sex, and race. Young adults born preterm had smaller kidneys (80±17 versus 90±18 cm3/m2; P<0.001), higher urine albumin-to-creatinine ratio (0.70; interquartile range, 0.47-1.14 versus 0.58, interquartile range 0.42 to 0.78 mg/mmol, P=0.007), higher 24-hour systolic (121±9 versus 116±8 mm Hg; P=0.001) and diastolic (69±5 versus 66±6 mm Hg; P=0.004) BP, but similar estimated glomerular filtration rate. BP was inversely correlated with kidney size in preterm participants. Plasma Ang I was higher in preterm versus term participants (36.3; interquartile range, 13.2-62.3 versus 19.4; interquartile range, 9.9-28.1 pg/mL; P<0.001). There was no group difference in renin, Ang II, Ang (1-7), and alamandine. In the preterm, but not in the term group, higher BP was significantly associated with higher renin and alamandine and lower birth weight and gestational age with smaller adult kidney size. Young adults born preterm have smaller kidneys, higher urine albumin-to-creatinine ratio, higher BP, and higher circulating Ang I levels compared with term controls. Preterm young adults with smaller kidneys have higher BP. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03261609.

Endothelial Colony-Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease.

BACKGROUND: Preterm birth is linked to cardiovascular risks and diseases. Endothelial progenitor cells play a critical role in vascular development and repair. Cord blood endothelial progenitor cells of preterm-born infants, especially endothelial colony-forming cells (ECFC), show enhanced susceptibility to prematurity-related pro-oxidant stress. Whether ECFC dysfunction is present in adulthood following preterm birth is unknown. METHODS AND RESULTS: This cross-sectional observational study includes 55 preterm-born (≤29 gestational weeks) young adults (18-29 years old, 38% male) and 55 sex- and age-matched full-term controls. ECFC were isolated from peripheral blood; cell proliferative and vascular cord formation capacities were assessed in vitro. Daytime systolic blood pressure was higher, whereas glucose tolerance and body mass index were lower in preterm-born subjects. ECFC colonies grew in culture for 62% of full-term- and 58% of preterm-born participants. Preterm-born participants have formed ECFC colonies later in culture and have reduced proliferation compared with controls. Only in preterm-born individuals, we observed that the later the ECFC colony grows in culture, the worse was overall ECFC function. In addition, in preterms, elevated systolic blood pressure significantly correlated with reduced ECFC proliferation (rS=-0.463; P=0.030) and numbers of branches formed on matrigel (rS=-0.443; P=0.039). In preterm-born subjects, bronchopulmonary dysplasia was associated with impaired ECFC function, whereas exposure to antenatal steroids related to better ECFC function. CONCLUSIONS: This study is the first to examine ECFC in preterm-born adults and to demonstrate ECFC dysfunction compared with full-term controls. In the preterm-born group, ECFC dysfunction was associated with bronchopulmonary dysplasia, the major prematurity-related neonatal morbidity, and with increased systolic blood pressure into adulthood.

Web-Based Intervention to Teach Developmentally Supportive Care to Parents of Preterm Infants: Feasibility and Acceptability Study.

BACKGROUND: Preterm birth affects 8% to 11% of the population and conveys a significant risk of developmental delays. Intervention programs that support child development have been shown to have a positive impact on early motor and cognitive development and on parental well-being. However, these programs are often difficult to implement in a real-life setting due to lack of resources. Hence, our multidisciplinary team developed Mieux Agir au Quotidien (MAQ) to teach developmentally supportive care to parents of preterm infants with the goal of improving child development and parental outcomes. Our intervention included 3 in-person workshops that occurred prior to hospital discharge and a Web-based platform with written and videotaped materials that addressed 5 main themes: (1) infant behavioral cues, (2) flexion positioning; (3) oral feeding support, (4) parent-infant interactions, and (5) anticipation of developmental milestones. OBJECTIVE: This study aimed to test the feasibility and acceptability of the intervention by parents of preterm infants and assess clinical benefits on child neurodevelopment and parental outcomes during the first year of life. METHODS: A total of 107 infants born at <30 weeks and admitted to Sainte-Justine Hospital neonatal intensive care unit and their parents were enrolled in a nonrandomized controlled before-and-after interventional study (intervention n=55, comparison n=52). Acceptability of the program was assessed with a user satisfaction questionnaire. When the infants were at 4 months' corrected age, all parents completed questionnaires on infant temperament, parenting stress, sense of competence, and parenting satisfaction. At 12 months' corrected age, neurodevelopmental testing was performed on infants using the Alberta Infant Motor Scale and the Bayley Scales of Infant and Toddler Development, Third Edition. Comparisons between the 2 groups were done using independent t tests, Wilcoxon rank-sum tests, and Fisher exact tests. RESULTS: The majority of parents (43/45) were satisfied with the intervention program and all would recommend MAQ to others. MAQ met their need for evidence-based information that proved useful to support their child development. No difference in parental or child neurodevelopmental outcomes was detected in this pilot study for most outcomes except for higher median scores for parental coercive behaviors in the intervention group, although proportions scoring in the coercive range did not differ. CONCLUSIONS: Acceptability of the program was high among parents thus supporting the relevance of such intervention. A larger study using a randomized controlled trial design is needed to better document impact on parent and children and investigate how Web-based technologies can efficiently complement individualized intervention to alleviate the burden on health care resources.

Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.

BACKGROUND: As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors. METHODS: The creation of Dlgap2 (-/-) mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident-intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 (-/-) mice. RESULTS: Dlgap2 (-/-) mice displayed exacerbated aggressive behaviors in the resident-intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 (-/-) mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 (-/-) mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC. CONCLUSIONS: Our findings clearly demonstrate that Dlgap2 plays a vital role in social behaviors and proper synaptic functions of the OFC. Moreover, these results may provide valuable insights into the neuropathology of autism.