Diabetes self-management education (DSME) for older persons in Western countries: A scoping review.

Diabetes mellitus is a chronic metabolic health condition affecting millions globally. Diabetes is a growing concern among aging societies, with its prevalence increasing among those aged 65 and above. Enabling disease self-management via relevant education is part of high-quality care to improve health outcomes and minimize complications for individuals living with diabetes. Successful diabetes self-management education (DSME) programs usually require tailoring for the intended audience; however, there is limited literature about the preferences of older persons in Western countries concerning DSME. As such, a broad overview of DSME for older persons was an identified need. To map the available evidence on DSME for persons aged 65 years and older in Western countries, the JBI methodology for conducting and reporting scoping reviews was used. In this scoping review, we considered all studies about DSME for older persons with T1D and T2D in Western countries where lifestyles, risks, prevention, treatment of diabetes, and approaches to self-management and DSME are similar (e.g., North America, Western and Northern Europe and Australasia). Systematic keyword and subject heading searches were conducted in 10 databases (e.g., MEDLINE, JBI EBP) to identify relevant English language papers published from 2000 to 2022. Titles and abstracts were screened to select eligible papers for full-text reading. Full-text screening was done by four independent reviewers to select studies for the final analysis. The review identified 2,397 studies, of which 1,250 full texts were screened for eligibility. Of the final 44 papers included in the review, only one included participants' understanding of DSME. The education programs differed in their context, design, delivery mode, theoretical underpinnings, and duration. Type of research designs, outcome measures used to determine the effectiveness of DSME, and knowledge gaps were also detailed. Overall, most interventions were effective and improved clinical and behavioural outcomes. Many of the programs led to improvements in clinical outcomes and participants' quality of life; however, the content needs to be adapted to older persons according to their culture, different degrees of health literacy, preference of education (e.g., individualized or group), preference of setting, degree of frailty and independence, and comorbidities. Few studies included the voices of older persons in the design, implementation, and evaluation of DSME programs. Such experiential knowledge is vital in developing educational programs to ensure alignment with this population's preferred learning styles, literacy levels, culture, and needs-such an approach could manifest more substantive, sustained results.

Machine learning dissection of human accelerated regions in primate neurodevelopment.

Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% of HARs have variants with large opposing effects on chromatin state and 14% on neurodevelopmental enhancer activity. This pattern, consistent with compensatory evolution, was confirmed using massively parallel reporter assays in chimpanzee and human neural progenitor cells. The species-specific enhancer activity of HARs was accurately predicted from the presence and absence of transcription factor footprints in each species. Despite these striking cis effects, activity of a given HAR sequence was nearly identical in human and chimpanzee cells. This suggests that HARs did not evolve to compensate for changes in the trans environment but instead altered their ability to bind factors present in both species. Thus, ML prioritized variants with functional effects on human neurodevelopment and revealed an unexpected reason why HARs may have evolved so rapidly.

"I Could Have Stood a Little More Education Rather than Just: 'Hey, you're Diabetic Man, Make the Best out of It'": Revisioning Diabetes Self-Management Education for Older Adults.

Objectives: Providing diabetes self-management education (DSME) in an evidence-based format that is accessible and tailored to the population needs is crucial for individuals living with diabetes mellitus. Our qualitative study explores the experiences of older adults living with diabetes while residing in a rural setting. Methods: Adults aged 65 or older and residing in a rural area of Ontario completed a photovoice activity and semi-structured interviews to illustrate their experience of living with diabetes and accessing DSME. Results: Fourteen participants (11 males; mean age = 74 years) completed the photovoice activity and interview. Four main themes were identified pertaining to learning about diabetes education, the depth and breadth of learning, applying knowledge to daily life, and engaging older adults in DSME. Discussion: Diabetes self-management education should account for older adults' preferences in learning about diabetes and self-management to promote access to evidence-based information, bolster knowledge and self-management efficacy, and improve disease control.

Diabetes self-management education for older adults in Western countries: a scoping review protocol.

OBJECTIVE: This scoping review will map the available evidence on diabetes self-management education programs for older adults in Western countries. INTRODUCTION: Self-management and education are crucial for controlling diabetes and its associated complications. The successful uptake of diabetes self-management education programs is not straightforward, and little is known about diabetes programs for older adults. Within this context, a broad overview of diabetes self-management education for older adults, considering all types of related evidence, is needed. INCLUSION CRITERIA: All studies in English concerning diabetes self-management education for older adults (aged 65 years and older) living with type 1 or 2 diabetes will be included. This review will not be specific to gender, sex, ethnicity, frailty, or other demographic variables. The review will be restricted to Western countries (North America, Western and Northern Europe, and Australasia), where approaches to diabetes self-management education will be similar. Studies including older adults with or without diabetes will not be considered unless they provide separate analyses for the 2 cohorts. METHODS: This scoping review will follow the JBI methodology for scoping reviews. We will conduct searches of electronic databases, including CINAHL, MEDLINE, and PubMed, from January 1, 2000, to the present to capture eligible articles. The review will consider all study designs, including quantitative, qualitative, mixed methods designs, as well as text and opinion papers, and systematic reviews that meet the inclusion criteria. After duplicates are removed, titles and abstracts will be screened independently by 2 reviewers, and the full texts will be reviewed. The screening criteria and data extraction protocol will be pilot-tested by the research team. The results will be summarized in tables accompanied by narrative text.

Gamma-glutamyl transferase and cardiovascular events in patients with congenital heart disease.

INTRODUCTION: Serum gamma-glutamyl transferase activity (GGT) seems to predict cardiovascular events in different populations. However, no data exist on patients with congenital heart disease (CHD). METHODS: Observational, analytic, prospective cohort study design involving CHD patients and a control population to determine the effect of GGT levels on survival. RESULTS: A total of 589 CHD patients (58% males, 29 ± 14 years old) and 2745 matched control patients were followed up. A total of 69 (12%) CHD patients had a major acute cardiovascular event (MACE) during the follow-up time (6.1 [0.7-10.4] years). Patients with CHD and a GGT >60 U/L were significantly older, more hypertensive and dyslipidemic, had a worse NYHA functional class and a greater anatomical complexity than CHD patients with a GGT ≤60 U/L. The binary logistic regression analysis showed that age, a great CHD anatomical complexity, and having atrial fibrillation/flutter were the predictive factors of higher GGT levels (>60 U/L). The Kaplan-Meier analysis showed that patients with CHD and a GGT concentration above 60 UL showed the lowest probability of survival compared to that of CHD with GGT ≤60 U/L and controls irrespective of their GGT concentrations (p < .001). Similarly, the multivariable Cox regression analysis found an independent association between higher GGT levels (>60 U/L) and a worse prognosis (HR 2.44 [1.34-4.44], p = .003) among patients with CHD. CONCLUSION: Patients with CHD showed significant higher GGT levels than patients in the control group having those with higher GGT concentrations (>60 U/L) the worst survival.

Early and surgical menopause associated with higher Framingham Risk Scores for cardiovascular disease in the Canadian Longitudinal Study on Aging.

OBJECTIVE: In women, the risk of cardiovascular disease (CVD) is higher in the postmenopausal period. The effect that menopausal type, natural versus surgical, or the age at natural menopause has on CVD needs further investigation. To this end, we assessed the association between menopausal type and timing and the 10-year office-based Framingham Risk Score (FRS) in women from the Canadian Longitudinal Study on Aging. METHODS: We included women aged 45 to 85 years from the Canadian Longitudinal Study on Aging Comprehensive cohort of seven Canadian provinces who were menopausal at the time of recruitment and had no prior CVD. Poisson regressions were used to evaluate the association between menopausal characteristics and the FRS. Natural menopause was defined as the cessation of menstrual periods for at least 1 year in women with no history of hysterectomy. Surgical menopause was defined as hysterectomy with or without oophorectomy prior to natural menopause. As main covariates, we examined age, education, province of residency, and hormone therapy. RESULTS: A total of 10,090 women (8,200 natural menopausal and 1,890 surgical menopausal) were eligible for the study. In the multivariable model, surgical menopause was associated with a higher mean FRS compared with natural menopause (CVD risk 12.4% vs 10.8%, P < 0.001). Compared with women with age at natural menopause from 50 to 54 years (CVD risk 10.2%), natural menopause before age 40, 40 to 44, or 45 to 49 had a higher CVD risk (12.2%, 11.4%, and 10.6%, respectively, P < 0.001). CONCLUSIONS: Our study supports an association between menopausal type and timing on CVD risk prediction and highlights the need to be judicious about surgical menopause. Preventative interventions for CVD should be considered in surgical menopausal women and women with an age at natural menopause less than 45 years.

Video Summary:http://links.lww.com/MENO/A701 .

Adaptation and Pilot Evaluation of an Intervention Addressing the Sexual Health Needs of Gay Men Living with HIV Infection in Colombia.

Interventions addressing the sexual health need of HIV-positive men who have sex with men (MSM) in Latin America are scarce. We adapted and evaluated GPS, a group-based intervention led by peers, developed using the Information-Motivation-Behavioral (IMB) model and motivational interviewing (MI). We used McKleroy et al framework to culturally adapt GPS to MSM living with HIV infection in Colombia. Then, a one-armed pilot trial examined changes in depressive symptoms, loneliness, self-efficacy for engaging in sexual risk reduction behaviors, sexual sensation seeking and sexual compulsivity at pre-intervention, post-intervention, and 3-month follow-up. These results were complemented with semistructured interviews with participants 3 months after the intervention. GPS was identified to be culturally acceptable with few changes in materials and exercises. Facilitators showed high levels of adherence and fidelity to MI principles. Seven of 11 eligible participants finished the intervention; GPS positively influenced self-efficacy for condom negotiation, depressive symptoms, and condomless anal sex with partners of unknown HIV status. Exit interviews revealed that GPS was well-designed, relevant, facilitated discussion of sex in a nonjudgmental manner, and helped make positive changes in participants' sexual lives. These results provided preliminary evidence of an intervention to address sexual and mental health of MSM living with HIV in Latin America.

Psychometric properties of a Spanish version of the 10-item Berger's stigma scale in Colombia: a validation study / Propiedades psicométricas de una versión en español de la escala de Berger de diez ítems en Colombia: un estudio de validación

Introduction: HIV-related stigma is detrimental to people living with HIV (PLH), and reducing it is essential for achieving an HIV/AIDS-free generation. Abbreviated stigma scales can improve the feasibility of surveys that broadly explore factors affecting PLH. This study tested the psychometric properties of a Spanish translation of the abbreviated 10-item Berger's HIV stigma scale. Methods:We recruited a sample of 105 PLH regularly attending a specialized clinic in Cali, Colombia. English-to-Spanish and Spanish-to-English back translation was performed of the Berger's 10-item HIV stigma scale.Exploratory and confirmatory factor analyses were carried out to assess its validity. Pre- and post-test reliability (15 days) was estimated with the intra-class correlation coefficient (ICC). Results: The Confirmatory Factor Analysis (CFA) was used to confirm a two-factor solution with three poor items removed, resulting in a 7-item HIV Stigma Scale. The resulting 7-item HIV stigma scale had a Cronbach's alpha of 0.73 with an ICC of 0.83 (CI 95%: 0.75­0.89). One factor loaded three items related to negative self-image (internalised stigma), and the other four items were related to personalized (enacted) HIV stigma. Both factors were related to depression and adherence to antiretroviral therapy. Conclusion: The Spanish translation of the 10-item HIV stigma scale did not perform well due to problems in items 4, 5, and 6. Rather, a modified 7-item version had a good fit with a two-factor loading in which both HIV stigma factors correlated significantly with depression and HIV medication adherence.

Introducción: el estigma asociado al VIH atenta contra la salud de las personas que viven con VIH (PVV), así que reducirlo es esencial para erradicar el VIH/SIDA. Las escalas abreviadas para estigma pueden facilitar la ejecución de encuestas amplias sobre factores que afectan a las PVV. Este estudio examinó las propiedades psicométricas de una traducción al español de la escala de Berger de 10 ítems. Métodos: se reclutaron 105 PVV en una clínica de VIH en Cali, Colombia. La escala de Berger de 10 ítems se tradujo del inglés al español y después del español al inglés. La validez de constructo se evaluó con análisis factoriales (exploratorios/confirmatorios). La confiabilidad pre y postest (15 días) se estimó con el coeficiente de correlación intraclase (CCI). Resultados: el análisis factorial confirmó una solución de dos factores carente de tres ítems de pobre desempeño, resultando en una escala final de siete ítems, la cual tuvo un coeficiente alfa de Cronbach de 0,73 y un CCI de 0,83 (IC 95%: 0,75-0,89). Un factor cargó tres ítems relacionados con autoimagen negativa (estigma internalizado), y otros cuatro ítems relacionados con el estigma personalizado (estigma declarado/ejercido por terceros). Ambos factores estuvieron asociados a depresión y baja adherencia a tratamiento antirretroviral. Conclusión: la escala de 10 ítems en español para estigma asociado al VIH tuvo pobre desempeño por problemas con los ítems 4, 5 y 6. En cambio, una versión modificada de siete ítems tuvo mejor desempeño, cargando dos factores correlacionados significativamente con depresión y adherencia al tratamiento antirretroviral.

Direct analysis of brain phenotypes via neural blastocyst complementation.

We provide a protocol for generating forebrain structures in vivo from mouse embryonic stem cells (ESCs) via neural blastocyst complementation (NBC). We developed this protocol for studies of development and function of specific forebrain regions, including the cerebral cortex and hippocampus. We describe a complete workflow, from methods for modifying a given genomic locus in ESCs via CRISPR-Cas9-mediated editing to the generation of mouse chimeras with ESC-reconstituted forebrain regions that can be directly analyzed. The procedure begins with genetic editing of mouse ESCs via CRISPR-Cas9, which can be accomplished in ~4-8 weeks. We provide protocols to achieve fluorescent labeling of ESCs in ~2-3 weeks, which allows tracing of the injected, ESC-derived donor cells in chimeras generated via NBC. Once modified ESCs are ready, NBC chimeras are generated in ~3 weeks via injection of ESCs into genetically programmed blastocysts that are subsequently transferred into pseudo-pregnant fosters. Our in vivo brain organogenesis platform is efficient, allowing functional and systematic analysis of genes and other genomic factors in as little as 3 months, in the context of a whole organism.

Application of the "syndemics" theory to explain unprotected sex and transactional sex: A crosssectional study in men who have sex with men (MSM), transgender women, and non-MSM in Colombia. / Aplicación de la teoría de la "sindemia" para entender el sexo sin protección y el sexo comercial: un estudio transversal en hombres que tienen sexo con hombres (HSH), mujeres transexuales y hombres que no tienen sexo con hombres en Colombia

INTRODUCTION: Men who have sex with men (MSM) and transgender women (TW) in Colombia are highly affected by HIV. To improve understanding of the role of HIV risk behaviors in HIV acquisition, we used the syndemic framework, a useful concept to inform prevention efforts. OBJECTIVE: To examine the effect of four psychosocial conditions, namely, forced sex, history of childhood sexual abuse, frequent alcohol use, and illicit drug use on unprotected sex and the synergistic effects ("syndemic" effects) of these conditions on HIV risk behavior. MATERIALS AND METHODS: We enrolled a total of 812 males (54.7% men who have sex with men, MSM; 7.3% transgender women, and 38% non-MSM). The participants were recruited from neighborhoods of low socioeconomic status through free HIV-counseling and -testing campaigns. We performed Poisson regression analysis to test the associations and interactions between the four psychosocial conditions and unprotected sex with regular, occasional, and transactional partners. To test the "syndemic" model, we assessed additive and multiplicative interactions. RESULTS: The prevalence of any psychosocial condition was 94.9% in transgender women, 60.1% in MSM, and 72.2% in non-MSM. A higher likelihood of transactional sex was associated in MSM (prevalence ratio (PR)=7.41, p<0.001) and non-MSM (PR=2.18, p< 0.001) with three or all four conditions compared to those with one condition. Additive interactions were present for all combinations of psychosocial problems on transactional sex n MSM. No cumulative effect or additive interaction was observed in transgender women. CONCLUSIONS: Our study highlights the need for bundled mental health programs addressing childhood sexual abuse, illicit drug use, and frequent alcohol use with other HIV prevention programs.

Introducción. Los hombres que tienen sexo con hombres (HSH), y las mujeres transgenero (MT) en Colombia continuan estando a mayor riesgo de VIH. Para entender como los comportamientos se asocian al VIH, se uso la teoria de la sindemia, la cual se ha considerado muy útil en el desarrollo de estrategias de prevención. Objetivo. Examinar el efecto de cuatro afecciones psicosociales, a saber: historia de sexo forzado, historia de abuso sexual infantil, consumo frecuente de alcohol y consumo de drogas ilícitas en las relaciones sexuales sin protección, así como los efectos sinérgicos (efectos "sindémicos") de estas afecciones sobre el comportamiento de riesgo para HIV. Materiales y métodos. Se hizo un estudio transversal que incluyó 812 participantes (hombres que tienen sexo con hombres, HSH: 54,7 %; mujeres transgénero: 7,3 % y hombres que no tenían sexo con otros hombres: 38 %). Los participantes se reclutaron en barrios de estratos socioeconómicos bajos a través de campañas gratuitas de asesoramiento y pruebas de HIV. Se hizo un análisis de regresión de Poisson para probar las asociaciones e interacciones entre las cuatro condiciones psicosociales y las relaciones sexuales sin protección con parejas regulares, ocasionales y comerciales. Para probar el modelo "sindémico" se evaluaron las interacciones aditivas y multiplicativas. Resultados. La prevalencia de cualquiera de las condiciones psicosociales fue de 94,9 % en mujeres transexuales, de 60,1 % en HSH y de 72,2 % en hombres que no tienen sexo con hombres. Se encontró una mayor probabilidad de tener sexo comercial en los HSH (razón de prevalencia (RP)=7,41, p<0,001) y en los que no tienen sexo con otros hombres (RP=2.18, p<0,001) con tres de las condiciones psicosociales, o con las cuatro, en comparación con aquellos con una sola condición. Las interacciones aditivas se registraron entre todas las combinaciones de problemas psicosociales con el sexo comercial en los HSH. No se observó un efecto acumulativo ni interacciones en mujeres transexuales. Conclusiones. El estudio resalta la necesidad de combinar programas de salud mental que aborden el abuso sexual infantil, el abuso de drogas y el consumo frecuente de alcohol con otros programas de prevención del HIV.

Application of the "syndemics" theory to explain unprotected sex and transactional sex: A cross- sectional study in men who have sex with men (MSM), transgender women, and non-MSM in Colombia / Aplicación de la teoría de la "sindemia" para entender el sexo sin protección y el sexo comercial: un estudio transversal en hombres que tienen sexo con hombres (HSH), mujeres transexuales y hombres que no tienen sexo con hombres en Colombia

Introduction: Men who have sex with men (MSM) and transgender women (TW) in Colombia are highly affected by HIV. To improve understanding of the role of HIV risk behaviors in HIV acquisition, we used the syndemic framework, a useful concept to inform prevention efforts. Objective: To examine the effect of four psychosocial conditions, namely, forced sex, history of childhood sexual abuse, frequent alcohol use, and illicit drug use on unprotected sex and the synergistic effects ("syndemic" effects) of these conditions on HIV risk behavior. Materials and methods: We enrolled a total of 812 males (54.7% men who have sex with men, MSM; 7.3% transgender women, and 38% non-MSM). The participants were recruited from neighborhoods of low socioeconomic status through free HIV-counseling and -testing campaigns. We performed Poisson regression analysis to test the associations and interactions between the four psychosocial conditions and unprotected sex with regular, occasional, and transactional partners. To test the "syndemic" model, we assessed additive and multiplicative interactions. Results:The prevalence of any psychosocial condition was 94.9% in transgender women, 60.1% in MSM, and 72.2% in non-MSM. A higher likelihood of transactional sex was associated in MSM (prevalence ratio (PR)=7.41, p<0.001) and non-MSM (PR=2.18, p< 0.001) with three or all four conditions compared to those with one condition. Additive interactions were present for all combinations of psychosocial problems on transactional sex in MSM. No cumulative effect or additive interaction was observed in transgender women. Conclusions: Our study highlights the need for bundled mental health programs addressing childhood sexual abuse, illicit drug use, and frequent alcohol use with other HIV prevention programs.

Introducción. Los hombres que tienen sexo con hombres (HSH), y las mujeres transgenero (MT) en Colombia continuan estando a mayor riesgo de VIH. Para entender como los comportamientos se asocian al VIH, se uso la teoria de la sindemia, la cual se ha considerado muy útil en el desarrollo de estrategias de prevención. Objetivo. Examinar el efecto de cuatro afecciones psicosociales, a saber: historia de sexo forzado, historia de abuso sexual infantil, consumo frecuente de alcohol y consumo de drogas ilícitas en las relaciones sexuales sin protección, así como los efectos sinérgicos (efectos "sindémicos") de estas afecciones sobre el comportamiento de riesgo para HIV. Materiales y métodos. Se hizo un estudio transversal que incluyó 812 participantes (hombres que tienen sexo con hombres, HSH: 54,7 %; mujeres transgénero: 7,3 % y hombres que no tenían sexo con otros hombres: 38 %). Los participantes se reclutaron en barrios de estratos socioeconómicos bajos a través de campañas gratuitas de asesoramiento y pruebas de HIV. Se hizo un análisis de regresión de Poisson para probar las asociaciones e interacciones entre las cuatro condiciones psicosociales y las relaciones sexuales sin protección con parejas regulares, ocasionales y comerciales. Para probar el modelo "sindémico" se evaluaron las interacciones aditivas y multiplicativas. Resultados. La prevalencia de cualquiera de las condiciones psicosociales fue de 94,9 % en mujeres transexuales, de 60,1 % en HSH y de 72,2 % en hombres que no tienen sexo con hombres. Se encontró una mayor probabilidad de tener sexo comercial en los HSH (razón de prevalencia (RP)=7,41, p<0,001) y en los que no tienen sexo con otros hombres (RP=2.18, p<0,001) con tres de las condiciones psicosociales, o con las cuatro, en comparación con aquellos con una sola condición. Las interacciones aditivas se registraron entre todas las combinaciones de problemas psicosociales con el sexo comercial en los HSH. No se observó un efecto acumulativo ni interacciones en mujeres transexuales. Conclusiones. El estudio resalta la necesidad de combinar programas de salud mental que aborden el abuso sexual infantil, el abuso de drogas y el consumo frecuente de alcohol con otros programas de prevención del HIV.

Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma.

Glioblastoma is a devastating form of brain cancer. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with single-cell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. We find that multiple GSC subtypes exist within a single tumor. Within these GSCs, we identify an invasive cell population similar to outer radial glia (oRG), a fetal cell type that expands the stem cell niche in normal human cortex. Using live time-lapse imaging of primary resected tumors, we discover that tumor-derived oRG-like cells undergo characteristic mitotic somal translocation behavior previously only observed in human development, suggesting a reactivation of developmental programs. In addition, we show that PTPRZ1 mediates both mitotic somal translocation and glioblastoma tumor invasion. These data suggest that the presence of heterogeneous GSCs may underlie glioblastoma's rapid progression and invasion.

The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation.

Although tumor-propagating cells can be derived from glioblastomas (GBM) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classic subtype has not been identified. It is unclear whether mesenchymal GSCs (mGSC) and/or proneural GSCs (pGSC) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/single-nucleus RNA sequencing of 28 gliomas, and single-cell ATAC sequencing for 8 cases. We found that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. In silico lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies can be derived from single-cell RNA signatures, to overcome intratumor heterogeneity. SIGNIFICANCE: Tumor-propagating cells can be derived from mesenchymal and proneural glioblastomas. However, a stem cell of the classic subtype has yet to be demonstrated. We show that classic-subtype gliomas are comprised of proneural and mesenchymal cells. This study sheds light on a long-standing debate regarding lineage relationships between glioma cell types.See related commentary by Fine, p. 1650.This article is highlighted in the In This Issue feature, p. 1631.

Age at natural menopause and physical functioning in postmenopausal women: the Canadian Longitudinal Study on Aging.

OBJECTIVE: The aim of this study was to evaluate the association between categories of age at natural menopause (ANM) and gait speed (slowness) and grip strength (weakness), common measures of physical functioning in older women. METHODS: We analyzed data from the Canadian Longitudinal Study on Aging, which included participants from seven cities across Canada collected in 2012. The sample was restricted to women who reported to have entered menopause (N = 9,920). Women who had a hysterectomy before menopause were excluded since the age at which this surgical procedure was performed was not available. ANM was categorized into five groups: less than 40 (premature), 40 to 44 (early), 45 to 49, 50 to 54, and more than 54. We conducted linear regressions to assess the association between ANM and gait speed (m/s) and grip strength (kg) adjusting for participant age, education, body mass index, smoking, use of hormone therapy, height, and province of residence. RESULTS: Mean ANM was 49.8 (95% confidence interval [CI]: 49.7-50.0), with 3.8% of women having a premature menopause; the average gait speed was 0.98 m/s (standard deviation: 0.22), the average grip strength was 26.6 kg (standard deviation: 6.39). Compared to women with ANM of 50 to 54, women with premature menopause had 0.054 m/s (95% CI -0.083, -0.026) lower gait speed when adjusting for age and study site. In the fully adjusted model, the association was attenuated, 0.032 m/s (95% CI -0.060, -0.004). ANM was not associated with grip strength. CONCLUSION: Our study suggests that premature menopause (<40 years) may be associated with lower gait speed (slowness) among Canadian women. No association was observed between ANM and grip strength. Future studies should include a life course approach to evaluate whether social and biological pathways modify the association between age at menopause and physical function in populations from different contexts.

Gender differences in four-year incidence of self-reported and performance-based functional disability: The International Mobility in Aging Study.

OBJECTIVES: To examine differences in incidence of functional disability between older women and men. METHODS: 2002 participants (65-74 years) were recruited in 2012 from Canada, Brazil, Colombia, and Albania, and re-assessed in 2016. Three measures of functional disability were used (1) Difficulty in any of five mobility-related Activities of Daily Living (ADL disability); (2) Self-reported difficulty climbing a flight of stairs or walking 400 m (mobility disability); and (3) Poor physical performance. We estimated the adjusted gender-specific incidence risk ratios (IRR) for each outcome in 2016. RESULTS: In 2016, 1506 participants (52% women) were re-examined, 80% of the surviving cohort. Among those not disabled in 2012, seventy-four (12.9%) men developed ADL disability, while 105 (19.2%) developed mobility disability, and 97 (16.1%) developed poor physical performance. For women, numbers were higher 120 (21.4%) developed ADL disability, 117 (26.5%) developed mobility disability, and 140 (23.0%) developed poor physical performance. Compared to men, women had a higher adjusted incidence of self-reported ADL disability (IRR 1.4; 95% CI 1.04-1.88) and mobility disability (IRR 1.4; 95% CI 1.06-1.77), but not of poor physical performance (IRR 1.03; 95% CI 0.88-1.32). CONCLUSIONS: Although women have a higher self-reported incidence of ADL and mobility disability than men, there was no significant difference in poor physical performance. Reasons for this discrepancy between self-reported and performance-based measures require further investigation. Understanding gender differences in functional disabilities can provide the basis for interventions to prevent mobility loss and minimize any gender gap.

Multimodal Single-Cell Analysis Reveals Physiological Maturation in the Developing Human Neocortex.

In the developing human neocortex, progenitor cells generate diverse cell types prenatally. Progenitor cells and newborn neurons respond to signaling cues, including neurotransmitters. While single-cell RNA sequencing has revealed cellular diversity, physiological heterogeneity has yet to be mapped onto these developing and diverse cell types. By combining measurements of intracellular Ca2+ elevations in response to neurotransmitter receptor agonists and RNA sequencing of the same single cells, we show that Ca2+ responses are cell-type-specific and change dynamically with lineage progression. Physiological response properties predict molecular cell identity and additionally reveal diversity not captured by single-cell transcriptomics. We find that the serotonin receptor HTR2A selectively activates radial glia cells in the developing human, but not mouse, neocortex, and inhibiting HTR2A receptors in human radial glia disrupts the radial glial scaffold. We show highly specific neurotransmitter signaling during neurogenesis in the developing human neocortex and highlight evolutionarily divergent mechanisms of physiological signaling.

Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution.

Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.

Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single-cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development.

Fear of Falling in Older Adults with Diabetes Mellitus: The IMIAS Study.

ABSTRACTSeveral determinants of developing fear of falling (FoF) overlap with the consequences of diabetes mellitus (DM). We compared the prevalence and severity of FoF in older adults with and without DM and identified which FoF determinants contribute to FoF severity in older adults with DM. We used Canadian baseline data from the International Mobility in Aging Study (IMIAS) which identified 141 older adults with DM (DM-group;age:68.88±2.80years) and 620 without DM (noDM-group;age:68.81±2.68years). FoF was quantified with Falls Efficacy Scale-International (FES-I). FoF determinants were evaluated in demographic/health-related, physical, psychological, and social domains. High concern of FoF was more prevalent and of higher severity in 10/16 FES-I activities in the DM-group compared to the noDM-group. Higher FoF severity in the DM-group was associated with poor physical performance, being female, fall history, and clinical depressive symptoms. Protocols developed for screening and interventions may reduce FoF severity in this population.