RESUMEN
Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.
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Neoplasias del Colon , Proteínas de Drosophila , Insulinas , Ratones , Animales , Humanos , Caquexia/etiología , Caquexia/metabolismo , Drosophila/metabolismo , Dinámicas Mitocondriales , Atrofia Muscular/patología , Músculo Esquelético/metabolismo , Neoplasias del Colon/metabolismo , Insulinas/metabolismo , Lípidos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMEN
The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate positioning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble cooperates with E-cadherin for sequential roles in daughter positioning. First Scribble stabilises E-cadherin at the mitotic cortex as well as the retraction fibres, to mediate spindle orientation. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction and subsequent cell positioning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division. This article has an associated First Person interview with the first author of the paper.
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Cadherinas , Huso Acromático , Humanos , Cadherinas/genética , Cadherinas/metabolismo , División Celular/genética , Polaridad Celular/fisiología , Uniones Intercelulares/metabolismo , Huso Acromático/metabolismoRESUMEN
BACKGROUND: Rates of dementia for Aboriginal and Torres Strait Islander peoples are three to five times greater compared to non-Indigenous Australians, with earlier age of onset. However, the risk and protective factors that drive these higher rates vary across existing cohort studies, with minimal findings on the role of vascular risk factors beyond stroke. Harmonisation of data across studies may offer greater insights through enhanced diversity and strengthened statistical capabilities. This study aims to combine three landmark cohort studies of Aboriginal and Torres Strait Islander participants to better understand the determinants of cognitive health and dementia. METHODS/DESIGN: Three cohort studies - the Kimberley Healthy Adults Project (KHAP, N = 363), Koori Growing Old Well Study (KGOWS, N = 336) and Torres Strait Dementia Prevalence Study (TSDPS, N = 274) - share a similar research methodology with demographic, medical history, psychosocial factors, cognitive tests and consensus clinical diagnoses of cognitive impairment and dementia. Associations between risk and protective factors of interest and the presence of dementia and/or cognitive impairment diagnoses will be evaluated by univariable and multivariable logistic regression in a harmonised cross-sectional cohort of 898 participants. Factors associated with incident dementia and/or cognitive impairment will be assessed in a subset of KHAP (n = 189) and KGOWS participants (n = 165) who were available in longitudinal follow-up, after exclusion of those with baseline dementia or cognitive impairment. Analyses in relation to outcome measure of death or dementia will be conducted to account for the competing risk of death. Logistic regression will be used to evaluate the association between the individual components of the 16-component Kimberley Indigenous Cognitive Assessment (KICA) tool and the presence of dementia and cognitive impairment determined by independent consensus diagnoses. Multivariable binary logistic regression will be used to adjust for the effect of confounding variables. Results will be reported as odds ratios (OR) with 95% confidence intervals (95% CI). DISCUSSION: Greater understanding of risk and protective factors of dementia and cognitive impairment relevant to Aboriginal and Torres Strait Islander peoples may improve approaches across the life course to delay cognitive decline and reduce dementia risk.
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Aborigenas Australianos e Isleños del Estrecho de Torres , Disfunción Cognitiva , Demencia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Australia/epidemiología , Australia/etnología , Disfunción Cognitiva/etnología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Estudios Transversales , Demencia/epidemiología , Demencia/etnología , Demencia/diagnóstico , Factores Protectores , Factores de RiesgoRESUMEN
BACKGROUND: Aboriginal and Torres Strait Islander people are ageing with high rates of comorbidity, yet little is known about suboptimal prescribing in this population. AIM: The prevalence of potentially suboptimal prescribing and associated risk factors were investigated among older patients attending primary care through Aboriginal Community Controlled Health Services (ACCHSs). METHODS: Medical records of 420 systematically selected patients aged ≥50 years attending urban, rural and remote health services were audited. Polypharmacy (≥ 5 prescribed medications), potentially inappropriate medications (PIMs) as per Beers Criteria and anticholinergic burden (ACB) were estimated and associated risk factors were explored with logistic regression. RESULTS: The prevalence of polypharmacy, PIMs and ACB score ≥3 was 43%, 18% and 12% respectively. In multivariable logistic regression analyses, polypharmacy was less likely in rural (odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.24-0.77) compared to urban patients, and more likely in those with heart disease (OR = 2.62, 95% CI = 1.62-4.25), atrial fibrillation (OR = 4.25, 95% CI = 1.08-16.81), hypertension (OR = 2.14, 95% CI = 1.34-3.44), diabetes (OR = 2.72, 95% CI = 1.69-4.39) or depression (OR = 1.91, 95% CI = 1.19-3.06). PIMs were more frequent in females (OR = 1.88, 95% CI = 1.03-3.42) and less frequent in rural (OR = 0.41, 95% CI = 0.19-0.85) and remote (OR = 0.58, 95% CI = 0.29-1.18) patients. Factors associated with PIMs were kidney disease (OR = 2.60, 95% CI = 1.37-4.92), urinary incontinence (OR = 3.00, 95% CI = 1.02-8.83), depression (OR = 2.67, 95% CI = 1.50-4.77), heavy alcohol use (OR = 2.83, 95% CI = 1.39-5.75) and subjective cognitive concerns (OR = 2.69, 95% CI = 1.31-5.52). High ACB was less common in rural (OR = 0.10, 95% CI = 0.03-0.34) and remote (OR = 0.51, 95% CI = 0.25-1.04) patients and more common in those with kidney disease (OR = 3.07, 95% CI = 1.50-6.30) or depression (OR = 3.32, 95% CI = 1.70-6.47). CONCLUSION: Associations between potentially suboptimal prescribing and depression or cognitive concerns highlight the importance of considering medication review and deprescribing for these patients.
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Nativos de Hawái y Otras Islas del Pacífico , Polifarmacia , Atención Primaria de Salud , Humanos , Femenino , Masculino , Estudios Transversales , Anciano , Persona de Mediana Edad , Factores de Riesgo , Prescripción Inadecuada/estadística & datos numéricos , Australia/epidemiología , Anciano de 80 o más Años , Lista de Medicamentos Potencialmente Inapropiados , PrevalenciaRESUMEN
BACKGROUND: The coronavirus (COVID-19) pandemic presented a significant stressor on the public health system in the United States. While we know the immediate effects of the pandemic on public health programming, no literature has examined the resultant long-term impact on programmatic capacity for sustainability. This paper aims to identify the impact that the COVID-19 pandemic had on state tobacco control program's capacity for sustainability. METHODS: From December 2018 to January 2022, we conducted 46 technical assistance calls with tobacco control program employees from 11 states. Calls were audio recorded and professionally transcribed. We analyzed calls (n = 20) that took place during the COVID-19 pandemic. Thematic analysis focused on the impact the COVID-19 pandemic had on tobacco control program's capacity for sustainability. RESULTS: We identified six domains of sustainability that were impacted by COVID-19: (1) funding stability; (2) organizational capacity; (3) partnerships; (4) communication; (5) strategic planning; and (6) program adaptation. CONCLUSIONS: Our study is the first to identify the impact of the pandemic on capacity for sustainability of tobacco control programs. Having an understanding of COVID-19's influence on these sustainability domains could help with future public health programming during significant public health events and emergency preparedness. GOV IDENTIFIER: NCT03598114. REGISTRATION DATE: Retrospectively registered 02-07-2018.
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COVID-19 , Pandemias , Humanos , Estados Unidos/epidemiología , Evaluación de Programas y Proyectos de Salud , Pandemias/prevención & control , COVID-19/epidemiología , COVID-19/prevención & control , Salud Pública , Control del TabacoRESUMEN
Public health programs, particularly tobacco control programs (TCPs) in state health departments, face numerous barriers and facilitators to sustainability, which affect delivery and, consequently, health outcomes achieved. We used the Program Sustainability Framework to review and analyze qualitative interview data from states that received training and technical assistance during the Plans, Actions, and Capacity to Sustain Tobacco Control (PACT) study to better understand the barriers and facilitators to sustainability capacity that these public health programs face at the state level. The PACT study was a multiyear, randomized controlled trial to assess the effectiveness of an action planning workshop and technical assistance in improving capacity for sustainability among 11 intervention and 12 control TCPs. Technical assistance calls focused on the progress and barriers of implementing the sustainability action plan created during the in-person workshops. Calls were audio recorded and professionally transcribed. Thematic analysis focused on the codes describing barriers and facilitators faced by TCPs in increasing their capacity for sustainability. Barriers were reported in the Organization Capacity, Environmental Support, Partnerships, Communication, and Funding Stability domains of the Program Sustainability Framework. Facilitators to action planning and building capacity for program sustainability were primarily in the Strategic Planning, Program Evaluation, Program Adaptation, and Partnership domains. Our study is the first to identify barriers and facilitators to increasing the capacity of program sustainability in TCPs. This work advances the understanding of program sustainability capacity and technical assistance for public health programs.
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Comunicación , Control del Tabaco , Humanos , Evaluación de Programas y Proyectos de SaludRESUMEN
BACKGROUND: No formal published recommendations exist about exercise and physical activity after stoma surgery and there is no consensus on advice among health professionals. Numerous difficulties after stoma surgery cause physical activity and exercise levels to decrease. Health professionals can feel ill equipped to advise, leaving patients confused and unsupported. AIM: Formal recommendations for exercise and physical activity are to be established. METHOD: An expert panel is working under the auspices of the Association of Stoma Care Nurses (ASCN) UK to review existing literature, explore clinical practice and develop formal Delphi consensus recommendations. The document will be aimed at health professionals but will also be available to individuals undergoing surgery. CONCLUSION: The formal document will be published by the end of 2024 through ASCN UK. The scope of the EXPASS recommendations will cover adults (aged ≥16 years) with any stoma. It will offer peer-reviewed Delphi guidance on physical activity and exercise before and immediately after surgery as well as for long-term living with a stoma. After peer review, the document will provide clarification, consensus and practical recommendations based on the expert panel's evidence, research and clinical opinion.
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Ejercicio Físico , Estomas Quirúrgicos , Humanos , Consenso , Conferencias de Consenso como AsuntoRESUMEN
BACKGROUND: Neurodevelopmental challenges are the most prevalent comorbidity associated with a diagnosis of critical CHD, and there is a high incidence of gross and fine motor delays noted in early infancy. The frequency of motor delays in hospitalised infants with critical CHD requires close monitoring from developmental therapies (physical therapists, occupational therapists, and speech-language pathologists) to optimise motor development. Currently, minimal literature defines developmental therapists' role in caring for infants with critical CHD in intensive or acute care hospital units. PURPOSE: This article describes typical infant motor skill development, how the hospital environment and events surrounding early cardiac surgical interventions impact those skills, and how developmental therapists support motor skill acquisition in infants with critical CHD. Recommendations for healthcare professionals and those who provide medical or developmental support in promotion of optimal motor skill development in hospitalised infants with critical CHD are discussed. CONCLUSIONS: Infants with critical CHD requiring neonatal surgical intervention experience interrupted motor skill interactions and developmental trajectories. As part of the interdisciplinary team working in intensive and acute care settings, developmental therapists assess, guide motor intervention, promote optimal motor skill acquisition, and support the infant's overall development.
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Procedimientos Quirúrgicos Cardíacos , Trastornos de la Destreza Motora , Recién Nacido , Lactante , Humanos , Desarrollo Infantil , Destreza MotoraRESUMEN
Infants and children born with CHD are at significant risk for neurodevelopmental delays and abnormalities. Individualised developmental care is widely recognised as best practice to support early neurodevelopment for medically fragile infants born premature or requiring surgical intervention after birth. However, wide variability in clinical practice is consistently demonstrated in units caring for infants with CHD. The Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative, formed a working group of experts to create an evidence-based developmental care pathway to guide clinical practice in hospital settings caring for infants with CHD. The clinical pathway, "Developmental Care Pathway for Hospitalized Infants with Congenital Heart Disease," includes recommendations for standardised developmental assessment, parent mental health screening, and the implementation of a daily developmental care bundle, which incorporates individualised assessments and interventions tailored to meet the needs of this unique infant population and their families. Hospitals caring for infants with CHD are encouraged to adopt this developmental care pathway and track metrics and outcomes using a quality improvement framework.
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Vías Clínicas , Cardiopatías Congénitas , Recién Nacido , Lactante , Niño , Humanos , Opinión Pública , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/terapia , Cardiopatías Congénitas/diagnósticoRESUMEN
BACKGROUND: Parastomal hernias are a common consequence of stoma surgery and can occur in up to 50% of patients. They are mangaged either conservatively, through support hosiery, or surgically. A patient feasibility study called the Hernia Active Living Trial (HALT) was designed to examine if a clinical pilates-based exercise programme offers an alternative approach to managing a parastomal hernia or bulge. METHOD: Adults with an ileostomy or colostomy who perceived they had a bulge around their stoma were included in the study. The intervention included up to 12 online sessions of an exercise booklet and videos with an exercise specialist. Interviews were conducted to explore participants' experiences of the intervention. The interview data were analysed systematically and thematically. Participants were also asked to complete patient diaries every week. RESULTS: Twelve of the 13 participants who completed the intervention agreed to be interviewed. Following analysis, three main themes emerged including managing a hernia/bulge, benefits and barriers. Participants talked about the benefits of this programme including: reduction of the size of their hernia, increased abdominal control, body confidence and posture, as well as increased physical activity levels. The barriers described were generally overcome allowing participants to engage in what was perceived to be a positive and potentially life-changing experience. CONCLUSIONS: A clinical pilates-based exercise programme for people with a parastomal hernia can bring both direct and indirect improvements to a patient's hernia management, sense of wellbeing and day-to-day life. Individuals with a hernia should be informed about the need for, and value of, exercise to strengthen core muscles, as part of their non-surgical options for self-management.
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Hernia , Estomas Quirúrgicos , Adulto , Humanos , Estomas Quirúrgicos/efectos adversos , Colostomía , Ileostomía , Terapia por EjercicioRESUMEN
OBJECTIVES: The aim of the study was to assess the prevalence of anxiety and depression in older Aboriginal and Torres Strait Islander adults. METHODS: A modified version of the PHQ-9 (KICA-dep) and the Geriatric Anxiety Inventory (GAI) were administered as part of a wider dementia prevalence study conducted in the Torres Strait. Results were compared to diagnoses obtained on Geriatric review to evaluate their applicability in the region. RESULTS: A total of 236 participants completed the KICA-dep and 184 completed the GAI short form. Of these, 10.6% were identified with depression and 15.8% with anxiety. Some participants found questions about suicide ideation and self-harm offensive and others had difficulty understanding concepts on the GAI. The KICA-dep performed poorly in comparison to diagnosis on geriatric clinical review, so results are unlikely to reflect the true prevalence of depression in the region. CONCLUSIONS: Further research is required to explore the underlying dimensions of depression and anxiety and terminology used to express mood symptoms in the Torres Strait. CLINICAL IMPLICATIONS: ⢠Current mental health screening tools are not applicable for the Torres Strait⢠More work is required to determine how symptoms of depression and anxiety are expressed within Torres Strait communities.
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Aborigenas Australianos e Isleños del Estrecho de Torres , Depresión , Humanos , Anciano , Depresión/diagnóstico , Depresión/epidemiología , Ansiedad/diagnóstico , Ansiedad/epidemiología , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , AfectoRESUMEN
BACKGROUND: Children whose parents have type 2 diabetes (T2D) are at high-risk for developing T2D. In youth, negative affect has been shown to predict insulin resistance (IR), and disinhibited-eating behaviors have been linked to IR. It is unknown if youth with a parent with T2D (P-T2D) report greater psychological and behavioral symptoms than those without a P-T2D. OBJECTIVE: To compare youth with and without a P-T2D on symptoms of negative affect and disinhibited-eating. METHODS: Nine-hundred thirty-two youth (13.3 ± 2.6 years; BMIz 1.06 ± 1.06; 67.8% female; 53.6% people of color; 10.7% with a P-T2D) completed questionnaires of anxiety and depressive symptoms, eating in the absence of hunger, and emotional-eating. Loss-of-control (LOC)-eating was assessed by interview. In two separate subsamples, energy intake was explored using laboratory test meals simulating eating in the absence of hunger and LOC-eating, respectively. Analyses were adjusted for age, sex, race/ethnicity. In follow-up analyses, fat mass (kg) and height, and IR were included as covariates, respectively. RESULTS: Adjusting for all covariates including adiposity and IR, compared to youth without a P-T2D, youth with a P-T2D reported more anxiety and depression symptoms, greater eating in the absence of hunger, and emotional-eating (ps < 0.05). No significant differences were found for LOC-eating, or in exploratory analyses of energy intake for either test meal (ps > 0.16). CONCLUSIONS: Self-reported negative affect and disinhibited-eating may be higher among youth with P-T2D compared to those without P-T2D. Prospective studies should examine, among those with a P-T2D, what role such symptoms may play for their subsequent risk for T2D.
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Diabetes Mellitus Tipo 2/dietoterapia , Conducta Alimentaria/psicología , Padres/psicología , Adolescente , Adulto , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 2/psicología , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
OBJECTIVES: Adolescent military-dependents experience distinct risk and protective factors, which may necessitate additional clinical considerations. In civilian youth, overweight/obesity is associated with eating, internalizing, and externalizing difficulties, with some studies reporting more difficulties among non-Hispanic White (vs. non-Hispanic Black) youth. It is unknown if these disparities exist among adolescent military-dependents, or between civilian and military-dependent youth. METHODS: Non-Hispanic Black (187 civilian, 38 military-dependent) and non-Hispanic White (205 civilian, 84 military-dependent) adolescents with overweight/obesity (14.7 ± 1.6 years; 73.9% girls; body mass index adjusted for age and sex 1.9 ± 0.5) completed a disordered-eating interview; parents completed a measure assessing their child's internalizing and externalizing difficulties. Multiple linear regressions examined parental military-status as a moderator of the relationship of participant race with eating, internalizing, and externalizing difficulties. RESULTS: White civilian youth with overweight/obesity reported significantly greater disordered-eating than their Black peers (p < .001); there were no other significant racial differences. In all regressions, parental military-status significantly moderated the association between race and each dependent variable (ps < .047). Black military-dependents (vs. civilians) reported more disordered-eating and internalizing difficulties (ps = .01). White military-dependents (vs. civilians) reported fewer externalizing difficulties (p = .01). CONCLUSIONS: Black adolescent military-dependents with overweight/obesity may experience more eating and internalizing difficulties (vs. civilians), a pattern not observed among White participants. Future work should examine if being a military-dependent and a historically marginalized racial group member accounts for these findings. Such data may inform providers of youth with intersecting minority identities.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Personal Militar , Adolescente , Índice de Masa Corporal , Niño , Femenino , Humanos , Masculino , Obesidad , Sobrepeso , PadresRESUMEN
BACKGROUND: There is a high prevalence of liver injury (LI) in patients with coronavirus disease 2019 (COVID-19); however, few large-scale studies assessing risk factors and clinical outcomes in these patients have been done. AIMS: To evaluate the risk factors and clinical outcomes associated with LI in a large inpatient cohort of COVID-19 patients. METHODS: Adult patients with COVID-19 between March 1 and April 30, 2020, were included. LI was defined as peak levels of alanine aminotransferase/aspartate aminotransferase that were 3 times the ULN or peak levels in alkaline phosphatase/total bilirubin that were 2 times the ULN. Mild elevation in liver enzymes (MEL) was defined as abnormal peak liver enzyme levels lower than the threshold for LI. Patients with MEL and LI were compared to a control group comprising patients with normal liver enzymes throughout hospitalization. RESULTS: Of 1935 hospitalized COVID-19 patients, 1031 (53.2%) had MEL and 396 (20.5%) had LI. Compared to control patients, MEL and LI groups contained proportionately more men. Patients in the MEL cohort were older compared to control, and African-Americans were more highly represented in the LI group. Patients with LI had an increased risk of mortality (relative risk [RR] 4.26), intensive care unit admission (RR, 5.52), intubation (RR, 11.01), 30-day readmission (RR, 1.81), length of hospitalization, and intensive care unit stay (10.49 and 10.06 days, respectively) compared to control. CONCLUSION: Our study showed that patients with COVID-19 who presented with LI had a significantly increased risk of mortality and poor clinical outcomes.
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COVID-19 , Hepatopatías , Adulto , Alanina Transaminasa , Aspartato Aminotransferasas , COVID-19/complicaciones , COVID-19/mortalidad , Femenino , Hospitalización , Humanos , Hepatopatías/epidemiología , Masculino , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
Public health agencies are increasingly concerned with ensuring that they are maximizing limited resources by delivering effective programs to enhance population-level health outcomes. Preventing mis-implementation (ending effective activities prematurely or continuing ineffective ones) is necessary to sustain public health efforts and resources needed to improve health and well-being. The purpose of this paper is to identify the important qualities of leadership in preventing mis-implementation of public health programs. In 2019, 45 state health department chronic disease employees were interviewed via phone and audio-recorded, and the conversations were transcribed verbatim. Thematic analysis focused on items related to mis-implementation and the manners in which leadership were involved in continuing ineffective programs. Final themes were based on a Public Health Leadership Competency Framework. The following themes emerged from their interviews regarding the important leadership competencies to prevent mis-implementation: '(1) leadership and communication; (2) collaborative leadership (3) leadership to adapt programs; (4) leadership and organizational learning and development; and (5) political leadership'. This first of its kind study showed the close interrelationship between mis-implementation and leadership. Increased attention to public health leader competencies might help to reduce mis-implementation in public health practice and lead to more effective and efficient use of limited resources.
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Liderazgo , Salud Pública , Enfermedad Crónica , Comunicación , Humanos , Práctica de Salud PúblicaRESUMEN
Muscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1-GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1-GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.
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Núcleo Celular/metabolismo , Proteína Forkhead Box O1/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Animales , Núcleo Celular/efectos de los fármacos , Femenino , Proteína Forkhead Box O1/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Imagen Óptica , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
A fundamental question in biology is how single cells can reliably produce progeny of different cell types. Notch signalling frequently facilitates fate determination. Asymmetric cell division (ACD) often controls segregation of Notch signalling by imposing unequal inheritance of regulators of Notch. Here, we assessed the functional relationship between Notch and ACD in mouse T cell development. To attain immunological specificity, developing T cells must pass through a pivotal stage termed ß-selection, which involves Notch signalling and ACD. We assessed functional interactions between Notch1 and ACD during ß-selection through direct presentation of Notch ligands, DL1 and DL4, and pharmacological inhibition of Notch signalling. Contrary to prevailing models, we demonstrate that Notch signalling controls the distribution of Notch1 itself and cell fate determinants, α-adaptin and Numb. Furthermore, Notch and CXCR4 signalling cooperated to drive polarity during division. Thus, Notch signalling directly orchestrates ACD, and Notch1 is differentially inherited by sibling cells.This article has an associated First Person interview with the first author of the paper.
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División Celular Asimétrica , Proliferación Celular , Receptor Notch1/metabolismo , Linfocitos T/citología , Animales , Comunicación Celular , Muerte Celular , Diferenciación Celular , Línea Celular , Polaridad Celular , Células Cultivadas , Células Madre Hematopoyéticas/citología , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal , Linfocitos T/inmunologíaRESUMEN
Cyanophora is the glaucophyte model taxon. Following the sequencing of the nuclear genome of C. paradoxa, studies based on single organelle and nuclear molecular markers revealed previously unrecognized species diversity within this glaucophyte genus. Here, we present the complete plastid (ptDNA) and mitochondrial (mtDNA) genomes of C. kugrensii, C. sudae, and C. biloba. The respective sizes and coding capacities of both ptDNAs and mtDNAs are conserved among Cyanophora species with only minor differences due to specific gene duplications. Organelle phylogenomic analyses consistently recover the species C. kugrensii and C. paradoxa as a clade and C. sudae and C. biloba as a separate group. The phylogenetic affiliations of the four Cyanophora species are consistent with architectural similarities shared at the organelle genomic level. Genetic distance estimations from both organelle sequences are also consistent with phylogenetic and architecture evidence. Comparative analyses confirm that the Cyanophora mitochondrial genes accumulate substitutions at 3-fold higher rates than plastid counterparts, suggesting that mtDNA markers are more appropriate to investigate glaucophyte diversity and evolutionary events that occur at a population level. The study of complete organelle genomes is becoming the standard for species delimitation and is particularly relevant to study cryptic diversity in microbial groups.
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Cyanophora/genética , Evolución Molecular , Variación Genética , Genoma Mitocondrial , Genoma de Plastidios , Evolución Biológica , ADN Mitocondrial/análisisRESUMEN
OBJECTIVE: Poorer executive function (EF) has been linked to disinhibited eating in youth, suggesting poor EF predisposes toward obesity, yet the specific nature and extent of interconnections between facets of these domains is unclear. Network analysis provides a promising framework for elucidating the relationship between poor EF and disinhibited eating, and offers insights into potential maintenance processes. METHOD: Among youth ages 8-17 years, a regularized partial correlation network of EF and disinhibited eating facets was estimated to examine expected influence centrality and bridge expected influence. Computerized neurocognitive tasks assessed EF variables, including decision-making, general and food-related inhibitory control, delayed gratification, cognitive flexibility, and working memory. Disinhibited eating variables included total carbohydrate-fat intake at a laboratory test meal and self-reported eating in the absence of hunger, emotional eating, and loss-of-control eating severity. RESULTS: In the current sample (N = 248; Mage = 12.5; 54.8% female; 43.5% non-Hispanic White; 25.8% non-Hispanic Black; BMI %ile = 65.8 ± 27.8), emotional eating in response to depressive symptoms emerged as a central symptom in the network. Carbohydrate-fat intake had the highest bridge expected influence and was most strongly connected to general inhibitory control (part r = .14). DISCUSSION: The link between general inhibitory control and objective palatable food intake may be particularly salient in maintaining maladaptive eating behavior. Interventions targeting behavioral disinhibition may disrupt associations among a network of disinhibited eating facets in youth and should be targets for longitudinal research.
Asunto(s)
Función Ejecutiva , Conducta Alimentaria , Adolescente , Niño , Ingestión de Alimentos , Femenino , Humanos , Hambre , Masculino , ObesidadRESUMEN
OBJECTIVE: Among youth with overweight, food cravings (FC) are associated with loss-of-control (LOC)-eating, but the impact of sex-associated biological characteristics on this relationship is unknown. We examined whether sex and gonadal hormone concentrations moderated the relationships between FC and LOC-eating severity among healthy boys and girls across the weight strata in natural and laboratory environments. METHOD: Using ecological momentary assessment (EMA), FC, and LOC-eating severity were reported 3-5 times a day for 2 weeks. In the laboratory, participants reported FC, consumed lunch from a buffet test meal designed to simulate LOC-eating, and rated LOC-eating severity during the meal. RESULTS: Eighty-seven youth (13.0 ± 2.7 years, 58.6% female, 32.2% with overweight/obesity) participated. EMA measured general and momentary FC were positively associated with LOC-eating severity (ps < .01), with no differences by sex (ps = .21-.93). Estradiol and progesterone significantly moderated the relationships between FC and LOC-eating such that general FC and LOC-eating severity were only positively associated among girls with greater (vs. lower) estradiol (p = .01), and momentary FC and LOC-eating severity were only positively associated among girls with greater (vs. lower) progesterone (p = .01). Boys' testosterone did not significantly moderate the associations between FC and LOC-eating severity (ps = .36-.97). At the test meal, pre-meal FC were positively related to LOC-eating severity (p < .01), without sex or hormonal moderation (ps = .20-.64). DISCUSSION: FC were related to LOC-eating severity in boys and girls. In the natural environment, gonadal hormones moderated this relationship in girls, but not boys. The mechanisms through which gonadal hormones might affect the relationship between FC and LOC-eating warrant investigation.