Fisetin Attenuates Cellular Senescence Accumulation During Culture Expansion of Human Adipose-Derived Stem Cells.

Mesenchymal stem cells (MSCs) have long been viewed as a promising therapeutic for musculoskeletal repair. However, regulatory concerns including tumorgenicity, inconsistencies in preparation techniques, donor-to-donor variability, and the accumulation of senescence during culture expansion have hindered the clinical application of MSCs. Senescence is a driving mechanism for MSC dysfunction with advancing age. Often characterized by increased reactive oxygen species, senescence-associated heterochromatin foci, inflammatory cytokine secretion, and reduced proliferative capacity, senescence directly inhibits MSCs efficacy as a therapeutic for musculoskeletal regeneration. Furthermore, autologous delivery of senescent MSCs can further induce disease and aging progression through the secretion of the senescence-associated secretory phenotype (SASP) and mitigate the regenerative potential of MSCs. To alleviate these issues, the use of senolytic agents to selectively clear senescent cell populations has become popular. However, their benefits to attenuating senescence accumulation in human MSCs during the culture expansion process have not yet been elucidated. To address this, we analyzed markers of senescence during the expansion of human primary adipose-derived stem cells (ADSCs), a population of fat-resident MSCs commonly used in regenerative medicine applications. Next, we used the senolytic agent fisetin to determine if we can reduce these markers of senescence within our culture-expanded ADSC populations. Our results indicate that ADSCs acquire common markers of cellular senescence including increased reactive oxygen species, senescence-associated ß-galactosidase, and senescence-associated heterochromatin foci. Furthermore, we found that the senolytic agent fisetin works in a dose-dependent manner and selectively attenuates these markers of senescence while maintaining the differentiation potential of the expanded ADSCs.

Minimal Mechanisms of Microtubule Length Regulation in Living Cells.

The microtubule cytoskeleton is responsible for sustained, long-range intracellular transport of mRNAs, proteins, and organelles in neurons. Neuronal microtubules must be stable enough to ensure reliable transport, but they also undergo dynamic instability, as their plus and minus ends continuously switch between growth and shrinking. This process allows for continuous rebuilding of the cytoskeleton and for flexibility in injury settings. Motivated by in vivo experimental data on microtubule behavior in Drosophila neurons, we propose a mathematical model of dendritic microtubule dynamics, with a focus on understanding microtubule length, velocity, and state-duration distributions. We find that limitations on microtubule growth phases are needed for realistic dynamics, but the type of limiting mechanism leads to qualitatively different responses to plausible experimental perturbations. We therefore propose and investigate two minimally-complex length-limiting factors: limitation due to resource (tubulin) constraints and limitation due to catastrophe of large-length microtubules. We combine simulations of a detailed stochastic model with steady-state analysis of a mean-field ordinary differential equations model to map out qualitatively distinct parameter regimes. This provides a basis for predicting changes in microtubule dynamics, tubulin allocation, and the turnover rate of tubulin within microtubules in different experimental environments.

Medical authority and expectations of conformity: crystallising a key barrier to person-centred care during labour and childbirth.

Those giving birth within modern maternity systems are recognised as facing a number of barriers to person-centred care. In this paper, I argue that in order to best facilitate the conditions for positive change, work needs to be done to provide a more granular articulation of the specific barriers. I then offer a nuanced and contextually aware articulation of one key component of the overall failure to ensure person-centred care: medical authority and the expectation of conformity. Articulating these barriers with increased specificity is valuable, as it creates a stronger foundation from which to challenge existing problems which serve to constrain the autonomy of birthing individuals. The analysis offered in this paper also underscores the need for change at an institutional, rather than individual, level.

Pregnancy and assisted reproductive technology use in Australian female transfusion-dependent haemoglobinopathy patients: a 20-year retrospective analysis.

BACKGROUND: In the last few decades, the life expectancy of patients with transfusion-dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi-disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population. AIMS: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion-dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort. METHODS: A 20-year retrospective analysis (1997-2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion-dependent haemoglobinopathy patients. RESULTS: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post-partum haemorrhage. There were no cardiac complications. Two-thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths. CONCLUSION: Pregnancy is an achievable goal for women with transfusion-dependent haemoglobinopathies, although the support of ART may be required in a subset of patients.

Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

BACKGROUND: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Racial/Ethnic Disparities Impact the Real-World Effectiveness of a Multicomponent Maternal Smoking Cessation Program: Findings from the CTTP Cohort.

INTRODUCTION: Smoking during pregnancy adversely affects perinatal outcomes for both women and infants. We conducted a retrospective cohort study of the state-funded Comprehensive Tobacco Treatment Program (CTTP) - the largest maternal tobacco cessation program in San Bernardino County, California - to determine the real-world program effectiveness and to identify variables that can potentially improve effectiveness. METHODS: During 2012-2019, women who smoked during pregnancy were enrolled in CTTP's multicomponent behavioral smoking cessation program that implemented components of known efficacy (i.e., incentives, biomarker testing, feedback, and motivational interviewing). RESULTS: We found that 40.1% achieved prolonged abstinence by achieving weekly, cotinine-verified, 7-day abstinence during 6 to 8 weeks of enrollment. Using intention-to-treat analyses, we computed that the self-reported point prevalence abstinence rate (PPA) at the six-month telephone follow-up was 36.7%. Cohort members achieving prolonged abstinence during the CTTP were five times more likely to achieve PPA six months after CTTP. Several non-Hispanic ethnicities (Black, Native American, White, or More than one ethnicity) in the cohort were two-fold less likely (relative to Hispanics) to achieve prolonged abstinence during CTTP or PPA at six months after CTTP. This disparity was further investigated in mediation analysis. Variables such as quitting during the first trimester and smoking fewer cigarettes at enrollment were also associated with achieving PPA at six months. DISCUSSION: Racial/ethnic health disparities that have long been linked to a higher rate of maternal smoking persist even when the pregnant smoker enrolls in a smoking cessation program.

The effects of fisetin on bone and cartilage: A systematic review.

As the worldwide population progresses in age, there is an increasing need for effective treatments for age-associated musculoskeletal conditions such as osteoporosis and osteoarthritis (OA). Fisetin, a natural flavonoid, has garnered attention as a promising pharmaceutical option for treating or delaying the progression of osteoporosis and OA. However, there is no systematic review of the effects of fisetin on bone and cartilage. The aim of this review is to report the latest evidence on the effects of fisetin on bone and cartilage, with a focus on clinical significance. The PubMed, Embase, and Cochrane Library databases were searched up to December 9th 2021 to evaluate the effects of fisetin on bone and cartilage in in vitro studies and in vivo preclinical animal studies. The risk of bias, quality, study design, sample characteristics, dose and duration of fisetin treatment, and outcomes of the 13 eligible studies were analyzed in this systematic review. Qualitative evaluation was conducted for each study due to differences in animal species, cell type, created disease model, dose and duration of fisetin treatment, and time between intervention and assessment among the eligible studies. The beneficial effects of fisetin on osteoporosis have been demonstrated in in vitro and in vivo preclinical studies across animal species. Similarly, the beneficial effects of fisetin on OA have been demonstrated in in vivo preclinical animal studies, but the reports on OA are still limited. Fisetin, a natural supplement can be use in orthobiologics treatment, as adjuvant to orthopaedic surgery, to improve clinical outcome.

The Medicalisation of Childbirth and Access to homebirth in the UK: Covid-19 and Beyond.

In this article, we explore how the law has perpetuated the medicalisation of childbirth, and outline why this may limit the ability of birthing persons to access and opt for homebirth. We argue that this is inherently problematic because it restricts choice and autonomy in childbirth. We suggest that the widespread blanket withdrawals of homebirthing services by National Health Service trusts during the Coronavirus (COVID-19) pandemic serves as an illustrative example of the broader failure to recognise, both socially and legally, the significance of homebirth for some. We argue that, if framed correctly, the law has the potential to support, rather than restrict, choice regarding place of birth.

Vaginal Examinations During Childbirth: Consent, Coercion and COVID-19.

In this paper I assess the labour ward admission policies introduced by some National Health Service (NHS) trusts during the COVID-19 pandemic, arguing that these intersected with other policies in a manner which may have coerced birthing people into consenting to vaginal examinations they might have otherwise refused. In order to fully understand the potential severity of these policies, I situate this critique in the historical and contemporary context of the problematic relationship between consent and vaginal examinations. Identifying the legal wrongs associated with performing coerced vaginal examinations, I highlight that the law is inadequately equipped to provide appropriate redress. Further, I illustrate that the issue explored in this paper reflects broader problems which exist with regard to the focus of, and the (under)investment in, the maternity services.

Maternal request caesareans and COVID-19: the virus does not diminish the importance of choice in childbirth.

It has recently been reported that some hospitals in the UK have placed a blanket restriction on the provision of maternal request caesarean sections (MRCS) as a result of the COVID-19 pandemic. Pregnancy and birthing services are obviously facing challenges during the current emergency, but we argue that a blanket ban on MRCS is both inappropriate and disproportionate. In this paper, we highlight the importance of MRCS for pregnant people's health and autonomy in childbirth and argue that this remains crucial during the current emergency. We consider some potential arguments-based on pregnant people's health and resource allocation-that might be considered justification for the limitation of such services. We demonstrate, however, that these arguments are not as persuasive as they might appear because there is limited evidence to indicate either that provision of MRCS is always dangerous for pregnant people in the circumstances or would be a substantial burden on a hospital's ability to respond to the pandemic. Furthermore, we argue that even if MRCS was not a service that hospitals are equipped to offer to all pregnant persons who seek it, the current circumstances cannot justify a blanket ban on an important service and due attention must be paid to individual circumstances.

Contributions of Public Health Social Work Students to Their Professions and Communities.

In the contemporary public health workforce environment, public health social workers (PHSW) bring integrated skills, from both fields, to meet the needs of vulnerable and underserved populations. They receive training in their Master of Public Health/Master of Social Work dual-degree programs, such as the one at New Mexico State University, which serves the U.S./Mexico border region. During their studies, dual-degree students are equipped to address health and human service issues at the micro, mezzo, and macro levels and complete field experience and practicum hours in their communities. Along with practical skills, these students learn culturally responsive/humble ways of being with communities of color and marginalized individuals. After graduation, these emerging career PHSWs enter the workforce in a variety of settings: nonprofit, educational, government, primary care, and more. In this article, the field of public health social work is described in its historic and present forms, followed by PHSWs' utility to the U.S./Mexico border region, in particular. Finally, we make the call to action for future career PHSWs to engage with this integrated, dynamic, innovative field, and its unique combination of community- and individual-based services and rewards.

Patient and Community Health Worker Perceptions of Community Health Worker Clinical Integration.

Traditional community health workers (CHWs) are expanding their role into clinical settings (cCHW) to support patients with care coordination and advocacy services. We investigated the potential to integrate cCHWs, via evaluation of patients' and CHWs' key demographics, needs, and abilities. This mixed-methods study, including adult patients and CHWs, was conducted in the Inland Valley of Southern California, between 2016 and 2017. Survey data, key informant interviews, and focus group discussions were evaluated to compare patient/CHW core demographics, and contrast patient-identified healthcare needs against CHW-identified cCHW service capabilities. Quantitative data were evaluated descriptively and bi-variably using two-sample independent t tests and Pearson's Chi square tests. Qualitative data were coded for emerging themes using a priori and standard grounded theory methods. Patients and CHWs were significantly similar in age, education, and income, but significantly differed in gender, race, United States generation, and marital status. For all healthcare-related services in which patients and CHWs exhibited significant differences, the odds CHWs perceived themselves capable of performing services were greater than patients' stated need of services. Patients and CHWs overlapped regarding their expectations of cCHWs. Although patients and CHWs differed somewhat, they shared many of the same expectations for cCHW integration. This information is critical to further contextualize cCHW training programs and emphasizes the need to education patients about this exciting new form of healthcare delivery. The active role of cCHWs in the clinical care team and the community may expand patient access to preventive healthcare, improve care quality, and minimize health inequities.

Three new silver uranyl diphosphonates: structures and properties.

The hydrothermal reaction of uranium trioxide and methylenediphosphonic acid in the presence of silver nitrate resulted in the formation of three new uranyl coordination polymers: AgUO2[CH2(PO3)(PO3H)] (Ag-1), [Ag2(H2O)1.5]{(UO2)2[CH2(PO3)2]F2}·(H2O)0.5 (Ag-2), and Ag2UO2[CH2(PO3)2] (Ag-3). All consist of uranyl pentagonal bipyramids that form two-dimensional layered structures. Ag-1 and Ag-3 possess the same structural building unit, but the structures are different; Ag-3 is formed through edge-sharing of F atoms to form UO5F2 dimers. The pH and silver cation have significant effects on the structure that is synthesized. Raman spectra of single crystals of Ag-1, Ag-2, and Ag-3 reveal v1 UO2(2+) symmetric stretches of 816 and 829, 822, and 802 cm(-1), respectively. Electronic structure calculations were performed using the projector augmented wave (PAW) method with density functional theory (DFT) to gain insight into the nature of bonding and electronic characteristics of the synthesized compounds. Herein, we report the syntheses, crystal structures, Raman spectroscopy, and luminescent behavior of these three compounds.

Minimal Mechanisms of Microtubule Length Regulation in Living Cells.

The microtubule cytoskeleton is responsible for sustained, long-range intracellular transport of mRNAs, proteins, and organelles in neurons. Neuronal microtubules must be stable enough to ensure reliable transport, but they also undergo dynamic instability, as their plus and minus ends continuously switch between growth and shrinking. This process allows for continuous rebuilding of the cytoskeleton and for flexibility in injury settings. Motivated by in vivo experimental data on microtubule behavior in Drosophila neurons, we propose a mathematical model of dendritic microtubule dynamics, with a focus on understanding microtubule length, velocity, and state-duration distributions. We find that limitations on microtubule growth phases are needed for realistic dynamics, but the type of limiting mechanism leads to qualitatively different responses to plausible experimental perturbations. We therefore propose and investigate two minimally-complex length-limiting factors: limitation due to resource (tubulin) constraints and limitation due to catastrophe of large-length microtubules. We combine simulations of a detailed stochastic model with steady-state analysis of a mean-field ordinary differential equations model to map out qualitatively distinct parameter regimes. This provides a basis for predicting changes in microtubule dynamics, tubulin allocation, and the turnover rate of tubulin within microtubules in different experimental environments.

Death and the artificial placenta.

Artificial Amnion and Placenta Technology (AAPT)-sometimes referred to as 'Artificial Womb Technology'-could provide an extracorporeal alternative to bodily gestations, allowing a fetus delivered prematurely from the human uterus to continue development while maintaining fetal physiology. As AAPT moves nearer to being used in humans, important ethical and legal questions remain unanswered. In this paper, we explore how the death of the entity sustained by AAPT would be characterized in law. This question matters, as legal ambiguity in this area has the potential to compound uncertainty and the suffering of newly bereaved parent(s). We first identify the existing criteria used to delineate the legal characterization of death, which occurs before birth or during the immediate neonatal period in England and Wales. We then demonstrate that attempting to apply these in the context of AAPT gives rise to a number of challenges, which make it impossible to reach a definitive conclusion as to the nature of death in AAPT using the current legal framework. In doing so, we demonstrate that the current legal framework in England and Wales may be unable to adequately capture the situation of an entity being sustained by AAPT.

Ending the HIV Epidemic in Black America: Qualitative Insights Following COVID-19.

BACKGROUND: The disproportionate effects of the human immunodeficiency virus (HIV) and the Coronavirus 2019 (COVID-19) on Black American communities highlight structural systems rooted in racism and must be addressed with national strategies that improve both biomedicine and social determinants of health. PURPOSE: The purpose of this study was to qualitatively examine the experiences and interpretations of experts in the HIV workforce (local, state, and national HIV-related organizations) regarding the state of HIV and COVID-19 among Black Americans. METHODS: Within key informant interviews and a focus group recorded and transcribed verbatim, fifteen members of the HIV workforce and Black community described their experiences and provided insights to inform ending the negative outcomes resulting from HIV and COVID-19. RESULTS: Data were analyzed using NVivo software, and eight themes emerged to address disease disproportionality through a Black lens. Themes reflected (1) accessing information and care; (2) key potential partners/stakeholders; (3) investing in Black communities; (4) governmental support; (5) increasing engagement and advocacy; (6) HIV-related community conversations; (7) developments since COVID-19; and (8) the Ending the HIV Epidemic (EHE) trajectory. CONCLUSIONS: Themes directly speak to recommendations to adjust education and policy strategies for HIV and COVID-19 prevention and intervention. Such recommendations, (1) amplifying Black voices, (2) investing sustainable dollars into Black communities, and (3) leaning into advocacy, can bolster the foundation for the HIV workforce and Black community to break ineffective response patterns and lead the fight against these systemic issues of inequity.

Applying Digital Health in Cancer and Palliative Care in Europe: Policy Recommendations from an International Expert Workshop (MyPal Project).

Background: Digital health interventions are becoming increasingly important for adults, children, and young people with cancer and palliative care needs, but there is little research to guide policy and practice. Objectives: To identify recommendations for policy development of digital health interventions in cancer and palliative care. Design: Expert elicitation workshop. Setting: European clinical (cancer and palliative care, adult and pediatric), policy, technical, and research experts attended a one-day workshop in London, England, in October 2022, along with MyPal research consortium members. Methods: As part of the European Commission-funded MyPal project, we elicited experts' views on global, national, and institutional policies within structured facilitated groups, and conducted qualitative analysis on these discussions. Results/Implementation: Thirty-two experts from eight countries attended. Key policy drivers and levers in digital health were highlighted. Global level: global technology regulation, definitions, access to information technology, standardizing citizens' rights and data safety, digital infrastructure and implementation guidance, and incorporation of technology into existing health systems. National level: country-specific policy, compatibility of health apps, access to digital infrastructure including vulnerable groups and settings, development of guidelines, and promoting digital literacy. Institutional level: undertaking a needs assessment of service users and clinicians, identifying best practice guidelines, providing education and training for clinicians on digital health and safe digital data sharing, implementing plans to minimize barriers to accessing digital health care, minimizing bureaucracy, and providing technical support. Conclusions: Developers and regulators of digital health interventions may find the identified recommendations useful in guiding policy making and future research initiatives. MyPal child study Clinical Trial Registration NCT04381221; MyPal adult study Clinical Trial Registration NCT04370457.