Group Model Building on causes and interventions for falls in Singapore: insights from a systems thinking approach.

BACKGROUND: Falls in older adults are the result of a complex web of interacting causes, that further results in other physical, emotional, and psychological sequelae. A conceptual framework that represents the reciprocal dynamics of these causal factors can enable clinicians, researchers, and policymakers to clarify goals in falls intervention in older adults. METHODS: A Group Model Building (GMB) exercise was conducted with researchers and clinicians from academic units and public healthcare institutes in Singapore. The aim of the exercise was to produce a shared visual representation of the causal structure for falls and engage in discussions on how current and future falls intervention programmes can address falls in the older adults, especially in the Asian context. It was conducted in four steps: 1) Outlining and prioritising desirable patient outcomes, 2) Conceptual model building, 3) Identifying key intervention elements of effective falls intervention programmes, 4) Mapping of interventions to outcomes. This causal loop diagram (CLD) was then used to generate insights into the current understanding of falls causal relationships, current efforts in falls intervention in Singapore, and used to identify gaps in falls research that could be further advanced in future intervention studies. RESULTS: Four patient outcomes were identified by the group as key in falls intervention: 1) Falls, 2) Injurious falls, 3) Fear of falling, and 4) Restricted mobility and life space. A CLD of the reciprocal relationships between risk factors and these outcomes are represented in four sub-models: 1) Fear of falling, 2) Injuries associated with falls, 3) Caregiver overprotectiveness, 4) Post-traumatic stress disorder and psychological resilience. Through this GMB exercise, the group gained the following insights: (1) Psychological sequelae of falls is an important falls intervention outcome. (2) The effects of family overprotectiveness, psychological resilience, and PTSD in exacerbating the consequences of falls are not well understood. (3) There is a need to develop multi-component falls interventions to address the multitude of falls and falls related sequelae. CONCLUSION: This work illustrates the potential of GMB to promote shared understanding of complex healthcare problems and to provide a roadmap for the development of more effective preventive actions.

Developing integration among stakeholders in the primary care networks of Singapore: a qualitative study.

BACKGROUND: Integrating healthcare services across and between the different health system levels can be achieved in a few ways; however, examining the social side of integration is essential and challenging. This paper explores the concept of integration perceived by general practitioners (GPs) and primary care network (PCN) representatives from the regional health systems (RHS) in a GP-RHS PCN and their perceived partnership success. METHODS: In this study, we explored three GP-RHS PCNs in Singapore. We used a qualitative research design and, overall, performed 17 semi-structured in-depth interviews with GPs (n = 11) and PCN representatives (n = 6) from the RHS. All interviews were audiotaped and transcribed verbatim. We conducted thematic analysis to inductively identify themes from the data. Singer's conceptual model of integration types was used as guiding principles to derive relevant and salient themes for integration. RESULTS: GPs and the RHS perceived the concept of integration through a series of interrelated strategies. Within the normative dimension, a sense of urgency motivated GPs to integrate improvements into their general practice. Participants perceived teamwork and relational climate as appropriate enablers for achieving interpersonal integration in a primary care partnership. While developing a trusted relationship was a perceived success of this partnership across the network, developing camaraderie and gaining knowledge in chronic disease management through the components of functional integration was a perceived success at an individual general practice level. The data also revealed some operational challenges within the structural dimension and some inabilities of the PCN to achieve complete process integration. CONCLUSIONS: Our study points to multi-faceted integration, comprising various forms that need to be manifested at all levels of care to achieve coordinated, seamless, and comprehensive care for patients suffering from chronic conditions. The present iteration of the PCN has been shown to offer integration at a level that warrants praise but still requires structural and process integration improvement.

Developing a toolkit for implementing evidence-based guidelines to manage hypertension and diabetes in Cambodia: a descriptive case study.

BACKGROUND: In Cambodia, economic development accompanied by health reforms has led to a rapidly ageing population and an increasing incidence and prevalence of noncommunicable diseases. National strategic plans recognize primary care health centres as the focal points of care for treating and managing chronic conditions, particularly hypertension and type 2 diabetes. However, health centres have limited experience in providing such services. This case study describes the process of developing a toolkit to facilitate the use of evidence-based guidelines to manage hypertension and type 2 diabetes at the health-centre level. METHODS: We developed and revised a preliminary toolkit based on the feedback received from key stakeholders. We gathered feedback through an iterative process of group and one-to-one consultations with representatives of the Ministry of Health, provincial health department, health centres and nongovernmental organizations between April 2019 and March 2021. RESULTS: A toolkit was developed and organized according to the core tasks required to treat and manage hypertension and type 2 diabetes patients. The main tools included patient identification and treatment cards, risk screening forms, a treatment flowchart, referral forms, and patient education material on risk factors and lifestyle recommendations on diet, exercise, and smoking cessation. The toolkit supplements existing guidelines by incorporating context-specific features, including drug availability and the types of medication and dosage guidelines recommended by the Ministry of Health. Referral forms can be extended to incorporate engagement with community health workers and patient education material adapted to the local context. All tools were translated into Khmer and can be modified as needed based on available resources and arrangements with other institutions. CONCLUSIONS: Our study demonstrates how a toolkit can be developed through iterative engagement with relevant stakeholders individually and in groups to support the implementation of evidence-based guidelines. Such toolkits can help strengthen the function and capacity of the primary care system to provide care for noncommunicable diseases, serving as the first step towards developing a more comprehensive and sustainable health system in the context of population ageing and caring for patients with chronic diseases.

Sequential Multiple Assignment Randomized Trial (SMART) to identify optimal sequences of telemedicine interventions for improving initiation of insulin therapy: A simulation study.

BACKGROUND: To examine the value of a Sequential Multiple Assignment Randomized Trial (SMART) design compared to a conventional randomized control trial (RCT) for telemedicine strategies to support titration of insulin therapy for Type 2 Diabetes Mellitus (T2DM) patients new to insulin. METHODS: Microsimulation models were created in R using a synthetic sample based on primary data from 63 subjects enrolled in a pilot study of a smartphone application (App), Diabetes Pal compared to a nurse-based telemedicine strategy (Nurse). For comparability, the SMART and an RCT design were constructed to allow comparison of four (embedded) adaptive interventions (AIs). RESULTS: In the base case scenario, the SMART has similar overall mean expected HbA1c and cost per subject compared with RCT, for sample size of n = 100 over 10,000 simulations. SMART has lower (better) standard deviations of the mean expected HbA1c per AI, and higher efficiency of choosing the correct AI across various sample sizes. The differences between SMART and RCT become apparent as sample size decreases. For both trial designs, the threshold value at which a subject was deemed to have been responsive at an intermediate point in the trial had an optimal choice (i.e., the sensitivity curve had a U-shape). SMART design dominates the RCT, in the overall mean HbA1c (lower value) when the threshold value is close to optimal. CONCLUSIONS: SMART is suited to evaluating the efficacy of different sequences of treatment options, in addition to the advantage of providing information on optimal treatment sequences.

Trends in functional disability and cognitive impairment among the older adult in China up to 2060: estimates from a dynamic multi-state population model.

BACKGROUND: Available evidence suggests that cognitive impairment (CI), which leads to deficits in episodic memory, executive functions, visual attention, and language, is associated with difficulties in the capacity to perform activities of daily living. Hence any forecast of the future prevalence of functional disability should account for the likely impact of cognitive impairment on the onset of functional disability. Thus, this research aims to address this gap in literature by projecting the number of older adults in China with functional disability and cognitive impairment while accounting for the impact of cognitive impairment on the onset of functional disability. METHODS: We developed and validated a dynamic multi-state population model which simulates the population of China and tracks the transition of Chinese older adults (65 years and older) from 2010 to 2060, to and from six health states-(i) active older adults without cognitive impairment, (ii) active older adults with cognitive impairment, (iii) older adults with 1 to 2 ADL limitations, (iv) older adults with cognitive impairment and 1 to 2 ADL limitations, (v) older adults with 3 or more ADL limitations, and (vi) older adults with cognitive impairment and 3 or more ADL limitations. RESULTS: From 2015 to 2060, the number of older adults 65 years and older in China is projected to increase, of which the number with impairment (herein referred to as individuals with cognitive impairment and/or activity of daily living limitations) is projected to increase more than fourfold from 17·9 million (17·8-18·0) million in 2015 to 96·2 (95·3-97·1) million by 2060. Among the older adults with impairment, those with ADL limitations only is projected to increase from 3·7 million (3·6-3·7 million) in 2015 to 23·9 million (23·4-24·6 million) by 2060, with an estimated annual increase of 12·2% (12·1-12·3); while that for cognitive impairment only is estimated to increase from 11·4 million (11·3-11·5 million) in 2015 to 47·8 million (47·5-48·2 million) by 2060-this representing an annual growth of 7·07% (7·05-7·09). CONCLUSION: Our findings suggest there will be an increase in demand for intermediate and long-term care services among the older adults with functional disability and cognitive impairment.

Coronavirus disease 2019 (COVID-19): an evidence map of medical literature.

BACKGROUND: Since the beginning of the COVID-19 outbreak in December 2019, a substantial body of COVID-19 medical literature has been generated. As of June 2020, gaps and longitudinal trends in the COVID-19 medical literature remain unidentified, despite potential benefits for research prioritisation and policy setting in both the COVID-19 pandemic and future large-scale public health crises. METHODS: In this paper, we searched PubMed and Embase for medical literature on COVID-19 between 1 January and 24 March 2020. We characterised the growth of the early COVID-19 medical literature using evidence maps and bibliometric analyses to elicit cross-sectional and longitudinal trends and systematically identify gaps. RESULTS: The early COVID-19 medical literature originated primarily from Asia and focused mainly on clinical features and diagnosis of the disease. Many areas of potential research remain underexplored, such as mental health, the use of novel technologies and artificial intelligence, pathophysiology of COVID-19 within different body systems, and indirect effects of COVID-19 on the care of non-COVID-19 patients. Few articles involved research collaboration at the international level (24.7%). The median submission-to-publication duration was 8 days (interquartile range: 4-16). CONCLUSIONS: Although in its early phase, COVID-19 research has generated a large volume of publications. However, there are still knowledge gaps yet to be filled and areas for improvement for the global research community. Our analysis of early COVID-19 research may be valuable in informing research prioritisation and policy planning both in the current COVID-19 pandemic and similar global health crises.

Impact of sugar-sweetened beverage tax on dental caries: a simulation analysis.

BACKGROUND: The tiered sugar-sweetened beverage (SSB) tax was implemented in Thailand to encourage industries to reduce sugar content in beverages, and consequently reduce sugar consumption in the population. The aim of the study is to explore the expected impact of the new SSB tax policy in Thailand, a middle-income country in Asia, and other alternative policies on oral health outcomes as measured by the prevalence and severity of dental caries among the Thai population. METHODS: A qualitative system dynamics model that captures the complex interrelationships among SSB tax, sugar consumption and dental caries, was elicited through participatory stakeholder engagement. Based on the qualitative model, a quantitative system dynamics model was developed to simulate the SSB tax policy and other alternative scenarios in order to evaluate their impact on dental caries among Thai adults from 2010 to 2040. RESULTS: Under the base-case scenario, the dental caries prevalence among the Thai population 15 years and older, is projected to increase from 61.3% in 2010 to 74.9% by 2040. Implementation of SSB tax policy is expected to decrease the prevalence of dental caries by only 1% by 2040, whereas the aggressive policy is projected to decrease prevalence of dental caries by 21% by 2040. CONCLUSIONS: In countries where a majority of the sugar consumed is from non-tax sugary food and beverages, especially Asian countries where street food culture is ubiquitous and contributes disproportionately to sugar intake, SSB tax alone is unlikely to have meaningful impact on oral health unless it is accompanied with a comprehensive public health policy that aims to reduce total sugar intake from non-SSB sources.

An evaluation of the impact of aggressive hypertension, diabetes and smoking cessation management on CVD outcomes at the population level: a dynamic simulation analysis.

BACKGROUND: Evidence from randomized control trials suggest that coupled with smoking cessation interventions, CVD events can be reduced significantly if hypertension and diabetes patients are properly managed, raising practical what-if questions at the population level. This research aims to develop a dynamic simulation model using the systems modelling methodology of system dynamics, to evaluate the medium to long-term impact of hypertension and diabetes management, as well as smoking cessation intervention on CVD events, CVD deaths and post-CVD population. METHODS: The systems modelling methodology of system dynamics was used to develop a simulation model to evaluate the impact of aggressive hypertension, diabetes and smoking cessation management on CVD outcomes at the population level. RESULT: The insights from this research suggest that despite that at the individual level, hypertension management is associated with the highest risk reduction for CVD (50%) compared to diabetes and smoking (20%) and is also the most prevalent risk factor, at the population level, diabetes management interventions are projected to have higher impact on reducing CVD events compared to hypertension management or smoking cessation interventions. However, a combined intervention of diabetes and hypertension management, as well as smoking cessation has the most impact on CVD outcomes. CONCLUSION: Due to aging population and the increasing prevalence of chronic conditions in Singapore, the number of CVD events in Singapore is projected to rise significantly in the near future-hence the need for proactive planning to implement needed interventions. Findings from this research suggest that CVD events and its associated deaths and disabilities could be reduced significantly if diabetes and hypertension patients are aggressively managed.

Systems modelling as an approach for understanding and building consensus on non-communicable diseases (NCD) management in Cambodia.

BACKGROUND: This paper aims to demonstrate how systems modeling methodology of Group Model Building (GMD) can be applied for exploring and reaching consensus on non-communicable disease (NCD) management. This exercise was undertaken as a first step for developing a quantitative simulation model for generating credible estimates to make an investment case for the prevention and management of NCDs. METHODS: Stakeholder engagement was facilitated through the use of a Group Model Building (GMB) approach. This approach combines various techniques in order to gain a whole system perspective. RESULTS: A conceptual qualitative model framework that connects prevention-via risk factors reduction-screening and treatment of non-communicable diseases (NCDs) was developed with stakeholders that draws on stakeholders personal experiences, beliefs, and perceptions through a moderated interactions to gain in-depth understanding of NCDs management. CONCLUSION: Managing NCDs in Cambodia will require concerted effort to tackle NCD risk factors, identifying individuals with NCDs through screening and providing adequate and affordable consistent care to improve health and outcomes of NCDs.

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death.

Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested that TIR-199 covalently binds each of the three catalytic subunits (ß1, ß2, and ß5) and revealed key interaction sites. In vitro and cell culture-based proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney tumor cell lines, with >250-fold higher anti-tumor activities than observed with the natural product syringolin A. In vivo studies in mice revealed a maximum tolerated dose of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.

Projecting the effects of long-term care policy on the labor market participation of primary informal family caregivers of elderly with disability: insights from a dynamic simulation model.

BACKGROUND: Using Singapore as a case study, this paper aims to understand the effects of the current long-term care policy and various alternative policy options on the labor market participation of primary informal family caregivers of elderly with disability. METHODS: A model of the long-term care system in Singapore was developed using System Dynamics methodology. RESULTS: Under the current long-term care policy, by 2030, 6.9 percent of primary informal family caregivers (0.34 percent of the domestic labor supply) are expected to withdraw from the labor market. Alternative policy options reduce primary informal family caregiver labor market withdrawal; however, the number of workers required to scale up long-term care services is greater than the number of caregivers who can be expected to return to the labor market. CONCLUSIONS: Policymakers may face a dilemma between admitting more foreign workers to provide long-term care services and depending on primary informal family caregivers.

Future requirements for and supply of ophthalmologists for an aging population in Singapore.

BACKGROUND: Singapore's population, as that of many other countries, is aging; this is likely to lead to an increase in eye diseases and the demand for eye care. Since ophthalmologist training is long and expensive, early planning is essential. This paper forecasts workforce and training requirements for Singapore up to the year 2040 under several plausible future scenarios. METHODS: The Singapore Eye Care Workforce Model was created as a continuous time compartment model with explicit workforce stocks using system dynamics. The model has three modules: prevalence of eye disease, demand, and workforce requirements. The model is used to simulate the prevalence of eye diseases, patient visits, and workforce requirements for the public sector under different scenarios in order to determine training requirements. RESULTS: Four scenarios were constructed. Under the baseline business-as-usual scenario, the required number of ophthalmologists is projected to increase by 117% from 2015 to 2040. Under the current policy scenario (assuming an increase of service uptake due to increased awareness, availability, and accessibility of eye care services), the increase will be 175%, while under the new model of care scenario (considering the additional effect of providing some services by non-ophthalmologists) the increase will only be 150%. The moderated workload scenario (assuming in addition a reduction of the clinical workload) projects an increase in the required number of ophthalmologists of 192% by 2040. Considering the uncertainties in the projected demand for eye care services, under the business-as-usual scenario, a residency intake of 8-22 residents per year is required, 17-21 under the current policy scenario, 14-18 under the new model of care scenario, and, under the moderated workload scenario, an intake of 18-23 residents per year is required. CONCLUSIONS: The results show that under all scenarios considered, Singapore's aging and growing population will result in an almost doubling of the number of Singaporeans with eye conditions, a significant increase in public sector eye care demand and, consequently, a greater requirement for ophthalmologists.

Preferences for Enhanced Primary Care Services Among Older Individuals and Primary Care Physicians.

OBJECTIVE: We aimed to identify the factors that are most important for community-dwelling older individuals (i.e., users) and primary care (PC) providers to enhance PC services. METHODS: Discrete choice experiment surveys were administered to 747 individuals aged ≥ 60 years and 242 PC physicians in Singapore between December 2020 and August 2021. Participants were asked to choose between two hypothetical PC clinics and their current clinic. Latent class models were used to estimate the relative attribute importance (RAI) and to calculate the predicted uptake for enhanced PC services. RESULTS: Based on the attributes and levels used in this study, the out-of-pocket cost (RAI: 47%) and types of services offered (RAI: 25%) were the most important attributes for users while working hours (RAI: 28%) and patient load (RAI: 25%) were the most important for providers. For out-of-pocket visit costs ranging from Singapore dollars (S)$100 to S$5, users' predicted uptake for enhanced PC services ranged from 46 to 84%. For daily patient loads ranging from 60 to 20 patients, providers' predicted uptake ranged from 64 to 91%, assuming their income remains unchanged. CONCLUSIONS: Our study provides timely insights for the development of strategies to support the government's new health care initiative (HealthierSG), which places PC at the center of Singapore's healthcare system. The ability to choose their preferred clinic, low out-of-pocket costs and types of services offered (for users), and reasonable working conditions (for providers) were the key factors for users and providers to participate in enhanced PC services.

Projecting the burden of dental caries and periodontal diseases among the adult population in the United Kingdom using a multi-state population model.

Objectives: With the aging United Kingdom population, oral diseases are expected to increase. Exploring credible projections is fundamental to understanding the likely impact of emerging population-level interventions on oral disease burden. This study aims at providing a credible, evidence-based projection of the adult population in the United Kingdom with dental caries and periodontal diseases. Methods: We developed a multi-state population model using system dynamics that disaggregates the adult population in the United Kingdom into different oral health states. The caries population was divided into three states: no caries, treated caries, and untreated caries. The periodontal disease population was disaggregated into no periodontal disease, pocketing between 4 and < 6 mm, 6 and < 9 mm, and 9 mm or more. Data from the 2009 dental health survey in the United Kingdom was used to estimate age and gender-specific prevalence rates as input to the multi-state population model. Results: Of the population 16 years and older, the number with carious teeth is projected to decrease from 15.742 million in the year 2020 to 15.504 million by the year 2050, representing a decrease of 1.5%. For individuals with carious teeth, the older adult population is estimated to constitute 62.06% by 2050 and is projected to increase 89.4% from 5.079 million in 2020 to 9.623 million by 2050. The adult population with periodontal pocketing is estimated to increase from 25.751 million in 2020 to 27.980 million by 2050, while those with periodontal loss of attachment are projected to increase from 18.667 million in 2020 to 20.898 million by 2050. The burden of carious teeth and periodontal diseases is anticipated to shift from the adult population (16-59 years) to the older adult population. The older adult population with carious teeth is estimated to rise from 32.26% in 2020 to 62.06% by 2050, while that for periodontal disease is expected to increase from 42.44% in 2020 to 54.57% by 2050. Conclusion: This model provides evidence-based plausible future demand for oral health conditions, allowing policymakers to plan for oral health capacity to address growing needs. Because of the significant delay involved in educating and training oral health personnel, such projections offer policymakers the opportunity to be proactive in planning for future capacity needs instead of being reactive.

A Causal View of the Role and Potential Limitations of Capitation in Promoting Whole Health System Performance.

For several decades, health systems in developed countries have faced rapidly rising healthcare costs without concomitant improvements in health outcomes. Fee for service (FFS) reimbursement mechanisms (RMs), where health systems are paid based on volume, contribute to this trend. In Singapore, the public health service is trying to curb rising healthcare costs by transitioning from a volume-based RM to a capitated payment for a population within a geographical catchment area. To provide insight into the implications of this transition, we developed a causal loop diagram (CLD) to represent a causal hypothesis of the complex relationship between RM and health system performance. The CLD was developed with input from government policymakers, healthcare institution administrators, and healthcare providers. This work highlights that the causal relationships between government, provider organizations, and physicians involve numerous feedback loops that drive the mix of health services. The CLD clarifies that a FFS RM incentivizes high margin services irrespective of their health benefits. While capitation has the potential to mitigate this reinforcing phenomenon, it is not sufficient to promote service value. This suggests the need to establish robust mechanisms to govern common pool resources while minimizing adverse secondary effects.

Effects of COVID-19 on coastal livelihoods in the central region of Ghana.

The COVID-19 outbreak effects and related state responses, especially mobility restriction interventions, contributed to disruption in livelihoods in the coastal communities in Ghana. This paper uses an ethnographic approach to analyse the effects of the COVID-19 pandemic and coping strategies adopted by small-scale fishers, fish traders and processors. We argued that focusing solely on the livelihoods of formal sector workers is problematic because it fails to consider the dynamics of informal coastal workers. Findings indicate that fishers, fish traders and processors experienced various effects on food, income, police harassment, and coping strategies, including migration, resorting to reusable face masks and food-compromising practices. Infectious diseases such as COVID-19 impact coastal people and their livelihoods. Therefore, implementing social protection measures to mitigate the effects of pandemics on livelihoods should be better coordinated and well-targeted to reach the most vulnerable. Findings from this study offer pointers to position preparedness and response efforts to future outbreaks in a similar context.

Systems modelling as an approach for eliciting the mechanisms for hip fracture recovery among older adults in a participatory stakeholder engagement setting.

Introduction: Due to an aging population, the rising prevalence and incidence of hip fractures and the associated health and economic burden present a challenge to healthcare systems worldwide. Studies have shown that a complex interplay of physiological, psychological, and social factors often affects the recovery trajectories of older adults with hip fractures, often complicating the recovery process. Methods: This research aims to actively engage stakeholders (including doctors, physiotherapists, hip fracture patients, and caregivers) using the systems modeling methodology of Group Model Building (GMB) to elicit the factors that promote or inhibit hip fracture recovery, incorporating a feedback perspective to inform system-wide interventions. Hip fracture stakeholder engagement was facilitated through the Group Model Building approach in a two-half-day workshop of 25 stakeholders. This approach combined different techniques to develop a comprehensive qualitative whole-system view model of the factors that promote or inhibit hip fracture recovery. Results: A conceptual, qualitative model of the dynamics of hip fracture recovery was developed that draws on stakeholders' personal experiences through a moderated interaction. Stakeholders identified four domains (i.e., expectation formation, rehabilitation, affordability/availability, and resilience building) that play a significant role in the hip fracture recovery journey.. Discussion: The insight that recovery of loss of function due to hip fracture is attributed to (a) the recognition of a gap between pre-fracture physical function and current physical function; and (b) the marshaling of psychological resilience to respond promptly to a physical functional loss via uptake of rehabilitation services is supported by findings and has several policy implications.

PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation with disease progression. Affymetrix microarray analysis was performed using 24 different neuroblastoma cell lines. Cell lines expressing low to intermediate levels of PEA15 were chosen for in vitro functional studies. The cell line results were verified by Affymetrix analysis of three different neuroblastic tumor types (total of 110 samples) PEA15 overexpression inhibited neuroblastoma migration in vitro. We verified that inhibition of motility required PEA15 interaction with its binding partners ERK and RSK2. Additionally, synthetic inhibitors of RSK2 suppressed integrin-dependent migration. PEA15 expression correlates with clinical parameters and a 25% increase in patient survival rate. The highest PEA15 levels were found in low stage, more differentiated and less metastatic neuroblastic tumors, and correlated with lack of MYCN amplification. PEA15 blocks neuroblastoma migration through inhibition of ERK/RSK2 signaling. PEA15 expression levels correlate with favorable clinical features suggesting that PEA15 limits metastatic progression of neuroblastoma. Thus, PEA15 and its partners ERK and RSK2 are potential targets for the development of new therapeutics to impede progression of minimal residual disease in patients with high-risk neuroblastoma.

Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases.

Expression of E-cadherin is used to monitor the epithelial phenotype, and its loss is suggestive of epithelial-mesenchymal transition (EMT). EMT triggers tumor metastasis. Exit from EMT is marked by increased E-cadherin expression and is considered necessary for tumor growth at sites of metastasis; however, the mechanisms associated with exit from EMT are poorly understood. Herein are analyzed 185 prostate cancer metastases, with significantly higher E-cadherin expression in bone than in lymph node and soft tissue metastases. To determine the molecular mechanisms of regulation of E-cadherin expression, three stable isogenic cell lines from DU145 were derived that differ in structure, migration, and colony formation on soft agar and Matrigel. When injected into mouse tibia, the epithelial subline grows most aggressively, whereas the mesenchymal subline does not grow. In cultured cells, ZEB1 and Src family kinases decrease E-cadherin expression. In contrast, in tibial xenografts, E-cadherin RNA levels increase eight- to 10-fold despite persistent ZEB1 expression, and in all ZEB1-positive metastases (10 of 120), ZEB1 and E-cadherin proteins were co-expressed. These data suggest that transcriptional regulation of E-cadherin differs in cultured cells versus xenografts, which more faithfully reflect E-cadherin regulation in cancers in human beings. Furthermore, the aggressive nature of xenografts positive for E-cadherin and the frequency of metastases positive for E-cadherin suggest that high E-cadherin expression in metastatic prostate cancer is associated with aggressive tumor growth.

Syringolin B-inspired proteasome inhibitor analogue TIR-203 exhibits enhanced biological activity in multiple myeloma and neuroblastoma.

CONTEXT: The bacterium Pseudomonas syringae pv. syringae (Pss) is a pathogen of many plant species and causes, for example, brown spot disease in bean plants (Phaseolus vulgaris). Pss excretes the syringolins, natural product molecules that act as a virulence factors and inhibit the proteasome of the host plants. OBJECTIVE: Proteasome inhibitors belong to an important class of anticancer agents and bortezomib (Velcade(®)) has been Food and Drug Administration-approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma. Syringolins represent a new class of proteasome inhibitors and the present work was undertaken to design a potent syringolin-inspired analogue (TIR-203) for anticancer drug development. MATERIALS AND METHODS: TIR-203 was tested against human MM and neuroblastoma (NB) cells. Cancer cells were treated with TIR-203 at various concentrations (0-10 µM) and the cell viability was measured using the MTS assay. To determine the effects on proteasomal activities, the cell culture-based proteasome inhibition assay was used. Syringolin A (SylA) and bortezomib were included as controls. RESULTS: TIR-203 inhibited the cell proliferation of MM and NB cells in a dose-dependent manner at significantly lower concentrations than SylA. In MM cells, TIR-203 effectively inhibited the chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) activities of the proteasome. In NB cells, TIR-203 inhibited the CT-L and C-L activities, but not the T-L activity. DISCUSSION AND CONCLUSIONS: The newly designed proteasome inhibitor TIR-203 is more potent than the natural product SylA and strongly inhibits the cell viability and proteasomal activity of MM and NB cells.