Search

In light of the increasing life expectancy of Europe’s population and the rising significance of active and healthy ageing relating thereto, an integrated approach of nutritional care within primary health care is gaining importance. The aim of the review was to summarize evidence on the effectiveness of nutritional interventions in primary health care. The scoping review is based upon a comprehensive literature search of relevant literature published between January 2010 and August 2021 in PubMed, CINAHL, Cochrane Database of Systematic Reviews, Embase and Medline databases. Overall, 15 studies were included for evidence synthesis and interventions were basically clustered according to their type, into 1) eHealth and tele-medical interventions; 2) targeted single interventions; and 3) comprehensive, multi-faceted interventions. The review presents diverging evidence regarding the efficacy and effectiveness of interventions for nutritional care in primary health care, however, demonstrates encouraging outcomes. eHealth and tele-medical interventions partly show a careful positive tendency. Likewise, manifold single interventions on patient level present significant improvements in patient health outcomes. Multifaceted and comprehensive interventions found in the literature also partly demonstrate significant changes in intervention groups. Primary health care represents a critical setting for the care of older citizens and patients with complex health needs. This scoping review provides an overview of current nutrition care practices in primary health care and results reinforce the need to strengthen implementation of multi-faceted interventions carried out by the inter-disciplinary primary care team for advanced nutritional care.

Introduction: Rates of falls increase with ageing and age-related biological and functional changes. Most falls in later life occur as a result of a complex interaction between multiple intrinsic and environmental risk factors. Falls and falls-related injuries are major public health problems that often require healthcare intervention and rehabilitation (1) and recurrent falls are a frequent trigger for older people and their families seeking long term institutional care. Therefore, the prevention and management of falls has substantial relevance for integrated care systems. This study sought to obtain international insight into the implementation of pathways or programs addressing balance, mobility and/or falls prevention in primary care or community services.Methods: A survey template was created to include the key elements detected during a literature review conducted by MUG. The template included questions on screening, assessment, intervention components, target group, professionals involved and tools used for assessment and/or monitoring experience and outcomes. Members of IFIC’s international Special Interest Groups(SIGs) on Ageing and Frailty, Intermediate Care were invited to complete an online EU Survey tool available from 01.06-01.08.2021. Responses were analysed by two researchers and results considered by the co-authors in an online focus group. Results: 16 people from 11 countries completed the online survey. 9/16 reported fully implemented falls programs or care pathways in their region or country: UK (3), Ireland (1), Spain (1), Indonesia (1), Peru (1), Australia (1) and Northwest USA (1). Seven examples are focused on older citizens but one is for older people with frailty & neurodegenerative diseases (New South Wales, Australia) and one is a pathway for patients in Indonesia, independent of disease and/or age limits. Professional disciplines involved differed across countries but allied health professionals and nurses were commonly involved. Family physicians were involved in only the examples from the USA and Indonesia. Specialist physicians in geriatric medicine were involved in five of the examples. Five programs involved pharmacists to advise on medication and two programs involved trained volunteers. Public/patient information and education was the most common intervention and was the sole intervention in the Spanish example reported. Three of the nine programs did not routinely evaluate patient experience or functional outcomes. Only three pathways enabled patient level data to flow through the electronic care record. Conclusion: The international survey offers initial insight into implemented pathways and programs for the prevention and management of falls in primary care and community settings in different countries. It paves the way for a more targeted survey and Delphi consensus process on the design and benchmarking of integrated services to address the challenge of falls in ageing societies.Implications: The evidence-based examples in the survey highlight processes and interventions that are readily transferable and where adoption will facilitate standardization and improved quality of care. The next phase aims to agree key components and performance indicators to allow future benchmarking and system-based evidence generation on prevention and management of falls in the community.References(1) World Health Organization. WHO global report on falls prevention in older age. World Health Organization; 2008.

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system3,4 and in haematopoietic cancers5. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones6,7, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2–ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.

Cell fate determinants Scrib and Llgl1 influence self-renewal capacity of hematopoietic stem cells (HSCs). Scrib-deficient HSCs are functionally impaired and lack sufficient repopulation capacity during serial transplantation and stress. In contrast, loss of Llgl1 leads to increased HSC fitness, gain of self-renewal capacity and expansion of the stem cell pool. Here, we sought to assess for shared and unique molecular functions of Llgl1 and Scrib by analyzing their interactome in hematopoietic cells. Interactome analysis was performed by affinity purification followed by mass spectrometry. Motility, migration and adhesion were assessed on primary murine HSCs, which were isolated by FACS sorting following conditional deletion of Scrib or Llgl1, respectively. Imaging of Scrib-deficient HSCs was performed by intravital 2-photon microscopy. Comparison of Scrib and Llgl1 interactome analyses revealed involvement in common and unique cellular functions. Migration and adhesion were among the cellular functions connected to Scrib but not to Llgl1. Functional validation of these findings confirmed alterations in cell adhesion and migration of Scrib-deficient HSCs in vitro and in vivo. In contrast, genetic inactivation of Llgl1 did not affect adhesion or migratory capacity of hematopoietic stem cells. Our data provide first evidence for an evolutionarily conserved role of the cell fate determinant Scrib in HSC adhesion and migration in vitro and in vivo, a unique function that is not shared with its putative complex partner Llgl1.

Myeloproliferative neoplasia (MPN) is a group of diseases which include polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) and is characterized by clonal proliferation of myeloid cells. In many cases there is also a striking inflammatory syndrome (CRP elevation, fever, elevation of pro-inflammatory cytokines in peripheral blood) in particular in advanced phases of the disease. Auto- and paracrine effects of pro-inflammatory cytokines may contribute to maintenance of the disease and aggravation of the inflammatory syndrome. Cold-shock proteins are multi-functional DNA/RNA-binding proteins and Ybx1 is the prototypic member. These proteins regulate the expression of a number of pro-inflammatory cytokines, as well as cytokine receptors, making them key players in the orchestration of inflammatory processes. Moreover, expression of Ybx1 is induced by cellular and oncogenic stress and mediates resistance to chemotherapy. As patients with MPNs may present with an inflammatory syndrome, we assessed for Ybx1 expression as a potential mediator of cytokine signaling. By immunohistochemistry we found expression of Ybx1 in primary human bone marrow (BM) biopsies derived from patients with MPN. In contrast, BM sections derived from healthy donors (or remission controls without any evidence for active disease) did not show any expression of Ybx1. Moreover, Ybx1 expression was increased in the cytoplasm of myeloid immune cells derived from the peripheral blood of MPN patients as assessed by flow cytometry. Lower levels of cytoplasmatic Ybx1 were detectable in healthy volunteers. Therefore, we hypothesized that inflammatory stimuli (e.g. secretion of pro-inflammatory cytokines) may contribute to Ybx1 expression and this may mediate resistance to JAK-kinase inhibitor therapy. To assess for a functional role of Ybx1 in MPN we used murine cell lines (32D and Ba/F3) transduced with mutated JAK2 (JAK2-V617F) or MPL-receptor (MPLW515L) as well as human cell lines harboring the respective mutations. Exposure of these murine cell lines to pro-inflammatory stimuli (e.g. pro-inflammatory cytokines) induced expression of Ybx1 as assessed by qPCR. As Ybx1-expression has been described to contribute to drug resistance, we aimed to assess for its function in the setting of JAK-kinase inhibitor therapy. Lentiviral knockdown of Ybx1 alone did neither affect proliferation nor induce apoptosis in JAK2V617F- and MPL-mutated murine cell lines. However, co-treatment with the JAK-kinase inhibitor ruxolitinib (RUX) after Ybx1 knockdown led to induction of apoptosis that significantly exceeded the amount of apoptotic cells (AnnexinV+, Caspase+) upon RUX-treatment alone. These effects could be re-capitulated in human leukemia cell lines (HEL and SETB2) harboring the JAK2V617F mutation. As knockdown of Ybx1 (to 40-50% of baseline) alone did not impair proliferation of murine cell lines in vitro, we asked whether reduction of Ybx1 would impair function of normal hematopoiesis. We used a straight knockout mouse model in which homozygous loss of Ybx1 is embryonically lethal. However, heterozygous animals are born without malformations. Ybx1+/- animals show regular steady state hematopoiesis with Ybx1 expression being reduced to 50%. When injected into lethally irradiated hosts, Ybx1+/- cells produced a stable chimerism during serial transplantations as compared to Ybx1+/+ controls. To assess for a role of Ybx1 in MPN development in vivo, we used a previously published JAK2V617F knock-in mouse model. By the use of a Vav1-Cre-recombinase, a PV-like phenotype was initiated in early hematopoiesis. Sorted LSK-cells from JAK2V617F-knockin-mice were infected with lentiviral Ybx1-shRNA constructs and injected into lethally irradiated hosts. Knockdown of Ybx1 led to a delay in disease onset, when compared to scrambled-shRNA controls. Co-treatment of recipient mice with JAK-kinase inhibitors is currently under way to recapitulate the synergy observed in cell culture models described above. Taken together, Ybx1 expression in MPN is induced by inflammatory stimuli and protects JAK2V617F or MPLW515L transformed cells from JAK-inhibitor induced apoptosis. Distinct requirement for hematopoiesis (versus disease) offers a therapeutic index to evaluate cold-shock proteins as target structures for inflammatory diseases in the future. Disclosures Heidel: Novartis: Consultancy.