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Recent international guidelines recommend rapid initiation and titration of basic treatments of heart failure but do not explain how to achieve this goal. Despite these recommendations, implementation of treatment in daily practice is poor. This may be partly explained by the profile of the patients (frailty, comorbidities), safety considerations and tolerability issues related to kydney function, low blood pressure or heart rate and hyperkalaemia. In this special article, we intended to help the physician, through an algorithmic approach, to quickly and safely introduce guideline-directed medical therapy in the field of heart failure with ejection fraction under 50%., Competing Interests: Déclaration de liens d'intérêts Le Pr M KOMAJDA déclare des activités de consultant, orateur ou membre de comités d'essais cliniques pour Bayer AstraZeneca, Boehringer Ingelheim, Servier. Les autres auteurs ne déclarent aucun lien d'intérêt en lien avec cet article., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: France is experiencing a steady increase in the number of residents living in nursing homes (NHs). Each year, 25% of these residents are hospitalized, half of them through emergency departments (EDs). A part of these transfers to EDs are unjustified and not without consequences. The first aim of our study is to evaluate the proportion of avoidable NHs resident transfer to EDs., Methods: An observational, prospective and multicentric study was conducted between January and August 2019 in the 6 EDs of a French county during 3 inclusion periods. A multidisciplinary expert panel determined the appropriateness of each ED transfer. The results were expressed in gross values and %. Expert agreement was assessed by Fleiss' kappa statistical measure., Results: Transfers were deemed avoidable in 12 to 35% of cases and appropriate in 53 to 81% of cases according to the experts. Fleiss' Kappa score on the concordance of the different experts' answers concerning the relevance of transfers was slight with k = 0.28 with a significant p-value (p < 0.0001). Infection could benefit of direct hospitalization whereas trauma/wound and acute heart/pulmonary failure are the most relevant reasons of presentation to the ED., Conclusions: Too many ED transfers of NH residents remain avoidable. There is a disparity of results among the experts reflecting a limitation of this study related to the subjective nature of relevance. In a society where demographic projections predict a continuing aging population anywhere EDs are regularly crowded, it would be interesting to identify and prevent factors predisposing to ED transfer and consider alternative managements with a better geriatric and emergency physicians collaboration for this specific population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap., Methods: INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome., Discussion: INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications., Trial Registration: The study is registered at ClinicalTrials.gov, NCT04389541., (© 2023. The Author(s).)

In vivo and in vitro assays, particularly reconstitution using artificial membranes, have established the role of synaptic soluble N-Ethylmaleimide-sensitive attachment protein receptors (SNAREs) VAMP2, Syntaxin-1A, and SNAP-25 in membrane fusion. However, using artificial membranes requires challenging protein purifications that could be avoided in a cell-based assay. Here, we developed a synthetic biological approach based on the generation of membrane cisternae by the integral membrane protein Caveolin in Escherichia coli and coexpression of SNAREs. Syntaxin-1A/SNAP-25/VAMP-2 complexes were formed and regulated by SNARE partner protein Munc-18a in the presence of Caveolin. Additionally, Syntaxin-1A/SNAP-25/VAMP-2 synthesis provoked increased length of E. coli only in the presence of Caveolin. We found that cell elongation required SNAP-25 and was inhibited by tetanus neurotoxin. This elongation was not a result of cell division arrest. Furthermore, electron and super-resolution microscopies showed that synaptic SNAREs and Caveolin coexpression led to the partial loss of the cisternae, suggesting their fusion with the plasma membrane. In summary, we propose that this assay reconstitutes membrane fusion in a simple organism with an easy-to-observe phenotype and is amenable to structure-function studies of SNAREs., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The prospective, non-interventional PERFORM study describes and analyzes the effectiveness of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) as first-line treatment for patients with locally advanced or metastatic HR+/HER2- breast cancer in the real-world setting in Germany and Austria. PERFORM will reflect current patient characteristics and routine treatment patterns including treatment sequences and time to subsequent (chemo)therapy. Besides, second-line treatment effectiveness and patient-relevant end points such as longitudinal patient-reported outcome measurements beyond disease progression will be analyzed. Accounting for the heterogenous real-world patient population, data on clinicopathologic subgroups underrepresented in clinical trials such as elderly or male will be analyzed. Taken together, PERFORM will close knowledge gaps from clinical trials in real world.

Exposure of the general population to pesticides, especially in agricultural areas, is a major public health concern. This review analyses the role of Land Use and Land Cover (LULC) in Residential Exposure to Agricultural Pesticides (REAP) and how it is measured and modelled. Some epidemiological studies have shown that basic LULC variables, such as distance to a crop and field size, are relevant for explaining REAP. However, the potential of LULC mitigation elements, such as vegetation barriers, grassy strips and buffer zones, to mitigate REAP has been poorly studied. The availability of recent low-cost and high-quality geospatial data enables REAP models to include alternative and more precise LULC variables. This review also highlights the need for (i) generic environmental sampling protocols, (ii) exposure and spraying datasets and (iii) assessment of the mitigation capacity of LULC to improve REAP modelling significantly.

Background: Prognosis of patients with multiple myeloma (MM) who have relapsed on or become refractory to immunomodulators and bortezomib is poor, and treatment options are limited. While pomalidomide plus low-dose dexamethasone (POM/DEX) has demonstrated efficacy in clinical trials, real-world evidence is scarce., Patients and Methods: POSEIDON was a prospective non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of POM/DEX in patients with relapsed or refractory MM (R/RMM) pretreated with at least two prior therapy lines including both lenalidomide and bortezomib in real world in Germany. Patients received POM/DEX according to physicians' choice. Data were analyzed descriptively., Results: Between 2014 and 2017, 151 patients were enrolled, 144 patients with a median of three prior therapy lines qualified for effectiveness analysis. Median age was 73.2 years. Median progression-free and overall survival were 6.3 months [95% confidence interval (CI) 5.2, 8.6] and 12.9 months [95% CI 10.6, 15.1]. Most frequent grade 3/4 adverse events were leukopenia (8.2%), pneumonia (7.5%) and anemia (5.5%). QoL was maintained after start of POM/DEX., Conclusion: The results of POSEIDON support the effectiveness and safety of POM/DEX in R/RMM patients pretreated with lenalidomide and bortezomib and highlight the clinical value of the POM/DEX regimen in the real-world setting. Registered at clinicaltrials.gov (NCT02075996)., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Volunteering is a way for people to develop meaningful relationships within a social group and can lead to the building of social capital, from which both individuals and the wider group can benefit in the form of enhanced well-being. This study aimed to explore and describe the impact of volunteering on the volunteer coordinators and volunteers themselves in the eastern suburbs of Christchurch, New Zealand, an area particularly impacted by the devastating earthquakes in the period 2010/2011. Data were collected via semi-structured interviews with volunteer coordinators and volunteers (n = 35; 16 men, 19 women) from November 2018 to mid-January 2019. Thematic analysis of data highlighted a key theme of Creating and strengthening valued community connections, with subthemes of Personal growth, Community connections and Role of coordination. The key theme illustrated how formal volunteering created effort and opportunities towards the strengthening of personal and community connectedness. Our study demonstrates the importance of social connection for both individual and community well-being, emphasises the important role of "champions" in facilitating the building of bridging and bonding relationships between individuals and communities, and suggests a role for healthcare professionals to prescribe volunteering as a way to improve individual health and well-being outcomes., (© 2021 John Wiley & Sons Ltd.)

Spores from 21 strains from different genera were heat-treated and stored in different sets of process conditions (4 temperatures and 3 pH levels) defined to prevent growth. In these conditions, spores surviving the heat treatment progressively lost viability during storage. Different inactivation curve shapes (linear, shoulder and tailing) and different sensitivities to storage were observed. B. coagulans showed the fastest inactivation kinetics, with more than 4-log reduction of spore population within 24 h after heating and G. stearothermophilus displayed slower inactivation kinetics, whereas all the anaerobic strains studied (M. thermoacetica and Thermoanaerobacterium spp.) proved resistant to storage conditions, with no destruction detected during 90 days in most cases. Inactivation rates were relatively unaffected by sub-lethal pH but sharply accelerated by temperature: Inactivation became faster as temperature increased (in the 8 °C-55 °C temperature range), with growth blocked by low pH in sub-lethal temperatures. There were changes in surviving spore numbers after the heat-treatment phase. This has implications and applications in canned food industries, as the probability of a retorted sample testing as non-stable, meaning possible spoilage, may decrease with time. In simple terms, a batch of low-acid canned food that tests as non-shelf-stable after an incubation test i.e. positive growth conditions, may later become negative if stored at room temperature (below the minimal growth temperature for thermophilic spores), which may change the marketability of the batch., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

The compartmentalisation achieved by confining cytoplasm into membrane-enclosed organelles in eukaryotic cells is essential for maintaining vital functions including ATP production, synthetic and degradative pathways. While intracellular organelles are highly specialised in these functions, the restricting membranes also impede exchange of molecules responsible for the synchronised and responsive cellular activities. The initial identification of contact sites between the ER and plasma membrane (PM) provided a potential candidate structure for communication between organelles without mixing by fusion. Over the past decades, research has revealed a far broader picture of the events. Membrane contact sites (MCSs) have been recognized as increasingly important actors in cell differentiation, plasticity and maintenance, and, upon dysfunction, responsible for pathological conditions such as cancer and neurodegenerative diseases. Present in multiple organelles and cell types, MCSs promote transport of lipids and Ca 2+ homoeostasis, with a range of associated protein families. Interestingly, each MCS displays a unique molecular signature, adapted to organelle functions. This review will explore the literature describing the molecular components and interactions taking place at ER-PM contact sites, their functions, and implications in eukaryotic cells, particularly neurons, with emphasis on lipid transfer proteins and emerging function of SNAREs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hewlett, Singh, Vannier and Galli.)

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect persisting after completion of neurotoxic chemotherapies. This observational study was designed to evaluate the effectiveness of the dietary supplement OnLife® (patented mixture of specific fatty acids and palmitoylethanolamide) in improving symptoms of CIPN in breast and colon cancer patients., Methods: Improvement of CIPN was evaluated in adult patients, previously treated with (neo)adjuvant paclitaxel- (breast cancer) or oxaliplatin-based (colon cancer) therapies, receiving OnLife® for 3 months after completion of chemotherapy. The primary endpoint was to compare the severity of peripheral sensory neuropathy (PSN) and peripheral motor neuropathy (PMN) before and at the end of OnLife® treatment. Secondary endpoints included the assessment of patient-reported quality of life and CIPN symptoms as assessed by questionnaires., Results: 146 patients (n = 75 breast cancer patients and n = 71 colon cancer patients) qualified for analysis; 31.1% and 37.5% of breast cancer patients had an improvement of PSN and PMN, respectively. In colon cancer patients, PSN and PMN improved in 16.9% and 20.0% of patients, respectively. According to patient-reported outcomes, 45.9% and 37.5% of patients with paclitaxel-induced PSN and PMN, and 23.9% and 22.0% of patients with oxaliplatin-induced PSN and PMN experienced a reduction of CIPN symptoms, respectively., Conclusion: OnLife® treatment confirmed to be beneficial in reducing CIPN severity and in limiting the progression of neuropathy, more markedly in paclitaxel-treated patients and also in patients with oxaliplatin-induced CIPN., (© 2021 S. Karger AG, Basel.)

Axons and dendrites are long and often ramified neurites that need particularly intense plasma membrane (PM) expansion during the development of the nervous system. Neurite growth depends on non-fusogenic Sec22b-Stx1 SNARE complexes at endoplasmic reticulum (ER)-PM contacts. Here, we show that Sec22b interacts with members of the extended synaptotagmin (E-Syt) family of ER lipid transfer proteins (LTPs), and this interaction depends on the longin domain of Sec22b. Overexpression of E-Syts stabilizes Sec22b-Stx1 association, whereas silencing of E-Syts has the opposite effect. Overexpression of wild-type E-Syt2, but not mutants unable to transfer lipids or attach to the ER, increase the formation of axonal filopodia and ramification of neurites in developing neurons. This effect is inhibited by a clostridial neurotoxin cleaving Stx1, and expression of the Sec22b longin domain and a Sec22b mutant with an extended linker between the SNARE and transmembrane domains. We conclude that Sec22b-Stx1 ER-PM contact sites contribute to PM expansion by interacting with LTPs, such as E-Syts.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Social and natural capital are fundamental to people's wellbeing, often within the context of local community. Developing communities and linking people together provide benefits in terms of mental well-being, physical activity and other associated health outcomes. The research presented here was carried out in Christchurch - Ōtautahi, New Zealand, a city currently re-building, after a series of devastating earthquakes in 2010 and 2011. Poor mental health has been shown to be a significant post-earthquake problem, and social connection has been postulated as part of a solution. By curating a disparate set of community services, activities and facilities, organised into a Geographic Information Systems (GIS) database, we created i) an accessibility analysis of 11 health and well-being services, ii) a mobility scenario analysis focusing on 4 general well-being services and iii) a location-allocation model focusing on 3 primary health care and welfare location optimisation. Our results demonstrate that overall, the majority of neighbourhoods in Christchurch benefit from a high level of accessibility to almost all the services; but with an urban-rural gradient (the further away from the centre, the less services are available, as is expected). The noticeable exception to this trend, is that the more deprived eastern suburbs have poorer accessibility, suggesting social inequity in accessibility. The findings presented here show the potential of optimisation modelling and database curation for urban and community facility planning purposes.

Objectives: To investigate risk factors for women with obesity of childbearing age., Methods: A cross-sectional survey of New Zealand women (15-49 years) with measured height and weight was used [unweighted (n = 3625) and weighted analytical sample (n = 1,098,372)] alongside sociodemographic-, behavioural- and environmental-level predictors. Multilevel logistic regression weighted for non-response of height and weight data was used., Results: Meeting physical activity guidelines (AOR (adjusted odds ratio) 0.66, 95% CI 0.54-0.80), Asian (AOR 0.15, 95% CI 0.10-0.23) and European/other ethnicity (AOR 0.46, 95% CI 0.36-0.58) and an increased availability of public greenspace (Q4 AOR 0.55, 95% CI 0.41-0.75) were related to decreased obesity risk. Older age (45-49 years AOR 3.01, 95% CI 2.17-4.16), Pacific ethnicity (AOR 2.81, 95% CI 1.87-4.22), residing in deprived areas (AOR 1.65, 95% CI 1.16-2.35) or secondary urban areas (AOR 1.49, 95% CI 1.03-2.18) were related to increased obesity risk. When examined by rural/urban classification, private greenspace was only related to increased obesity risk in main urban areas., Conclusions: This study highlights factors including but not limited to public greenspace, which inform obesity interventions for women of childbearing age in New Zealand.

Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.

Inside eukaryotic cells, membrane contact sites (MCSs), regions where two membrane-bound organelles are apposed at less than 30 nm, generate regions of important lipid and calcium exchange. This review principally focuses on the structure and the function of MCSs between the endoplasmic reticulum (ER) and the plasma membrane (PM). Here we describe how tethering structures form and maintain these junctions and, in some instances, participate in their function. We then discuss recent insights into the mechanisms by which specific classes of proteins mediate nonvesicular lipid exchange between the ER and PM and how such phenomena, already known to be crucial for maintaining organelle identity, are also emerging as regulators of cell growth and development.