Metal-organic frameworks (MOFs) are promising carriers for drug delivery applications due to their large tunable porosity, structural flexibility, biocompatibility and high drug-loading capacities. Nonetheless, precise, on-demand release remains challenging. Here, we designed a magnetic field-responsive nanocomposite comprising superparamagnetic iron oxide nanoparticles (IONP) coated with a ZIF-8 shell and loaded with cresyl violet, a fluorescent cytotoxic probe. The particles were stabilized with a fluorescein-functionalized amphiphilic polymer that improves colloidal stability, prevents unspecific sustained release, and protects the ZIF-8 shell from premature degradation, enabling efficient intracellular uptake in pancreatic cancer cells and cancer-associated fibroblasts. This study conducted a direct comparison between high-frequency alternating (AMF) or low-frequency rotating (RMF) magnetic fields inducing respectively nanoscale heating or mechanical actuation in a single magnetic MOF system. Both stimuli triggered significant cargo release and reduced cell viability in 2D cell cultures and 3D tumoral heterospheroids. These results strongly highlight the potential of MOF-based advanced drug delivery nanosystems responsive to dual-mode magnetic actuation strategy, paving the way for further evaluation in in vivo models to establish its translational relevance.

A seeded growth strategy was developed to synthesize core-shell magnetic metal-organic framework (MOF) composites for magnetic hyperthermia (MHT) and MHT-triggered drug delivery. Cubic or spherical iron oxide nanoparticles, with nanocubes selected for their superior MHT performance, were coated with cetyltrimethylammonium bromide to enable aqueous ZIF-8 shell growth. Shell thickness strongly influenced heating efficiency under alternating magnetic fields (AMFs), with thinner shells and cubic cores yielding enhanced MHT performance. Doxorubicin (Doxo) was used as a model chemotherapeutic drug and loaded either by surface adsorption or via in-situ encapsulation during ZIF-8 growth, the latter achieving an exceptional loading efficiency of 98%. To ensure stability in physiological environments, an amphiphilic polymer coating was applied, improving dispersion while regulating shell degradation and drug release. Doxo-loaded composites exhibited efficient cellular uptake and lysosomal localization in glioblastoma and breast cancer cells. Confocal microscopy revealed that magnetic field exposure induced lysosomal permeabilization and redistribution of Doxo, indicating a potential lysosomal escape mechanism. Notably, enhanced cytotoxicity occurred only when AMFs were applied to Doxo-loaded composites, despite no measurable bulk temperature increase, suggesting localized MHT-induced intracellular damage. Overall, shell-tunable magnetic-MOF nanohybrids emerge as promising platforms for controlled, heat-free intracellular drug activation for targeted cancer therapy.

OBJECTIVES:To identify distinct profiles among elderly patients in primary care so that general practitioners (GPs) can develop more targeted care strategies. DESIGN:A cross-sectional analysis of baseline data from the French nationwide 'Elderly Appropriate Treatment in Primary Care' trial. SETTING:Primary care in France: 277 GPs included patients. PARTICIPANTS:The study participants were aged 75 or over, living at home, and taking five or more prescription medications. Of the 2724 patients included, 2651 were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES:To identify specific patterns of multimorbidity, polypharmacy and frailty, we applied an unsupervised clustering analysis with self-organising maps. RESULTS:Seven clusters were identified: cluster 1 (16% of the patients) comprised frail men and women with cardiovascular, respiratory, musculoskeletal and endocrine diseases and marked polypharmacy; cluster 2 (9.3%, mainly men) comprised frail patients with cancer and cardiovascular or urogenital/renal diseases; cluster 3 (15.5%, mainly men) comprised not-very-frail patients with cardiovascular and urogenital/renal diseases; cluster 4 (18.1%) comprised not-very-frail men and women with cardiovascular diseases; cluster 5 (13.5%, mainly women) comprised mainly lonely, very frail patients with hypertension and endocrine, musculoskeletal and neuropsychiatric disorders; cluster 6 (19.1%, mainly women) comprised frail, socially isolated patients with digestive, musculoskeletal and neuropsychiatric diseases; lastly, cluster 7 (8.6%, mainly women) comprised frail, socially isolated patients with hypertension, cancer, or musculoskeletal, psychological and digestive disorders. CONCLUSION:Our phenotypic classification of elderly patients might facilitate efforts to align healthcare services with the care needs that are encountered by GPs in their everyday practice. TRIAL REGESTRATION NUMBER: (NCT03298386).

BACKGROUND:Although there is a clear distinction between the management of typically acute diseases (e.g., a sore throat) and the management of typically chronic diseases (e.g., diabetes), there is also a 'fluctuating' zone that includes many medical conditions with a major impact on the healthcare system and the management of which is usually judged to be unsatisfactory. OBJECTIVE:To understand how general practitioners (GPs) identify and manage acute, chronic and 'fluctuating' (i.e., subacute or recurrent acute) conditions on a day-to-day basis. METHODS:In a qualitative focus group study, 33 French GPs were invited to discuss their management of typical acute diseases, typical chronic diseases, and 'fluctuating' conditions. Data saturation was achieved after five focus groups. Thematic content analyses and matrix analyses (disease management key factors vs. diseases studied) were performed. RESULTS:The disease management key factors were classified into in seven themes: physician-patient negotiation; complex consultations; greater vigilance for patients with multimorbidity; the absence of standard treatments; patient education over time; inapplicable guidelines; and difficult multidisciplinary coordination. The specific management key factors of 'fluctuating' conditions were frequent, erratically scheduled consultations; consultations focused on social relationships, work, and the family; the lack of effective drug treatment in most cases; a break in the patient pathway; a lack of initial medical education about these diseases; and medical guidelines judged to be inappropriate with regard to actual practice. CONCLUSIONS:These results challenge the acute/chronic dichotomy that is still applied to disease management but also highlight possible ways of improving the management of 'fluctuating' conditions.

Current public health guidelines emphasize the necessity to optimize medication prescriptions for multimorbid patients with multiple medications to ensure patient adherence while minimizing harm and waste. Nevertheless, there is limited understanding of how these patients choose to follow their medication regimen. This study aimed to describe the variations in the way patients account for their adherence (and non-adherence) to multiple medications and to draw links between these variations and patients’ socioeconomic status. Twenty semi-structured interviews were conducted with patients aged 47–82 years with cardiovascular disease and multiple medically treated chronic conditions. They were transcribed and analyzed using reflexive thematic analysis. We first describe shared concerns about multiple medication taking and situations of medical uncertainty which arose when patients encounter conflicting medical instructions. We then highlight two overarching approaches through which patients conceptualized following their medical prescriptions. Some patients predominantly deferred the choice of medication to their physicians, while others steered the decision-making process and closely monitored what they were prescribed. These styles reflected different ways of engaging with doctors, dealing with side effects, and evaluating prescriptions and were linked to patients’ socioeconomic status. We discuss our results by borrowing from Hirschman’s theory of voice, exit, and loyalty. Findings argue in favor of better coordinated care to reduce prescription ambiguities and highlight the importance of patients with multimorbidity being given sufficient time and space to voice their concerns.

BACKGROUND In France, general practitioners (GPs) prescribe benzodiazepines and Z-drugs (BZD/ZDs) widely, and especially to older adults. Several characteristics of patients and/or GPs linked to BZD/ZD overprescription have been described in the general population but not among older patients in primary care. OBJECTIVES To estimate the proportion of GP consultations by patients aged 65 and over that resulted in a BZD/ZD prescription, and determine whether any GP-related factors predicted BZD/ZD overprescription in this setting. METHODS We analyzed sociodemographic and practice-related GP characteristics, and aggregated data on consultations recorded prospectively by 117 GPs in a database between 2000 and 2010. Next, we used logistic regression models to look for factors potentially associated with BZD/ZD overprescription (defined as an above-median prescription rate). RESULTS The GPs' mean age at inclusion was 47.4 (7.1), and 87.9% were male. During the study period, the median (95% confidence interval) proportion of consultations with patients aged 65 and over resulting in a BZD/ZD prescription was 21.8% (18.1-26.1) (range per GP: 5-34.1%). In a multivariable analysis, a greater number of chronic disease (OR [95% CI] = 2.10 [1.22-3.64]), a greater number of drugs prescribed per consultation (5.29 [2.72-10.28]), and shorter study participation were independently associated with BZD/ZD overprescription. CONCLUSIONS BZD/ZD overprescription was associated with a greater chronic disease burden and the number of drugs prescribed per consultation but not with any sociodemographic or practice-related GP characteristics. Targeted actions are needed to help GPs limit their prescription of BZD/ZDs to older patients with multiple comorbidities and polypharmacy.

Background. . Frailty is associated with a significant risk of falls, but studies are contradictory concerning the association of frailty with repeated falls in the elderly in primary care. The hypothesis of this work was that frailty, defined by a global approach to the vulnerabilities of the elderly, is a major factor in repeated falls. The aim of this study was to identify the risk factors associated with repeated falls among elderly people in primary care. Method. . From the FOPAS cohort conducted between April 2016 and January 2017, patients aged 75 and over, living at home or in a nursing home, polymedicated (at least 5 active molecules) were included by their GP and followed for six months. Sociodemographic, medical and social data were collected. The SEGAm frailty score was calculated for each patient. The frequency of repeated falls was estimated in this population. Univariate and multivariate analyses were performed to identify factors associated with repeated falls. Results. . 1,811 patients aged 83.4 +/- 5.1 years were included. The rate of repeated falls was 13% (CI95% = 11.5%-14.5%). Repeated falls were significantly more frequent in frail or very frail patients (ORa = 8.9; CI95% = 5.6-14), with a recent decrease in mobility (ORa = 1.8; CI95% = 1.3-2.5), receiving professional or material assistance (ORa = 1.6; CI95% = 1.1-2.3) and with a history of hospitalization in the last three months (ORa = 1.5; CI95% = 1.02.2). Conclusion. . In patients aged 75 and over, frailty is a major risk factor associated with repeated falls. Preventing repeated falls requires front-line strategies to identify and resolve markers of frailty.

The origin of cell death in the magnetomechanical actuation of cells induced by magnetic nanoparticle motion under low-frequency magnetic fields is still elusive. Here, a miniaturized electro-magnet fitted under a confocal microscope is used to observe in real time cells specifically targeted by superparamagnetic nanoparticles and exposed to a low-frequency rotating magnetic field. Our analysis reveals that the lysosome membrane is permeabilized in only a few minutes after the start of magnetic field application, concomitant with lysosome movements toward the nucleus. Those events are associated with disorganization of the tubulin microtubule network and a change in cell morphology. This miniaturized electromagnet will allow a deeper insight into the physical, molecular, and biological process occurring during the magnetomechanical actuation of magnetic nanoparticles.

The destruction of cells using the mechanical activation of magnetic nanoparticles with low-frequency magnetic fields constitutes a recent and interesting approach in cancer therapy. Here, we showed that superparamagnetic iron oxide nanoparticles as small as 6 nm were able to induce the death of pancreatic cancer-associated fibroblasts, chosen as a model. An exhaustive screening of the amplitude, frequency, and type (alternating vs. rotating) of magnetic field demonstrated that the best efficacy was obtained for a rotating low-amplitude low-frequency magnetic field (1 Hz and 40 mT), reaching a 34% ratio in cell death induction; interestingly, the cell death was not maximized for the largest amplitudes of the magnetic field. State-of-the-art kinetic Monte-Carlo simulations able to calculate the torque undergone by assemblies of magnetic nanoparticles explained these features and were in agreement with cell death experiments. Simulations showed that the force generated by the nanoparticles once internalized inside the lysosome was around 3 pN, which is in principle not large enough to induce direct membrane disruption. Other biological mechanisms were explored to explain cell death: the mechanical activation of magnetic nanoparticles induced lysosome membrane permeabilization and the release of the lysosome content and cell death was mediated through a lysosomal pathway depending on cathepsin-B activity. Finally, we showed that repeated rotating magnetic field exposure halted drastically the cell proliferation. This study established a proof-of-concept that ultra-small nanoparticles can disrupt the tumor microenvironment through mechanical forces generated by mechanical activation of magnetic nanoparticles upon low-frequency rotating magnetic field exposure, opening new opportunities for cancer therapy.

Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.

Background: The long-term issues faced by COVID-19 survivors remain unclear. Symptoms may persist for several months, even in non-hospitalized patients, probably impacting the quality of life. Objective: To assess the health-related quality of life of outpatients one year after SARS-CoV-2 infection. Design, Settings, and Participants: This prospective multicentre study, conducted in France from February 2020 to February 2022, compared 150 COVID-19 cases (PCR+ and/or CT scan+) and 260 controls (PCR-) selected from a database of four COVID centres. Main outcomes: Health-related quality of life assessed using the EQ-5D-5L scale. Results: COVID-19 outpatients (n = 96) had significantly lower health-related quality of life than controls (n = 81) one year after SARS-CoV-2 infection: the EQ-5D-5L index averaged 0.87 in cases and 0.95 in controls (p = 0.002); the EQ- VAS averaged 78 in cases and 86.7 in controls (p < 0.001). This alteration in quality of life was more intense in the areas of pain or discomfort and daily activities. Conclusions: This study is the first to show an alteration in the quality of life of COVID-19 outpatients after one year. Appropriate guidance and community rehabilitation programs are required for outpatients with persistent symptoms of COVID-19. Research must continue to confirm these results in larger cohorts.

At the beginning of the Covid-19 epidemic in France, the mobilization of primary care professionals was not driven by the government, which focused its attention on hospitals. As a result of ministerial orders to delay medical consultations as much as possible and to close most of the paramedical practices, one might have expected that primary care activity would be strongly reduced and uncoordinated. However, in some territories, primary care actors consulter each other, adopting a systemic ...

Comment une organisation territoriale des soins primaires se construit-elle en temps d’épidémie, en prenant appui sur un système d’action préexistant à l’échelle du territoire ? L’étude de cas menée entre mars et septembre 2020 mêle observation participante et entretiens sociologiques avec 21 professionnels impliqués dans cette organisation, à l’échelle d’un canton sous-doté en offre de soins, centré sur une métropole urbaine défavorisée au plan socioéconomique. L’histoire des relations entre les acteurs du territoire, incarnées depuis peu dans une Communauté professionnelle territoriale de santé (CPTS), apparaît centrale dans la construction d’une organisation des soins primaires en temps d’épidémie, permettant aux acteurs - libéraux, élus locaux et hospitaliers - d’exercer un mandat de santé publique. Cette expérience questionne la capacité des CPTS à poursuivre leur contribution, après l’épidémie, à l’organisation des soins primaires répondant à une démarche de promotion de la santé, dans un système où des logiques professionnelles, gestionnaires et politiques peuvent entrer en tension.

Background: The association between multimorbidities and polypharmacy among elderly individuals is well documented, and polypharmacy has been shown to increase the risk of adverse drug events (ADEs). However, little information is available about the risks associated with the lifelong use of medications to treat chronic multimorbidities. Objective: To determine the prevalence and nature of high-risk prescriptions among primary-care patients with chronic multimorbidities. Methods: We studied a weighted stratified random sample of 105 prescriptions for different patients with chronic multimorbidities taken from the Polychrome database established using information from the French primary-care record database (Observatoire de la MedecineGenerale). A medication review was conducted to identify contra-indications and potential drug-drug interactions for each prescription. Results: Contra-indications were identified for 60 (57.1%) prescriptions, potential drug-drug interactions for 70 (66.7%), absolute contra-indications for 9 (8.6%), and inadvisable drug combinations for 11 (10.5%). In all, 19 (18.1%) different patients were at risk for major ADEs. Cardiovascular and nervous-system drugs contributed 66.2% of contra-indications and 69.3% of potential drug-drug interactions. Conclusions: This exploratory study confirms the high prevalence and potential seriousness of prescriptions at risk for ADEs in a population of primary-care patients with chronic multimorbidities. The high prevalence of interactions involving the cardiovascular and nervous systems indicates that efforts to improve prescription practices should target these two categories of conditions and drugs in patients with chronic multimorbidities.

Background. The definition of chronic disease appears heterogeneous and a reflection of compartmentalized management, dependent on the actors (patient, doctor, insurer, government institution). the definition of a situation is necessary to monitor the health status of the population, conduct clinical investigations, evaluate professionals practices and make decisions in terms of public policies. Objectives. Our aim was to identify invariants used to define chronic disease, and to discuss major issues for medical decision in primary care. Methods. We conducted a review of the literature until the date of January 30, 2018. A systematic search for published original articles was conducted in the Medline database with the following search equation: "chronic disease" or "chronic illness" or "chronic conditions" and "defining" or "definition" and "primary care" or "general practice" or "general practitioner". Results. We found 6 different elements to define chronic disease. Three criteria were frequently found: a disease that lasts, a regular follow-up with long-term treatment, an impairment in quality of life. Disease's expression could be very varied, stable or not, severe or not, with episodes or not, and multifactorial etiology. Definition of chronic disease depended on the viewpoints and we identified three visions of "patient", "physician" and "care system" that never overlapped completely. Conclusions. The literature review does not allow a unique, homogeneous definition of chronic disease to be found, and it remains an illusion. Behind the intellectual nature of reflection, there are strong issues of care in a context where multimorbidity is predominant. Medical decision must better take into account clinical severity, disability and multimorbid context of patient with chronic disease. These factors draw a research agenda on chronic diseases and multimorbidity.

Background No study has investigated factors associated with non-participation or partial participation in the different combination patterns of screening programmes for all three cancers, that is, breast, colorectal and cervical cancer. Methods In a retrospective cohort study, we sought to describe combinations of cancer screening participation rates among women in the Val-de-Marne area of France and to identify individual and contextual factors associated with non-participation or partial participation. Results Women aged between 50 and 65 and who were eligible for all three screening programmes (n = 102 219) were analysed in multilevel logistic models, with the individual as the Level 1 variable and the place of residence as the Level 2 variable. The women who did not participate in any of the screening programmes were 34.4%, whereas 30.1%, 24% and 11.5% participated in one, two or all three screening programmes, respectively. Age below 55, a previous false-positive mammography, prior opportunistic mammography only, no previous mammography, membership of certain health insurance schemes (all P < 0.05) and residence in a deprived area (P < 0.001) were independently associated with non-participation or partial participation. We observed a stronger effect of deprivation on non-participation in all three cancers than in combinations of screening programmes. Conclusion Our findings suggest that the health authorities should focus on improving cancer screenings in general rather than screenings for specific types of cancer, especially among younger women and those living in the most socially deprived areas.