Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

A Yeast Mitotic Tale for the Nucleus and the Vacuoles to Embrace

The morphology of the nucleus is roughly spherical in most eukaryotic cells. However, this organelle shape needs to change as the cell travels through narrow intercellular spaces during cell migration and during cell division in organisms that undergo closed mitosis, i.e., without dismantling the nuclear envelope, such as yeast. In addition, the nuclear morphology is often modified under stress and in pathological conditions, being a hallmark of cancer and senescent cells. Thus, understanding nuclear morphological dynamics is of uttermost importance, as pathways and proteins involved in nuclear shaping can be targeted in anticancer, antiaging, and antifungal therapies. Here, we review how and why the nuclear shape changes during mitotic blocks in yeast, introducing novel data that associate these changes with both the nucleolus and the vacuole. Altogether, these findings suggest a close relationship between the nucleolar domain of the nucleus and the autophagic organelle, which we also discuss here. Encouragingly, recent evidence in tumor cell lines has linked aberrant nuclear morphology to defects in lysosomal function

Topoisomerase II deficiency leads to a postreplicative structural shift in all <i>Saccharomyces cerevisiae</i> chromosomes

The key role of Topoisomerase II (Top2) is the removal of topological intertwines between sister chromatids. In yeast, inactivation of Top2 brings about distinct cell cycle responses. In the case of the conditional top2-5 allele, interphase and mitosis progress on schedule but cells suffer from a chromosome segregation catastrophe. We here show that top2-5 chromosomes fail to enter a Pulsed-Field Gel Electrophoresis (PFGE) in the first cell cycle, a behavior traditionally linked to the presence of replication and recombination intermediates. We distinguished two classes of affected chromosomes: the rDNA-bearing chromosome XII, which fails to enter a PFGE at the beginning of S-phase, and all the other chromosomes, which fail at a postreplicative stage. In synchronously cycling cells, this late PFGE retention is observed in anaphase; however, we demonstrate that this behavior is independent of cytokinesis, stabilization of anaphase bridges, spindle pulling forces and, probably, anaphase onset. Strikingly, once the PFGE retention has occurred it becomes refractory to Top2 re-activation. DNA combing, two-dimensional electrophoresis, genetic analyses, and GFP-tagged DNA damage markers suggest that neither recombination intermediates nor unfinished replication account for the postreplicative PFGE shift, which is further supported by the fact that the shift does not trigger the G(2)/M checkpoint. We propose that the absence of Top2 activity leads to a general chromosome structural/topological change in mitosis

Precocious and supernumerary sensory neuron specification in <i>sox10</i>^<i>baz1</i> mutants.

<p>A,B) <i>neurod1</i> expression is seen in more cells (close-ups in left panels; arrowheads indicate a subset of <i>neurod1</i>^<i>+</i> cells) and extending more posteriorly (right panels; arrowhead marks posteriormost <i>neurod1</i>^<i>+</i> DRG) in <i>baz1</i> mutants compared with WT siblings at both 36 and 45 hpf. C) Counts of <i>neurod1</i>^<i>+</i> cells on one side of embryo at 36 and 45 hpf embryos (N = 11 for all conditions except 36 hpf <i>baz1</i>, where N = 13). <i>baz1</i> mutants significantly different to WT siblings (Student’s <i>t</i> test; ***, p<0.0001. In this and all subsequent images, embryos are shown in lateral view with dorsal to the top and anterior to the left, unless otherwise stated. Scale bar, 100 μm.</p

Medial pathway neural precursors undergo precocious and supernumerary differentiation into neurons in baz1 mutants.

<p>Confocal images of developing trunk DRGs of WT (A, D, G, J), <i>baz1</i> (B, E, H, K) and <i>m618</i> mutants (C, F, I, L) showing Elav1/Hu (red) and <i>sox10</i>:<i>GFP</i> (green) at each of 36 (A-C), 42 (D-F), 48 hpf (G-I) and 5 dpf (J-L). Arrowheads indicate subset of Elav1/Hu⁺ DRG sensory neurons. M-P) Counts (mean±s.d.) of trunk (Tr) and tail (Ta) and total (TOT) Elav1⁺ cells in DRGs of <i>baz1</i> (yellow) and <i>m618</i> (blue) mutants and their respective WT siblings. Significantly elevated numbers of neurons are indicated (two-tailed Student’s <i>t</i> test; **, p<0.01; ***, p<0.001). Note in panels J-L) that variable prominence of Elav1/Hu detection in spinal cord is an artefact of antibody penetration into CNS at this late stage. Scale bar, 50 μm.</p

deltaA and deltaD gene expression overlaps with neurog1 in the nascent DRGs.

<p>A-C) <i>deltaA</i> expression (red) clearly overlaps with <i>neurog1</i> (green) in the nascent DRG (arrows) at 30 hpf. D-F) At 38 hpf, <i>deltaA</i> expression is clearly seen in the DRGs, but weaker signals make it difficult to discern if expression is in the same cells as express <i>neurog1</i> or simply in other cells of the ganglia. G-I) <i>deltaD</i> expression (red) clearly overlaps with <i>neurog1</i> (green) in the nascent DRG (arrows) at 38 hpf. All main panels are confocal images of fluorescent dual-color <i>in situ</i> hybridisations in lateral view, with insets showing <i>y-z</i> planes (left) and <i>x-z</i> planes (above) for each. Insets in the bottom right of panels C, F and I show enlargements of the double-labeled cells indicated by the arrows. nc, notochord; sc, spinal cord.</p