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

Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease-associated T183A variant

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP

Mechanism of misfolding of the human prion protein revealed by a pathological mutation

The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant

Mechanism of misfolding of the human prion protein revealed by a pathological mutation

The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant.ISSN:0027-8424ISSN:1091-649

Ensembles from dynamic refinement of non-phosphorylated and phosphorylated phospholamban-SERCA complexes

Full GROMACS ensembles of SERCA-PLN and SERCA-pS16PLN complexes (40 ps time-step, 10200 frames, 400 ns) - SERCA_PLN_E2_apo_Ensemble (6.6 GB). Topology file: SERCA_PLN_E2_apo_frame0.gro (7.8 MB) - SERCA_PLN_E2_pS16_Ensemble.xtc (6.6 GB). Topology file: SERCA_PLN_E2_pS16_frame0.gro (7.8 MB) Stripped GROMACS ensembles of SERCA-PLN and SERCA-pS16PLN complexes (40 ps time-step, 10200 frames, 400 ns) - no water or lipids - nonP_PLN_SERCA_E2_8rep_dt40.xtc (633.8 MB). Topology file: nonP_PLN_SERCA_E2.gro (735.9 kB) - pS16_PLN_SERCA_E2_8rep_dt40.xtc (634.1 MB). Topology file: pS16_PLN_SERCA_E2.gro (736.0 kB) Configuration and restraint files use to generate ensembles Analytical scripts and processed data for: - Principal component analysis - Distance measurements - Contact analysis - Helix allostery Raw experimental data: - All SE-SAMPI4 spectra of PLN and pPLN alone and in complex with SERCA - Raw FID files - Processing script (NMRPipe) - AssignmentsAnalysis, setup and ensembles of the dynamic refinement of phospholamban-SERCA complexes in the calcium-free E2 state. Includes trajectory files, analytic scripts, restraint files, setup files, simulation code, raw data (including OS-ssNMR data) and processed data used for the associated citations as per transparent reporting requirements.National Institutes of Health R01GM064742National Institutes of Health R01HL144100National Institutes of Health R01HL139065National Institutes of Health R37AG026160American Heart Association Postdoctoral Fellowship 19POST34420009European Research Council CoG - BioDisOrder 81964

Identification of the first structurally validated covalent ligands of the small GTPase RAB27A.

Rab27A is a small GTPase, which mediates transport and docking of secretory vesicles at the plasma membrane via protein-protein interactions (PPIs) with effector proteins. Rab27A promotes the growth and invasion of multiple cancer types such as breast, lung and pancreatic, by enhancing secretion of chemokines, metalloproteases and exosomes. The significant role of Rab27A in multiple cancer types and the minor role in adults suggest that Rab27A may be a suitable target to disrupt cancer metastasis. Similar to many GTPases, the flat topology of the Rab27A-effector PPI interface and the high affinity for GTP make it a challenging target for inhibition by small molecules. Reported co-crystal structures show that several effectors of Rab27A interact with the Rab27A SF4 pocket (WF-binding pocket) via a conserved tryptophan-phenylalanine (WF) dipeptide motif. To obtain structural insight into the ligandability of this pocket, a novel construct was designed fusing Rab27A to part of an effector protein (fRab27A), allowing crystallisation of Rab27A in high throughput. The paradigm of KRas covalent inhibitor development highlights the challenge presented by GTPase proteins as targets. However, taking advantage of two cysteine residues, C123 and C188, that flank the WF pocket and are unique to Rab27A and Rab27B among the >60 Rab family proteins, we used the quantitative Irreversible Tethering (qIT) assay to identify the first covalent ligands for native Rab27A. The binding modes of two hits were elucidated by co-crystallisation with fRab27A, exemplifying a platform for identifying suitable lead fragments for future development of competitive inhibitors of the Rab27A-effector interaction interface, corroborating the use of covalent libraries to tackle challenging targets

Clinical Features and Risk Factors for Mortality Among Long-term Care Facility Residents Hospitalized Due to COVID-19 in Spain.

COVID-19 severely impacted older adults and long-term care facility (LTCF) residents. Our primary aim was to describe differences in clinical and epidemiological variables, in-hospital management, and outcomes between LTCF residents and community-dwelling older adults hospitalized with COVID-19. The secondary aim was to identify risk factors for mortality due to COVID-19 in hospitalized LTCF residents. This is a cross-sectional analysis within a retrospective cohort of hospitalized patients ≥75 years with confirmed COVID-19 admitted to 160 Spanish hospitals. Differences between groups and factors associated with mortality among LTCF residents were assessed through comparisons and logistic regression analysis. Of 6 189 patients ≥75 years, 1 185 (19.1%) were LTCF residents and 4 548 (73.5%) were community-dwelling. LTCF residents were older (median: 87.4 vs 82.1 years), mostly female (61.6% vs 43.2%), had more severe functional dependence (47.0% vs 7.8%), more comorbidities (Charlson Comorbidity Index: 6 vs 5), had dementia more often (59.1% vs 14.4%), and had shorter duration of symptoms (median: 3 vs 6 days) than community-dwelling patients (all, p Basal functional status and COVID-19 severity are risk factors of mortality in LTCF residents. The lower adjusted mortality rate in LTCF residents may be explained by earlier identification, treatment, and hospitalization for COVID-19

Peri-implant mucositis.

OBJECTIVES This narrative review was prepared for the 2017 World Workshop of the American Academy of Periodontology and European Federation of Periodontology to address key questions related to the clinical condition of peri-implant mucositis, including: 1) the definition of peri-implant mucositis, 2) conversion of peri-implant health to the biofilm-induced peri-implant mucositis lesion, 3) reversibility of peri-implant mucositis, 4) the long-standing peri-implant mucositis lesion, 5) similarities and differences between peri-implant mucositis at implants and gingivitis at teeth, and 6) risk indicators/factors for peri-implant mucositis. METHODS A literature search of MEDLINE (PubMed) and The Cochrane Library up to and including July 31, 2016, was carried out using the search strategy (peri-implant[All Fields] AND ("mucositis"[MeSH Terms] OR "mucositis"[All Fields])) OR (periimplant[All Fields] AND mucosits[All Fields]). Prospective, retrospective, and cross-sectional studies and review papers that focused on risk factors/indicators for peri-implant mucositis as well as experimental peri-implant mucositis studies in animals and humans were included. FINDINGS Peri-implant mucositis is an inflammatory lesion of the soft tissues surrounding an endosseous implant in the absence of loss of supporting bone or continuing marginal bone loss. A cause-and-effect relationship between experimental accumulation of bacterial biofilms around titanium dental implants and the development of an inflammatory response has been demonstrated. The experimental peri-implant mucositis lesion is characterized by an inflammatory cell infiltrate present within the connective tissue lateral to the barrier epithelium. In long-standing peri-implant mucositis, the inflammatory cell infiltrate is larger in size than in the early (3-week) experimental peri-implant mucositis lesion. Biofilm-induced peri-implant mucositis is reversible at the host biomarker level once biofilm control is reinstituted. Reversal of the clinical signs of inflammation may take longer than 3 weeks. Factors identified as risk indicators for peri-implant mucositis include biofilm accumulation, smoking, and radiation. Further evidence is required for potential risk factors, including diabetes, lack of keratinized mucosa, and presence of excess luting cement. CONCLUSIONS Peri-implant mucositis is caused by biofilm accumulation which disrupts the host-microbe homeostasis at the implant-mucosa interface, resulting in an inflammatory lesion. Peri-implant mucositis is a reversible condition at the host biomarker level. Therefore, the clinical implication is that optimal biofilm removal is a prerequisite for the prevention and management of peri-implant mucositis. An understanding of peri-implant mucositis is important because it is considered a precursor for peri-implantitis