Medication use in Italian nursing homes: preliminary results from the national monitoring system.

Background: The aging population has increased concerns about the affordability, quality, and nature of long-term care for older people, emphasizing the role of nursing homes. Unlike acute hospital and primary care, there is a lack of drug consumption data in long-term care to understand regional or national healthcare policies. Objectives: This study aimed to describe medication consumption by older adults and expenditure in Italian nursing homes (NHs). Methods: Data on drug consumption and costs from the administrative medicine informational flows that detect medicines packages supplied to patients in health facilities and NHs were used. Data on the characteristics of the healthcare residence were from the Italian Health Ministry. Records for the year 2019, selecting the nursing homes exclusively providing elderly or mixed (elderly and disabled) were used. Results: In 2019, the total expenditure on medicines in NHs amounted to 25.38 million euros, the average cost to 1.30 and the expenditure per bed to 436.18 euros. Cardiovascular drugs were the highest-consuming therapeutic class (177.0 defined daily doses-DDDs/100 days of NH stay; 22.2% of total) followed by drugs acting on the alimentary tract and metabolism (167.6% and 21.0%) and blood drugs (160.4% and 20.1%). The treatment of hypertension and heart failure was widely the most frequently used, with the consumption being driven mainly by furosemide and ramipril. Antiulcer drugs were used on average in more than half of the days of NH stay (58.5 DDDs/100 days of NH stay), representing a therapeutic category for which deprescribing initiatives are recommended. On average, almost all patients received a dose of benzodiazepines, antipsychotics and antidepressants (37.6, 35.9, and 17.7 DDDs/100 days of NH stay, respectively), confirming the high prevalence of use for these medicines. Antibiotics reached 6.8 DDDs/100 days of NH stay. Conclusion: The availability of data in this specific setting allows the identification of the main interventions toward improving appropriateness and represents a challenge for drug utilization research. Data from this study suggest that proton pump inhibitors (PPIs), benzodiazepines and antibacterials can be areas of improving prescribing appropriateness.

Socio-economic inequalities in the use of drugs for the treatment of chronic diseases in Italy.

BACKGROUND: Since the use of medicines is strongly correlated to population health needs, higher drug consumption is expected in socio-economical deprived areas. However, no systematic study investigated the relationship between medications use in the treatment of chronic diseases and the socioeconomic position of patients. The purpose of the study is to provide a description, both at national level and with geographical detail, of the use of medicines, in terms of consumption, adherence and persistence, for the treatment of major chronic diseases in groups of population with different level of socioeconomic position.  METHODS: A cross-sectional study design was used to define the "prevalent" users during 2018. A longitudinal cohort study design was performed for each chronic disease in new drug users, in 2018 and the following year. A retrospective population-based study, considering all adult Italian residents (i.e. around 50.7 million people aged ≥ 18 years). Different medications were used as a proxy for underlying chronic diseases: hypertension, dyslipidemia, osteoporosis, diabetes and chronic obstructive pulmonary disease. Only "chronic" patients who had at least 2 prescriptions within the same subgroup of drugs or specific medications during the year were selected for the analysis. A multidimensional measures of socio-economic position, declined in a national deprivation index at the municipality level, was used to identify and estimate the relationship with drug use indicators. The medicine consumption rate for each pharmacological category was estimated for prevalent users while adherence and persistence to pharmacologic therapy at 12 months were evaluated for new users. RESULTS: The results highlighted how the socioeconomic deprivation is strongly correlated with the use of medicines: after adjustment by deprivation index, the drug consumption rates decreased, mainly in the most disadvantaged areas, where consumption levels are on average higher than in other areas. On the other hand, the adherence and persistence indicators did not show the same trend. CONCLUSIONS: This study showed that drug consumption is influenced by the level of deprivation consistently with the distribution of diseases. For this reason, the main levers on which it is necessary to act to reduce disparities in health status are mainly related to prevention. Moreover, it is worth pointing out that the use of a municipal deprivation indicator necessarily generates an ecological bias, however, the experience of the present study, which for the first-time deals with the complex and delicate issue of equity in Italian pharmaceutical assistance, sets the stage for new insights that could overcome the limits.

Starting dose and dose adjustment of non-vitamin K antagonist oral anticoagulation agents in a nationwide cohort of patients with atrial fibrillation.

This study aims to provide real-world data about starting-dose of NOACs and dose-adjustment in patients with atrial fibrillation (AF). In fact, even if new oral anticoagulation agents (NOACs) have a predictable effect without need for regular monitoring, dose-adjustments should be performed according to the summary of product information and international guidelines. We employed the Italian Medicines Agency monitoring registries comprising data on a nationwide cohort of patients with AF treated with NOACs from 2013 to 2018. Logistic regression analysis was used to evaluate the determinants of dosage choice. During the reference period, treatment was commenced for 866,539 patients. Forty-five percent of the first prescriptions were dispensed at a reduced dose (dabigatran 60.3%, edoxaban 45.2%, apixaban 40.9%, rivaroxaban 37.4%). The prescription of reduced dose was associated with older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, but not with CHA2DS2-VASc and HAS-BLED. A relative reduction of the proportion of patients treated with low dosages was evident overtime for dabigatran and rivaroxaban; whereas prescription of low dose apixaban and edoxaban increased progressively among elderly patients. Evidence based on real-world data shows a high frequency of low dose prescriptions of NOACs in AF patients. Except for older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, other factors that may determine the choice of reduced dose could not be ascertained. There may be potential under-treatment of AF patients, but further evaluation is warranted.

Non-vitamin K antagonist oral anticoagulation agents in patients with atrial fibrillation: Insights from Italian monitoring registries.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with an increased risk of stroke and thromboembolism. Anticoagulation with Vitamin K antagonists (VKAs) or with novel oral anti-coagulants (NOACs) represents the cornerstone of the pharmacological treatment to reduce the risk of thromboembolism. This study aims to provide real-world data from a whole large European country about NOAC use in "non-valvular atrial fibrillation" (NVAF). METHODS: We analysed the Italian Medicines Agency (AIFA) monitoring registries collecting data of a nationwide cohort of patients with "NVAF" treated with NOACs. Using logistic regression analysis, baseline characteristics and treatment discontinuation information were compared among initiators of the 4 NOACs. RESULTS: In the reference period, the NOAC database collected data for 683,172 patients. The median age was 78 years with 19.5% aged 85 or older. Overall, the treatments were in accordance with guidelines. About 1/3 of patients switched from a prior VKA treatment; in the 72.3% of cases, these patients had a labile International Normalized Ratio (INR) at first prescription. The most prescribed NOAC was rivaroxaban, followed by apixaban, dabigatran and edoxaban. CONCLUSIONS: This study is the largest European real-world study ever published on NOACs. It includes all Italian patients treated with NOACs since 2013 accounting for about 1/3 of subjects with AF. The enrolled population consisted of very elderly patients, at high risk of ischemic adverse events. The AIFA registries are consolidated tools that guarantee the appropriateness of prescription and provide important information for the governance of National Health System by collecting real-world data.

Lipid- and polymer-based plexes as therapeutic carriers for bioactive molecules.

Recently, promising strategies of plexes include the complexation of nucleic acids with lipids (lipoplexes) and different kinds of polymers (polyplexes) for delivery of actives and genetic material in abnormal conditions like cancer, cystic fibrosis and genetic disorders. The present review article focuses on the comparative aspects of lipoplexes and polyplexes associated with molecular structure, cellular transportation and formulation aspects. The major advantages of lipoplexes and polyplexes over conventional liposomes involve non-immunogenic viral gene transfer, facile manufacturing and preservation of genetic material encapsulated within the nanocarriers. Lipoplexes and polyplexes enhance the transfection of DNA into the cell by stepwise electrostatic cationic-anionic interaction with DNA backbones. The ease and cost-effective formation of complexes extend their applications in the treatment of cancer and genetic disorders. Lipoplexes and polyplexes necessitate intensive research in the fields of quality, toxicity and methods of preparation for commercialization.

Cyclic nigerosyl-1,6-nigerose-based nanosponges: An innovative pH and time-controlled nanocarrier for improving cancer treatment.

The design and structural optimisation of a novel polysaccharide-based nanomaterial for the controlled and sustained release of doxorubicin are here reported. A cross-linked polymer was obtained by reacting a tetraglucose, named cyclic nigerosyl-1-6-nigerose (CNN), with pyromellitic dianhydride. The cross-linking reaction formed solid nanoparticles, named nanosponges, able to swell as a function of the pH. Nanoparticle sizes were reduced using High Pressure Homogenization, to obtain uniform nanosuspensions. Doxorubicin was incorporated into the CNN-nanosponges in a good extent. DSC and solid state NMR analyses proved the drug interaction with the polymer matrix. In vitro studies demonstrated pH-dependent slow and prolonged release kinetics of the drug from the nanoformulation. Doxorubicin-loaded CNN-nanosponges were easily internalized in A2780 cell line. They might considered an intracellular doxorubicin reservoir, able to slowly release the drug over time. CNN-nanosponges may be promising biocompatible nanocarriers for the sustained delivery of doxorubicin with potential localised application in cancer treatments.

O2 selective membranes based on a dextrin-nanosponge (NS) in a PVDF-HFP polymer matrix for Li-air cells.

A novel oxygen selective highly hydrophobic membrane is prepared by non-solvent induced phase separation in which a dextrin-based nanosponge is incorporated into a poly(vinylidene fluoride co-hexafluoropropylene) (PVDF-HFP) matrix. The membrane presents high capability to entrap moisture from air as well as good hydrophobic behaviour. The membrane was assembled in a pouch type Li-air cell, which was cycled in a galvanostatic mode at curtailed capacity, in air with 17% relative humidity (RH). Owing to the protection of the membrane, the Li-air cell was able to discharge and re-charge for approximately 145 cycles, which correspond to about 1450 h of cell operation.

Non-Pharmacological Interventions to Prevent or Treat Delirium in Older Patients: Clinical Practice Recommendations The SENATOR-ONTOP Series.

DESCRIPTION: The ONTOP project aims to undertake a literature search of systematic reviews concerning evidence-based non-pharmacological interventions of prevalent medical conditions affecting older people, including delirium. OBJECTIVES: To develop explicit and transparent recommendations for non-pharmacological interventions in older subjects at risk of developing delirium, as well as in older subjects with delirium, based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to rating the quality of evidence and the strength of recommendations. METHODS: A multidisciplinary panel was constituted comprising geriatricians, research nurse and a clinical epidemiologist. The panel developed a systematic overview of non-pharmacological interventions to prevent or treat delirium. The GRADE approach was used to rate the evidence and to formulate recommendations. RESULTS: The critical outcomes were delirium incidence, for delirium prevention, and delirium improvement and functional status, for delirium treatment. The non-pharmacological interventions were identified and categorized as multicomponent and single component. Strong recommendations in favor of multicomponent interventions to prevent delirium, in surgical or medicals wards, were formulated. In the latter case the evidence applied to older patients at intermediate - high risk of developing delirium. Weak recommendations, to prevent delirium, were formulated for multicomponent interventions provided by family members (medical ward), staff education (medical ward), ear plugs (intensive care unit), reorientation protocol (intensive care unit), and the use of a software to perform drug review. Weak recommendations were provided for the use of multicomponent interventions to prevent delirium in medical wards in patients not selected according to the risk of delirium. Strong recommendations not to use bright light therapy to prevent delirium in intensive care unit settings were articulated. Weak recommendations not to use music therapy to prevent delirium for patients undergoing surgical interventions were specified. The ability to make strong recommendations was limited by the low quality of evidence and the presence of uncertainty. Moreover, weak recommendations were provided for the use of multicomponent interventions to treat delirium of older patients (medical wards). CONCLUSIONS: Overall, the panel developed 12 recommendations for the delivery of non-pharmacological interventions to older patients at risk of developing or, with delirium.

The diagnosis and clinical management of the neuropsychiatric manifestations of lupus.

Neuropsychiatric (NP) involvement in Systemic Lupus Erythematosus (SLE), can be a severe and troubling manifestation of the disease that heavily impacts patient's health, quality of life and disease outcome. It is one of the most complex expressions of SLE which can affect central, peripheral and autonomous nervous system. Complex interrelated pathogenetic mechanisms, including genetic factors, vasculopathy, vascular occlusion, neuroendocrine-immune imbalance, tissue and neuronal damage mediated by autoantibodies, inflammatory mediators, blood brain barrier dysfunction and direct neuronal cell death can be all involved. About NPSLE a number of issues are still matter of debate: from classification and burden of NPSLE to attribution and diagnosis. The role of neuroimaging and new methods of investigation still remain pivotal and rapidly evolving as well as is the increasing knowledge in the pathogenesis. Overall, two main pathogenetic pathways have been recognized yielding different clinical phenotypes: a predominant ischemic-vascular one involving large and small blood vessels, mediated by aPL, immune complexes and leuko-agglutination which it is manifested with more frequent focal NP clinical pictures and a predominantly inflammatory-neurotoxic one mediated by complement activation, increased permeability of the BBB, intrathecal migration of autoantibodies, local production of immune complexes and pro-inflammatory cytokines and other inflammatory mediators usually appearing as diffuse NP manifestations. In the attempt to depict a journey throughout NPSLE from diagnosis to a reasoned therapeutic approach, classification, epidemiology, attribution, risk factors, diagnostic challenges, neuroimaging techniques and pathogenesis will be considered in this narrative review based on the most relevant and recent published data.

Vibrational signatures of the water behaviour upon confinement in nanoporous hydrogels.

The fundamental question of how the reorganization of the hydrogen-bond (HB) network of water is influenced by the combination of nano-confinement and hydrophobic/hydrophilic solvation effects is addressed here using a spectroscopic study of water absorbed in a model, pH-sensitive polysaccharide hydrogel. The effects of temperature, hydration level and pH on the vibrational dynamics associated with the water molecules and the polymer skeleton are disentangled and analysed by a complementary and combined use of UV-Raman scattering and IR spectroscopy. The experimental data give evidence that the solvation effects in the hydrogel matrix are essentially dominated by the hydration of more hydrophobic parts of the polymer network, while the effect of pH on the HB reorganization of confined water molecules is found to be similar to that induced by cooling of the system. A tentative explanation of these results has been provided in terms of interplay between different kinds of interactions, i.e. hydrophobic vs. hydrophilic.

Brain unidentified bright objects ("UBO") in systemic lupus erythematosus: sometimes they come back. A study of microembolism by cMRI and Transcranial Doppler ultrasound.

OBJECTIVES: The objectives of this report are to assess the occurrence of microembolic signals (MES) detected by transcranial Doppler ultrasound (TCD) in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (SLE) neuropsychiatric involvement, and to verify the correlation between MES, clinical characteristics, especially the patent foramen ovale (PFO), and the presence of punctuate T2-hyperintense white matter lesions (WMHLs) detected by conventional magnetic resonance imaging (cMRI). METHODS: A TCD registration to detect MES from the middle cerebral artery was carried out in SLE and NPSLE patients after exclusion of aortic and/or carotid atheromatous disease. In all patients conventional brain magnetic resonance imaging (cMRI) and transesophageal echocardiography were performed. Patients were stratified in two groups, with and without WMHLs, and compared. RESULTS: Twenty-three SLE patients (16 NPSLE and seven SLE) were enrolled in the study. Overall MES were detected in 12 patients (52.1%), WHMLs were detectable in 15 patients (13 NPSLE and two SLE) while eight patients had normal cMRI (three NPSLE and five SLE). Matching TCD ultrasound and neuroimaging data, MES were detected in 10 (nine NPSLE and one SLE) out of 15 patients with WHMLs and in only two out of eight patients (two NPSLE and six SLE) with normal cMRI, both with NP involvement. A PFO was confirmed in all cases of MES detection. CONCLUSION: MES are frequent findings in SLE patients, especially in those with focal WMHLs detected by cMRI and correlating with PFO. These findings should be taken into account and suggest caution in the interpretation of cMRI pictures along with a careful evaluation of MES in patients with cMRI abnormalities that should be included in the workup of SLE patients.

Combining Raman and infrared spectroscopy as a powerful tool for the structural elucidation of cyclodextrin-based polymeric hydrogels.

A detailed experimental and theoretical vibrational analysis of hydrogels of ß-cyclodextrin nanosponges (ß-CDNS), obtained by polymerization of ß-cyclodextrin (ß-CD) with the cross-linking agent ethylenediaminetetraacetic acid (EDTA), is reported here. Thorough structural characterization is achieved by exploiting the complementary selection rules of FTIR-ATR and Raman spectroscopies and by supporting the spectral assignments by DFT calculations of the spectral profiles. The combined analysis of the FTIR-ATR spectra of the polymers hydrated with H2O and D2O allowed us to isolate the HOH bending of water molecules not involved in symmetrical, tetrahedral environments. The analysis of the HOH bending mode was carried out as a function of temperature, showing the existence of a supercooled state of the water molecules. The highest level of cooperativity of the hydrogen bond scheme was reached at a value of the ß-CD/EDTA molar ratio n = 6. Finally, the connectivity pattern of "uncoupled" water molecules bound to the nanosponge backbone was found to be weakened by increasing T. The temperature above which the population of non-tetracoordinated water molecules becomes predominant turned out to be independent of the parameter n.

Diagnosing and treating depression in older and oldest old.

Depression is very common in older people and it is associated with negative consequences such as functional decline, increased morbidity and mortality and higher healthcare costs. Despite this, it is still underdiagnosed and undertreated and the issue is particularly relevant for people older than 80 years. The main reasons for underdiagnosis are: atypical presentation, concomitant cognitive decline, inadequate diagnostic tools, and prejudice that depression is a normal part of ageing. On the other hand, the main reasons for undertreatment are: multimorbidity, concerns about adverse events and drug interactions, lack of confidence in the efficacy and safety of pharmacological and non-pharmacological treatments in the oldest old depressed patients, who are underrepresented in clinical studies. The new antidepressants are the drugs most frequently used, due to their perceived more favorable safety profile than older antidepressants. Psychotherapy is equally effective but less frequently used and should request some adaptive strategies for the peculiarities of octogenarians. Electroconvulsive therapy is limited to severe psychotic late-life depression resistant to other treatments. In light of the heterogeneity of people aged 80 years and over, with multiple and different medical, functional, socioeconomic problems, a multidimensional approach is probably the most suitable both for diagnosis and treatment, in order to develop an individualized care plan. These considerations should guide the formulation of future research studies, specifically tailored for the oldest depressed patients.

Probing the molecular connectivity of water confined in polymer hydrogels.

The molecular connectivity and the extent of hydrogen-bond patterns of water molecules confined in the polymer hydrogels, namely, cyclodextrin nanosponge hydrogels, are here investigated by using vibrational spectroscopy experiments. The proposed spectroscopic method exploits the combined analysis of the vibrational spectra of polymers hydrated with water and deuterated water, which allows us to separate and selectively investigate the temperature-evolution of the HOH bending mode of engaged water molecules and of the vibrational modes assigned to specific chemical groups of the polymer matrix involved in the physical interactions with water. As main results, we find a strong experimental evidence of a liquid-like behaviour of water molecules confined in the nano-cavities of hydrogel and we observe a characteristic destructuring effect on the hydrogen-bonds network of confined water induced by thermal motion. More interestingly, the extent of this temperature-disruptive effect is found to be selectively triggered by the cross-linking degree of the hydrogel matrix. These results give a more clear picture of the molecular mechanism of water confinement in the pores of nanosponge hydrogel and open the possibility to exploit the spectroscopic method here proposed as investigating tools for water-retaining soft materials.

Water and polymer dynamics in a model polysaccharide hydrogel: the role of hydrophobic/hydrophilic balance.

The molecular dynamics of water and a polymer matrix is here explored in a paradigmatic model of a polysaccharide hydrogel, by the combined use of UV Raman scattering and infrared measurements. The case example of cyclodextrin nanosponges (CDNS)/hydrogel is chosen since the simultaneous presence in the structure of the polymer matrix of both hydrophilic and hydrophobic sites mimics the complexity of polysaccharide hydrogels. In this way, the contributions provided by the balance between the hydrophilicity/hydrophobicity and the grade of entanglement of the polymer hydrogel to lead to the formation of the gel phase are separately accounted and evaluated. As main results, we found that the hydrophobic CH groups inserted on the aromatic ring of CDNS experience a more pronounced dynamic perturbation with respect to the carbonyl groups due to the collision between the solvent and vibrating atoms of the polymer. The overall results provide a detailed molecular picture of the swelling phenomena occurring when a chemically cross-linked polymer contacts with water or biological fluids and exploits the potentiality of UV Raman spectroscopy to retrieve dynamic information besides their structural counterpart obtained by the classical analysis of the basic features of vibrational spectra.

How do the EMA and FDA decide which anticancer drugs make it to the market? A comparative qualitative study on decision makers' views.

BACKGROUND: The process leading to a regulatory outcome is guided by factors both related and unrelated to the data package, defined in this analysis as 'formal and informal factors', respectively. The aim of this qualitative study was to analyse which formal and informal factors drive the decision-making process of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulators with regard to anticancer drugs, using in-depth semi-structured interviews with regulators of the two agencies. METHODS: In line with the theory and practice of qualitative research, no set sample size was defined a priori. Respondent enrolment continued until saturation and redundancy were reached. Data were collected through means of in-depth semi-structured interviews conducted either in a face-to-face setting or via Skype(®) with each regulator. The interviews were audio-recorded and verbatim transcribed. The analysis was manually carried out on the transcribed text. Data were independently coded and categorized by two researchers. Interpretation of the findings emerged through a process of triangulation between the two. RESULTS: Seven EMA and six FDA regulators, who had extensive experience with making decisions about anticancer medicines, were interviewed between April and June 2012. There is an open dialogue between the FDA and EMA, with the two moving closer and exchanging information, not opinions. Differences in decision-making between the agencies may be due to a different evaluation of end points. Different interaction modalities with industry and patients represent an additional source of divergence with a potential impact on decision-making. The key message of our respondents was that the agencies manage uncertainty in a different way: unlike the EMA, the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments. CONCLUSIONS: Although formal factors are the main drivers for regulatory decisions, the influence of informal factors plays an important role in the drug evaluation process.

Systematic review of 2008-2012 literature and update of recommendations for the use of methotrexate in rheumatic diseases, with a focus on rheumatoid arthritis.

The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases. The literature published between 2008 and 2012 was systematically reviewed and updated recommendations on MTX use in rheumatic diseases, particularly RA, were formulated. These recommendations were approved by a panel of expert Italian Rheumatologists. A total of 10,238 references were identified, among which 70 studies were selected for critical evaluation. Sufficient evidence had accumulated to warrant changes to several of the recommendations in the new version. A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed.