Nursing Assessment of Wound-Related Pain: An Italian Learning Survey.

BACKGROUND: Pain is an important symptom in wound management, and the choice of treatment directly affects the patient's quality of life. Pain assessment (PA) is essential for quality wound care and, in Italy, mandatory by law. OBJECTIVE: To administer a dedicated learning survey to obtain a better sense of current PA practices, ensure more training, improve procedures, and reduce malpractice. METHODS: A 16-month learning survey of nurses based on a validated questionnaire developed for this project. RESULTS: The survey sample comprised 512 questionnaires. Of respondents, 78% were female, 56.1% were older than 40 years, 94% were RNs, and 6% were wound care specialist nurses. Participants performed a range of dressing changes per week (1-5, 46.3%; 6-20, 34.4%; >21, 19.3%). Although 93% of respondents considered PA important, only 26% recognized it as a vital parameter, and barely one-quarter (25.4%) were aware of current legislation mandating PA. The majority (95.3%) believed that PA is not consistent with pain perceived by the patient. Further, 87.3% stated that they did not have adequate knowledge to conduct a PA, 91.4% did not consider themselves up-to-date on PA, and 81% did not document PA results. However, specific wound care training leads to significantly better PA (P < .001): 71.9% of wound care specialist nurses recognized pain as a vital parameter, and 59.4% were aware of current legislation regarding PA; further, 81.3% consistently evaluated pain, 59.4% documented PA results, and 50% communicated the outcome to the physician in charge. CONCLUSIONS: The results illustrate the lack of sensitivity, training, and education that Italian RNs have regarding PA in wound care.

[Errors in Medicine: perceptions of nursing students in Rome]. / Errori in medicina: la percezione degli studenti in Infermieristica di Roma.

INTRODUCTION: The error in medicine has long been discussed in scientific debates. The purpose of this study is to evaluate the degree knowledge, attitude and behavior of students in Nursing for the failure in the health sector. METHODS: It was administered to 231 students of Nursing of the Sapienza University of Rome (171 females and 60 males), aged between 21 and 45 years, a structured questionnaire in three questions that explore the experiences and opinions about the errors found in medical practice, the causes underlying them and the mistakes that should never be committed. Data were collected, stratified by sex, age, marital status, and analyzed using the χ2 test. Significance was set at p≤0.05. RESULTS: The 5 errors found more frequently in clinical practice by the students were the following: Errors that favors the onset of hospital infections (58.9%); Non adherence to protocols (50.2%); Patient care (45.9%); Errors due to the administration of therapies and drugs (45.9%); Errors relating to the execution of withdrawals (35.9%). The five cases considered most frequently responsible for such errors were: the rush (70.1%), followed by neglect / superficial (55%); disorganization (51.5%); not hygienically / infertility (50.6%) and inattention (42.9%). With regard to the errors that you should never commit, students have shown more frequently: the errors of administration of therapies / medications (69.3%); errors of prescription therapies / medications (58.9%); errors related to surgery (52.8%); the exchange of patient or misidentification of the patient (50.6%); errors that favor the occurrence of hospital infections (48.1%). CONCLUSIONS: The results of this study shows the importance of a culture of error in medicine, also as part of undergraduate education, in order to train and educate future health professionals to this issue in order to promoting patient safety and quality of health.

A Systematic Review on the Cost-Effectiveness of Genetic and Electrocardiogram Testing for Long QT Syndrome in Infants and Young Adults.

BACKGROUND: Recent improvements in the identification of the genetic basis of long QT syndrome (LQTS) have led to significant changes in the diagnosis and management of this life-threatening condition. Genetic and electrocardiogram (ECG) tests are the most relevant examples among testing strategies for LQTS, yet their cost-effectiveness remains controversial. OBJECTIVE: The aim of this work was to review the available evidence on the cost-effectiveness of genetic and ECG testing strategies for the diagnosis of LQTS. METHODS: We performed a systematic review of the literature on the cost-effectiveness of genetic and ECG screening strategies for the early detection of LQTS using MEDLINE, EMBASE, and CRD databases between 2000 and 2013. A weighted version of Drummond checklist was instrumental in further assessing the quality of the included studies. RESULTS: We identified four eligible articles. Among them, genetic testing in the early detection of LQTS was cost-effective compared with no testing in symptomatic cases and not cost-effective when compared with watchful waiting in asymptomatic first-degree relatives of patients with established LQTS although it reached cost-effectiveness in higher risk subgroups, whereas ECG testing in neonates was highly cost-effective when compared with any screening strategy. CONCLUSIONS: LQTS profiling and patients' stratification have the potential to improve the disease management. Because of the limited current knowledge in this field, the present review recommends to perform further cost-effectiveness evaluations of the genetic and ECG screening alternatives, especially within European health care systems, which are still not available in the literature on genetic testing.

Extracorporeal Photopheresis for Second-Line Treatment of Chronic Graft-versus-Host Diseases: Results from a Health Technology Assessment in Italy.

OBJECTIVES: To develop a comparative, cost-effectiveness, and budget impact analysis of Therakos online extracorporeal photopheresis (ECP) compared with the main alternatives used for the treatment of steroid-refractory/resistant chronic graft-versus-host disease (cGvHD) in Italy. METHODS: The current therapeutic pathway was identified by searching medical databases and from the results of a survey of practice in Italian clinical reference centers. A systematic review was performed to evaluate the efficacy and safety of second-line alternatives. Budget impact and cost-effectiveness analyses were performed from the Italian National Health Service perspective over a 7-year time horizon through the adaption of a Markov model. The following health states were considered: complete and partial response, stable disease, and progression. A discount rate of 3% was applied to costs and outcomes. RESULTS: The most common alternatives used in Italy for the management of steroid-refractory/resistant cGvHD were ECP, mycophenolate, pentostatin, and imatinib. The literature review highlighted that complete and partial responses are higher with ECP than with the alternatives while serious adverse events are less common. The economic analysis showed that Therakos online ECP represents the dominating alternative, in that it delivers greater benefit at a lower cost. In fact, according to the alternatives considered, cost saving ranged from €3237.09 to €19,903.51 per patient with 0.04 to 0.21 quality-adjusted life-year gained. CONCLUSIONS: Therakos online ECP should be considered an effective, safe, and cost-effective alternative in steroid-refractory/resistant cGvHD. There is inequality in access, and a dedicated reimbursement tariff, however, should be introduced to overcome these barriers.

Economic impact of adult obesity on health systems: a systematic review.

BACKGROUND: Obesity represents an important public health issue. An assessment of its costs would be useful to provide recommendations for policy and decision-making strategies. The aims of our study were to carry out a systematic review to assess the economic burden of adult obesity in terms of direct and indirect costs and to perform a quality appraisal of the analysed studies. METHODS: A literature search was carried out on PubMed, Scopus and Cochrane Library to retrieve cost-of-illness (COI) analyses focused on adult (aged 18 years or more) overweight or obese people and published up to 2013. COI analyses that considered direct and indirect costs were included. Each included manuscript was independently appraised by three groups of researchers on the basis of the British Medical Journal Drummond's checklist. RESULTS: Approximately 2044 articles were initially retrieved, and 17 were included in the current review. The included studies showed a medium-high-quality level. The available studies seemed to be heterogeneous both in terms of methodology and results reporting. However, as many studies have been conducted from the payer perspective, just direct medical costs can be considered exhaustive. As only three studies included considered also indirect costs, there is no strong evidence to give a comprehensive picture of this phenomenon also from the societal perspective. CONCLUSION: The review confirmed that obesity absorbs a huge amount of health-care resources. Further research is therefore needed to better understand the economic impact and to identify and promote public health strategies to tackle obesity.

Haemophilia A: pharmacoeconomic review of prophylaxis treatment versus on-demand.

OBJECTIVES: Haemophilia A is a congenital disorder of coagulation that mainly affects males and causes a considerable use of resources, especially when hemophilic patients are treated with prophylaxis. The aim of the present review was to discuss and appraise the methodological aspects and results of published economic evaluations of haemophilia A treatments in the last decade. METHODS: The literature search, performed by consulting four engines, covered studies published between 2002 and 2014. Full economic evaluations published in English language were identified and included in the review. A quality assessment of the studies was also carried out based on Drummond's checklist. RESULTS: After careful evaluations of the identified records, 5 studies were reviewed. Primary and secondary prophylaxis resulted cost-effective compared to on-demand therapy: the ICER of primary prophylaxis ranged from € 40.236 to € 59.315/QALY gained, while the ICER of secondary prophylaxis was € 40.229/QALY gained. Furthermore, 60% were high quality and 40% were medium quality studies. CONCLUSIONS: The review underlines the cost-effectiveness of prophylaxis versus on-demand treatment and the different methodological approaches applied. Further economic evaluations are required with models that reflect the clinical reality and consumption of resources in each country.

Building successful collaborations between Public Health and Primary Health Care.

Public Health (PH) and Primary Health Care (PHC) need to be better integrated, at different levels of the healthcare system, in order to improve health and social outcomes. The aim of this study was to review international models and approaches supporting the integration of PH and PHC and to classify these according to their main focus. A literature search was performed using the main scientific databases, to identify national and international journal publications regarding models to support integration between PH and PHC. The final set of the documents provided a broad coverage of the topic. Four models of integration were identified: general integration, chronic disease prevention, targeted prevention or care delivery and infection control. Models differed in their levels of implementation, stages of development and focus. This review, by classifying the main characteristics and results of the experiences retrieved, indicates a relatively scarce use of integration models in the global health care landscape, with the exception of Canada. In fact, Canada has been a leader in developing models of integrated health systems that combine tailored approaches to influence personal health behaviour and community-oriented approaches to influence the health of the population. The review also revealed a general lack of experience in evaluating the sustainability of integration between PH and PHC, not only in terms of cost-effectiveness, but also in terms of better health and work conditions and self-perceived quality of care in the population. Collaboration between PH and PHC seems to be an important strategy for achieving principles of equity and access in health care and for ensuring a more equal distribution of health care services.

Fatty acid acylated peptide therapeutics: discovery of omega-n oxidation of the lipid chain as a novel metabolic pathway in preclinical species.

We recently described C18 fatty acid acylated peptides as a new class of potent long-lasting single-chain RXFP1 agonists that displayed relaxin-like activities in vivo. Early pharmacokinetics and toxicological studies of these stearic acid acylated peptides revealed a relevant oxidative metabolism occurring in dog and minipig, and also seen at a lower extent in monkey and rat. Mass spectrometry combined to NMR spectroscopy studies revealed that the oxidation occurred, unexpectedly, on the stearic acid chain at ω-1, ω-2 and ω-3 positions. Structure-metabolism relationship studies on acylated analogues with different fatty acids lengths (C15-C20) showed that the extent of oxidation was higher with longer chains. The oxidized metabolites could be generated in vitro using liver microsomes and engineered bacterial CYPs. These systems were correlating poorly with in vivo metabolism observed across species; however, the results suggest that this biotransformation pathway might be catalyzed by some unknown CYP enzymes.

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.

Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapy-experienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC(90) values 15- to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC(50) only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC(90) values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility.

Peer pressure and public reporting within healthcare setting: improving accountability and health care quality in hospitals.

In the last few years, the need of public reporting of health outcomes has acquired a great importance. The public release of performance results could be a tool for improving health care quality and many attempts have been made in order to introduce public reporting programs within the health care context at different levels. It would be necessary to promote the introduction of a standardized set of outcome and performance measures in order to improve quality of health care services and to make health care providers aware of the importance of transparency and accountability.

Oligomerization, albumin binding and catabolism of therapeutic peptides in the subcutaneous compartment: An investigation on lipidated GLP-1 analogs.

Lipidation, a common strategy to improve half-life of therapeutic peptides, affects their tendency to oligomerize, their interaction with plasmatic proteins, and their catabolism. In this work, we have leveraged the use of NMR and SPR spectroscopy to elucidate oligomerization propensity and albumin interaction of different analogs of the two marketed lipidated GLP-1 agonists liraglutide and semaglutide. As most lipidated therapeutic peptides are administered by subcutaneous injection, we have also assessed in vitro their catabolism in the SC tissue using the LC-HRMS-based SCiMetPep assay. We observed that oligomerization had a shielding effect against catabolism. At the same time, binding to albumin may provide only limited protection from proteolysis due to the higher unbound peptide fraction present in the subcutaneous compartment with respect to the plasma. Finally, identification of catabolites in rat plasma after SC dosing of semaglutide showed a good correlation with the in vitro data, with Tyr19-Leu20 being the major cleavage site. Early characterization of the complex interplay between oligomerization, albumin binding, and catabolism at the injection site is essential for the synthesis of lipidated peptides with good pharmacokinetic profiles.

DPP-IV-resistant, long-acting oxyntomodulin derivatives.

Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capitò E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use.

[Pay for performance in primary care]. / Pay for Performance nell'assistenza primaria: per una sanità di qualità

Pay for Performance is a tool that links payment of healthcare professionals to the quality of health outcomes and processes. In this article the authors discuss the results of a literature review on the subject, highlighting the importance of introducing a Pay for Performance system in primary care, and the advantages and critical issues associated with the system. The experience of the British National Health Service and possible uses of the described payment system in Italy are also briefly discussed.

Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases.

The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).

Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.

Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease containing a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addition to being potent inhibitors of HCV subgenomic replication, optimized analogues within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.

ApoA-I mimetic peptides promote pre-ß HDL formation in vivo causing remodeling of HDL and triglyceride accumulation at higher dose.

Reverse cholesterol transport promoted by HDL-apoA-I is an important mechanism of protection against atherosclerosis. We have previously identified apoA-I mimetic peptides by synthesizing analogs of the 22 amino acid apoA-I consensus sequence (apoA-I(cons)) containing non-natural aliphatic amino acids. Here we examined the effect of different aliphatic non-natural amino acids on the structure-activity relationship (SAR) of apoA-I mimetic peptides. These novel apoA-I mimetics, with long hydrocarbon chain (C(5-8)) amino acids incorporated in the amphipathic α helix of the apoA-I(cons), have the following properties: (i) they stimulate in vitro cholesterol efflux from macrophages via ABCA1; (ii) they associate with HDL and cause formation of pre-ß HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-ß HDL formation in vivo, with a corresponding increase in ABCA1-dependent cholesterol efflux capacity ex vivo; (iv) at high dose they associate with VLDL and induce hypertriglyceridemia in mice. These results suggest our peptide design confers activities that are potentially anti-atherogenic. However a dosing regimen which maximizes their therapeutic properties while minimizing adverse effects needs to be established.

Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System.

The blood-brain barrier (BBB) is responsible for the homeostasis between the cerebral vasculature and the brain and it has a key role in regulating the influx and efflux of substances, in healthy and diseased states. Stem cell technology offers the opportunity to use human brain-specific cells to establish in vitro BBB models. Here, we describe the establishment of a human BBB model in a two-dimensional monolayer culture, derived from human induced pluripotent stem cells (hiPSCs). This model was characterized by a transendothelial electrical resistance (TEER) higher than 2000 Ω∙cm2 and associated with negligible paracellular transport. The hiPSC-derived BBB model maintained the functionality of major endothelial transporter proteins and receptors. Some proprietary molecules from our central nervous system (CNS) programs were evaluated revealing comparable permeability in the human model and in the model from primary porcine brain endothelial cells (PBECs).

Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides.

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS.

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies.