Applications to augment patient care for Internal Medicine specialists: a position paper from the EFIM working group on telemedicine, innovative technologies & digital health.

Telemedicine applications present virtually limitless prospects for innovating and enhancing established and new models of patient care in the field of Internal Medicine. Although there is a wide range of innovative technological solutions in Europe, there are overarching elements associated with such technologies when applied to the practices of Internal Medicine specialists. The European Federation of Internal Medicine (EFIM) strongly advocates for active leadership and influence from the Internal Medicine societies and specialist physicians across Europe in the development and application of telemedicine and digital technologies in healthcare. This position paper's conclusions were drawn via Delphi method, which was developed collaboratively from July 2021 to December 2023. The panel, consisting of experts in clinical medicine, public health, health economics and statistics, assessed various aspects related to telemedicine. Participants assigned scores on a Likert scale reflecting perceived value and potential risks. The findings were consolidated in a comprehensive checklist aligning with relevant literature and a SWOT analysis. Specifically, key issues that need to be addressed include promoting the professional development of e-health competencies in the healthcare and medical workforce, using educational campaigns to promote digital literacy among patients and caregivers, designing and implementing telemedicine applications tailored to local conditions and needs and considering the ethical and legal contexts under which these applications are employed. Importantly, there is currently no consensus on care models or standardized protocols among European Internal Medicine specialists regarding the utilization of telemedicine. This position paper aims to outline the opportunities and challenges associated with the application of telemedicine in Internal Medical practice in Europe.

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib.

BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Cost-Effectiveness Analysis of Lesinurad/Allopurinol Versus Febuxostat for the Management of Gout/Hyperuricemia in Italy.

BACKGROUND: Until very recently the only therapeutic alternative for the management of patients affected by gout/hyperuricemia that did not respond to a first-line treatment based on allopurinol alone or who cannot tolerate allopurinol was febuxostat, a xanthine oxidase non-purine-selective inhibitor. Lately, however, a new therapeutic alternative has become available for the management of this pathology: lesinurad, a urate transporter inhibitor. OBJECTIVE: To objective of this study was to evaluate the cost effectiveness of lesinurad/allopurinol in comparison with febuxostat as a second-line therapeutic strategy for the management of patients affected by gout and hyperuricemia that did not respond to a first-line therapy based on allopurinol alone. METHODS: A Markov model was built based on the natural history of the pathology; patients entered the model according to their level of serum uric acid concentration and flowed across it according to their response to the therapy. The analysis was carried out considering the perspective of the Italian National Health Service on a lifetime horizon and 6-month cycles. Costs and quality-adjusted life-years (QALYs) were discounted at a 3.5% yearly rate. The results of the model were expressed in terms of incremental cost-effectiveness ratio (ICER). Both a one-way and a multi-way Monte-Carlo analysis were carried out in order to check the robustness of the results achieved. RESULTS: The ICER derived from the comparison was equal to €77.53/QALY on the lifetime horizon, as there was a higher level of costs associated with the combination as compared with febuxostat (€10,658.27 vs. €10,645.87, for a differential of €12.40) and a higher level of QALYs achieved (7.77 vs. 7.61, for a differential of 0.16). CONCLUSIONS: The lesinurad/allopurinol combination is recommended for the treatment of patients affected by gout/hyperuricemia in the Italian Health System as it appears to be cost effective and thus sustainable for the Italian healthcare sector.

Economic evaluation of Zepatier for the management of HCV in the Italian scenario.

BACKGROUND: Hepatitis C virus (HCV) is a major health issue worldwide. New generation of direct-active antiviral medications is an epoch-making turning point in the management of HCV infections. OBJECTIVE: Conducing a cost-effectiveness analysis comparing the combination of elbasvir/grazoprevir and sofosbuvir + pegylated interferon/ribavirin for the management of all HCV patients (even those in the initial stages of fibrosis). METHODS: A Markov model was built on the natural history of the disease to assess the efficacy of the alternatives. The outcomes are expressed in terms of quality adjusted life-years (QALYs) and result in terms of incremental cost-effectiveness ratio). RESULTS: Elbasvir/grazoprevir implies an expenditure of €21,104,253.74 with a gain of 19,287.90 QALYs and sofosbuvir + pegylated interferon/ribavirin implies an expenditure of €31,904,410.11 with a gain of 18,855.96 QALYs. Elbasvir/grazoprevir is thus a dominant strategy. CONCLUSION: Consideration should be given to the opportunity cost of not treating patients with a lower degree of fibrosis (F0-F2).

Liver Transplantation Using Prolonged Cold Ischemia Time Grafts Preserved With Institute George-Lopez-1 Solution.

Institute George-Lopez-1 (IGL-1) solution is a preservation solution with lower potassium and lower viscosity than the University of Wisconsin solution that has been recently used in liver transplantation. In the present series, we compare the outcome of liver grafts from brain-dead donors preserved in IGL-1cold storage solution, with cold ischemia times (CITs) longer than 8 hours and those less than 8 hours. Two hundred fifty-two liver transplantations performed from January 2014 to December 2016 at Hospital Santa Isabel, Blumenau, Brazil, were retrospectively analyzed. The patients were divided in two groups according to the CIT. Group I patients (N = 155) had less than 8 hours of CIT with a mean age of 54 ± 11.35 years, whereas group II patients (N = 97) had more than 8 hours of CIT with a mean age of 52 ± 12.5 years. There was no difference between the groups related to indication for liver transplantation and donor characteristics. The only difference statically significant on laboratory data was between the levels of aspartate aminotransferase at day 1 after transplantation. On day 7 post-transplantation there was no difference statistically significant between aspartate aminotransferase, alanine aminotransferase, and bilirubin levels between the two groups. Similar 1-year patient survival rates were found in both groups, with 85.88% for group I and 85.75% in group II. The IGL-1 solution has been shown to be safe, effective, and with good results in liver transplantations. Early graft function and 1-year patient survival rates did not differ when grafts preserved for less than 8 hours were compared to those with CIT greater than 8 hours.

[Personality characteristics, defence mechanisms and binge eating in obese patients]. / Caratteristiche di personalità, meccanismi di difesa e binge in un gruppo di pazienti obesi.

AIMS: This study aimed to investigate defence mechanisms and personality characteristics in obese subjects. In particular, we compared the use of defence mechanisms in two groups: obese persons vs. normal weight subjects. We also compared the defence mechanisms and personality characteristics of two groups of obese subjects: those with Binge Eating Disorder vs. those without this disorder. Finally, we investigated the presence of possible differences linked to gender or to age of onset of obesity. METHODS: 93 obese subjects and 68 normal weight subjects were administered a test battery composed of the following self-complete questionnaires (in the Italian version): Binge Eating Scale, Response Evaluation Measure-71, Eating Disorder Inventory-2 and Minnesota Multiphasic Personality Inventory). RESULTS: Obese subjects appear to use specific defence mechanisms. A gender effect was found on the use of defence mechanisms, on the psychological characteristics associated to an Eating Disorder and on personality features. Obese subjects with Binge Eating Disorder showed a marked tendency to manifest anxiety and bulimic behaviour. Obesity with onset in adolescence was associated with the possibility of developing drug dependence. CONCLUSION: Specific defence characteristics and personality features in obese subjects should be taken into account in designing a slimming program.

Economic Analysis and Budget Impact of Tenofovir and Entecavir in the First-Line Treatment of Hepatitis B Virus in Italy.

BACKGROUND: Chronic hepatitis B is a common, progressive disease, particularly when viral replication is detected. Oral antivirals can suppress viral replication and prevent or delay the development of cirrhosis and liver-related complications. The treatments of chronic hepatitis B cannot totally cure the disease but can prevent its progression to hepatocellular carcinoma, decreasing the levels of both morbidity and mortality. To date, there are several therapies indicated by the international guidelines as first-line treatments for the management of hepatitis B; two of the most effective are those based on either tenofovir or entecavir. OBJECTIVE: The aim of this study is to evaluate the cost-effectiveness of tenofovir and entecavir in the treatment of naïve patients with chronic hepatitis B. The two treatments are compared with the "no treatment" and to one another. METHODS: The cost-effectiveness analysis was conducted using a Markov model; patients entered one of the following health states: chronic hepatitis, cirrhosis (compensated or decompensated), hepatocellular carcinoma, liver transplantation or death. The analysis was carried out from the perspective of the Italian National Health Service by considering a life-time horizon with cycles lasting 1 year and with costs and QALYs (quality-adjusted life years) discounted at a rate of 3.5%. The results of the model were analysed in terms of incremental cost-effectiveness ratio (ICER). RESULTS: ICERs for tenofovir and entecavir emerging from the comparison versus "no treatment" were equal to €10,274.73 and €16,300.44 per QALY gained, respectively, on the life-time horizon. Tenofovir was dominant in the direct comparison with entecavir, indicating more QALYs and a lower consumption of resources. The Monte Carlo simulation demonstrated that in 97% (tenofovir) and in 85% (entecavir) of the scenarios performed, the cost per QALY fell below the threshold of €30,000/QALY. The budget impact analysis showed savings for tenofovir amounting to 33% compared to entecavir in the first year on treatment and to 31% in following years. CONCLUSIONS: Entecavir and tenofovir are recommended for the treatment of patients with chronic Hepatitis B in the Italian Health System. In particular, tenofovir appeared to be the more cost-effective drug for the management of chronic hepatitis B virus (HBV) infections. These results could help decision makers and clinicians to address their decision when choosing a first-line treatment for the management of people affected by chronic HBV.

A prospective study to assess osseointegration of dental endosseous implants with the Periotest instrument.

Long-term studies have documented the successful treatment of edentulous and partially edentulous patients with titanium implants. However, the inability to identify some non-osseointegrated implants before occlusal loading is costly to practitioners and patients. This study followed all patients (n = 40) who had implants placed over a 6-month period. The Periotest instrument was used at Stage II surgery, final impression, prosthesis placement, and 6 and 12 months after occlusal loading to quantify mobility/lack of mobility of implants with conventional 1-piece temporary healing abutments in place. The positive predictive value was 64%. The Periotest instrument was able to identify non-integrated implants only when measured at Stage II surgery and 12 months after occlusal loading, 64% of the time. However, Periotest values recorded at Stage II surgery are not valid predictors of non-osseointegrated implants 12 months post-occlusal loading.

Early detection of hepatocellular carcinoma in patients with cirrhosis by alphafetoprotein, ultrasound and fine-needle biopsy.

Hepatocellular carcinoma (HCC) may be detected at a relatively early stage in patients with liver cirrhosis regularly followed by screening programs using ultrasonography (US) and alpha-fetoprotein (AFP) measurement. Using both tests in 214 consecutive cirrhotic patients with no clinical signs of liver cancer, we detected HCC in 20 cases (9.4%). The sensitivity of US was greater (85%) than that of AFP (75%), and the combination of the two methods had a sensitivity of 100%. Only 50% of patients with focal liver lesions at US had a final diagnosis of HCC that was obtained in the majority of cases by US-guided fine needle biopsy.

Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity.

Smac mimetics (SMs) comprise a class of small molecules that target members of the inhibitor of apoptosis family of pro-survival proteins, whose expression in cancer cells hinders the action of conventional chemotherapeutics. Herein, we describe the activity of SM83, a newly synthesised dimeric SM, in two cancer ascites models: athymic nude mice injected intraperitoneally with IGROV-1 human ovarian carcinoma cells and immunocompetent BALB/c mice injected with murine Meth A sarcoma cells. SM83 rapidly killed ascitic IGROV-1 and Meth A cells in vivo (prolonging mouse survival), but was ineffective against the same cells in vitro. IGROV-1 cells in nude mice were killed within the ascites by a non-apoptotic, tumour necrosis factor (TNF)-dependent mechanism. SM83 administration triggered a rapid inflammatory event characterised by host secretion of TNF, interleukin-1ß and interferon-γ. This inflammatory response was associated with the reversion of the phenotype of tumour-associated macrophages from a pro-tumoural M2- to a pro-inflammatory M1-like state. SM83 treatment was also associated with a massive recruitment of neutrophils that, however, was not essential for the antitumoural activity of this compound. In BALB/c mice bearing Meth A ascites, SM83 treatment was in some cases curative, and these mice became resistant to a second injection of cancer cells, suggesting that they had developed an adaptive immune response. Altogether, these results indicate that, in vivo, SM83 modulates the immune system within the tumour microenvironment and, through its pro-inflammatory action, leads cancer cells to die by necrosis with the release of high-mobility group box-1. In conclusion, our work provides evidence that SMs could be more therapeutically active than expected by stimulating the immune system.

Tercer reporte de eventos adversos con tratamientos biológicos en Argentina. Informe de registro biobadasar / Thrid report of adverse events with biologics in Argentina. Report from biobadasar registry

Introducción: BIOBADASAR (Registro Argentino de Eventos Adversos con Tratamientos Biológicos en Reumatología) comenzó en agosto de 2010. La importancia de este registro es mostrar datos locales que, probablemente, puedan diferir de otros registros. El objetivo es comunicar los resultados del tercer reporte de BIOBADASAR. Métodos: Todos los pacientes con enfermedades reumáticas que requirieron tratamiento con agentes biológicos y pacientes controles sin estos tratamientos fueron incluidos en la base de datos provenientes de 32 centros participando a lo largo de la Argentina. Tres áreas de datos son analizados: características de los pacientes, tratamientos y eventos adversos...

Introduction: BIOBADASAR (Argentine Registry of Adverse Events with Biological Treatments in Rheumatology) began in August 2010. The importance of this registry is to show local data that may probably differ from other registries. The objective is to communicate the results of the third BIOBADASAR report. Methods: All patients with rheumatic diseases who required treatment with biological agents and control patients without these treatments were included in the database from 32 participating centers throughout Argentina. Three areas of data are analyzed: patient characteristics, treatments and adverse events...

Stage I surgical indexing: clinical and laboratory procedures.

This article will describe the clinical and laboratory procedures used to treat a patient with implant retained crowns including Stage I indexing, fabrication of fixed provisional crowns to be inserted at the time the implants were uncovered (Stage II surgery), and the insertion of the definitive cement-retained crowns after the soft tissues had healed. All of the components described in this article were made by Implant Innovations, Inc., Palm Beach Gardens, FL. The reader may consider this type of treatment using components made by various manufacturers.

Tarnish and corrosion with the use of intraoral magnets.

Intraoral magnets are small enough and provide sufficient retentive forces to be used in various prosthodontic procedures. This study described 25 patients with 60 magnetic attachments. All implant abutments gave evidence of tarnish, as did 68% of the magnetic keepers in patients with natural teeth. Corrosion was found in 41.7% of the magnetic keepers. Although 88% of the patients were satisfied at 3 months, only 28% were satisfied at 2 years. Rare earth magnets probably can be used for retention of removable prostheses. However, the magnets are likely to tarnish and corrode, making them unacceptable for use intraorally at this time.

Rates of osseointegration of dental implants with regard to anatomical location.

PURPOSE: Implantation of commercially pure titanium dental implants can be obtained predictably and consistently. The initial research focused on the edentulous population, with most of the fixtures being placed into the anterior mandibular area. There has been increased use of dental implants for partially edentulous patients. MATERIALS AND METHODS: This study reports the results of 169 consecutively treated patients with 673 fixtures. Patients were observed for 7 months to 8 years following occlusal loading. RESULTS: Implant osseointegration was 89.1% in the anterior maxillae; 71.4% in the posterior maxillae; 96.7% in the anterior mandible; and 98.7% in the posterior mandible. CONCLUSION: Osseointegration may be most dependent on anatomical location in the jaws.

Irreversible hydrocolloid impressions for full-banded orthodontic patients.

A technique has been described to obtain intact accurate irreversible hydrocolloid impressions in patients who are in the process of full-banded orthodontic therapy. When this technique is used, the maxillary and mandibular casts are produced with sufficient accuracy to make a maxillary occlusal splint that requires minimal adjustment.

The use of stainless steel keepers for tissue-integrated prostheses.

Dentists treating patients with complete tissue-integrated prostheses need a way of converting the preexisting transitional complete denture to a fixture-supported denture. Gold cylinders 3 to 5 mm in vertical height can be used after the abutments are connected to the fixtures at the second surgical appointment. However, because of their size, the cylinders require extensive relief of the denture base. Stainless steel keepers 1 mm in vertical height can be used instead. They require less relief inside the denture, reduce the likelihood of fracture of the denture base, and minimize the risk of aspiration or swallowing because the keeper is a one-piece system and the gold cylinders require the use of a small gold screw with each cylinder.