Securing wider EU commitment to the elimination of hepatitis C virus.

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes-from the municipality level to the EU level-were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call-to-Action' statement supported by all the major relevant European associations in the field.

Verification of stereotactic radiosurgery plans for multiple brain metastases using a virtual phantom-based procedure.

Background: The purpose of this study was to describe the use of the VIPER software for patient-specific quality assurance (PSQA) of single-isocenter multitarget (SIMT) stereotactic radiosurgery (SRS) plans. Materials and methods: Twenty clinical of intensity-modulated (IMRT) SIMT SRS plans were reviewed. A total of 88 brain metastases were included. Number of lesions per plan and their individual volumes ranged from 2 to 35 and from 0.03 to 32.8 cm3, respectively. Plans were designed with the Eclipse system, and delivered using a Varian CLINAC linac. SRS technique consisted of non-coplanar static-field sliding-window IMRT. Each plan was mapped onto a virtual cylindrical water phantom (VCP) in the Eclipse to calculate a 3D dose distribution (verification plan). The VIPER software reconstructed the 3D dose distribution inside the VCP from the acquired in-air electronic portal image device (EPID) images of the treatment fields. A 3D gamma analysis was used to compare the reconstructed doses to the Eclipse planned doses on the VCP. Gamma passing rates (GPRs) were calculated using 3% global/2 mm criteria and dose thresholds ranged from 10% to 90% of the maximum dose. Results: The averages (± 1 SD) of the 3D GPRs over the 20 SRS plans were: 99.9 ± 0.2%, 99.7 ± 0.3%, 99.6 ± 0.5%, 99.3 ± 0.9%,99.1 ± 1.6%, 99.0 ± 1.6%, and 98.5 ± 3.3%, for dose thresholds of 10%, 20%, 30%, 50%, 70%, 80% and 90% respectively. Conclusions: This work shows the feasibility of the VIPER software for PSQA of SIMT SRS plans, being a reliable alternative to commercially available 2D detector arrays.

Clinical Experience in Prostate Ultrahypofractionated Radiation Therapy With an Online Adaptive Method.

PURPOSE: This study aimed to describe the feasibility of the online adaptive radiation therapy (oART) method developed at the Hospital Quirónsalud Barcelona for prostate cancer, using a standard C-arm linear accelerator (linac) and without the support of artificial intelligence. METHODS AND MATERIALS: The first 18 patients treated at the Hospital Quirónsalud Barcelona with the developed oART method were included. An ultrahypofractionated radiation therapy scheme consisting of 7 × 6.1 Gy was used. Patients were treated on 2 conventional Varian C-arm linacs. For each patient, a reference plan based on a planning computed tomography (pCT) scan was generated using the Eclipse system. On each treatment session, the pCT scan was rigidly registered with the daily cone beam computed tomography (CT) scan. The pCT-based target (prostate) and organs at risk were mapped onto the cone beam CT images and manually adapted to take into account the anatomy of the day. The reference plan was then copied to the cone beam CT scan, and a full reoptimization was done for the current anatomy (adapted plan). For each treatment session, the unaltered reference plan was recomputed on the daily cone beam CT scan by mimicking the soft-tissue alignment performed per our standard procedure (nonadapted plan). Over the 126 adapted sessions from the 18 patients, a dosimetric comparison of adapted against nonadapted plans was done. RESULTS: A significant difference in the target coverage was found between the adapted and nonadapted plans (97.1 vs 90.4; P < .001) in favor of adapting. Without online adaptation, the optimal coverage of the prostate was not attained in 35% of fractions. Adapting allows for the improvement of the target coverage with compliance of all organ-at-risk dose constraints in all treatment fractions. CONCLUSIONS: The oART technique described in this study is technically feasible with a C-arm linac. To our knowledge, this is the first clinical experience with oART for prostate cancer including full replanning and delivered with a C-arm linac without artificial intelligence capability.

Validation of virtual water phantom software for pre-treatment verification of single-isocenter multiple-target stereotactic radiosurgery.

The aim of this study was to benchmark the accuracy of the VIrtual Phantom Epid dose Reconstruction (VIPER) software for pre-treatment dosimetric verification of multiple-target stereotactic radiosurgery (SRS). VIPER is an EPID-based method to reconstruct a 3D dose distribution in a virtual phantom from in-air portal images. Validation of the VIPER dose calculation was assessed using several MLC-defined fields for a 6 MV photon beam. Central axis percent depth doses (PDDs) and output factors were measured with an ionization chamber in a water tank, while dose planes at a depth of 10 cm in a solid flat phantom were acquired with radiochromic films. The accuracy of VIPER for multiple-target SRS plan verification was benchmarked against Monte Carlo simulations. Eighteen multiple-target SRS plans designed with the Eclipse treatment planning system were mapped to a cylindrical water phantom. For each plan, the 3D dose distribution reconstructed by VIPER within the phantom was compared with the Monte Carlo simulation, using a 3D gamma analysis. Dose differences (VIPER vs. measurements) generally within 2% were found for the MLC-defined fields, while film dosimetry revealed gamma passing rates (GPRs) ≥95% for a 3%/1 mm criteria. For the 18 multiple-target SRS plans, average 3D GPRs greater than 93% and 98% for the 3%/2 mm and 5%/2 mm criteria, respectively. Our results validate the use of VIPER as a dosimetric verification tool for pre-treatment QA of single-isocenter multiple-target SRS plans. The method requires no setup time on the linac and results in an accurate 3D characterization of the delivered dose.

Discovery of EST73502, a Dual µ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the µ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

[Monitoring and evaluation of hiv in catalonia, getting closer to the 90-90-90 objectives]. / Monitorización y evaluación del VIH en Cataluña, cada vez más cerca de los objetivos 90-90-90.

OBJECTIVE: Epidemiological surveillance of HIV infection allows monitoring its incidence as well as possible epidemiological changes, allowing specific interventions to be planned and their impact monitored. The objective of this article is to describe the results of the monitoring and evaluation of the response to the HIV epidemic in Catalonia, based on data included in the Integrated System of Epidemiological Surveillance of AIDS/HIV and Sexually Transmitted Infections of Catalonia (SIVES). METHODS: A descriptive analysis of the data from the different sources of information of the SIVES was performed. The time period was defined based on the availability of data from each of the sources of information included in the analysis. The information was structured according to the conceptual representation of the cascade of HIV care, as described in the World Health Organization consolidated strategic information guidelines for HIV. RESULTS: Of the total of 4,849 new diagnoses notified (2012-2018), 86% were men, of these; the most frequently reported transmission group was men having sex with men with 65%. The trend in the number of new diagnoses decreased in all transmission groups. It is estimated that in 2018 there were 32,429 people living with HIV in Catalonia, of which 89% were diagnosed, of these, 83% were under follow-up in a specialized unit and 78% of them were under treatment. 73% of people in treatment had suppressed the viral load. CONCLUSIONS: SIVES as an integrated system of different sources of strategic information allows monitoring the HIV epidemic in Catalonia and evaluating the response to it, identifying key populations and determinants to acquire HIV, as well as the barriers to which people living with HIV they face to achieve viral suppression.

OBJETIVO: La vigilancia epidemiológica de la infección por el VIH permite monitorizar su incidencia así como eventuales cambios epidemiológicos, permitiendo planificar intervenciones específicas y monitorizar su impacto. El objetivo de este artículo fue describir los resultados de la monitorización y evaluación de la respuesta a la epidemia del VIH en Cataluña, a partir de los datos incluidos en el Sistema Integrado de Vigilancia Epidemiológica del Sida/VIH e Infecciones de transmisión sexual de Cataluña (SIVES). METODOS: Se realizó un análisis descriptivo de los datos de las diferentes fuentes de información del SIVES. El periodo de tiempo se definió a partir de la disponibilidad de los datos de cada una de las fuentes de información incluidas en el análisis. La información se estructuró de acuerdo a la representación conceptual de la cascada de diagnóstico y tratamiento de VIH, tal y como se describe en las directrices de información estratégica consolidada de la Organización Mundial de la Salud para el VIH. RESULTADOS: Del total de 4.849 nuevos diagnósticos notificados (2012-2018), el 86% eran hombres. De estos, el grupo de transmisión informado más frecuente fueron los hombres que tiene sexo con hombres con un 65%. La tendencia del número de nuevos diagnósticos descendió en todos los grupos de transmisión. Se estima que en 2018 había 32.429 personas viviendo con el VIH en Cataluña, de las cuales el 89% estaban diagnosticadas. De estas, el 83% estaban en seguimiento en una unidad especializada, y el 78% de ellas estaban en tratamiento. El 73% de las personas en tratamiento tenían la carga viral suprimida. CONCLUSIONES: El SIVES, como sistema integrado de diferentes fuentes de información estratégica, permite monitorizar la epidemia del VIH en Cataluña y evaluar la respuesta a la misma, identificando poblaciones claves y determinantes para adquirir el VIH, así como las barreras a las que se enfrentan las personas que viven con VIH para lograr a supresión viral.

A closer look at the conventional Winston-Lutz test: Analysis in terms of dose.

AIM: To investigate whether the target-isocenter deviations reported by a conventional Winston-Lutz (WL) test actually reflect the shifts of the measured prescription isodose line with respect to the target. BACKGROUND: A conventional WL test uses a metallic ball as a target that aims at several fields. But this test does not report information on the accuracy of the delivery in terms of dose. MATERIALS AND METHODS: A conventional WL test using a metallic pointer as a target (Pointer-WL test) has been recreated in the Eclipse treatment planning system over an acrylic phantom containing a radiochromic film (Dose-WL test). After Dose-WL test delivery, the shift of the 80% prescription isodose line with respect to the target center (d80%-center) was measured using film dosimetry. The Pointer-WL and Dose-WL tests were performed in 10 different sessions. The isocenter deviation reported by the Pointer-WL test was compared to the d80%-center vector, according to the three patient's directions (Left-Right or LR; Anterior-Posterior or AP; and Superior-Inferior or SI). RESULTS: The deviations (mean ± SD) found for the Dose-WL tests (LR: 0.5 ± 0.4 mm; AP: 0.5 ± 0.4 mm; SI: 0.6 ± 0.2 mm) were in most cases less than 1 mm, and they were significantly smaller (all p < 0.05) than the maximum deviations reported by the Pointer-WL tests (LR: 1.3 ± 0.3 mm; AP: 1.2 ± 0.4 mm; SI: 1.1 ± 0.3 mm). CONCLUSIONS: The Dose-WL test described in this study allows estimating the spatial accuracy of the prescription isodose line.

Systematic review of guidelines in estimating social costs on drugs.

OBJECTIVE: To systematically review guidance documents for the estimation of the social cost of illegal drugs, and to define standards for this estimation. METHOD: A systematic literature search was conducted between April and May 2015 and updated in November 2015. Pubmed, Scopus, and Google Scholar were searched. Studies were included only if they provided indications of analytical methods for calculating the social cost of illegal drugs consumption. RESULTS: A total of 21 papers were selected for a final review. Four main areas of discussion were identified: a) alternative theories for the framework design; b) basic concepts definition; c) theoretical issues in the application of the framework and; d) definition of the cost matrix and its elements. The review exercise enabled the definition of two analytical approaches, which are proposed as references for estimation in the field. CONCLUSIONS: although social cost is a well-established method in the literature, there is a lack of agreement on the most appropriate approaches in the area of estimation of the social cost of illegal drugs consumption. Moreover, the two analytical approaches proposed are aimed at promoting more research focused at sophisticating the methodology in the field.

Investigating the spatial accuracy of CBCT-guided cranial radiosurgery: A phantom end-to-end test study.

PURPOSE: To evaluate the spatial accuracy of a frameless cone-beam computed tomography (CBCT)-guided cranial radiosurgery (SRS) using an end-to-end (E2E) phantom test methodology. METHODS AND MATERIALS: Five clinical SRS plans were mapped to an acrylic phantom containing a radiochromic film. The resulting phantom-based plans (E2E plans) were delivered four times. The phantom was setup on the treatment table with intentional misalignments, and CBCT-imaging was used to align it prior to E2E plan delivery. Comparisons (global gamma analysis) of the planned and delivered dose to the film were performed using a commercial triple-channel film dosimetry software. The necessary distance-to-agreement to achieve a 95% (DTA95) gamma passing rate for a fixed 3% dose difference provided an estimate of the spatial accuracy of CBCT-guided SRS. Systematic (∑) and random (σ) error components, as well as 95% confidence levels were derived for the DTA95 metric. RESULTS: The overall systematic spatial accuracy averaged over all tests was 1.4mm (SD: 0.2mm), with a corresponding 95% confidence level of 1.8mm. The systematic (Σ) and random (σ) spatial components of the accuracy derived from the E2E tests were 0.2mm and 0.8mm, respectively. CONCLUSIONS: The E2E methodology used in this study allowed an estimation of the spatial accuracy of our CBCT-guided SRS procedure. Subsequently, a PTV margin of 2.0mm is currently used in our department.

A Varian DynaLog file-based procedure for patient dose-volume histogram-based IMRT QA.

In the present study, we describe a method based on the analysis of the dynamic MLC log files (DynaLog) generated by the controller of a Varian linear accelerator in order to perform patient-specific IMRT QA. The DynaLog files of a Varian Millennium MLC, recorded during an IMRT treatment, can be processed using a MATLAB-based code in order to generate the actual fluence for each beam and so recalculate the actual patient dose distribution using the Eclipse treatment planning system. The accuracy of the DynaLog-based dose reconstruction procedure was assessed by introducing ten intended errors to perturb the fluence of the beams of a reference plan such that ten subsequent erroneous plans were generated. In-phantom measurements with an ionization chamber (ion chamber) and planar dose measurements using an EPID system were performed to investigate the correlation between the measured dose changes and the expected ones detected by the reconstructed plans for the ten intended erroneous cases. Moreover, the method was applied to 20 cases of clinical plans for different locations (prostate, lung, breast, and head and neck). A dose-volume histogram (DVH) metric was used to evaluate the impact of the delivery errors in terms of dose to the patient. The ionometric measurements revealed a significant positive correlation (R² = 0.9993) between the variations of the dose induced in the erroneous plans with respect to the reference plan and the corresponding changes indicated by the DynaLog-based reconstructed plans. The EPID measurements showed that the accuracy of the DynaLog-based method to reconstruct the beam fluence was comparable with the dosimetric resolution of the portal dosimetry used in this work (3%/3 mm). The DynaLog-based reconstruction method described in this study is a suitable tool to perform a patient-specific IMRT QA. This method allows us to perform patient-specific IMRT QA by evaluating the result based on the DVH metric of the planning CT image (patient DVH-based IMRT QA).

Feasibility of double-blind clinical trials with oral diacetylmorphine: a randomized controlled phase II study in an inpatient setting.

The aim of this study was to evaluate the feasibility of conducting double-blind controlled randomized clinical trials using twice-a-day immediate-release oral diacetylmorphine (DAM) in heroin-dependent patients, by means of measuring the capacity of oral DAM to block opiate withdrawal and clinicians' ability to distinguish it from morphine and methadone. This was a randomized, phase II, double-blind, multicenter pilot study comparing immediate-release oral DAM, slow-release oral morphine and oral methadone administered twice a day during 10 days. Forty-five heroin-dependent patients were randomly assigned to these three treatment groups in an inpatient regime. Patients were stabilized with a mean of 350 mg (SD = 193) of immediate-release oral DAM, 108 mg (SD = 46.2) of slow-release oral morphine and 40 mg (SD = 17.9) of methadone. No statistically significant differences were found between any studied medication in clinical outcome. Neither patients nor clinicians were able to identify the administered medication. This study shows the feasibility of double-blind clinical trials using b.i.d. immediate-release oral DAM allowing further phase III clinical trials in the process of introducing oral DAM as a medication for heroin-dependent patients not responding to standard maintenance treatments.

A regiospecific synthesis of both positional isomers of 4,6-disubstituted 2-dicyanomethylene-1, 2-dihydropyridin-3-carbonitriles.

A protocol allowing the regiospecific synthesis of both positional isomers of 4,6-disubstituted 2-dicyanomethylene-1,2-dihydropyridin-3-carbonitriles, precursors of 1,6-naphthyridines, is presented. Thus, treatment of enaminoketones with the propanedinitrile dimer yields one regioisomer while the treatment of the corresponding (3-chloro-allylidene)-dimethylammonium perchlorates (easily obtained from enaminoketones and POCl(3)), in which the nature of the reactive centers is inverted with respect to the enaminoketone, yields the other regioisomer.

4-(Dimethyl-amino)phenyl ethynyl telluride.

The title compound, C(10)H(11)NTe, is the first organyl ethynyl telluride, R-Te-C C-H, to be structurally characterized. In the L-shaped mol-ecule, the aryl moiety, viz. Me(2)NC(6)H(4)Te, is almost perpendicular to the Te-C C-H fragment. The Te-Csp(2) bond [2.115 (3) Å] is significantly longer than the Te-Csp bond [2.041 (4) Å]. The Te-C C group is approximately linear [Te-C-C = 178.5 (4)° and C C = 1.161 (5) Å], while the coordination at the Te atom is angular [C-Te-C = 95.92 (14)°]. In the crystal structure, there are Csp-H⋯N hydrogen bonds which are perpendicular to the CNMe(2) group; the N atom displays some degree of pyramidalization. Centrosymmetrically related pairs of mol-ecules are linked by Te⋯π(ar-yl) inter-actions, with Te⋯Cg = 3.683 (4) Šand Csp-Te⋯Cg = 159.1 (2)° (Cg is the centroid of the benzene ring). These inter-actions lead to the formation of zigzag ribbons which run along c and are approximately parallel to (110).

Twinning by merohedry in bis(4-methoxyphenyl)tellurium(IV) diiodide dimethyl sulfoxide hemisolvate.

Green crystals of the title compound, C(14)H(14)I(2)O(2)Te x 0.5 C(2)H(6)OS, space group P3(2), show twinning by merohedry (class II). The asymmetric unit contains two organotellurium molecules and one dimethyl sulfoxide (DMSO) molecule. The crystal structure displays secondary Te...I and Te...O(DMSO) bonds that lead to [(4-MeOC(6)H(4))(2)TeI(2)](2) x DMSO supramolecular units in which the two independent organotellurium molecules are bridged by the DMSO O atom. In addition to these secondary bonds, I...I interactions link translationally equivalent organotellurium molecules to form nearly linear ...I-Te-I...I-Te-I... chains. These chains are crosslinked, forming two-dimensional arrays parallel to (001). The crystal packing consists of a stacking of these sheets, which are related by the 3(2) axis. This study describes an unusual dimeric arrangement of X-Te-X groups.

[Detection and handling of alcohol problems in primary care in Catalonia]. / Detección y abordaje de los problemas de alcohol en la atención primaria de Cataluña.

OBJECTIVE: To gain information on how well strategies for alcohol problem detection and interventions are being implemented in primary care in Catalonia, Spain. DESIGN: Longitudinal pre/post study to evaluate the impact of the distribution to primary care professionals of a training programme for detecting alcohol problems and intervening in them. Descriptive analysis of the basic situation, using interviews with patients and professionals and examination of clinical histories (CH). SETTING: Health districts that existed in Catalonia in 2001. PARTICIPANTS: Twenty eight health districts, 973 patients, 80 professionals, and 852 clinical histories examined. MAIN MEASUREMENTS: Data were collected, by means of questionnaires for professionals and patients and of ad-hoc instruments for examining clinical histories, on the levels of primary care screening for alcohol consumption and of intervention. RESULTS: There was a major disparity in the data between the 3 sources. Thus the screening of consumption and counselling was recorded much less in the CHs than amounts that patients said they received and that professionals said they performed. In addition, most of the at-risk drinkers that were seen in PC were not detected. On comparing them with non-risk drinkers we found significant differences in sex, job, familiarity with the centre and having been asked or not about their alcohol consumption. CONCLUSIONS: Given the deficiencies found in PC preventive activity on alcohol consumption and as alcohol consumption has such huge social and health repercussions on the general population, we think it is fully justified to introduce into PC specific training programmes on screening and brief intervention techniques for alcohol problems.