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Francesca Alberton,1 Laura Galli,2 Riccardo Lolatto,2 Caterina Candela,1 Nicola Gianotti,2 Matteo Chiurlo,2 Martina Ranzenigo,2 Martina Strano,2 Alessia Uglietti,3 Antonella Castagna1,2 1Infectious Diseases Unit, Vita Salute San Raffaele University, Milan, Italy; 2Infectious Diseases Unit, San Raffaele Scientific Institute, Milan, Italy; 3Medical Affairs Department, Infectious Diseases and Vaccines & Rare Diseases, Johnson&Johnson, Milan, ItalyCorrespondence: Alessia Uglietti, Medical Affairs Department, Infectious Disease and Vaccines & Rare Diseases, Johnson&Johnson, viale Fulvio Testi 280/6, Milan, 20126, Italy, Tel +39-344 2665502, Email augliett@its.jnj.comObjective: To evaluate the virological outcome of darunavir–cobicistat (DRVc)‐based regimens in adults living with HIV who had experienced virological failure (VF) on any previous drug combination.Methods: This was a retrospective cohort study (CSLHIV Cohort) of adults living with HIV who started a DRVc‐based regimen with HIV‐RNA > 50 copies/mL after VF on any previous drug combination. Data on demographics, antiretroviral treatment since HIV diagnosis, and immunological and metabolic parameters from baseline (start of DRVc) to 48 weeks were analyzed in order to assess the cumulative proportion of those who achieved virological success (VS), defined as at least one instance of HIV‐RNA < 50 copies/mL within 12 months from baseline. Follow-up lasted from the start of the DRVc-based regimen (baseline) to the first instance of HIV-RNA < 50 copies/mL, last available visit, or loss to follow‐up or death, whichever occurred first. Univariate and multivariate Cox proportional-hazard regression models were used to identify baseline factors associated with VS.Results: A total of 176 individuals were included, and 120 (68.2%) achieved < 50 HIV‐RNA copies/mL within 12 months since baseline. On multivariate analysis, baseline HDL cholesterol was independently associated with the occurrence of VS (adjusted HR 1.021, 95% CI 1.004– 1.038; p=0.014). Among the 120 subjects with VS, 27 (22.5%) had had VF during a median follow-up of 20.8 months since the first undetectable HIV-RNA. Resistance testing after VF was available in two cases, which harboured the HIV variant–bearing protease inhibitor–resistance mutations D30N, I50V, and N88D. During a median follow-up of 38.4 months, 65 of 176 (36.9%) individuals discontinued DRVc for any reason (37 of 120, 30.8%) and achieved VS vs. 28 of 56 (50%) without VS (p=0.019). Time to discontinuation was longer in people with VS (41.5 vs. 23.0 months, p=0.0007). No statistically significant changes were observed in immunological or lipid profiles during follow-up.Conclusion: Most individuals in this study achieved VS within 12 months from the beginning of a DRVc-based regimen; therefore, this treatment represent a viable option for people who have experienced VF on other regimens.Keywords: HIV infection, antiretroviral therapy, ART, darunavir–cobicistat, DRVc, virological failure, VF

Abstract Antiretroviral therapy (ART) significantly reduced Human Immunodeficiency Virus (HIV) morbidity and mortality; nevertheless, stigma still characterises the living with this condition. This study explored patients’ coping experience by integrating narrative medicine (NM) in a non-interventional clinical trial. From June 2018 to September 2020 the study involved 18 centres across Italy; enrolled patients were both D/C/F/TAF naïve and previously ART-treated. Narratives were collected at enrolment (V1) and last visit (V4) and then independently analysed by three NM specialist researchers through content analysis. One-hundred and fourteen patients completed both V1 and V4 narratives. Supportive relationships with clinicians and undetectable viral load facilitated coping. Conversely, lack of disclosure of HIV-positive status, HIV metaphors, and unwillingness to narrate the life before the diagnosis indicated internalised stigma. This is the first non-interventional study to include narratives as patient reported outcomes (PROs). Improving HIV awareness and reducing the sense of guilt experienced by patients helps to overcome stigma and foster coping.

Several conductor designs featuring High Temperature Superconducting (HTS) stacked tapes for fusion coils are being proposed. These conductors are planned to operate in time-varying magnetic field and current; thus, the estimation of AC losses is fundamental for the conductor design and the accurate analysis of its performance in operation. The case study of an HTS conductor proposed for the hybrid (HTS-LTS) Central Solenoid coil for the EU DEMO tokamak is considered in this work. Here, a numerical model based on the finite element method (FEM) and the H-formulation is used, in order to estimate the hysteresis losses. The FEM model is first benchmarked against available analytical formulae as well as available literature data. Then it is applied to the real case operational scenario. It is shown that for the conductor design analyzed, the coupling losses are orders of magnitude lower than the hysteresis ones. The impact of the hysteresis+coupling losses on the temperature margin of the coil is assessed with a thermal-hydraulic model. It is shown that the heat generated in the HTS layers is partially transferred to the LTS layers, leading these layers to quench. An alternative conductor concept is also analyzed, showing that, however, in the top and bottom modules of the CS coil, due to the bending of the magnetic field, a too large heat deposition is present.

The Swiss Plasma Center (SPC) is planning a divertor upgrade for the TCV tokamak. The upgrade aims at extending the research of conventional and alternative divertor configurations to operational scenarios and divertor regimes of greater relevance for a fusion reactor. The main elements of the upgrade are the installation of an in-vessel structure to form a divertor chamber of variable closure and enhanced diagnostic capabilities, an increase of the pumping capability of the divertor chamber and the addition of new divertor poloidal field coils. The project follows a staged approach and is carried out in parallel with an upgrade of the TCV heating system. First calculations using the EMC3-Eirene code indicate that realistic baffles together with the planned heating upgrade will allow for a significantly higher compression of neutral particles in the divertor, which is a prerequisite to test the power dissipation potential of various divertor configurations.

Despite numerous spectacular archaeological discoveries worldwide related to melting ice patches and the emerging field of glacial archaeology, governing processes related to ice patch development during the Holocene and their sensitivity to climate change are still largely unexplored. Here we present new results from an extensive 6-year (2009–2015) field experiment at the Juvfonne ice patch in Jotunheimen in central southern Norway. Our results show that the ice patch has existed continuously since the late Mesolithic period. Organic-rich layers and carbonaceous aerosols embedded in clear ice show ages spanning from modern at the surface to ca. 7600 cal years BP at the bottom. This is the oldest dating of ice in mainland Norway. The expanding ice patch covered moss mats appearing along the margin of Juvfonne about 2000 years ago. During the study period, the mass balance record showed a strong negative balance, and the annual balance is highly asymmetric over short distances. Snow accumulation is poorly correlated with estimated winter precipitation, and single storm events may contribute significantly to the total winter balance. Snow accumulation is approx. 20 % higher in the frontal area compared to the upper central part of the ice patch. There is sufficient meltwater to bring the permeable snowpack to an isothermal state within a few weeks in early summer. Below the seasonal snowpack, ice temperatures are between −2 and −4 °C. Juvfonne has clear ice stratification of isochronic origin.

High-altitude glaciers and ice caps from midlatitudes and tropical regions contain valuable signals of past climatic and environmental conditions as well as human activities, but for a meaningful interpretation this information needs to be placed in a precise chronological context. For dating the upper part of ice cores from such sites, several relatively precise methods exist, but they fail in the older and deeper parts, where plastic deformation of the ice results in strong annual layer thinning and a non-linear age–depth relationship. If sufficient organic matter such as plant, wood or insect fragments were found, radiocarbon (14C) analysis would have thus been the only option for a direct and absolute dating of deeper ice core sections. However such fragments are rarely found and, even then, they would not be very likely to occur at the desired depth and resolution. About 10 years ago, a new, complementary dating tool was therefore introduced by our group. It is based on extracting the µg-amounts of the water-insoluble organic carbon (WIOC) fraction of carbonaceous aerosols embedded in the ice matrix for subsequent 14C dating. Since then this new approach has been improved considerably by reducing the measurement time and improving the overall precision. Samples with ∼ 10 µg WIOC mass can now be dated with reasonable uncertainty of around 10–20 % (variable depending on sample age). This requires about 300 to 800 g of ice for WIOC concentrations typically found in midlatitude and low-latitude glacier ice. Dating polar ice with satisfactory age precision is still not possible since WIOC concentrations are around 1 order of magnitude lower. The accuracy of the WIOC 14C method was validated by applying it to independently dated ice. With this method, the deepest parts of the ice cores from Colle Gnifetti and the Mt Ortles glacier in the European Alps, Illimani glacier in the Bolivian Andes, Tsambagarav ice cap in the Mongolian Altai, and Belukha glacier in the Siberian Altai have been dated. In all cases a strong annual layer thinning towards the bedrock was observed and the oldest ages obtained were in the range of 10 000 years. WIOC 14C dating was not only crucial for interpretation of the embedded environmental and climatic histories, but additionally gave a better insight into glacier flow dynamics close to the bedrock and past glacier coverage. For this the availability of multiple dating points in the deepest parts was essential, which is the strength of the presented WIOC 14C dating method, allowing determination of absolute ages from principally every piece of ice.

In 2011 four ice cores were extracted from the summit of Alto dell'Ortles (3859 m), the highest glacier of South Tyrol in the Italian Alps. This drilling site is located only 37 km southwest from where the Tyrolean Iceman, ∼ 5.3 kyrs old, was discovered emerging from the ablating ice field of Tisenjoch (3210 m, near the Italian–Austrian border) in 1991. The excellent preservation of this mummy suggested that the Tyrolean Iceman was continuously embedded in prehistoric ice and that additional ancient ice was likely preserved elsewhere in South Tyrol. Dating of the ice cores from Alto dell'Ortles based on 210Pb, tritium, beta activity and 14C determinations, combined with an empirical model (COPRA), provides evidence for a chronologically ordered ice stratigraphy from the modern glacier surface down to the bottom ice layers with an age of ∼ 7 kyrs, which confirms the hypothesis. Our results indicate that the drilling site has continuously been glaciated on frozen bedrock since ∼ 7 kyrs BP. Absence of older ice on the highest glacier of South Tyrol is consistent with the removal of basal ice from bedrock during the Northern Hemisphere Climatic Optimum (6–9 kyrs BP), the warmest interval in the European Alps during the Holocene. Borehole inclinometric measurements of the current glacier flow combined with surface ground penetration radar (GPR) measurements indicate that, due to the sustained atmospheric warming since the 1980s, an acceleration of the glacier Alto dell'Ortles flow has just recently begun. Given the stratigraphic–chronological continuity of the Mt. Ortles cores over millennia, it can be argued that this behaviour has been unprecedented at this location since the Northern Hemisphere Climatic Optimum.

Objective: To evaluate the cost-effectiveness of bedaquiline plus background drug regimens (BR) for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in Italy. Methods: A Markov model was adapted to the Italian setting to estimate the incremental cost-effectiveness ratio (ICER) of bedaquiline plus BR (BBR) versus BR in the treatment of MDR-TB and XDR-TB over 10 years, from both the National Health Service (NHS) and societal perspective. Cost-effectiveness was evaluated in terms of life-years gained (LYG). Clinical data were sourced from trials; resource consumption for compared treatments was modelled according to advice from an expert clinicians panel. NHS tariffs for inpatient and outpatient resource consumption were retrieved from published Italian sources. Drug costs were provided by reference centres for disease treatment in Italy. A 3% annual discount was applied to both cost and effectiveness. Deterministic and probabilistic sensitivity analyses were conducted. Results: Over 10 years, BBR vs. BR alone is cost-effective, with ICERs of €16,639/LYG and €4081/LYG for the NHS and society, respectively. The sensitivity analyses confirmed the robustness of the results from both considered perspectives. Conclusion: In Italy, BBR vs. BR alone has proven to be cost-effective in the treatment of MDR-TB and XDR-TB under a range of scenarios.