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Background: The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and wider society. Research methodology, demographics and initial insights from the survey have been previously reported. The cost of illness (healthcare resource use, productivity loss, out-of-pocket spending) and drivers of the economic impact of OI are reported here. Methods: IMPACT was an international mixed-methods online survey in eight languages (fielded July–September 2021) targeting adults (aged ≥ 18 years) or adolescents (aged ≥ 12–17 years) with OI, caregivers with or without OI and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, quality of life and health economics. The health economic domain for adults, which included questions on healthcare resource use, productivity loss and out-of-pocket spending, was summarised. Regression and pairwise analyses were conducted to identify independent drivers and associations with respondent characteristics. Results: Overall, 1,440 adults with OI responded to the survey. Respondents were mostly female (70%) and from Europe (63%) with a median age of 43 years. Within a 12-month period, adults with OI reported visiting a wide range of healthcare professionals. Two-thirds (66%) of adults visited a hospital, and one-third (33%) visited the emergency department. The mean total number of diagnostic tests undergone by adults within these 12 months was 8.0. Adults had undergone a mean total of 11.8 surgeries up to the time point of the survey. The proportions of adults using queried consumables or services over 12 months ranged from 18–82%, depending on the type of consumable or service. Most adults (58%) were in paid employment, of which nearly one-third (29%) reported missing a workday. Of the queried expenses, the mean total out-of-pocket spending in 4 weeks was €191. Respondent characteristics such as female sex, more severe self-reported OI and the experience of fractures were often associated with increased economic burden. Conclusion: IMPACT provides novel insights into the substantial cost of illness associated with OI on individuals, healthcare systems and society at large. Future analyses will provide insights into country-specific economic impact, humanistic impact and the healthcare journey of individuals with OI. [ABSTRACT FROM AUTHOR]

Background and Aims: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. Methods: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti‐HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV‐positive and HDV‐negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver‐related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause‐specific multivariable Cox regression. Results: Of 2793 HBsAg‐positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%–17.1%) and 66% (132/200) of HDV‐positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%–55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%–5.9%) among other participants. During a median follow‐up of 10.8 years (interquartile range 5.6–17.8), 82 (34.6%) HDV‐positive and 265 (20.1%) HDV‐negative individuals died. 41.5% (34/82) of deaths were liver‐related in HDV‐positive individuals compared to 17.7% (47/265) in HDV‐negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2–2.1), liver‐related death (2.9, 1.6–5.0) and HCC (6.3, 2.5–16.0). Conclusion: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver‐related mortality and HCC incidence. [ABSTRACT FROM AUTHOR]

Background: The European AIDS Clinical Society (EACS) Guidelines were revised in 2021 for the 17th time with updates on all aspects of HIV care. Key points of the Guidelines update: Version 11.0 of the Guidelines recommend six first‐line treatment options for antiretroviral treatment (ART)‐naïve adults: tenofovir‐based backbone plus an unboosted integrase inhibitor or plus doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. Recommendations on preferred and alternative first‐line combinations from birth to adolescence were included in the new paediatric section made with Penta. Long‐acting cabotegravir plus rilpivirine was included as a switch option and, along with fostemsavir, was added to all drug–drug interaction (DDI) tables. Four new DDI tables for anti‐tuberculosis drugs, anxiolytics, hormone replacement therapy and COVID‐19 therapies were introduced, as well as guidance on screening and management of anxiety disorders, transgender health, sexual health for women and menopause. The sections on frailty, obesity and cancer were expanded, and recommendations for the management of people with diabetes and cardiovascular disease risk were revised extensively. Treatment of recently acquired hepatitis C is recommended with ongoing risk behaviour to reduce transmission. Bulevirtide was included as a treatment option for the hepatitis Delta virus. Drug‐resistant tuberculosis guidance was adjusted in accordance with the 2020 World Health Organization recommendations. Finally, there is new guidance on COVID‐19 management with a focus on continuance of HIV care. Conclusions: In 2021, the EACS Guidelines were updated extensively and broadened to include new sections. The recommendations are available as a free app, in interactive web format and as an online pdf. [ABSTRACT FROM AUTHOR]

Background: The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. Guideline highlights: The 2019 Guidelines were extended with a new section focusing on drug–drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment‐naïve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two‐drug regimen with dolutegravir and lamivudine, and a three‐drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10‐year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. Conclusions: The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web‐based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish. [ABSTRACT FROM AUTHOR]

Entomopathogenic fungi are used for biological control of insect pests. Metarhizium brunneum Petch (Hypocreales) has potential to control Diabrotica virgifera virgifera LeConte (Chrysomelidae), which is a major pest of maize in North America and has recently invaded Europe. The inundative application of an entomopathogenic fungal strain in biological control results in high densities of fungal propagules in the soil which can potentially affect soil microbial communities and their multiple functions in soil. The objective of the present study was to assess potential effects of M. brunneum on soil fungal and prokaryotic communities in a pot experiment over a time course of 4 months using high-throughput sequencing (HTS) of ribosomal markers. The application of M. brunneum formulated as fungus colonised barley kernels (FCBK) led to a significant increase of the applied strain in soil, as assessed by cultivation-dependent (plating on selective medium followed by genotyping of Metarhizium isolates) and cultivation-independent (HTS of ribosomal markers) approaches. Data revealed that soil fungal and prokaryotic community structures did not change after the application of M. brunneum. Temporal changes of the fungal and prokaryotic communities were observed and the prokaryotic communities showed minor changes to barley kernels (BK), the matrix of the formulation. Results of this study are in accordance with other investigations lacking any evidence for adverse effects on microbial communities caused by applied entomopathogenic fungi. [ABSTRACT FROM AUTHOR]

We study trade in Europe after the fall of the Iron Curtain, and show that the countries of the former Austro-Hungarian monarchy trade significantly more with one another after 1989 than predicted by a standard gravity model. Cultural trading capital, established under Habsburg rule and maintained in the period of the Iron Curtain, seems to have survived over four decades of separation and gives an initial boost to trade. This surplus trade disappeared rapidly after 1990 as countries rearranged themselves with the new geopolitical circumstances. We document the rate of decay of these forces. [ABSTRACT FROM AUTHOR]

Background: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV‐positive persons in geographically diverse areas. Guideline highlights: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and bone toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non‐alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug–drug interaction tables have been updated and new tables are included. Treatment options for direct‐acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three‐drug combination may be as effective as a five‐drug regimen, and may reduce treatment duration from 18‐24 to 6‐10 months. Conclusions: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages. [ABSTRACT FROM AUTHOR]

This paper outlines a proposal for a 'European Democratic Citizen Service', and summarises some reactions to this proposal from several feedback discussions with young people and students. The paper is written as a programmatic proposal like a 'business plan' or an 'ERASMUS for all' - describing the objectives and then an appropriate possible structure. The second part reports the experiences of the two-dozen informal feedback group discussions with young people. Overall, the proposal of a multiculturally designed Citizen Service is welcomed by most young people; they, however, need moderate financial support. Formulating a structural design is an exercise, which could give the impetus for a new foundation for European identity building, for multicultural understanding and pan-national cohesion. This article aims to encourage discussion about how to structure and organise inter-national groups for cooperation on partially very difficult tasks. Multicultural education can happen while learning 'on the job'; young people travelling in different European countries in pursuit of a common task means practical education, thereby appropriately reflecting the common challenge of our century. The proposed participation can become a large social experiment relating to truly cross-national, cross-ethnic, cross-cultural organisation-building, i.e. especially if intelligently and with care 'multicultural teams' are composed. [ABSTRACT FROM AUTHOR]

Background Discontinuation of rheumatoid arthritis (RA) treatment for lack or loss of initial response, tolerability issues, or development of antibodies against the therapeutic agent remains a challenge in clinical practice. Here we present a 6-month interim analysis of a 2-year prospective observational trial in Europe and Canada aiming to assess the real-world effectiveness, safety, and tolerability of intravenous abatacept for the treatment of moderateto- severe RA. Methods ACTION (AbataCepT In rOutiNe clinical practice) is a prospective, observational study assessing effectiveness, safety, and tolerability of abatacept in patients with RA enrolled in Europe and Canada between May 2008 and January 2011. The patient population was divided into two groups: biologic naïve (‘first-line’) patients and patients who had previously failed treatment with at least one biologic agent (‘second-line’). Retention rates were calculated using Kaplan–Meier curve estimates. Effectiveness was measured using European League Against Rheumatism (EULAR) response criteria, the 28-item Disease Activity Score, the Clinical Disease Activity Index (CDAI), and physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Serious adverse events (SAEs) were reported for all enrolled patients. Results Of 1138 consecutively enrolled patients, 1114 and 1079 patients were evaluable for retention and effectiveness, respectively. Overall, retention rates were 88.6% (95% confidence interval [CI]: 86.4, 90.4); 67.4% of patients achieved good/moderate EULAR response; 32.8% had a CDAI Low Disease Activity State (LDAS); and 44.7% a HAQ-DI response. Retention rates among first- and second-line patients were 93.0% (95% CI: 85.9, 96.6) and 88.1% (95% CI: 85.7, 90.0), respectively. The percentage of patients achieving CDAI LDAS was 40.0% (95% CI: 26.4, 53.6) for first- and 32.2% (95% CI: 28.4, 36.0) for second-line patients and the proportion achieving a HAQ-DI response was 60.3% (95% CI: 47.8, 72.9) versus 43.1% (95% CI: 39.0, 47.2), respectively. The incidence of SAEs was 4.7%. Conclusions Evidence from this 6-month interim analysis suggests that abatacept offers an effective and well-tolerated treatment option for patients with RA, including those who have previously failed anti-tumor necrosis factor treatment. In addition, higher retention rates and effectiveness outcomes were observed when abatacept treatment was initiated earlier in the course of the disease. [ABSTRACT FROM AUTHOR]

This article analyzes Special Purpose Acquisition Companies (SPACs) in Europe. We document various aspects associated with European SPACs by using a unique, hand-collected data sample encompassing the 19 SPACs that have been listed on European stock exchanges since 2005. The article shows that in spite of being listed on European stock exchanges, many SPACs do not have a European focus, neither in terms of investors, nor in their choice of target companies. Additionally, our results show that there is a great heterogeneity in the choice of target companies among SPACs, especially with regard to financial performance, and that SPAC investors react negatively to the choice of an underperforming target company. [ABSTRACT FROM AUTHOR]

The article focuses on a study about the impact of simulated heat wave on the photophysiology and gene expression of Zostera (Z.) marina high- and low-latitude populations in Europe. It recalls that populations of Z. marina or seagrass exhibited a decline in summer 2003 in which results of an experimental work confirm that the losses have been caused by high water temperatures. Findings of the study are discussed, one is the significant upregulation of the antioxidant gene superoxidase dismutase (SOD Mn) due to thermal stress. It is said that the resilience shown by low-latitude populations to thermal events leads to the assumption that targeted colonization of such populations to high-latitude areas can help the seagrass withstand climate projections.

Psychiatric neurosurgery, specifically stereotactic ablation, has continued since the 1940s, mainly at a few centers in Europe and the US. Since the late 1990s, the resurgence of interest in this field has been remarkable; reports of both lesion procedures and the newer technique of deep brain stimulation (DBS) have increased rapidly. In early 2009, the US FDA granted limited humanitarian approval for DBS for otherwise intractable obsessive-compulsive disorder (OCD), the first such approval for a psychiatric illness. Several factors explain the emergence of DBS and continued small-scale use of refined lesion procedures. DBS and stereotactic ablation have been successful and widely used for movement disorders. There remains an unmet clinical need: current drug and behavioral treatments offer limited benefit to some seriously ill people. Understandings of the neurocircuitry underlying psychopathology and the response to treatment, while still works in progress, are much enhanced. Here, we review modern lesion procedures and DBS for OCD in the context of neurocircuitry. A key issue is that clinical benefit can be obtained after surgeries targeting different brain structures. This fits well with anatomical models, in which circuits connecting orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), basal ganglia, and thalamus are central to OCD pathophysiology and treatment response. As in movement disorders, dedicated interdisciplinary teams, here led by psychiatrists, are required to implement these procedures and maintain care for patients so treated. Available data, although limited, support the promise of stereotactic ablation or DBS in carefully selected patients. Benefit in such cases appears not to be confined to obsessions and compulsions, but includes changes in affective state. Caution is imperative, and key issues in long-term management of psychiatric neurosurgery patients deserve focused attention. DBS and contemporary ablation also present different patterns of potential benefits and burdens. Translational research to elucidate how targeting specific nodes in putative OCD circuitry might lead to therapeutic gains is accelerating in tandem with clinical use. [ABSTRACT FROM AUTHOR]

The Carpathians belong to the European Alpine system, which was formed during the convergence and collision of the European and African plates. The study area, which comprises the Magura and Silesian nappes of the Outer Western Carpathians, were the locations of intensive folding and nappe transport during the Tertiary. There are a number of models depicting the changes in shapes and positions of the original sedimentary basins as a consequence of the above processes. However, it is this study that provides the first palaeomagnetic constraints for reconstructing the displacement history of the Silesian and Magura nappes during Tertiary. For the palaeomagnetic and anisotropy of the low-field magnetic susceptibility (AMS) studies 554 independently oriented cores were drilled, mostly from claystones, at 57 geographically distributed localities of Oligocene (and partly of Late Eocene in the Magura nappe) age. In the laboratory, the magnetic mineral identified was always magnetite, invariably accompanied by paramagnetic pyrite. The AMS measurements showed that the magnetic fabric was dominantly foliated. The foliation and bedding poles were very close at most of the localities, suggesting that the foliation was of sedimentary/compaction origin. Magnetic lineations, even if clustered at the locality level, did not exhibit a regional pattern for the Magura nappe. On the other hand, lineations related to folding were NE–SW oriented in the western and E–W oriented in the central and eastern segments of the Silesian nappe. Following the AMS measurements the samples were subjected to detailed stepwise demagnetization and analysis of the demagnetization curves that provided the input data for regional tilt tests. Both the tilt and inclination only tests suggested that the remanence is of post-folding age for the Magura nappe, showing a general 50° counterclockwise (CCW) rotation. Similar palaeomagnetic directions were observed for the central and eastern segments of the Silesian nappe, whereas a significantly larger CCW rotation for the western segment. The orientations of the AMS lineation directions averaged for the central, the eastern and the western segments of the Silesian nappe correspond to a ‘rotated’ palaeomagnetic pattern, as they are practically E–W oriented for the first two and NE–SW oriented for the third. The palaeomagnetic results of this study are interpreted in terms of a 50°‘en bloc’ rotation in the CCW sense of the Magura and Silesian nappes during their Miocene emplacement. This result has two important implications. The first is that the CCW rotation of the nappes that accompanied the displacement of the flysch basins from SW to NE is not of Palaeogene age, as earlier suggested, but younger. The second is that the change in the stress field orientation during the Miocene, observed for the Silesian nappe is not a CW far field stress rotation, but the consequence of CCW block rotations. The larger CCW rotation observed in both the palaeomagnetic and AMS data sets for the western segment of the Silesian nappe relative to the central and eastern segments is connected to local block rotations in a left-lateral wrench corridor. [ABSTRACT FROM AUTHOR]

The HLA-B*5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B*5701. The HCP5SNPwas present in all 98 HLA-B*5701-positive individuals and was absent in 999 of 1005 HLA-B*5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P<.0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available. [ABSTRACT FROM AUTHOR]

Historical, high-resolution rain series are the backbone of modern combined sewer overflow (CSO) Structure design. These rain series are the input to the computational estimation of the performance of the measures with respect to CSO pollution abatement. However, those historical precipitation measurements are available at only a few locations. Frequently rain series have to be used from gauging stations at a significant distance. In order to judge and to compensate for this influence an estimate between rain characteristics and combined sewer outflow (CSO) performance indicators would be useful. In this paper such correlations have been sought for a collection of 37 rain series covering large areas of Europe. It was found that the mean annual rain volume can explain most of the variances for the performance indicators Number of overflows and CSO volume. For explaining the spatial differences in the efficiency of the CSO structure another rain characteristic, i.e. the maximum event with a return period of one year, is to be used. [ABSTRACT FROM AUTHOR]

Abstract In the last decennia heart failure has become one of the most important diseases worldwide in terms of prevalence, morbidity, life expectancy, and in health care management and costs. Despite significant improvements in prevention and treatment, heart failure remains a frequently occurring disorder with increasing incidence and a high hospitalisation and death rate. As major health care problem it deserves full attention of health care authorities. Unfortunately, the seriousness of heart failure and the therapeutic possibilities are often not recognised by those directly involved, i.e. the doctor, the patient or his relatives, let alone that they are known to the general public and health care authorities. [ABSTRACT FROM AUTHOR]

This paper presents a systematic literature review on both the risks affecting wood supply security and risk mitigation strategies by quantitative and qualitative data analysis. It describes wood-specific supply chain risks, thereupon resulting impacts and counteracting strategies to ensure supply. Risks, impacts, and strategies are documented as basis for a comparative analysis, discussion of results, challenges and research gaps. Finally, the suitability and the limitations of the chosen methodology and the achieved results are discussed. Scanning wood supply chain risks and supply strategies, most of the reviewed papers focus on wood supply for bioenergy generation and only a few studies investigate wood supply chain risk issues for the sawing, wood panel, pulp and paper industries, or biorefineries. This review differs significantly from other reviews in this field as it considers the entire wood value chain including recent studies on new chemical wood-based products and thus provides a more complete picture of the wood-based bioeconomy. Consequently, it contributes to the literature by providing an overarching investigation of the risks affecting wood supply security and possible side effects of a growing wood-based bioeconomy. It was found that comprehensive value chain analyses considering established wood products, large-volume bioenergy products, as well as established and new chemical wood-based products in the context of wood supply security are missing. Studies that map the entire wood value chain with its multilevel interdependences and integrating cascading use of wood are lacking. • Most studies focus on fuelwood supply chain risks affecting bioenergy generation. • Regulations stimulated studies on bioenergy feedstock supply strategies. • Europe especially shows a research topic in securing bioenergy production. • Supply security analyses in the context of the wood supply chain are rare. • Comprehensive analyses of the entire wood value chain are missing. [ABSTRACT FROM AUTHOR]

Forestry faces frequent and severe natural calamities causing high amounts of salvage wood. Especially under mountainous conditions, regional available self-loading truck capacity is often the main limiting factor causing transport capacity bottlenecks. Therefore, innovative logistics strategies are needed to ensure quick transport of high amounts of salvage wood. Consequently, a multi-echelon unimodal transport concept, where timber is synchronously transshipped at a truck terminal with four transshipment lots from self-loading trucks to semitrailers, was modeled by means of a discrete event simulation. The simulation model calculates key performance indicators such as transshipped volumes and costs and support estimations of optimal truck fleet configuration. The results provide cost-optimal truck fleet configurations in terms of the number of self-loading trucks, semitrailers and prime mover trucks for varying transshipment volumes, delivery time to terminal and legal truck payload scenarios. Applying the truck terminal concept considerably decreases the number of self-loading trucks needed to transport the same volume when compared to unimodal wood transport, which is most common under mountainous conditions in Europe. In the majority of delivery time to terminal and terminal transshipment volume scenarios, the number of self-loading trucks was reduced by more than 50%. Increasing the legal gross vehicle weight for timber transport from 44 t up to 50 t reduces the number of self-loading trucks needed by 20% to 38%, depending on the scenario setting. Additionally, less self-loading trucks arriving at the terminal also cuts queuing times and system efficiency increases as transport cost/t is reduced by 6% to 11% depending on the scenario setting. Expanding the truck terminal concept by adding storage capacity as well as varying the number of transshipping lots and also including costs for terminal construction and operations in the economic analyses are promising topics for future studies. [ABSTRACT FROM AUTHOR]

Over 4000 agricultural and grazing land soil samples were collected for the “Geochemical Mapping of Agricultural and Grazing Land Soil of Europe” (GEMAS) project carried out by the EuroGeoSurveys Geochemistry Expert Group. The samples were collected in 33 European countries, covering 5.6 million km 2 at a density of 1 sample site per 2500 km 2 . All samples were analysed by ICP-MS following an aqua regia extraction. The European median Cd concentration is 0.182 mg/kg in agricultural soil and 0.197 mg/kg in grazing land soil (including eastern Ukraine). The Cd map demonstrates the existence of two different geochemical background regimes in northern and southern Europe, separated by the southern limit of the Quaternary glaciation. Cadmium shows two times higher background concentrations in the older and more weathered southern European soil than in northern European soil. The spatial distribution patterns of Cd in the collected soil samples are mainly governed by geology (parent material and mineralisation), as well as weathering, soil formation and climate since the last glaciation period. Locally, in several areas, the natural anomaly pattern is overprinted by anthropogenic emissions from former mining, ore processing and related metal industries. Some Cd anomalies can be attributed to urbanisation and the use of fertilisers. A comparison of the raw data Cd concentration map with its clr-transformed counterpart and selected single element ratio maps demonstrates that substantial additional information about sources and processes governing the distribution of Cd in agricultural soil at the European scale can be obtained. Results of a PCA, carried out following the classical approach (standardised) versus a PCA based on the statistically acceptable approach, using clr-transformed data, are quite comparable. [ABSTRACT FROM AUTHOR]

• Over 32,673 patient-years of follow-up, 60 (1.7%) HIV/HBV-coinfected individuals developed HCC. • In cirrhotic patients on TDF-containing antiretroviral therapy, the incidence of HCC was 5.90 per 1,000 patient-years. • In non-cirrhotic patients on TDF-containing antiretroviral therapy, the incidence was 1.17 per 1,000 patient-years. • HCC incidence stayed below the recognized screening threshold in non-cirrhotics who started TDF when <46 years old. Robust data on hepatocellular carcinoma (HCC) incidence among HIV/hepatitis B virus (HBV)-coinfected individuals on antiretroviral therapy (ART) are needed to inform HCC screening strategies. We aimed to evaluate the incidence and risk factors of HCC among HIV/HBV-coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing ART in a large multi-cohort study. We included all HIV-infected adults with a positive hepatitis B surface antigen test followed in 4 prospective European cohorts. The primary outcome was the occurrence of HCC. Demographic and clinical information was retrieved from routinely collected data, and liver cirrhosis was defined according to results from liver biopsy or non-invasive measurements. Multivariable Poisson regression was used to assess HCC risk factors. A total of 3,625 HIV/HBV-coinfected patients were included, of whom 72% had started TDF-containing ART. Over 32,673 patient-years (py), 60 individuals (1.7%) developed an HCC. The incidence of HCC remained stable over time among individuals on TDF, whereas it increased steadily among those not on TDF. Among individuals on TDF, the incidence of HCC was 5.9 per 1,000 py (95% CI 3.60–9.10) in cirrhotics and 1.17 per 1,000 py (0.56–2.14) among non-cirrhotics. Age at initiation of TDF (adjusted incidence rate ratio per 10-year increase: 2.2, 95% CI 1.6–3.0) and the presence of liver cirrhosis (4.5, 2.3–8.9) were predictors of HCC. Among non-cirrhotic individuals, the incidence of HCC was only above the commonly used screening threshold of 2 cases per 1,000 py in patients aged >45 years old at TDF initiation. Whereas the incidence of HCC was high in cirrhotic HIV/HBV-coinfected individuals, it remained below the HCC screening threshold in patients without cirrhosis who started TDF aged <46 years old. We investigated the incidence of hepatocellular carcinoma in HIV/hepatitis B virus-coinfected individuals from a large multi-cohort study in Europe. Over 32,673 patient-years, 60 individuals (1.7%) developed hepatocellular carcinoma. The incidence of hepatocellular carcinoma remained low in patients without cirrhosis, who started on tenofovir disoproxil fumarate when aged <46 years old. [ABSTRACT FROM AUTHOR]

Background: Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens., Methods: This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI., Findings: Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (p interaction =0·46 for hypertension; p interaction =0·31 for dyslipidaemia)., Interpretation: Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV., Funding: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences., Competing Interests: Declaration of interests AM has received travel support and lecture and consultancy fees from Gilead Sciences, ViiV Healthcare, Eiland, and Bonnin, all outside the submitted work. VV is an employee of and has stocks in ViiV Healthcare. CC is an employee of and has stocks in Gilead Sciences. EB is an employee of and has stocks in MSD. ML has received sitting fees from Certa Therapeutics data safety monitoring board. KG-P has served on advisory boards and provided lectures for Gilead Sciences and ViiV Healthcare. AR has received support for attending meetings and travel from Gilead Sciences and Pfizer, received an investigator-initiated trial grant from Gilead Sciences, and participated on a data safety monitoring board or advisory board for MSD and Pfizer (all paid to the institution). All other authors declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation., Setting: International multicohort collaboration., Methods: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation., Results: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months., Conclusions: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Background and Aims: To investigate the uptake of hepatitis C virus (HCV) therapy among HIV/HCV-coinfected patients in the pan-European EuroSIDA study between 2011 and 2016., Methods: All HCV-RNA+ patients were included. Baseline was defined as latest of anti-HCV+, January 2011 or enrolment in EuroSIDA. The incidence of starting first interferon-free direct-acting antiviral (DAA) therapy was calculated. Factors associated with starting interferon-free DAA were determined by Poisson regression., Results: Among 4308 HCV-RNA+ patients (1255, 970, 663, 633, 787 from South, West, North, Central East and East Europe, respectively) with 11 863 person-years of follow-up, 1113 (25.8%) started any HCV therapy. Among patients with at least F3 fibrosis, more than 50% in all regions remained untreated. The incidence (per 1000 person-years of follow-up, 95% confidence interval) of starting DAA increased from 7.8 (5.9-9.8) in 2014 to 135.2 (122.0-148.5) in 2015 and 128.9 (113.5-144.3) in 2016. The increase was highest in North and West and intermediate in South, but remained modest in Central East and Eastern Europe. After adjustment, women, individuals from Central East or East, genotype 3, antiretroviral therapy naïve and those with detectable HIV-RNA were less likely to start DAA. Older persons, those with HCV-RNA more than 500 000 IU/ml and those with more advanced liver fibrosis were more likely to start DAA., Conclusion: Uptake of DAA therapy among HIV/HCV-coinfected patients increased considerably in Western Europe between 2014 and 2016, but was modest in Central East and East. In all regions more than 50% with at least F3 fibrosis remained untreated. Women were less likely to start DAA.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.