Conflict, violence, and warfare among early farmers in Northwestern Europe.

Bioarchaeological evidence of interpersonal violence and early warfare presents important insights into conflict in past societies. This evidence is critical for understanding the motivations for violence and its effects on opposing and competing individuals and groups across time and space. Selecting the Neolithic of northwestern Europe as an area for study, the present paper examines the variation and societal context for the violence recorded in the human skeletal remains from this region as one of the most important elements of human welfare. Compiling data from various sources, it becomes apparent that violence was endemic in Neolithic Europe, sometimes reaching levels of intergroup hostilities that ended in the utter destruction of entire communities. While the precise comparative quantification of healed and unhealed trauma remains a fundamental problem, patterns emerge that see conflict likely fostered by increasing competition between settled and growing communities, e.g., for access to arable land for food production. The further development of contextual information is paramount in order to address hypotheses on the motivations, origins, and evolution of violence as based on the study of human remains, the most direct indicator for actual small- and large-scale violence.

Three years of COVID-19 and life satisfaction in Europe: A macro view.

Every country in Europe experienced an adverse impact from the COVID-19 pandemic on life satisfaction, though on average, satisfaction with life in the summer of 2022 is about the same as the pre-pandemic value in the autumn of 2019. Typically, an upsurge in the severity of the pandemic (measured by the number of COVID-related deaths) is associated with declining life satisfaction and an ebbing, with increasing life satisfaction. Of the three waves of the pandemic between March 2020 and the autumn of 2022, the most severe impact typically occurred in 2021 during the second wave; in the third wave, the response declined due to the spread of effective vaccines and the takeover of omicron variants.

Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations.

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.

Dating the emergence of dairying by the first farmers of Central Europe using 14C analysis of fatty acids preserved in pottery vessels.

Direct, accurate, and precise dating of archaeological pottery vessels is now achievable using a recently developed approach based on the radiocarbon dating of purified molecular components of food residues preserved in the walls of pottery vessels. The method targets fatty acids from animal fat residues, making it uniquely suited for directly dating the inception of new food commodities in prehistoric populations. Here, we report a large-scale application of the method by directly dating the introduction of dairying into Central Europe by the Linearbandkeramik (LBK) cultural group based on dairy fat residues. The radiocarbon dates (n = 27) from the 54th century BC from the western and eastern expansion of the LBK suggest dairy exploitation arrived with the first settlers in the respective regions and were not gradually adopted later. This is particularly significant, as contemporaneous LBK sites showed an uneven distribution of dairy exploitation. Significantly, our findings demonstrate the power of directly dating the introduction of new food commodities, hence removing taphonomic uncertainties when assessing this indirectly based on associated cultural materials or other remains.

No evidence for persistent natural plague reservoirs in historical and modern Europe.

Caused by Yersinia pestis, plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.

Tuberculosis Disease in Immunocompromised Children and Adolescents: A Pediatric Tuberculosis Network European Trials Group Multicenter Case-control Study.

BACKGROUND: In high-resource settings, the survival of children with immunocompromise (IC) has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools, and outcome of IC children with tuberculosis (TB) in Europe. METHODS: Multicenter, matched case-control study within the Pediatric Tuberculosis Network European Trials Group, capturing TB cases <18 years diagnosed 2000-2020. RESULTS: A total of 417 TB cases were included, comprising 139 children who are IC (human immunodeficiency virus, inborn errors of immunity, drug-induced immunosuppression, and other immunocompromising conditions) and 278 non-IC children as controls. Nonrespiratory TB was more frequent among cases than controls (32.4% vs 21.2%; P = .013). Patients with IC had an increased likelihood of presenting with severe disease (57.6% vs 38.5%; P < .001; odds ratio [95% confidence interval], 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs 6.0%; P < .001) and QuantiFERON-TB Gold assay (30.0% vs 7.3%; P < .001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs 49.3%; P = .083). Although the mortality in children with IC was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs 6.1%; P = .004). CONCLUSIONS: Children with IC and TB in Europe have increased rates of nonrespiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in patients with IC, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.

Burden of Stroke in Europe: An Analysis of the Global Burden of Disease Study Findings From 2010 to 2019.

BACKGROUND: While most European Regions perform well in global comparisons, large discrepancies within stroke epidemiological parameters exist across Europe. The objective of this analysis was to evaluate the stroke burden across European regions and countries in 2019 and its difference to 2010. METHODS: The GBD 2019 analytical tools were used to evaluate regional and country-specific estimates of incidence, prevalence, deaths, and disability-adjusted life years of stroke for the European Region as defined by the World Health Organization, with its 53 member countries (EU-53) and for European Union as defined in 2019, with its 28 member countries (EU-28), between 2010 and 2019. Results were analyzed at a regional, subregional, and country level. RESULTS: In EU-53, the absolute number of incident and prevalent strokes increased by 2% (uncertainty interval [UI], 0%-4%), from 1 767 280 to 1 802 559 new cases, and by 4% (UI, 3%-5%) between 2010 and 2019, respectively. In EU-28, the absolute number of prevalent strokes and stroke-related deaths increased by 4% (UI, 2%-5%) and by 6% (UI, 1%-10%), respectively. All-stroke age-standardized mortality rates, however, decreased by 18% (UI, -22% to -14%), from 82 to 67 per 100 000 people in the EU-53, and by 15% (UI, -18% to -11%), from 49.3 to 42.0 per 100 000 people in EU-28. Despite most countries presenting reductions in age-adjusted incidence, prevalence, mortality, and disability-adjusted life year rates, these rates remained 1.4×, 1.2×, 1.6×, and 1.7× higher in EU-53 in comparison to the EU-28. CONCLUSIONS: EU-53 showed a 2% increase in incident strokes, while they remained stable in EU-28. Age-standardized rates were consistently lower for all-stroke burden parameters in EU-28 in comparison to EU-53, and huge discrepancies in incidence, prevalence, mortality, and disability-adjusted life-year rates were observed between individual countries.

Predictive Mapping of Antimicrobial Resistance for Escherichia coli, Salmonella, and Campylobacter in Food-Producing Animals, Europe, 2000-2021.

In Europe, systematic national surveillance of antimicrobial resistance (AMR) in food-producing animals has been conducted for decades; however, geographic distribution within countries remains unknown. To determine distribution within Europe, we combined 33,802 country-level AMR prevalence estimates with 2,849 local AMR prevalence estimates from 209 point prevalence surveys across 31 countries. We produced geospatial models of AMR prevalence in Escherichia coli, nontyphoidal Salmonella, and Campylobacter for cattle, pigs, and poultry. We summarized AMR trends by using the proportion of tested antimicrobial compounds with resistance >50% and generated predictive maps at 10 × 10 km resolution that disaggregated AMR prevalence. For E. coli, predicted prevalence rates were highest in southern Romania and southern/eastern Italy; for Salmonella, southern Hungary and central Poland; and for Campylobacter, throughout Spain. Our findings suggest that AMR distribution is heterogeneous within countries and that surveillance data from below the country level could help with prioritizing resources to reduce AMR.

Molecular Epidemiology of Underreported Emerging Zoonotic Pathogen Streptococcus suis in Europe.

Streptococcus suis, a zoonotic bacterial pathogen circulated through swine, can cause severe infections in humans. Because human S. suis infections are not notifiable in most countries, incidence is underestimated. We aimed to increase insight into the molecular epidemiology of human S. suis infections in Europe. To procure data, we surveyed 7 reference laboratories and performed a systematic review of the scientific literature. We identified 236 cases of human S. suis infection from those sources and an additional 87 by scanning gray literature. We performed whole-genome sequencing to type 46 zoonotic S. suis isolates and combined them with 28 publicly available genomes in a core-genome phylogeny. Clonal complex (CC) 1 isolates accounted for 87% of typed human infections; CC20, CC25, CC87, and CC94 also caused infections. Emergence of diverse zoonotic clades and notable severity of illness in humans support classifying S. suis infection as a notifiable condition.

Tick-Borne Encephalitis, Lombardy, Italy.

Tick-borne encephalitis was limited to northeast portions of Italy. We report in Lombardy, a populous region in the northwest, a chamois displaying clinical signs of tickborne encephalitis virus that had multiple virus-positive ticks attached, as well as a symptomatic man. Further, we show serologic evidence of viral circulation in the area.

Parechovirus A Circulation and Testing Capacities in Europe, 2015-2021.

Parechovirus infections usually affect neonates and young children; manifestations vary from asymptomatic to life-threatening. We describe laboratory capacity in Europe for assessing parechovirus circulation, seasonality, and epidemiology. We used retrospective anonymized data collected from parechovirus infection case-patients identified in Europe during January 2015-December 2021. Of 21 laboratories from 18 countries that participated in the study, 16 (76%) laboratories with parechovirus detection capacity reported 1,845 positive samples; 12/16 (75%) with typing capability successfully identified 517 samples. Parechovirus A3 was the most common type (n = 278), followed by A1 (153), A6 (50), A4 (13), A5 (22), and A14 (1). Clinical data from 1,269 participants highlighted correlation of types A3, A4, and A5 with severe disease in neonates. We observed a wide capacity in Europe to detect, type, and analyze parechovirus data. To enhance surveillance and response for PeV outbreaks, sharing typing protocols and data on parechovirus-positive cases should be encouraged.

Drug-Resistant Tuberculosis, Georgia, Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, 2017-2022.

In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).

Interventional Study of Nonpharmaceutical Measures to Prevent COVID-19 Aboard Cruise Ships.

Cruise ships carrying COVID-19-vaccinated populations applied near-identical nonpharmaceutical measures during July-November 2021; passenger masking was not applied on 2 ships. Infection risk for masked passengers was 14.58 times lower than for unmasked passengers and 19.61 times lower than in the community. Unmasked passengers' risk was slightly lower than community risk.

Differences in survival and recurrence of colorectal cancer by stage across population-based European registries.

Recurrence after colorectal cancer resection is rarely documented in the general population while a key clinical determinant for patient survival. We identified 8785 patients with colorectal cancer diagnosed between 2010 and 2013 and clinically followed up to 2020 in 15 cancer registries from seven European countries (Bulgaria, Switzerland, Germany, Estonia, France, Italy, and Spain). We estimated world age-standardized net survival using a flexible cumulative excess hazard model. Recurrence rates were calculated for patients with initially resected stage I, II, or III cancer in six countries, using the actuarial survival method. The proportion of nonmetastatic resected colorectal cancers varied from 58.6% to 78.5% according to countries. The overall 5-year net survival by country ranged between 60.8% and 74.5%. The absolute difference between the 5-year survival extremes was 12.8 points for stage II (Bulgaria vs Switzerland), 19.7 points for stage III (Bulgaria vs. Switzerland) and 14.8 points for Stage IV and unresected cases (Bulgaria vs. Switzerland or France). Five-year cumulative rate of recurrence among resected patients with stage I-III was 17.7%. As compared to the mean of the whole cohort, the risk of developing a recurrence did not differ between countries except a lower risk in Italy for both stage I/II and stage III cancers and a higher risk in Spain for stage III. Survival after colorectal cancer differed across the concerned European countries while there were slight differences in recurrence rates. Population-based collection of cancer recurrence information is crucial to enhance efforts for evidence-based management of colorectal cancer follow up.

Differences in time to patient access to innovative cancer medicines in six European countries.

Patients across Europe face inequity regarding access to anticancer medicines. While access is typically evaluated through reimbursement status or sales data, patients can receive first access through early access programs (EAPs) or off-label use. This study aims to assess the time to patient access at the hospital level, considering different indications and countries. (Pre-)registered access to six innovative medicines (Olaparib, Niraparib, Ipilimumab, Osimeritinib, Nivolumab and Ibritunib) was measured using a cross-sectional survey. First patient access to medicines and indications were collected using the hospital databases. Nineteen hospitals from Hungary, Italy, the Netherlands, Belgium, Switzerland and France participated. Analysis showed that some hospitals achieved patient access before national reimbursement, primarily through EAPs. The average time from EMA-approval to patient access for these medicines was 2.1 years (Range: -0.9-7.1 years). Hospitals in Italy and France had faster access compared to Hungary and Belgium. Variation was also found within countries, with specialized hospitals (x̄: -0.9 years; SD: 2.0) more likely to provide patient access prior to national reimbursement than general hospitals (x̄: 0.4 years; SD: 2.9). Contextual differences were observed, with EAPs or off-label use being more prevalent in Switzerland than Hungary. Recent EMA-approved indications and drug combinations reached patients at a later stage. Substantial variation in patient access time was observed between and within countries. Improving pricing and reimbursement timelines, fostering collaboration between national health authorities and market authorization holders, and implementing nationally harmonized, data-generating EAPs can enhance timely and equitable patient access to innovative cancer treatments in Europe.

Inequities in primary liver cancer in Europe: The state of play.

Given the increasing burden of liver cancer in Europe, it is crucial to investigate how social determinants of health (SDoH) affect liver cancer risk factors and access to care in order to improve health outcomes equitably. This paper summarises the available evidence on the differential distribution of liver cancer risk factors, incidence, and health outcomes in the European Economic Area and the United Kingdom from an SDoH perspective. Vulnerable and marginalised populations have low socio-economic and educational levels and are the most affected by liver cancer risk factors. Reasons for this include varied access to hepatitis B virus vaccination and limited access to viral hepatitis B and C screening, harm reduction, and treatment. Additionally, alcohol-related liver disease remains highly prevalent among individuals with low education, insecure employment, economic instability, migrants, and deprived populations. Moreover, significant variation exists across Europe in the proportion of adults with steatotic liver disease, overweight/obesity, and diabetes, based on geographical area, gender, socio-economic and educational background, and density of ultra-processed food outlets. Inequities in cirrhosis mortality rates have been reported, with the highest death rates among individuals living in socio-economically disadvantaged areas and those with lower educational levels. Furthermore, insufficient healthcare access for key populations with primary liver cancer is influenced by complex healthcare systems, stigmatisation, discrimination, low education, language barriers, and fear of disclosure. These challenges contribute to inequities in liver cancer care pathways. Future studies are needed to explore the different SDoH-interlinked effects on liver cancer incidence and outcomes in European countries. The ultimate goal is to develop evidence-based multilevel public health interventions that reduce the SDoH impact in precipitating and perpetuating the disproportionate burden of liver cancer in specific populations.

Tissue distribution and transmission of Rift Valley fever phlebovirus in European Culex pipiens and Aedes albopictus mosquitoes following intrathoracic inoculation.

Rift Valley fever virus (Phlebovirus riftense, RVFV) poses significant economic challenges, particularly in African nations, causing substantial livestock losses and severe haemorrhagic disease in humans. In Europe, the risk of RVFV transmission is deemed moderate due to the presence of competent vectors like Culex pipiens and Aedes albopictus, along with susceptible animal vertebrate hosts across member states. This study investigates RVFV infection dynamics in European mosquito populations, aiming to enhance our understanding of their vectorial capacity and virus transmission, which can be useful for future investigations to improve RVFV surveillance, control programmes, and preventive treatments. Intrathoracic inoculation of European Cx. pipiens and Ae. albopictus with an RVFV virulent strain (RVF 56/74) enabled the assessment of virus tissue distribution and transmission. Immunohistochemistry analyses revealed widespread RVFV infection in all analysable anatomical structures at 5 and 14 days post-inoculation. Notably, the ganglionic nervous system exhibited the highest detection of RVFV in both species. Cx. pipiens showed more frequently infected structures than Ae. albopictus, particularly in reproductive structures. The identification of an RVFV-positive egg follicle in Cx. pipiens hints at potential vertical transmission. Saliva analysis indicated a higher transmission potential in Cx. pipiens (71.4%) compared to Ae. albopictus (4.3%) at the early time point. This study offers the first description and comparison of RVFV tissue distribution in Ae. albopictus and Cx. pipiens, shedding light on the susceptibility of their nervous systems, which may alter mosquito behaviour, which is critical for virus transmission. Overall, enhancing our knowledge of viral infection within mosquitoes holds promise for future vector biology research and innovative approaches to mitigate RVFV transmission.

European cancer mortality predictions for the year 2024 with focus on colorectal cancer.

BACKGROUND: We predicted cancer mortality figures for 2024 for the European Union (EU), its five most populous countries, and the UK. We focused on mortality from colorectal cancer (CRC). MATERIALS AND METHODS: Based on cancer death certification and population data from the World Health Organization and Eurostat databases from 1970 until the most available year, we predicted deaths and age-standardized rates (ASRs) for 2024 for all cancers and the 10 most common cancer sites. We fitted a linear regression to the most recent trend segment identified by the joinpoint model. The number of avoided deaths since the peak in 1988-2024 was estimated for all cancers and CRC. RESULTS: We predicted 1 270 800 cancer deaths for 2024 in the EU, corresponding to ASRs of 123.2/100 000 men (-6.5% versus 2018) and 79.0/100 000 women (-4.3%). Since 1988, about 6.2 million cancer deaths have been avoided in the EU and 1.3 million in the UK. Pancreatic cancer displayed unfavorable predicted rates for both sexes (+1.6% in men and +4.0% in women) and lung cancer for women (+0.3%). The focus on CRC showed falls in mortality at all ages in the EU, by 4.8% for men and 9.5% for women since 2018. The largest declines in CRC mortality are predicted among those 70+ years old. In the UK, projected ASRs for CRC at all ages are favorable for men (-3.4% versus 2018) but not for women (+0.3%). Below age 50 years, CRC mortality showed unfavorable trends in Italy and the UK, in Poland and Spain for men, and in Germany for women. CONCLUSIONS: Predicted cancer mortality rates remain favorable in the EU and the UK, mainly in males due to earlier smoking cessation compared to females, underlining the persisting major role of tobacco on cancer mortality in Europe. Attention should be paid to the predicted increases in CRC mortality in young adults.

Trends in the activity of mold-active azole agents against Aspergillus fumigatus clinical isolates with and without cyp51 alterations from Europe and North America (2017-2021).

Azole resistance in Aspergillus fumigatus (AFM) is increasing and often associated with cyp51 alterations. We evaluated the activity of isavuconazole and other mold-active azoles against 731 AFM isolates causing invasive aspergillosis collected in Europe (EU; n = 449) and North America (NA; n = 282). Isolates were submitted to CLSI susceptibility testing and epidemiological cutoff value (ECV) criteria. A posaconazole ECV of 0.5 mg/L was used as no CLSI ECV was determined. Azole non-wild-type (NWT) isolates were submitted for cyp51 sequencing by whole genome sequencing. Overall, isavuconazole activity (92.7%/94.0% WT in EU/NA) was comparable to other azoles (WT rate range, 90.9%-96.4%/91.8%-98.6%, respectively), regardless of the region. A total of 79 (10.8%) azole NWT isolates were detected, and similar rates of these isolates were noted in EU (10.7%) and NA (11.0%). Although most AFM were WT to azoles, increasing azole NWT rates were observed in NA (from 6.0% in 2017 to 29.3% in 2021). Azole NWT rates varied from 4.9% (2019) to 20.6% (2018) in EU without an observed trend. cyp51 alterations occurred in 56.3%/54.8% of azole NWT from EU/NA, respectively. The cyp51A TR34/L98H alteration was observed only in EU isolates (72.0% of EU isolates), while cyp51A I242V occurred only in NA isolates (58.3%). Isavuconazole remained active (MIC, ≤1 mg/L) against 18.5/47.1% of azole NWT AFM exhibiting cyp51 alterations in EU/NA, along with voriconazole (29.6/82.4%; MIC, ≤1 mg/L) and posaconazole (48.1/88.2%; MIC, ≤0.5 mg/L). Fourteen different cyp51 alterations were detected in 44 of 79 NWT isolates. The in vitro activity of the azoles varied in AFM that displayed cyp51 alterations. IMPORTANCE A few microbiology laboratories perform antifungal susceptibility testing locally for systemically active antifungal agents. The identification of emerging azole-resistant Aspergillus fumigatus is worrisome. As such, there is a critical role for antifungal surveillance in tracking emerging resistance among both common and uncommon opportunistic fungi. Differences in the regional prevalence and antifungal resistance of these fungi render local epidemiological knowledge essential for the care of patients with a suspected invasive fungal infection.

HIV pre-exposure prophylaxis services, provision, and delivery in the European treatment network of HIV, hepatitis and global emerging infectious diseases (NEAT ID).

OBJECTIVES: We conducted a survey to evaluate HIV pre-exposure prophylaxis (PrEP) practices in a European clinical research network on HIV, hepatitis, and global infectious diseases (NEAT ID). METHODS: An online survey comprising 22 questions was sent via a secure electronic tool to the investigating physician of each of the 342 NEAT ID study centres across 15 European countries in November 2020. RESULTS: In total, 50 sites from 12 countries responded (15% response rate). Most sites were in Western Europe, two were in Poland, and one was in Hungary. Of the responding sites, 45 provided PrEP services for a total of 27 416 PrEP users, with 1361 new PrEP initiators each month. These centres supplied PrEP for men who have sex with men (100%), people who inject drugs (84%), sex workers (84%), women (62%), and transgender women (31%). PrEP persistence after 1 year was >90%, 75%-90%, and 40%-75% in 17, 24, and 4 centres, respectively. In total, 32/45 (71%) centres reported strong community-based organization commitment at their site, and 15/45 (33%) centres developed task-shifting processes to deliver PrEP through nurses (11/15), pharmacists (5/15), and key-population peers (2/15). The biggest barriers to implementation of PrEP were low awareness of and knowledge about PrEP (47%), unwillingness to disclose sexual identity or at-risk behaviour (36%), and lack of administrative support (29%). Of the 45 centres, 32 (71%) have already been involved in PrEP research and 43 (96%) were interested in participating in such studies. CONCLUSIONS: The few NEAT ID centres that responded to the survey showed disparities in PrEP deployment and practices despite a common interest in participating in research in this field.