Evidence for the Impact of Stress and Trauma on Sexual Function in Women: Review and Clinical Recommendations.

Stressors occur in a spectrum, ranging from daily hassles to life-threatening experiences, and can significantly impact sexual functioning. Thus, this review summarizes the intricate relationship between trauma spectrum experiences and women's sexual functioning. Biological mechanisms are described to elucidate the physiologic complexity that manifests because of trauma-related experiences. Additionally, both psychological and social implications are discussed. Treatment recommendations for practitioners working with women are discussed, underscoring the importance of adopting a trauma-informed care model.

Outcomes of COVID-19 re-infections: a single-center cohort of 167 patients with systemic rheumatic diseases.

Data on COVID-19 re-infections in patients with systemic rheumatic diseases (SRDs) are lacking. We aimed to describe the course and outcomes of COVID-19 re-infections in these patients versus controls. In this single-center retrospective study, we included 167 consecutive SRD patients with at least one COVID-19 re-infection (mean age 47.3 years, females 70.7%). SRD patients were compared in terms of patient-perceived COVID-19 re-infection severity and hospitalizations/deaths with 167 age/sex-matched non-SRD controls. Logistic regression analysis was performed to assess potential milder re-infection versus primary infection severity, adjusting for study group, demographics (age, sex), vaccination status, body mass index, smoking, and comorbidities. 23 and 7 out of 167 re-infected SRD patients experienced two and three re-infections, respectively, which were comparable to the re-infection rates in controls (two: 32; and three: 2) who also had comparable COVID-19 vaccination history (89% and 95% vaccinated, respectively). In the initial infection, patients with SRDs were hospitalized (7.2% versus 1.8%, p = 0.017), and had received antiviral treatment (16.1% versus 4.7%, p < 0.001) more frequently than controls. However, hospitalizations (1.8% vs 0.6%) and antiviral treatment (7.8% vs 3.5%) did not differ (p > 0.05) between patients and controls at the first re-infection, as well as during the second and third re-infection; no deaths were recorded. Perceived severity of re-infections was also comparable between patients and controls (p = 0.847) and among those on biologic DMARDs or not (p = 0.482). In multivariable analysis, neither SRDs presence nor demographics or comorbidities were associated with COVID-19 re-infection severity. COVID-19 re-infection severity (patient-perceived/hospitalizations/deaths) did not differ between SRDs and controls.

Glucocorticoid discontinuation rate and risk factors for relapses in a contemporary cohort of patients with giant cell arteritis.

The rates of relapses and therapy discontinuation in patients with giant cell arteritis (GCA) in the modern therapeutic era have not been defined. We aimed to evaluate the glucocorticoid (GC) discontinuation rate and the factors associated with relapses in a contemporary GCA cohort. Patient and treatment data were collected cross-sectionally at first evaluation and 2 years later (second evaluation), in a multicenter, prospective GCA cohort. Predictors of relapses were identified by logistic regression analyses. 243 patients with GCA were initially included (67% women, mean age at diagnosis: 72.1 years, median disease duration: 2 years) while 2 years later complete data for 160 patients were available and analyzed. All patients had received GCs at diagnosis (mean daily prednisolone dose: 40 mg) while during follow-up, 37% received non-biologic and 16% biologic agents, respectively. At second evaluation, 72% of patients were still on therapy (GCs: 58% and/or GC-sparing agents: 29%). Relapses occurred in 27% of patients during follow-up; by multivariable logistic regression analysis, large vessel involvement at diagnosis [odds ratio (OR) = 4.22], a cardiovascular event during follow-up (OR = 4.60) and a higher initial GC daily dose (OR = 1.04), were associated with these relapses. In this large, real-life, contemporary GCA cohort, the rates of GC discontinuation and relapses were 40% and 27%, respectively. Large vessel involvement, a higher GC dose at diagnosis and new cardiovascular events during follow-up were associated with relapses.

The Role of Interleukins in HBV Infection: A Narrative Review.

Hepatitis B virus (HBV) infection is a worldwide medical issue with significant morbidity and mortality, as it is the main cause of chronic liver disease and hepatocellular carcinoma (HCC). Both innate and adaptive immune responses play a key role in HBV replication and suppression. Recently, the pathophysiological function of interleukins (IL) in the natural course of HBV has gained much attention as a result of the broad use of anti-interleukin agents for a variety of autoimmune diseases and the accompanying risk of HBV reactivation. We present a narrative review regarding the role of IL in HBV infection. Collectively, the pro-inflammatory ILs, namely IL-1, IL-5, IL-6, IL-12 and IL-21, seem to play a critical role in the suppression of HBV replication. In contrast, the anti-inflammatory cytokines IL-10, IL-23 and IL-35 probably act as HBV replication enhancers, while IL-17 has been correlated with HBV-related liver injury. Interestingly enough, IL-2, IL-4 and IL-12 have been tried as therapeutic options against HBV infection with contradictory results. Lastly, the role of IL-22 remains largely ill defined, although preliminary data suggest that it may play a significant role in HBV replication, proliferation and subsequent liver damage.

Virtual Reality in Laparoscopic Colorectal Surgery Training.

Introduction: The advantages of laparoscopic colorectal surgery have been proven in several studies, but its use is limited in some countries and not widely practiced. One of the primary benefits of laparoscopic surgery is that it reduces patient discomfort and hospital stays compared to traditional open surgery. This study presents an overview of the virtual reality training method for laparoscopic colorectal surgery and offers evidence for the effectiveness of this training curriculum and the associated learning curve. Material and methods: To conduct this research, we conducted a thorough review of the relevant literature in the PubMed database, focusing on studies related to "Virtual reality and colorectal laparoscopic surgery training". Material and methods: To conduct this research, we conducted a thorough review of the relevant literature in the PubMed database, focusing on studies related to "Virtual reality and colorectal laparoscopic surgery training". Material and methods: To conduct this research, we conducted a thorough review of the relevant literature in the PubMed database, focusing on studies related to "Virtual reality and colorectal laparoscopic surgery training".

Omicron variant dominance and anti-SARS-CoV-2 vaccination are key determinants for a milder course of COVID-19 in patients with systemic autoimmune rheumatic diseases.

INTRODUCTION: This study aimed to determine whether the introduction of anti-SARS-CoV-2 vaccines and the dominance of the omicron variant had a significant impact on the outcome of COVID-19 in patients with systemic autoimmune rheumatic diseases (SAIRDs). METHODS: Using data entered to the Greek Rheumatology Society COVID-19 registry, we investigated the incidence of hospitalization and death due to COVID-19, during the successive periods of the pandemic according to the prevalent strain (wild-type, Alpha, Delta, Omicron) in vaccinated and unvaccinated patients. Variables independently associated with hospitalization and death were explored using multivariate regression analyses, while Kaplan-Meier curves were used to depict survival data. RESULTS: From August 2020 until June 30, 2022, 456 cases (70.2% females) of COVID-19 with a mean age (± SD) of 51.4 ± 14.0 years were reported. In unvaccinated patients, the proportions of hospitalization and death were 24.5% and 4%, compared to 12.5% and 0.8% in the vaccinated group (p < 0.001 for both comparisons). The rates of hospitalization for the wild-type, Alpha, Delta, and Omicron periods were 24.7%, 31.3%, 25.9%, and 8.1% respectively (p < 0.0001), while the case fatality rates were 2.7%, 4%, 7%, and 0%, respectively (p = 0.001). Using multivariable regression analysis, factors independently associated with hospitalization were infection by a non-Omicron variant, being non-vaccinated, exposure to rituximab, older age, and respiratory and cardiovascular disease. Independent predictors for death were contracting COVID-19 during the Alpha or Delta period, pulmonary disease, and older age, while being vaccinated was protective. CONCLUSIONS: In this 2-year analysis, the rates of hospitalization and death among patients with SAIRDs have declined significantly. Vaccination and the dominance of the Omicron variant appear to be the major determinants for this shift. Key points • During the late phase of the pandemic, the proportion of severe COVID-19 cases, defined as requiring hospitalization or resulting in death, in patients with systemic autoimmune rheumatic diseases has declined. • Anti-SARS-CoV-2 vaccination and the dominance of the Omicron strain are the key factors that have independently contributed to this shift.

A randomized clinical trial of bermekimab treatment for clinical improvement of systemic sclerosis.

Increased concentrations of interleukin (IL)-1α have been recently described in tissues of patients with systemic sclerosis (SSc) suggesting that IL-1α inhibition may be a target for treatment. We conducted a double-blind, placebo-controlled study to assess the safety and efficacy of the fully humanized IL-1α blocking monoclonal antibody bermekimab in SSc. To evaluate response to treatment, we developed the score of inhibition of progression of SSc which was validated using the CRISS index and the modified CRISS index. The primary endpoint was met in 80% of bermekimab-treated patients vs. 20% of placebo-treated patients (p: 0.023). Most of efficacy was found for increase of carbon monoxide lung diffusion capacity. Production of IL-1α and TNF by circulating mononuclear cells was decreased and the absolute count of CD42/Cd62-platelets was decreased. Results suggest that bermekimab is a promising treatment for SSc.

Higher frequency but similar recurrence rate of uveitis episodes in axial spondylarthritis compared to psoriatic arthritis. A multicentre retrospective study.

BACKGROUND/OBJECTIVE: Data on risk factors predicting uveitis development in spondyloarthritis (SpA) is scarce. Our aim was to examine associations between demographic, clinical and/or laboratory characteristics of SpA with the occurrence and the course of uveitis, including ocular damage and recurrence rate. METHODS: Characteristics (at disease diagnosis and ever-present) from axSpA and Psoriatic arthritis (PsA) patients followed in 3 tertiary rheumatology-clinics were retrospectively recorded. Comparisons were made between patients with and without uveitis, as well as between those with uveitis-rate [episodes/year] above the median uveitis-rate in the whole cohort ("recurrent"-uveitis) and the remaining uveitis patients ("non-recurrent uveitis"). In multivariable models, age, gender and variables significantly different in univariate analyses were included. RESULTS: 264 axSpA and 369 PsA patients were enrolled. In axSpA, uveitis occurred in 11.7% and was associated with HLA-B27 (OR = 4.15, 95%CI 1.16-14.80, p = 0.028) and ever-present peripheral arthritis (OR = 3.05 (1.10-8.41, p = 0.031). In contrast, uveitis in PsA occurred only in 2.7% of patients and was associated with SpA family-history (OR = 6.35 (1.29-31.27), p = 0.023) axial disease at diagnosis (OR = 5.61 [1.01-28.69], p = 0.038) and disease duration (OR = 1.12 [1.04-1.21], p = 0.004). Median uveitis recurrence rate was comparable between axSpA and PsA (0.205 and 0.285 episodes/year, respectively). No associations were found between recurrent uveitis and demographic/clinical/laboratory characteristics. Ocular damage (e.g. synechiae) was seen in 16.1% of axSpA and 30% of PsA patients, all of them with recurrent uveitis. CONCLUSION: Uveitis occurred more commonly in axSpA than in PsA patients, while uveitis recurrence rate was similar. Permanent ocular damage may occur more often in PsA than axSpA.

Systemic Lupus Erythematosus and COVID-19.

PURPOSE OF REVIEW: To describe the current state of knowledge regarding COVID-19 in patients with systemic lupus erythematosus (SLE). We focus on (i) SARS-CoV-2 vaccination uptake, immunogenicity and safety, and (ii) outcomes of COVID-19 in patients with SLE and pertinent risk factors for adverse sequelae. RECENT FINDINGS: Notwithstanding the potential concern of patients about possible post-vaccination side-effects, the safety of anti-SARS-CoV-2 vaccines in patients with SLE has been undisputedly confirmed in numerous studies. Humoral immunogenicity is generally attained in SLE, although affected by the use of background immunosuppressive drugs, especially rituximab. The latter has also clearly been implicated with adverse COVID-19 outcomes in SLE, including need for hospitalization, mechanical ventilation and death. Although the wide adoption of vaccination has significantly improved COVID-19 outcomes, patients with SLE continue to pose challenges during the pandemic, mainly owing to administered immunosuppressive medications.

Augmented oxidative stress, accumulation of DNA damage and impaired DNA repair mechanisms in thrombotic primary antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a rare autoimmune disorder with complex pathogenesis. Studies have shown that oxidative stress may contribute to APS pathophysiology. In peripheral blood mononuclear cells (PBMCs) from thrombotic Primary APS (thrPAPS) patients and age/sex-matched healthy controls (HC), as well as a control group of asymptomatic antiphospholipid antibody (aPL) positive individuals without APS (aPL+/non-APS), we examined oxidative stress, abasic (apurinic/apyrimidinic) sites, and DNA damage response (DDR)-associated parameters, including endogenous DNA damage (single- and double-strand breaks) and DNA repair mechanisms, namely nucleotide excision repair (NER) and double-strand breaks repair (DSB/R). We found that thrPAPS patients exhibited significantly higher levels of endogenous DNA damage, increased oxidative stress and abasic sites, as well as lower NER and DSB/R capacities versus HC (all P < 0.001) and versus aPL+/non-APS subjects (all P < 0.05). Our findings demonstrate that oxidative stress and decreased DNA repair mechanisms contribute to the accumulation of endogenous DNA damage in PBMCs from thrPAPS patients and, if further validated, may be exploited as therapeutic targets and potential biomarkers.

Effect of body mass index on treatment response of biologic/targeted-synthetic DMARDs in patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis. A systematic review.

BACKGROUND: Overweight and/or obese patients with inflammatory arthritis (IA) have higher disease activity and lower chances of achieving and/or maintaining the treatment targets. Weight/obesity also appears to negatively affect the response to tumor necrosis factor (TNF) inhibitors in IA patients, including rheumatoid arthritis -RA, psoriatic arthritis -PsA, axial spondyloarthritis -AxSpA. We conducted a systematic literature review (SLR) for the effect of weight/body-mass-index (BMI) in the efficacy of all approved biologic (b) and targeted-synthetic (ts) DMARDs for the treatment of IA. METHODS: For this PROSPERO-registered SLR, we searched PubMed, Scopus and Cohrane-Library from inception up to June 21st 2022. Clinical-trials (randomized and non-randomized) and observational studies of RA, PsA or AxSpA patients that reported the effect of weight/BMI on response (all possible outcomes) to b/ts-DMARDs were included. Risk-of-bias was assessed via RoB2-Cochrane-tool and Newcastle-Ottawa-scale for randomized and non-randomized studies, respectively. FINDINGS: Out of 996 references, 75 eventually fulfilled the inclusion criteria (of which 10 studies were retrieved through manual-search). Among the included studies (TNF-inhibitors: 34, IL-12/23 inhibitors: 4, IL-23 inhibitor: 1, IL-17 inhibitors: 7, tocilizumab: 18, abatacept: 8, rituximab: 3, JAK-inhibitors: 5), most had medium RoB. Efficacy of TNF-inhibitors was affected by BMI in all forms of IA. Data are not robust to compare the effect among various TNF-inhibitors. In contrast, favorable results of IL-23 and IL-17 inhibitors did not appear to be influenced by increased BMI in PsA or AxSpA patients. Similar evidence exists for tocilizumab (in RA) and for abatacept (in RA and PsA), while no conclusion can be drawn for rituximab. More data are needed for JAK-inhibitors, although the effect of weight/BMI does not seem to be significant so far. INTERPRETATION: Weight/BMI should be considered in the treatment-plan of IA patients, with its effect being more pronounced for TNF-inhibitors compared to other b/ts-DMARDs.

Unidirectional and phase-gated signaling synchronizes murine presomitic mesoderm cells.

Oscillator systems achieve synchronization when oscillators are coupled. The presomitic mesoderm is a system of cellular oscillators, where coordinated genetic activity is necessary for proper periodic generation of somites. While Notch signaling is required for the synchronization of these cells, it is unclear what information the cells exchange and how they react to this information to align their oscillatory pace with that of their neighbors. Combining mathematical modeling and experimental data, we found that interaction between murine presomitic mesoderm cells is controlled by a phase-gated and unidirectional coupling mechanism and results in deceleration of their oscillation pace upon Notch signaling. This mechanism predicts that isolated populations of well-mixed cells synchronize, revealing a stereotypical synchronization in the mouse PSM and contradicting expectations from previously applied theoretical approaches. Collectively, our theoretical and experimental findings reveal the underlying coupling mechanisms of the presomitic mesoderm cells and provide a framework to quantitatively characterize their synchronization.

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age.

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Geriatric Frailty Is Associated With Oxidative Stress, Accumulation, and Defective Repair of DNA Double-Strand Breaks Independently of Age and Comorbidities.

Defects in the DNA damage response and repair (DDR/R) network accumulate during the aging process. Physical frailty, a state of reduced physiological function and decreased resilience to biological stressors, is also exacerbated by aging, but its link with DDR/R aberrations beyond the effect of age and comorbidities is unclear. Fifty-three community-dwelling older adults, aged 65-102 years, who underwent frailty classification according to the Rockwood Clinical Frailty Scale (CFS), and 51 healthy adults younger than 45 years were examined in parallel. The following DDR/R parameters were determined in their peripheral blood mononuclear cells (PBMCs): (a) oxidative stress and abasic (apurinic/apyrimidinic; AP) sites, (b) endogenous DNA damage (alkaline comet assay olive tail moment [OTM] indicative of DNA single-strand breaks [SSBs] and double-strand breaks [DSBs] and γH2AX levels by immunofluorescence [DSBs only]), (c) capacity of the 2 main DNA repair mechanisms (DSB repair and nucleotide excision repair). Older individual-derived PBMCs displayed reduced-to-oxidized glutathione ratios indicative of increased levels of oxidative stress and increased AP sites, as well as increased accumulation of endogenous DNA damage (OTM and γH2AX) and defective DSB-repair capacity, compared with younger controls. These DDR/R aberrations were more pronounced in frail versus nonfrail older adults. Notably, oxidative stress, AP sites, DSBs, and DSB-repair capacity were associated with individual CFS levels after adjusting for chronological age, sex, Charlson Comorbidity Index, and polypharmacy. Geriatric frailty is independently associated with increased DNA damage formation and reduced DSB-R capacity, supporting further research into these measures as potential frailty biomarkers.

Deregulated DNA damage response network in Behcet's disease.

Behcet's disease (BD) is a chronic, relapsing systemic vasculitis of unknown etiology. Since the DNA repair enzyme NEIL1 has been identified as one of the two genetic risk factors for BD by whole exome study, we examined the potential involvement of the DNA damage response (DDR) network in BD. Peripheral blood mononuclear cells from 26 patients and 26 age-/sex-matched healthy controls were studied. Endogenous DNA damage levels were increased in active BD patients compared to controls or patients in remission. In parallel, BD patients had defective nucleotide excision repair capacity. RNA-sequencing revealed reduced expression of NEIL1 that negatively correlated with DNA damage accumulation. On the other hand, expression of genes involved in senescence and senescence-associated secretory phenotype positively correlated with individual endogenous DNA damage levels. We conclude that deregulated DDR contributes to the proinflammatory environment in BD.

Normal C-reactive protein in active psoriatic arthritis: results from real-world clinical practice.

Background: The value of normal C-reactive protein (CRP) in psoriatic arthritis (PsA) is debatable. Objectives: To test the hypothesis that CRP is frequently normal in contemporary real-world PsA patients, despite active disease. Design: In this cross-sectional study, patients were divided into two groups: CRP ⩽ 0.5 mg/dl (normal) and CRP > 0.5 mg/dl (increased). Having as dependent variable the CRP status, these groups were compared for disease-related features, including composite disease activity indices [clinical Disease Activity in PSoriatic Arthritis (cDAPSA) and minimal disease activity (MDA)] and patient-reported outcomes (PROs). Agreement between CRP status and cDAPSA/MDA scores was calculated (Cohen's kappa). Methods: Data from consecutive PsA patients attending two outpatient rheumatology clinics (January 2019-June 2021) were analysed. Results: From 128 patients enrolled (51.6% females; mean ± standard deviation age: 53.4 ± 11.7 years; 23.4%, 48.4% and 64.1% treated with glucocorticoids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biologic DMARDs, respectively), two-thirds (66.4%, n = 85) had normal CRP values. CRP status was not associated with any of the disease-related parameters and PROs, but only with ESR [odds ratio: 1.04 (95% confidence interval: 1.01-1.06), p = 0.005]. Among patients with normal CRP, 45.9% (39/85) were on non-MDA state, while 21.2% (18/85) had cDAPSA-moderate and 5.9% (5/85) had cDAPSA-high disease activities. Conversely, 54.2% (39/72) of patients on non-MDA state and 52.3% (23/44) of those with cDAPSA-moderate or cDAPSA-high disease activity had normal CRP values. Cohen's kappa between normal CRP and MDA, cDAPSA-remission, and cDAPSA-remission/low disease activity was -0.26, -0.21 and -0.22, respectively, displaying total disagreement. Conclusion: Normal CRP in PsA should not be used as surrogate marker of remission or low/MDA, therefore needs to be interpreted with caution in clinical decision-making.

Real-Life Outcome of Lupus Nephritis with Current Therapies: Study Protocol of a Multicentre Observational Study.

Lupus nephritis (LN) affects a significant proportion of patients with systemic lupus erythematosus (SLE) and is characterised by increased morbidity and mortality. The updated joint EULAR/European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendations for the management of LN have set as target of therapy the optimisation (preservation or improvement) of kidney function, accompanied by a reduction in proteinuria of at least 25% by 3 months, 50% by 6 months, and below 500-700 mg/g by 12 months (complete clinical response). It is currently unknown what proportion of Greek patients with LN reach these proposed targets with the current available treatments. At the same time, recent successful phase 3 trials have led to the approval of both belimumab and voclosporin for the treatment of patients with LN and have steered discussions as to whether the "induction-maintenance" paradigm should be substituted by an early combination treatment for all patients. To inform future therapeutic decisions and facilitate the positioning of these new drugs in the therapeutic algorithm of LN, the current study protocol aims to map the unmet needs in the treatment of LN in Greece, by quantifying the proportion of patients who attain the recommended treatment targets in everyday clinical practice.

Ancient mitochondrial diversity reveals population homogeneity in Neolithic Greece and identifies population dynamics along the Danubian expansion axis.

The aim of the study is to investigate mitochondrial diversity in Neolithic Greece and its relation to hunter-gatherers and farmers who populated the Danubian Neolithic expansion axis. We sequenced 42 mitochondrial palaeogenomes from Greece and analysed them together with European set of 328 mtDNA sequences dating from the Early to the Final Neolithic and 319 modern sequences. To test for population continuity through time in Greece, we use an original structured population continuity test that simulates DNA from different periods by explicitly considering the spatial and temporal dynamics of populations. We explore specific scenarios of the mode and tempo of the European Neolithic expansion along the Danubian axis applying spatially explicit simulations coupled with Approximate Bayesian Computation. We observe a striking genetic homogeneity for the maternal line throughout the Neolithic in Greece whereas population continuity is rejected between the Neolithic and present-day Greeks. Along the Danubian expansion axis, our best-fitting scenario supports a substantial decrease in mobility and an increasing local hunter-gatherer contribution to the gene-pool of farmers following the initial rapid Neolithic expansion. Οur original simulation approach models key demographic parameters rather than inferring them from fragmentary data leading to a better understanding of this important process in European prehistory.