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Abstract Background The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented observational studies. This study focuses on additional limitations frequently reported in the literature, providing an overview of the challenges and biases inherent to analyzing routine clinical care data, including health claims data (hereafter: routine data). Methods We conducted a literature search on routine data studies in four high-impact journals based on the Journal Citation Reports (JCR) category “Medicine, General & Internal” as of 2022 and three oncology journals, covering articles published from January 2018 to October 2023. Articles were screened and categorized into three scenarios based on their potential to provide meaningful RWE: (1) Burden of Disease, (2) Safety and Risk Group Analysis, and (3) Treatment Comparison. Limitations of this type of data cited in the discussion sections were extracted and classified according to different bias types: main bias categories in non-randomized studies (information bias, reporting bias, selection bias, confounding) and additional routine data-specific challenges (i.e., operationalization, coding, follow-up, missing data, validation, and data quality). These classifications were then ranked by relevance in a focus group meeting of methodological experts. The search was pre-specified and registered in PROSPERO (CRD42023477616). Results In October 2023, 227 articles were identified, 69 were assessed for eligibility, and 39 were included in the review: 11 on the burden of disease, 17 on safety and risk group analysis, and 11 on treatment comparison. Besides typical biases in observational studies, we identified additional challenges specific to RWE frequently mentioned in the discussion sections. The focus group had varied opinions on the limitations of Safety and Risk Group Analysis and Treatment Comparison but agreed on the essential limitations for the Burden of Disease category. Conclusion This review provides a comprehensive overview of potential limitations and biases in analyzing routine data reported in recent high-impact journals. We highlighted key challenges that have high potential to impact analysis results, emphasizing the need for thorough consideration and discussion for meaningful inferences.

Abstract Background Glioblastoma is a highly heterogeneous brain tumor, posing challenges for precision therapies and patient stratification in clinical trials. Understanding how genetic mutations influence tumor imaging may improve patient management and treatment outcomes. This study investigates the relationship between imaging features, spatial patterns of tumor location, and genetic alterations in IDH-wildtype glioblastoma, as well as the likely sequence of mutational events. Methods We conducted a retrospective analysis of 357 IDH-wildtype glioblastomas with pre-operative multiparametric MRI and targeted genetic sequencing data. Radiogenomic signatures and spatial distribution maps were generated for key mutations in genes such as EGFR, PTEN, TP53, and NF1 and their corresponding pathways. Machine and deep learning models were used to identify imaging biomarkers and stratify tumors based on their genetic profiles and molecular heterogeneity. Results Here, we show that glioblastoma mutations produce distinctive imaging signatures, which are more pronounced in tumors with less molecular heterogeneity. These signatures provide insights into how mutations affect tumor characteristics such as neovascularization, cell density, invasion, and vascular leakage. We also found that tumor location and spatial distribution correlate with genetic profiles, revealing associations between tumor regions and specific oncogenic drivers. Additionally, imaging features reflect the cross-sectionally inferred evolutionary trajectories of glioblastomas. Conclusions This study establishes clinically accessible imaging biomarkers that capture the molecular composition and oncogenic drivers of glioblastoma. These findings have potential implications for noninvasive tumor profiling, personalized therapies, and improved patient stratification in clinical trials.

Abstract Maternal trauma influences infant and adult health outcomes and may impact future generations through epigenetic modifications such as DNA methylation (DNAm). Research in humans on the intergenerational epigenetic transmission of trauma effects is limited. In this study, we assessed DNAm signatures of war-related violence by comparing germline, prenatal, and direct exposures to violence across three generations of Syrian refugees. We compared families in which a pregnant grandmother versus a pregnant mother was exposed to violence and included a control group with no exposure to war. We collected buccal swab samples and survey data from mothers and 1–2 children in each of 48 families (n = 131 participants). Based on an epigenome-wide association study (EWAS), we identified differentially methylated regions (DMPs): 14 were associated with germline and 21 with direct exposure to violence. Most DMPs showed the same directionality in DNAm change across germline, prenatal, and direct exposures, suggesting a common epigenetic response to violence. Additionally, we identified epigenetic age acceleration in association with prenatal exposure to violence in children, highlighting the critical period of in utero development. This is the first report of an intergenerational epigenetic signature of violence, which has important implications for understanding the inheritance of trauma.

Abstract This study tests the association of whole-blood DNA methylation and antidepressant exposure in 16,531 individuals from Generation Scotland (GS), using self-report and prescription-derived measures. We identify 8 associations and a high concordance of results between self-report and prescription-derived measures. Sex-stratified analyses observe nominally significant increased effect estimates in females for four CpGs. There is observed enrichment for genes expressed in the Amygdala and annotated to synaptic vesicle membrane ontology. Two CpGs (cg15071067; DGUOK-AS1 and cg26277237; KANK1) show correlation between DNA methylation with the time in treatment. There is a significant overlap in the top 1% of CpGs with another independent methylome-wide association study of antidepressant exposure. Finally, a methylation profile score trained on this sample shows a significant association with antidepressant exposure in a meta-analysis of eight independent external datasets. In this large investigation of antidepressant exposure and DNA methylation, we demonstrate robust associations which warrant further investigation to inform on the design of more effective and tolerated treatments for depression.

Abstract Risk stratification models based on cytogenetics and disease burden help identify high-risk patients with newly diagnosed multiple myeloma (NDMM). However, some high-risk patients remain undetected. This study evaluated the prognostic utility of the proportion of clonal plasma cells in the S-phase of the cell cycle for NDMM. Patients with active multiple myeloma diagnosed between 01/01/2013 and 01/31/2023 who underwent S-phase assessment were included. The S-phase proportion was calculated by analyzing DNA content between G0/G1 and G2/M peaks. Among 823 patients, 16% (135) had S-phase ≥2% at diagnosis. Patients with S-phase ≥2% exhibited significantly worse median progression-free survival (PFS) of 1.4 years (95% CI: 1.2–1.9) compared to 2.9 years (95% CI: 2.6–3.3) for those with S-phase

Abstract Muscle mass and strength are crucial for physiological function and performance in athletes, playing a significant role in maintaining health and optimal athletic performance. Skeletal muscle, which constitutes the majority of lean soft tissue (LST) and appendicular lean soft tissue (ALST) when measured by dual-energy X-ray absorptiometry (DXA), represents a commonly used surrogate for strength. Research has investigated alternative measures of body composition, such as the assessment of ALST through bioelectrical impedance analysis (BIA) and the determination of whole-body muscle mass from creatine pool size using the deuterated creatine (D3Cr) dilution method, for their associations to strength. While the relationship between body composition measures and strength has been studied in older adults, this relationship remains unexplored in athletic populations. This study examined muscle body composition measures using DXA, D3Cr, and BIA and their association with strength in a sample of collegiate athletes. The study enrolled 80 collegiate athletes (40 females) of differing sports disciplines who consumed a 60 mg dose of D3Cr and completed DXA and BIA measures in addition to trunk and leg strength tests. Analysis was sex-stratified using Pearson’s correlations, linear regression, and quartile p trend significance. With an average participant age of 21.8 years, whole-body DXA correlations to muscle strength surpassed height- or mass-normalized values. This trend was especially pronounced in trunk strength’s relationship with body composition over leg strength, across measurement methods. While DXA LST values were higher than BIA and D3Cr in predicting strength, the values did not differ significantly. Adjustments for age, BMI, and BIA variables didn’t enhance this association. A significant trend between DXA LST and all strength measures underscored the equal relevance of DXA and D3Cr muscle mass to strength, favoring whole-body over regional assessments. This calls for future research on muscle mass’s effects on LST and functional outcomes in broader groups, highlighting the importance of comprehensive body composition analysis in athletic performance studies.

Abstract Background Refugee experiences significantly challenge personal identity, especially for youth orienting themselves in new cultural contexts. The study explores the complex process of balancing expectations from two cultures: how do formative encounters in Norway mold the self-perception and sense of belonging of those who arrived as child and adolescent refugees? Methods A qualitative approach in which life story interviews were conducted with eight young refugees who arrived in Norway between the ages of 8 and 17 years was used. Through thematic analysis grounded in hermeneutical phenomenology, we analyzed their narratives to identify core experiences and perspectives. The interviews lasted 90–150 min, providing insights into personal identity development amid cultural adaptation. Results A recurring and overarching theme is that participants grapple with feelings of “outsiderness” both in Norwegian society and within their culture of origin, creating a dual sense of alienation. This experience is painful, but they also perceive that it has given them the opportunity to develop open-mindedness and a unique perspective on cultural existence. Three subthemes were identified that describe various aspects of these narratives in greater detail: (1) Experiences of being a stranger; (2) value conflicts, but value reconciliation is possible; and (3) a unique perspective: navigating between two cultures. The narratives highlight the complex negotiation between maintaining heritage and adapting to Norwegian norms. Conclusions The study of participants’ narrative identities reveals ways of coping with these transitions, revealing how participants continuously reconstruct their self-narratives to adapt to their new cultural environment. The findings suggest that while acculturation is a challenging process characterized by psychological tension and existential vulnerability, it can also foster personal resilience and new opportunities for meaning-making. The research contributes to understanding the refugee experience in Norway, emphasizing the need for social support systems that acknowledge both the struggles and potential for growth inherent in cultural integration.

Abstract We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Differences in expression of macrophage phenotype markers occurred as early as day 1, persisted to at least day 28, and were associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.

What is the relationship between solidarity and international migration law? For migrants facing a contemporary politics of nationalism and xenophobia, solidarity offers the potential to transcend borders, reshaping the popular imaginary and potentially the law. This essay presents a conversation between a legal scholar, a solidarian, and a social scientist, exploring the challenges that must be carefully navigated to avoid replicating prevailing power hierarchies and undermining existing humanitarian ethics. It engages with three questions: whether international law can further solidarity with migrants; whether human rights law can address the risk that solidarity will replicate existing power hierarchies; and whether solidarity downgrades existing international legal obligations toward migrants, rendering them optional benevolent acts toward “outsiders” rather than legal duties toward “insiders.” The essay contends that a viable path forward must recognize both the ambivalence of solidarity and international law's shortcomings in enabling solidarity.

Abstract: DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19–related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19–related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.

Abstract Background Brazilian spotted fever is a tick-borne disease caused by the bacterium Rickettsia rickettsii, whose main vector in Brazil is the tick Amblyomma sculptum. Amplifying hosts are essential for the perpetuation of this bacterium in the tick population as they can be sources of infection during bacteremic periods. Recent studies demonstrated the ability of suids (Sus scrofa) to sustain populations of A. sculptum, one of the main tick species found parasitizing wild boars in the midwestern and southeastern regions of Brazil. In this study, wild boars were experimentally infected with R. rickettsii by tick infestation and were evaluated for their ability to transmit the infection to A. sculptum ticks, under laboratory conditions. Methods Four wild boars were infected with R. rickettsii through infestation with R. rickettsii-infected A. sculptum adults (infected group); a fifth wild boar was infested with uninfected A. sculptum adults (control group). Simultaneously, the animals were infested with uninfected larvae and nymphs of A. sculptum. The wild boars were monitored for 28 days by clinical examination and hematological tests, real-time quantitative PCR (qPCR) of blood for the detection of Rickettsia and inoculation of blood in guinea pigs. IgG antibody titers were followed until the end of the experiment. Unfed nymphs and adults, molted from engorged larvae and nymphs that fed on wild boars, were used to infest susceptible guinea pigs and rabbits; some of these unfed ticks were tested by qPCR for rickettsial detection. Results The wild boars showed no clinical or hematological alterations, and bacteremia was not detected by qPCR or inoculation of wild boar blood into guinea pigs. Furthermore, wild boars showed a moderate humoral response, with anti-R. rickettsii endpoint titers up to 256 or 512. Rickettsial DNA was not detected in molted ticks after acquisition feeding on wild boars. Moreover, no disease or seroconversion was observed in guinea pigs and rabbits that were infested with ticks originated from wild boar acquisition feeding. Conclusions Wild boars seroconverted to Rickettsia spp. after being infested with R. rickettsii-infected A. sculptum; however, they did not develop bacteremia and did not act as competent amplifying hosts of R. rickettsii for A. sculptum ticks. Graphical Abstract

Background Deficits in sensorimotor gating have been reported in individuals with autism spectrum disorder (ASD), as well as in ASD murine models. However, this behavior has not been examined in the neuronal subset-specific (NS)- Pten knockout (KO) model of ASD. NS-Pten KO mice exhibit hyperactivity of the PI3K/AKT/mTOR signaling pathway which is implicated in the onset of autistic deficits. This study investigates the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating. Methods To assess sensorimotor gating in NS- Pten KO mice we utilized a three-day paradigm. On day 1 (habituation) the mice were administered 80 repetitions of a 120-dB startle stimulus. On day 2, prepulse inhibition was measured with 90 trials of the startle stimulus that was paired with a smaller (2, 7, or 12 dB) prepulse stimulus. Day 3 was assessed one week later, consisting of randomized startle trials and trials with no stimulus and was used to determine the startle response. Results No significant difference between NS- Pten KO or wildtype (WT) mice was found for habituation ( p > 0.05). No significant differences were found between groups when assessing the percentage of prepulse inhibition at 2, 7, and 12 dB ( p > 0.05). There was also no difference in startle response between groups ( p > 0.05). Conclusion Our study found that the NS- Pten KO model does not display significant deficits in sensorimotor gating processes. The present findings help to elucidate the relationship between PI3K/AKT/mTOR hyperactivation and sensory reactivity.