Search Results (1,423)

Background/Objectives: Congenital heart defects (CHDs) are associated with disruptions in one-carbon metabolism. In a family-based trio design, we investigated whether plasma concentrations of choline, betaine, and folate are associated with CHD severity. Methods: The study included 72 children with CHD, 69 of their mothers and 64 of the fathers. CHD clinical severity was classified according to the European network of population-based registries for the epidemiological surveillance of congenital anomalies (EUROCAT) system and the German PAN study (Prevalence of Congenital Heart Defects in Newborns). Concentrations of choline, betaine, and folates were quantified in plasma and urine samples from a subgroup of the participants. Results: The children [mean (SD) age 3.1 (3.2) years, 59.7% males] presented with varying CHD severities according to EUROCAT (62.5% severe and 37.5% mild) and PAN classifications (45.8% severe, 30.6% moderate and 23.6% mild). The means (SD) of plasma concentrations of choline were 14.0 (10.0) µmol/L in the children, 9.5 (5.1) µmol/L in the mothers and 10.3 (5.4) µmol/L in the fathers. Plasma choline concentrations < 10 µmol/L were observed in 38 mothers (66.7%) and were associated with having a child with severe CHD [adjusted odds ratio (aOR) 3.7; 95% confidence intervals (95%CIs) = 1.1, 12.2] compared to mothers with choline ≥ 10 µmol/L. Lowered plasma choline concentrations were detected in 27 fathers (62.8%) and were also associated with severe CHD (aOR 7.4; 95%CIs = 1.7, 31.5). Child concentrations of choline, betaine and folate and parents’ concentrations of betaine and folate were not associated with disease severity. Conclusions: Lower plasma choline in the parents detectable several years after conception was related to having a child with severe CHD compared to families of children with higher plasma choline. Maternal and paternal choline metabolism may have a role in modulating CHD severity. Etiological studies aiming at the prevention of congenital anomalies should focus on maternal and paternal risk factors in the preconception and early pregnancy. Full article

Artificial Intelligence (AI) is rapidly changing the format, style and content of scientific publishing. Traditional reviews are likely to give way to more personalized, AI-generated literature surveys on the one hand and more innovative, perhaps even controversial hypothesis, opinion or essay-style contributions on the other. Original publications based on experimental data are still less affected even if AI teams up with robots. Eventually, science and scientific publishing are social activities and although the AI-driven tools and technologies at hand may accelerate and also refine scientific publishing, scientists, as always, are well equipped to adapt and to turn these challenges into new opportunities, for instance in handling, processing and illustrating experimental data. Full article

Lipid nanoparticles (LNPs) have become the cornerstone of nucleic acid delivery platforms, particularly in RNA-based vaccines and therapeutics. However, the conventional methods of LNP production, which are primarily reliant on microfluidic mixing of aqueous and organic solvent phases, pose limitations in terms of mRNA stability, residual organic contamination, scalability, cost, and environmental impact. These limitations prompted a renewed search for non-conventional strategies with the promise of improving mRNA-LNP encapsulation approaches. These emerging approaches aim to address key bottlenecks, including mRNA hydrolysis-driven degradation, high production losses, and complex downstream purification. Moreover, the ability to decouple LNP synthesis from mRNA encapsulation could enable streamlined, modular manufacturing workflows and customizable payload delivery, including single- or multiple-mRNA payloads, thereby expanding the therapeutic scope of LNPs. This review offers an early insight into the design principles and scalability potential of emerging non-conventional LNP encapsulation approaches, including solvent-free and microfluidics-free methodologies, and pre-built LNP workflows. We also examine trends in emerging LNP encapsulation tools, including high-shear mixing, sonication, membrane contraction, and other approaches. Finally, we extrapolate the suitability of the methods for scale-up approaches and their economic implications based on the process information. Full article

Background/Objectives: Synthetic stimulants represent the most prevalent subclass on the new psychoactive substances (NPSs) market. However, the toxicokinetic properties of M-ALPHA, a regioisomer of MDMA and N-methyl-cyclazodone a pemoline derivative, are not yet characterized. Methods: Therefore, this study investigated the metabolism of both NPSs in pooled liver S9 fraction and rat urine, characterized cytochrome P450 (CYP) kinetics and plasma protein binding (PPB), and assessed the CYP inhibition potential of M-ALPHA, using high-performance liquid chromatography coupled to high resolution tandem mass spectrometry (HPLC-HRMS/MS). Results: Four metabolites of M-ALPHA were detected including one phase I and three phase II metabolites, resulting from demethylenation followed by subsequent methylation or glucuronidation. For N-methyl-cyclazodone, one phase I metabolite formed via N-demethylation was identified. The primary enzymes involved in M-ALPHA metabolism were CYP2B6 and CYP2D6. Notably, M-ALPHA inhibited these enzymes to a strong or moderate extent, respectively. In contrast, the metabolism of N-methyl-cyclazodone was primarily mediated by CYP2A6. PPB studies indicated low-to-moderate binding for both compounds, suggesting that significant protein-binding interactions are unlikely. Conclusions: As M-ALPHA only formed metabolites that overlapped with those of MDMA, differing only by minor retention time shifts, reliable HPLC-HRMS/MS-based identification may be challenging in clinical and forensic toxicology settings as well as doping analysis. Furthermore, drug–drug interactions following polydrug use cannot be excluded for either NPS, particularly when co-ingested with other CYP substrates metabolized by the same isoforms. Full article

Background/Objectives: Loss of heterozygosity (LOH) in meningioma has been known for more than two decades. It has been shown that LOH on chromosome 1p36 is an independent marker of meningioma recurrence and progression. ARID1A, a tumor suppressor gene located on chromosome 1p36.11, is part of the chromatin-regulating SWI/SNF complex whose subunits are altered in 20% of cases across all tumor entities. Methods: Using our newly developed indirect enzyme-linked immunosorbent assay (ELISA), we investigated whether tumors with or without LOH 1p differ in ARID1A expression in 61 meningiomas. To study possible links between ARID1A and ARID1B, we tested for LOH 6q in association with LOH 1p using a PCR-based microsatellite approach. ARID1B, another member of the SWI/SNF complex, is located on 6q25.3. Additionally, we compared our ELISA results with immunohistochemistry data staining of ARID1A in tissue sections known to harbor LOH 1p. Results: Our results indicate that meningiomas harboring LOH 1p have significantly lower ARID1A levels compared to tumors without LOH 1p. In free nuclear protein fractions, reductions were up to 32% (CI: 6–58.7%). Interestingly, we found that ARID1A levels were significantly lower in tumors with recurrence and/or multiple localizations. In addition, our analysis of chromosome 6q uncovered a significantly strong correlation between LOH 1p and LOH 6q (p < 0.0001). Conclusions: These results highlight the importance of ARID1A in meningioma malignization and indicate for the first time functional evidence for LOH 1p. Full article

Background: Professional identity formation (PIF) and wellbeing are increasingly being recognised in postgraduate Family Medicine (FM) education. Role models are central to both, yet traditional learning activities often struggle to implement them effectively. Podcasts offer a flexible medium that may support these goals. This study examines the potential of postgraduate medical education (PGME) podcasts, such as the European Young Family Doctor’s Movement (EYFDM) podcast, to promote PIF and wellbeing. Methods: This mixed-methods study analyses podcast use, role modelling effects, and PIF among young general practitioners (GPs). In 2024, 57 participants, including students, FM trainees, and specialists, completed an online questionnaire with quantitative and qualitative items. Descriptive and analytical statistics were combined with qualitative content analysis (Kuckartz). Sentiment analysis was conducted using artificial intelligence, and triangulation enhanced credibility. Results: Within the trainees and specialists of the study population, most participants (70%; 32/46 SPs) reported regularly using podcasts for PGME, and particularly young female GPs in Western Europe. In our study population, 90% (27/30 SPs) agreed that the podcasts broadened their perspective on professional opportunities in FM. Many participants reported reflections on potential career pathways and PIF. Exposure to role models significantly increased motivation to work in FM (χ² (1) = 10.7, p < 0.001). Conclusions: Podcasts may help address gaps in affective competency training, including wellbeing and PIF, while integrating easily into busy routines. Findings suggest a positive influence on career attitudes, with role modelling supporting PIF and motivation in FM. Full article

Background: The role of immune checkpoint inhibition in treating head and neck squamous cell carcinoma (HNSCC) is expanding, yet response rates to PD-L1 therapy remain inconsistent and generally poor. Although several studies have examined heterogeneous intratumoral PD-L1 expression, the disparity in response to PD-L1 therapy between primary tumors and their associated lymph node metastases remains unclear. Methods: Primary tumor samples and two matching lymph node metastases were obtained from a cohort of 50 patients and immunohistochemically stained with a PD-L1 antibody. PD-L1 expression, assessed using the combined positive score (CPS) and tumor proportion score (TPS), and immune infiltration, measured with an immunoreactive score (IRS), were compared between the primary tumor and lymph node metastases. These measures were then correlated with other histopathological and clinical features. Results: PD-L1 expression, evaluated by CPS and TPS, showed no significant differences between the primary tumor and matched lymph node metastases. Discordance relative to established regulatory cut-offs was observed in a subset of patients, affecting 18% (CPS; 95% CI, 8.0–30.0%) and 4% (TPS; 95% CI, 0.0–10.0%) of cases. CPS and TPS values were not influenced by primary tumor subsite or HPV status. Conversely, immune infiltration measured by IRS was significantly affected by primary tumor subsite location. Both HPV tumor status and primary tumor subsite were statistically significantly associated with overall survival. Conclusions: Our findings highlight variability in PD-L1 expression in HNSCC and may offer context for differential responses of primary tumors and lymph node metastases to immune checkpoint therapy reported in recent clinical studies. These observations support the need for a more comprehensive characterization of PD-L1 expression across tumor sites in head and neck cancer. Further investigation is required to determine whether, and in which settings, reassessment of PD-L1 status in metastatic lesions—including lymph node metastases—may provide additional clinically relevant information when initial testing does not meet established therapeutic cut-offs. Full article

Background: The global demographic shift towards an aging population has driven a steady, exponential increase in the utilization of cardiac implantable electronic devices (CIEDs). Consequently, device-related infectious complications have emerged as a leading cause of morbidity and healthcare expenditure. Patients in their eighth decade of life—octogenarians (aged 80–90 years)—represent an exceptionally high-risk demographic due to the compounding factors of physiological frailty, immunosenescence, and complex multi-morbidity. Despite this growing demographic, their specific clinical presentations, microbiological profiles, and procedural outcomes following infection remain poorly defined in the current literature. This study aimed to comprehensively compare the clinical characteristics, pathogen distribution, and in-hospital outcomes of CIED infections in an octogenarian cohort against a younger patient population. Methods: We conducted a robust retrospective cohort analysis of 383 consecutive patients treated for confirmed CIED infections at one major tertiary referral center (Heidelberg University Hospital) between January 2002 and December 2022. The cohort was stratified by age into octogenarians (n = 76) and a younger control group (n = 307). We systematically extracted and compared data regarding baseline clinical presentation, chronic comorbidities, detailed microbiological cultures (pocket, blood, and extracted leads), and definitive in-hospital outcomes, primarily mortality and length of stay. Results: The octogenarian cohort exhibited a significantly heavier comorbidity burden, notably higher rates of coronary artery disease (51.3% vs. 29.6%, p < 0.001), systemic hypertension (55.3% vs. 38.1%, p = 0.007), and chronic obstructive pulmonary disease (7.9% vs. 1.6%, p = 0.003). Furthermore, therapeutic systemic anticoagulant use was substantially more prevalent in the elderly group (60.5% vs. 45.0%, p = 0.015). Octogenarians presented overwhelmingly with localized generator pocket infections (73.0% vs. 30.0%, p < 0.001) but paradoxically also demonstrated higher rates of systemic bacteremia and sepsis (26.3% vs. 15.0%, p = 0.019). Microbiological analysis revealed a unique pathogen profile, with Staphylococcus capitis found with significantly higher frequency in the generator pockets of the elderly cohort. Remarkably, despite possessing a higher average lead burden (2.1 vs. 1.2 leads) and extreme comorbidity profiles, octogenarians demonstrated no statistically significant differences in in-hospital mortality (3.9% vs. 4.2%, p = 1.000) or overall length of hospital stay (14.7 vs. 17.2 days, p = 0.386) when compared to the younger cohort. Conclusions: Octogenarians suffering from CIED infections display highly distinct clinical and microbiological profiles, characterized predominantly by elevated rates of localized pocket infections, specific opportunistic pathogens, and a severe underlying comorbidity burden. Crucially, our findings indicate that with the application of modern extraction and management protocols, advanced age alone does not intrinsically correlate with increased in-hospital mortality. Future prevention and perioperative management strategies tailored to this rapidly expanding demographic must heavily prioritize the mitigation of pocket-related complications, particularly considering the high prevalence of concurrent anticoagulation therapy. Full article

Background: In-person conferences (IPCs) in family medicine remain central for cross-border collaboration and early-career development. With the rise of digital formats, the motivations of young general practitioners (GPs) to attend or organise IPCs require closer investigation. Methods: Using a modified two-round Delphi design, we surveyed 107 participants and 23 organisers of the 2024 and 2025 EYFDM (European Young Family Doctors’ Movement) Forums. Round one included open and closed questions; round two involved prioritisation tasks. Quantitative data were analysed with non-parametric statistics; qualitative responses were thematically coded. Results: Participants primarily attended in-person conferences for networking (56.1%), workshops, and inspiration, while formal content played a secondary role. Organisers emphasised personal development, citing project management and teamwork as key benefits, though 34.8% reported workload and lack of recognition as major barriers. A strong preference for in-person formats (94.4%) reflected the perceived importance of interpersonal interaction, which online formats could not replicate. Conclusions: The findings highlight IPC as key environments for identity formation, motivation, and sustainable European collaboration in family medicine. Organising offers learning opportunities but demands better structural support. Future conference planning must prioritise in-person interaction, while using hybrid formats as complementary tools. IPCs remain essential for fostering authentic networks and collaboration among young GPs. Full article

Purpose: To study the time course of the differentiation process and its regulatory networks in primary limbal epithelial cells (pLECs) using serum-free, low calcium Keratocyte growth medium 3 (KGM3) and CnT-2D differentiation medium. Methods: pLECs were isolated from corneoscleral rims from healthy donors and cultured in serum-free low calcium (0.06 mM Ca²⁺) KGM3. Differentiation was induced by supplementation with CnT-2D differentiation medium, while control cells were maintained in low-calcium KGM3 medium. Gene and protein expression analyses were performed using qPCR and Western blotting, respectively, at 72 h and at 5, 7, 10, and 14 days post-supplementation to determine the optimal time course of differentiation induction. Results: CnT-2D differentiation medium supplementation resulted in a significant upregulation of differentiation-associated markers, including desmoglein 1 (DSG1), paired box domain 6 (PAX6), keratin 3 (KRT3), fatty acid binding protein 5 (FABP5), cellular retinoic acid binding protein 2 (CRABP2), alcohol dehydrogenase 7 (ADH7), aldehyde dehydrogenase 1A1 (ALDH1A1), with the most pronounced changes observed at day 10 post-supplementation (p ≤ 0.05). Conclusions: CnT-2D differentiation medium effectively initiates differentiation of limbal epithelial cells in vitro. The gradual increase in the expression of key differentiation markers, including DSG1, KRT3, and PAX6, indicates that CnT-2D medium successfully induces differentiation in 2D cultured primary limbal epithelial cells. However, subcellular localization of these markers, epithelial barrier function, and differentiation in 3D models were not assessed and remain to be investigated. Full article

Purpose: The posterior tibial plateau offset (PTPO) is a parameter of sagittal plane bony tibia morphology with high variability and clinical relevance, particularly in cases involving stemmed tibial implants, where posterior tibial cortex interference may occur. However, its change during total knee arthroplasty (TKA), and its relationship to tibial component positioning remain unknown. Methods: Pre- and postoperative sagittal radiographs of 98 patients undergoing primary, mechanically aligned TKA using a single implant system were retrospectively analyzed. PTPO was measured as the distance between the tibial anatomical axis and the center of the tibial plateau or tibial component. Tibial component placement (TCP) was assessed anteriorly and posteriorly and categorized as anatomical (0–1 mm), mild (1–3 mm), or moderate (>3 mm) underhang (TCU) or overhang (TCO). Pre- and postoperative changes in PTPO were analyzed, preoperative PTPO was compared across TCP categories. Correlations with absolute anterior and posterior deviation from anatomical component placements were calculated. Results: PTPO showed high preoperative variability (mean 6.89 ± 3.69 mm) and was significantly reduced after TKA (5.89 ± 3.44 mm; mean change −1.06 ± 3.44 mm; p < 0.001). Higher preoperative PTPO was associated with anterior (p = 0.01) and posterior TCU (p = 0.02). PTPO showed a moderate correlation with anterior (r = 0.53, p < 0.01) and a strong correlation with posterior implant deviation (r = 0.68, p < 0.01). Conclusions: PTPO shows high variability among patients undergoing TKA, is significantly altered through surgery and correlates with tibial component malposition, particularly TCU. Surgeons should consider PTPO during preoperative planning to optimize tibial component positioning and reduce the risk of implant-to-bone conflict, especially when using stemmed implants. In patients with a high preoperative PTPO, accuracy-enhancing techniques such as computer navigation or robotic assistance may be considered. Full article

The ultra-precision machining of micro-optics from low glass transition temperature (T_g) hydrophobic polymers is frequently compromised by thermal instability and kinematic constraints imposed by on-axis turning. To address these challenges, this study presents a novel clamping–cooling system engineered for the off-axis diamond turning of low-T_g polymers. The design integrates vacuum clamping for workpiece stabilization with an embedded microchannel network for efficient thermal management. Strategic material selection effectively balances thermal insulation with mechanical stability. Performance evaluations demonstrated robust thermal regulation: lens blank surface temperatures stabilized at 6 °C during stationary testing, and the system was able to drop below 0 °C under maximum cooling targets. This strict thermal control enabled achieving nanometer surface roughness. Ultimately, this modular system facilitates the scalable, simultaneous production of high-quality, polishing-free intraocular lenses (IOLs), advancing manufacturing capabilities for complex precision optics. Full article

The level and development of cognitive ability are associated with parental socioeconomic status (SES). Some of these cognitive differences are presumably due to individual differences in genetic predispositions, but the potential mechanisms and influencing factors are still relatively unclear. Previous research has identified factors that show a relation with both cognitive abilities and SES (e.g., parental cognitive ability, home environment, and polygenic scores). Regarding these factors, we analysed three age cohorts (N = 6715; 5, 11, and 17 years old) at a 6-year interval using multiple regressions and decomposition analyses. Firstly, results indicated that cognitive differences linked to SES emerged particularly between the ages of 5 and 11. A substantial part of the SES effect was associated with parental cognitive ability. Secondly, particularly in the oldest cohort, the polygenic score for cognitive ability was related to the SES-associated change in cognitive ability. Finally, in several analyses, the influence of SES on cognitive ability was no longer significant after considering the attendance of the academic track in secondary school. This pattern could indicate that SES-associated differences in secondary school recommendations shown in previous studies may also be associated with SES-related differences in cognitive ability, which should be investigated in future studies. Full article

Background: Stroke is a time-critical emergency in which rapid diagnosis and treatment are essential to improve outcomes. While Emergency Medical Services (EMS) facilitate structured prehospital stroke care, a proportion of patients bypass EMS and self-present to emergency departments (EDs), potentially causing treatment delays. This study compares process times and outcomes between EMS-transported and self-presenting stroke patients. Methods: We conducted a retrospective analysis of prospectively collected data from 1805 patients with suspected stroke admitted between May 2019 and June 2021 to two hospitals in Germany. Patients were classified as EMS-transported or self-presenting. Process times included door-to-needle time (DNT), symptom onset to first medical contact (FMC), and intravenous thrombolysis (IVT) rates. Data are presented as mean ± standard deviation or median [interquartile range] for continuous variables and as number (%) for categorical variables. Results: A total of 1940 patients with suspected stroke were included. For the main analysis comparing EMS transport and self-presentation, 1805 patients (1525 EMS, 280 self-presenting) were evaluated. EMS patients were significantly older than self-presenting patients (73.1 ± 15.1 vs. 65.3 ± 14.9 years, p < 0.001). The median time from symptom onset to first medical contact was 114 [95–132] minutes in EMS patients and 727 [420–1440] minutes in self-presenting patients (p < 0.001). IVT was administered in 119/1197 (9.9%) EMS patients and 18/254 (7.1%) self-presenting patients (p = 0.158) among those with documented information on thrombolysis. Door-to-needle time was slightly but significantly longer in self-presenting patients (median 35 [32–54] vs. 30 [28–34] minutes, p < 0.001), while both groups remained well within certification targets. Conclusions: Self-presenting stroke patients experienced markedly longer prehospital delays and lower intravenous thrombolysis rates compared to EMS-transported patients, although the difference in IVT rates was not statistically significant. In-hospital door-to-needle times were comparable between groups. These findings highlight the need for targeted public education to improve stroke symptom recognition and timely EMS activation. Full article

Background: Cardiac implantable electronic device (CIED) lead perforation is a rare but potentially catastrophic complication. As global device implantations increase, understanding the clinical spectrum and optimal management of this complication is essential. This study characterizes the clinical presentation, diagnostic strategies, and outcomes of lead perforation over a 25-year period. Methods: A retrospective analysis was conducted on 32 patients diagnosed with CIED lead perforation between 2000 and 2025 at a high-volume center. Perforations were classified by timing: acute (<24 h), subacute (1–30 days), and chronic (>30 days). Data included demographics, comorbidities, imaging modalities, and procedural interventions. Results: The mean patient age was 76.0 ± 11.7 years, with a mean body mass index (BMI) of 25.5 ± 3.4 kg/m². Subacute presentation was the most frequent (59.3%, n = 19), followed by acute (28.1%, n = 9) and chronic (12.5%, n = 4) cases. The right ventricle was the primary site of perforation (90.6%). While chest X-rays served as an initial screening tool in 62.5% of cases, diagnosis relied on multimodal imaging, with Computed Tomography (CT) providing definitive confirmation in 31.3% of the cohort, particularly when lead parameters remained stable. Management was risk-stratified based on hemodynamic status. The majority of patients (71.9%, n = 23) underwent successful transvenous lead removal via simple traction. However, 25% (n = 8) presented with hemodynamic instability, and 21.9% (n = 7) suffered from cardiac tamponade. These high-risk cases required surgical intervention, including sternotomy (n = 4), thoracotomy (n = 2), or pericardiotomy (n = 3). Notably, 62.5% of hemodynamically unstable patients were on oral anticoagulants. All patients survived to discharge, with no in-hospital mortality. The median length of hospital stay was 3 days. Conclusions: CIED lead perforation often presents subacutely with subtle clinical signs. CT imaging has emerged as the gold standard for definitive diagnosis. While percutaneous transvenous removal is safe and effective for stable patients, immediate surgical backup is vital, as patients—particularly those on anticoagulation—can deteriorate rapidly. Full article