Primary care physicians frequently face situations in which social and environmental determinants strongly impact health outcomes. Using a clinical vignette, this article applies the Solar and Irwin framework to analyze the mechanisms underlying social health inequalities. A simple collective intervention, such as a supervised walking group, illustrates how primary care teams can impact social isolation, local environments, and treatment adherence. Intersectoral collaboration and strong territorial anchoring enhance both effectiveness and sustainability. Such initiatives encourage a shift in perspective, viewing care as a community-based process that complements traditional medical consultations. Les soins primaires confrontent les professionnels de santé à des situations dans lesquelles les déterminants sociaux et environnementaux impactent fortement la santé. À partir d’une vignette clinique, cet article mobilise le modèle de Solar et Irwin pour analyser les mécanismes à l’origine des inégalités sociales de santé. Une action collective simple, comme un groupe de marche encadré, illustre la manière d’agir concrètement sur l’isolement, l’appropriation de l’environnement de proximité et l’adhésion aux soins. L’intersectorialité et l’ancrage territorial permettent de renforcer l’efficacité et la pérennité de ces initiatives. Ces démarches invitent à repenser le soin comme un processus communautaire et complémentaire à la consultation médicale.
Dual antiplatelet therapy reduces ischaemic complications after percutaneous coronary intervention, but increases bleeding risk, especially in patients who are already at high bleeding risk. Current guidelines therefore recommend abbreviated dual antiplatelet therapy in this population. To evaluate the real-world use of abbreviated dual antiplatelet therapy (≤3 months) after percutaneous coronary intervention according to bleeding risk, using data from the nationwide FRANCE-PCI registry. All consecutive patients undergoing percutaneous coronary intervention for either acute or chronic coronary syndrome between 2014 and 2023 across 56 hospitals, who were alive at 1 year, and in whom dual antiplatelet therapy duration was known, were included. High bleeding risk was defined as the presence of at least one of the following: age≥75 years; chronic oral anticoagulant therapy; previous stroke; or chronic kidney disease. Among 115,992 patients included, 41.4% met the criteria for high bleeding risk. Abbreviated dual antiplatelet therapy was prescribed in 23.1% of patients with a high bleeding risk versus 3.6% of patients without a high bleeding risk. Among patients with a high bleeding risk, factors independently associated with prolonged (>3 months) dual antiplatelet therapy use were: increasing age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.02-1.03); female sex (OR 1.18, 95% CI 1.11-1.25); diabetes mellitus (OR 1.15, 95% CI 1.08-1.22); previous stroke (OR 1.54, 95% CI 1.39-1.69); chronic kidney disease (OR 1.24, 95% CI 1.15-1.34); acute coronary syndrome (OR 1.52, 95% CI 1.44-1.61); and stent length≥60mm (OR 1.18, 95% CI 1.09-1.28). In real-word practice, less than one third of patients with a high bleeding risk received abbreviated dual antiplatelet therapy after percutaneous coronary intervention. The use of prolonged dual antiplatelet therapy remained driven by ischaemic risk markers, highlighting persistent uncertainty in bleeding risk/ischaemic risk trade-offs.
Climate change is intensifying drought stress in temperate forests, but its effects on tree reproduction, central to forest regeneration and migration capability, remain poorly understood. Here, we analyze 221 time series of beech (Fagus sylvatica) seed production across Europe to test whether drought reduces seed output. We isolate drought exposure during the flowering, pollination, and seed maturation phases of reproduction, and test for legacy effects on future reproduction. Seed production was not impaired by summer drought, and dry spring conditions were associated with increased output, likely via enhanced pollen dispersal. Thus, once initiated, beech reproduction is not reduced by drought, with no suppression of reproduction the following year. Reproduction was not reduced at the driest sites during exceptional European summer droughts in 2003, 2018, and 2022. Considered alongside prior evidence that drought suppresses forest growth and elevates mortality, these findings indicate that vital rates can respond in opposite directions to the same stressor. Such contrasts may sustain forest reproduction during heat-drought events yet shift demographic balance toward higher mortality and turnover as climatic extremes intensify.
BACKGROUND: Infertility distress is a major concern for couples. The primary aim of this study was to predict ability to share feelings about infertility using the Fertility Problems Inventory (FPI) depression, anxiety and additional variables. METHODS: Randomly selected couples responded to paper-pencil instruments that measured ability to share feelings about infertility, fertility stress, coping, stress, anxiety and depression as key variables. Selected participants were adults diagnosed with infertility undergoing assisted reproductive treatment for at least 6 months in Hungary. Multiple linear regression analysis was applied to predict fertility related stress scores separately for female and male participants. RESULTS: A total of 94 couples participated. Employing Wilcoxon tests, a significant difference was identified in the use of emotional coping (females using more emotional coping compared to males) (z = -4.18, p < 0.001). No significant difference was found in the utilization of problem-solving coping. With regard to the ability to share feelings about infertility, no significant difference was identified in favor of either gender. With regard to the impact of treatment on everyday life, female respondents indicated a significantly greater effect (z = -2.67, p = 0.008). One-point increase in anxiety scores increased fertility distress by 0.83 and 1.25 points for women and men, respectively. One-year increase since infertility diagnosis was linked to a 1.61-point increase in fertility distress for males. For women, for every one-point increase in the perception of their inability to discuss personal issues with someone else, there was a five-fold increase in infertility-related distress. CONCLUSIONS: Stress, anxiety, and depression were linked to problem-solving in women, but were associated with emotional coping in men. Regression analysis showed a difference between women and men in predicting stress related to infertility. In women, the inability to talk about their feelings related to infertility was significantly negatively associated with fertility stress. However, in men, feelings related to infertility were not predictors of infertility stress. This result requires further research to clarify the reason for the difference. Infertility distress is a significant issue for couples. The main goal of this study was to predict fertility distress using the Fertility Problems Inventory (FPI).Here’s how we did it: We asked 94 couples to answer questions on a questionnaire about their coping strategies, stress levels, anxiety levels, and depression levels.Here are the results: It turned out that women used more emotional coping strategies than men. Female respondents said that the treatment had a much bigger impact on their everyday life. For both women and men, higher anxiety was linked to more distress related to fertility. Each one-point increase in anxiety scores led to an 0.83-point increase in distress for women and a 1.25-point increase for men. Additionally, each year since being diagnosed with infertility was associated with a 1.61-point increase in distress for men. For women, every one-point increase in the feeling that they could not talk about personal issues with someone else was linked to a fivefold increase in infertility-related distress.In light of these findings, we can draw the following conclusions: Women who were stressed, anxious, or depressed tended to use problem-solving strategies, while men were more likely to rely on emotional coping. However, the study did not find a significant link between coping strategies, depression, stress, and infertility distress.Finally, among women, an inability to discuss feelings related to infertility was associated with higher levels of fertility stress. However, in men, feelings related to infertility did not predict infertility distress.
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The representation of anatomical variations in Renaissance art offers a unique opportunity to explore the historical perception of normality and deformity. This study aims to analyse a previously undescribed anatomical feature in the marble statue of Adam (c. 1490-1495) by Tullio Lombardo. A detailed visual and morphological analysis of the statue was performed, focusing on the lateral aspect of the forefoot. The observed features were compared with current clinical descriptions of bunionette deformity and interpreted within the broader context of Renaissance anatomical representation. The statue shows a prominence of the fifth metatarsal head associated with a varus deviation of the fifth toe, consistent with a bunionette (tailor's bunion). The anatomical precision of Lombardo's work suggests that this feature is unlikely to be accidental or due to technical limitations, but rather represents a deliberate inclusion within an otherwise idealized figure. Comparable variations in foot anatomy have been reported in other Renaissance artworks. Although bunionette deformity is currently associated with mechanical stress and external factors, its presence in an idealized nude figure suggests that such variations may not have been perceived as pathological in their original context. This case highlights the limitations of applying modern diagnostic categories to historical representations and supports the view that minor anatomical variations could be incorporated into Renaissance depictions of the human body without implying disease.
The molecular mechanisms governing internal fluctuations in intrinsically disordered protein (IDP) assemblies are crucial to the stability and dynamics of both regulated and aberrant toxic cellular aggregates, but remain poorly understood. By comprehensively combining high-resolution quasi-elastic neutron scattering with all-atom molecular dynamics simulations, we probe the motions of [Formula: see text]-casein, a model IDP, inside its assemblies. We uncover a previously unresolved slow relaxation process with phenomenological characteristics of anomalous non-Fickian diffusion. This anomalous signature emerges from a continuous mobility gradient governed by density and crowding within the assemblies; the core is denser and more compact, and mobility increases progressively toward the exterior. This dynamical heterogeneity underlies the non-Gaussian behavior and accounts for the observed spectral broadening. Our findings provide insight into how disorder and extreme local crowding within IDP assemblies can result in a fundamentally different behavior compared to, e.g., clusters of well-folded proteins. The deviations from Fickian diffusion arise from dynamic heterogeneity and can be captured within the framework by a model typically used for the jump diffusion observed in liquids, thereby extending its applicability.
Specialisation into different ecological niches is assumed as an important driver of speciation in sympatry. Here, we focused on male-male competition fuelling population divergence, without assuming any ecological specialisation. We investigated how antagonistic interactions between males can promote divergent evolution of timings of reproductive activities during the day, as observed in some closely related insect species living in sympatry. We used a multilocus, comprehensive stochastic model to investigate the evolution of (1) the timing of reproductive activity as a quantitative trait and (2) neutral loci that may generate genetic incompatibilities among divergent individuals. We specifically explored how male-male competition for female access can generate negative frequency-dependence on the timing of reproductive activities and fuel population divergence. Our simulations in finite populations highlight the strong effect of male-male competition and operational sex-ratio on the evolution of divergent temporal niches. They also show how genetic incompatibilities promote the differentiation among populations with divergent temporal niches, but may also impair their coexistence. Our model therefore highlights male-male competition as an important factor shaping the evolution of diel niches, that may fuel sympatric speciation.
Background/Objectives: Dysregulation of purinergic signaling, particularly CD73 overexpression, influences tumor progression, immune evasion, and chemoresistance in hepatocellular carcinoma (HCC). We aimed to characterize the transcriptional landscape of this system, identify prognostic markers, and investigate how the tumor microenvironment modulates pharmacological response to combined sorafenib and doxazosin in 3D spheroid models. Methods: We integrated RNA-seq data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) to identify differentially expressed genes, pathway enrichment, gene co-expression networks, prognostic associations, and machine learning-based biomarker selection. Modulation of key targets was assessed in HepG2 and HepG2/LX-2 spheroids treated with sorafenib and doxazosin using qPCR and flow cytometry. Results: Transcriptomics revealed dysregulation and network fragmentation. Specifically, analysis of the TCGA cohort indicated that high expression of ADA, NT5E, and ADORA1 correlated with poor overall survival. Given the critical role of CD73 in therapy resistance, we evaluated these findings in 3D models. Co-treatment significantly downregulated NT5E and ADORA1 mRNA expression, while ADORA2A was specifically reduced in the co-culture setting. For the ADA, effect-size analysis revealed a large magnitude of inhibition in HepG2 spheroids. Although flow cytometry showed that high CD73 protein expression remained stable across treatments in co-culture, the combination therapy overcame stromal protection, significantly increasing apoptosis (active caspase-3) in both mono- and co-culture spheroids compared with vehicle and monotherapy. Conclusions: We identified a purinergic prognostic signature in HCC and demonstrated that the combination therapy of sorafenib and doxazosin targets the adenosine pathway and specific receptors. We show that the stromal microenvironment sustains CD73 protein expression even under transcriptional inhibition, highlighting the critical role of 3D co-culture models in deciphering therapeutic resistance mechanisms.
The growing use of radionuclides in nuclear medicine for therapy and diagnosis requires the development of chelators that combine high complexation performance with strong radiolytic stability. Macropa, an ether-crown ligand, displays a strong affinity for large trivalent cations and can be used as a chelator for radionuclides such as 225Ac, 149/161Tb, and 132/135La. Here, we investigated the γ-radiolysis of Macropa in water and evaluated the impact of complexation by studying Ln-Macropa complexes. Samples were irradiated up to 30 kGy, and degradation was monitored by ESI-MS and HPLC-ESI-MS, while quantification was made by 1H NMR. For free Macropa, the major degradation pathways involve carbon-carbon bond cleavages and the loss of the picolinate arm, together with additional minor hydroxylated and unsaturated products. In contrast, Ln-Macropa complexes mainly form hydroxylated products arising from HO˙ attack, and no La decomplexation was detected. Radiolytic degradation yields indicate that Macropa is already highly resistant (G0 ≈ -1.25 × 10-7 mol J-1) and that complexation with La further enhances stability (G0 ≈ -0.76 × 10-7 mol J-1). DFT calculations (BDE and Fukui indices) support these observations by showing increased C-C bond strengths upon La(III) complexation, as well as a shift in atomic positions most susceptible to radical attack from the crown ether to the pyridine ring of the carboxylate arm. Overall, these results highlight Macropa as a robust chelator under γ-irradiation and show that complexation can both improve stability and change degradation pathways toward products that preserve the ligand's chelating functions.
To evaluate heart rate variability (HRV) as a biomarker of autonomic dysfunction in anorexia nervosa (AN), examining differences across clinical stages and the influence of HRV recording duration. Quantitative studies comparing HRV parameters between individuals with AN and healthy controls were identified through a systematic search of six databases following PRISMA guidelines. Random-effects meta-analyses and meta-regressions were conducted, with HRV recording duration (5-min vs. 24-h recordings) examined as a moderator. Meta-regression by clinical stage was not feasible due to an insufficient number of studies. Risk of bias was assessed using the Joanna Briggs Institute tool, and certainty of evidence was rated with GRADE. Nineteen studies were included, with 16 contributing to the meta-analysis (805 participants). Acute AN was associated with significantly lower heart rate (SMD = -1.807; 95% CI: [-3.36, -0.26]; p = 0.022) and reduced LF/HF ratio (SMD = -0.74; 95% CI: [-1.179, -0.301]; p < 0.001). These results indicate parasympathetic predominance. Time-domain indices (SDNN and RMSSD) tended to be higher in AN but were not statistically significant and were supported by low-certainty evidence. Meta-regression analyses revealed that short-term (5-min) HRV recordings yielded significant differences for SDNN (SMD = 0.539; p = 0.008) and HF (SMD = 0.679; p = 0.037). Overall, HRV reflects autonomic alterations in AN, particularly in the acute phase characterised by parasympathetic predominance. HRV does not consistently normalise during recovery. These findings are strongly moderated by recording duration. Short-term recordings show more consistent effects.
Switching spectroscopy piezoresponse force microscopy (SSPFM) is widely used to probe local polarization reversal in ferroelectric thin films, but resonance-enhanced implementations remain difficult to apply to large datasets because they typically rely on repeated frequency sweeps, leading to longer acquisition times, higher noise levels, and fitting-related instability. Here, we introduce an approach that combines SSPFM with real-time dual-frequency resonance tracking (DFRT), allowing the excitation frequency to remain locked to the instantaneous contact-resonance frequency throughout the spectroscopy sequence. This strategy extends the benefits of real-time resonance tracking, commonly exploited in continuous measurements, to pulsed switching spectroscopy, while avoiding repeated reconstruction of the full resonance peak at each voltage step. The method is evaluated on a Pb(Zr0.2Ti0.8)O3 thin film and compared with two conventional SSPFM approaches: sweep-based and fixed-frequency measurements. At short segment durations, sweep-based SSPFM becomes increasingly affected by phase noise, phase-inversion artifacts, and fitting errors, whereas SSPFM-DFRT preserves low noise and measurement stability. In addition, the conversion of raw data into hysteresis loops is substantially faster because no repeated resonance fitting is required. Compared with fixed-frequency SSPFM, it also compensates resonance shifts, which become critical during prolonged measurements such as point matrix acquisitions and would otherwise reduce measurement repeatability and robustness. Finally, SSPFM-DFRT is demonstrated in mapping mode on a 50 × 30 point matrix, where it enables robust extraction of switching parameters with high fit quality across the dataset. Overall, this approach provides a practical route to faster, more stable, and more robust resonance-enhanced SSPFM for spectroscopy and mapping, particularly when short measurement times and reliable large-scale measurements are required.
The (NRG1)-ERBB4 signaling pathway has been identified to be pathophysiologically meaningful for cognitive impairments in schizophrenia. The in the 1960s approved mineralocorticoid antagonist spironolactone has been shown to be effective to modulate (NRG1)-ERBB4 signaling in preclinical and animal models. Thus, a proof-of-concept drug repurposing trial in patients with schizophrenia was justified. We conducted a multi-site proof-of-concept randomized controlled trial. 90 patients with schizophrenia were randomized to a three-week trial of two different spironolactone dosages (100 mg or 200 mg) or placebo. The primary endpoint was predefined as change in working memory performance after three weeks of treatment. A naturalistic follow-up was performed nine weeks after the end of intervention. The trial was registered at the WHO International Clinical Trials Registry platform ( http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE ). Despite large numerical improvements in working memory functions, particularly in the spironolactone 200 mg group, the pre-specified analyses do not demonstrate significant superiority of either intervention over placebo. However, post-hoc sensitivity analyses suggest a significant advantage of spironolactone for the primary endpoint. Safety measures show that both interventions are well tolerated. This finding suggests a potential positive effect of spironolactone on working memory in people with schizophrenia and the good safety outcomes may justify further trials with longer intervention periods or higher spironolactone dosages. Individuals diagnosed with schizophrenia frequently experience cognitive deficits, including challenges related to everyday memory and attention. We evaluated whether spironolactone, a drug available since the 1960s and today used to treat heart failure is effective in treating cognitive impairment in people with schizophrenia. For that, we conducted a placebo-controlled clinical trial where participants received either 100 mg or 200 mg spironolactone or placebo for three weeks. Before and after this intervention, we tested cognition. We were able to show that our intervention with spironolactone has the potential to improve cognition in people with schizophrenia. Further trials are needed before this intervention can be offered as part of the clinical routine.
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Severe mental illness (SMI) is frequently accompanied by substantial impairments in psychosocial functioning. Psychosocial interventions (PSI), therefore, represent an essential component of evidence-based treatment. A key prerequisite for the utilization is adequate knowledge. The aim of this study was to assess the level of knowledge about PSI among individuals with SMI. A cross-sectional multicenter study was conducted among individuals with SMI aged 18 to 65 years (n = 397). Knowledge of PSI, along with sociodemographic, clinical and additional contextual characteristics was assessed. Linear regression analyses were performed to examine associations between PSI knowledge and potential predictors. Overall, participants with SMI were familiar with an average of 10 out of the 17 assessed interventions. Better knowledge was associated with the presence of a chronic physical illness (p = .027), a longer duration of psychiatric problems (p = .030) and higher GAF scores (p = .010). In contrast, having experienced divorce, separation, or widowhood compared to being single (p = .040), as well as having a migration background (p = .003), were associated with lower levels of knowledge. The findings highlight the need for more targeted dissemination of guideline-based information on PSI to individuals with SMI.
This study assessed the combined effect of 12 weeks melatonin supplementation (5mg/day) and Dual-task training (DTT) on functional capacity and quality of life in patients with Parkinson's disease (PD). Thirty-six participants were randomised into three groups: DTT + melatonin (TMG, n = 13), DTT + placebo (TPG, n = 11), and placebo (PG, n = 12). During bipedal stance, post-intervention centre-of-pressure mean velocity (CoPVm) was lower in TMG and TPG than in PG under both eyes-opened and eyes-closed conditions. During unipedal stance, CoPVm decreased only in TMG under eyes-closed conditions and was lower than in PG. Leg muscle strength was higher in TMG than in TPG and PG, and higher in TPG than in PG at post-intervention. Both training groups demonstrated better motor capacity, freezing-of-gait, and quality-of-life outcomes than PG. Overall, DTT enhanced motor capacity, bipedal static balance, freezing of gait and quality of life, while melatonin provided additional benefits for unipedal static balance and leg strength.