Search Results (4,804)

Purpose: This study aimed to evaluate the effects of active transcranial direct current stimulation (tDCS) compared with sham stimulation on circulating brain-derived neurotrophic factor (BDNF), pain-related outcomes, working memory, and inflammatory and neuroplasticity biomarkers. Methods: PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov were searched from inception to May 2026. Randomized and controlled clinical trials comparing active with sham tDCS in adults were included. The primary outcome was post-treatment BDNF concentration. Secondary outcomes included pain intensity, pain catastrophizing, pain-related disability and functional interference, working memory, and circulating inflammatory or neuroplasticity biomarkers. Risk of bias was assessed using the revised Cochrane risk-of-bias tool. Mean differences (MDs) with 95% confidence intervals (CIs) were pooled using random-effects models. Serum and plasma BDNF were analyzed separately. Results: Twenty-one studies were included in the systematic review, of which 15 contributed to at least one quantitative synthesis and 12 study comparisons contributed to the primary BDNF analyses. Active tDCS did not significantly affect serum BDNF (MD = −0.01 [−0.15, 0.13], p = 0.890) or plasma BDNF (MD = 0.02 [−0.25, 0.29], p = 0.870) compared with sham stimulation. In contrast, active tDCS was associated with lower pain intensity (MD = −1.79 [−2.34, −1.23], p < 0.00001). No statistically significant difference was observed in the PCS total score or in the helplessness, magnification, or rumination subscales, although the point estimates generally favored active tDCS. For pain-related disability and functional interference, active tDCS was associated with lower PCP:S total scores and lower emotional interference, whereas no significant differences were observed for interference with daily activities or pain frequency. No significant differences were observed for working memory, interleukins, tumor necrosis factor-alpha, glial cell line-derived neurotrophic factor, interleukin-18, or soluble tumor necrosis factor receptors. Substantial heterogeneity was present in several pain-related and inflammatory biomarker analyses. Conclusions: Active tDCS was not associated with consistent differences in circulating serum or plasma BDNF or in the assessed peripheral inflammatory and neuroplasticity biomarkers compared with sham stimulation; however, these null peripheral findings should not be interpreted as evidence of absent central neuroplastic effects, because circulating measures may not adequately capture localized or transient biological changes within the central nervous system. Active tDCS was associated with improvements in some pain-related outcomes; however, the limited number of studies, substantial heterogeneity, and low certainty of the available evidence preclude firm conclusions regarding its clinical effectiveness for pain management. Full article

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or the PARP inhibitor AZD2461 (iP) in CRPC cell lines 22Rv1 and PC3. DHA enhanced the cytotoxic effect of iP in both cell lines and of ENZ in 22Rv1 cells. In PC3 cells, DHA-mediated potentiation of iP cytotoxicity was associated with downregulation of the AKT pathway, reduced expression of ERα and the lipid sensors PPARγ and LXRβ, and a shift in programmed cell death toward necroptosis. In 22Rv1 cells, the additive effects of DHA with ENZ or iP were independent of PI3K/pAKT and AR-FL/AR-V7 modulation but were associated with regulation of LXRβ, PPARγ, and TNFR1, along with activation of apoptosis. Wound-healing assays showed that DHA blocked the anti-migratory effects of ENZ and iP in 22Rv1 cells and did not alter iP effects in PC3 cells, indicating epithelial–mesenchymal transition heterogeneity. Overall, DHA potentiates the cytotoxic effects of iP in both models and of ENZ in 22Rv1 cells via differential modulation of cell death in a molecular context-dependent manner. Full article

Diabetic foot ulcers (DFU) are among the most severe complications of diabetes, resulting from a combination of metabolic dysregulation, vascular insufficiency, neuropathy, chronic inflammation, and impaired tissue repair, whereas diabetic foot infection (DFI) may develop within this compromised wound environment and frequently involves polymicrobial communities and biofilms. This review evaluates the mechanistic and translational basis for the use of antimicrobial peptides (AMP) in DFU and DFI, with emphasis on the diabetic wound microenvironment, polymicrobial ecology, endogenous AMP dysregulation, mechanisms of action, therapeutic development, and barriers to clinical translation. Hyperglycemia, ischemia, oxidative and proteolytic stress, and impaired innate immunity sustain inflammation, delay tissue repair, and promote microbial persistence. These conditions may also complicate antibiotic treatment through impaired tissue exposure and biofilm-associated tolerance. Depending on the peptide and experimental context, AMP may provide direct antimicrobial or antibiofilm activity and may also exert immunomodulatory or pro-reparative effects involving inflammatory signaling, angiogenesis, keratinocyte and fibroblast migration, and re-epithelialization. Approaches under investigation include engineered peptides, combination regimens, and local biomaterial-based platforms, including hydrogels, dressings, scaffolds, and nanoparticle-conjugated systems. Clinical translation remains constrained by proteolytic instability, potential host-tissue toxicity, limited selectivity, limited predictive value of preclinical models, heterogeneous clinical populations, nonstandardized endpoints, and manufacturing and regulatory requirements. Preclinical evidence supports further evaluation of approaches for local delivery of AMP, whereas clinical evidence in DFU and DFI remains limited and heterogeneous, with no AMP-based intervention yet demonstrating sufficiently consistent clinical benefit to support routine use. Full article

Urothelial carcinoma predominantly affects older patients, who often exhibit frailty, comorbidities, renal impairment, and reduced physiological reserve. We evaluated overall survival (OS) and progression-free survival (PFS) with first-line immune-based strategies in patients aged ≥65 years with advanced or metastatic urothelial carcinoma. The aim was to characterize treatment effects within this age-defined subgroup, not to determine whether age modifies treatment efficacy compared with younger patients. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized trials published from January 2015 to May 2026 reporting age-specific survival outcomes. Combination regimens were compared with platinum-based chemotherapy using random-effects models. Results: Combination strategies improved OS versus chemotherapy (HR 0.79, 95% CI 0.64–0.96), although heterogeneity was substantial (I² = 69.7%) and the prediction interval crossed the null (0.48–1.27). Class-specific HRs were 0.56 (95% CI 0.26–1.20) for ADC plus ICI, 0.85 (0.77–0.95) for ICI plus chemotherapy, and 0.91 (0.34–2.42) for dual-checkpoint inhibition. PFS favoured experimental treatment but remained imprecise (HR 0.54, 95% CI 0.27–1.08; I² = 89.5%). Excluding ADC plus ICI trials attenuated the OS effect (HR 0.88, 95% CI 0.80–0.96), indicating that the pooled estimate was influenced by these trials. ICI monotherapy did not improve OS. Conclusions: First-line immune-based combinations improved survival in selected patients aged ≥65 years, but benefit varied across treatment classes and should not be considered uniform across regimens. These findings do not establish whether age modifies treatment efficacy. Age-specific safety data were insufficient to define the benefit–risk profile of individual strategies. Full article

China’s decentralized governance system relies partly on governance tournaments. We exploit the staggered award of the 5A Tourist Attraction Designation, China’s highest official rating for tourist attractions, as a quasi-natural experiment. We combine city-level designation records with panel data on Chinese A-share listed firms from 2000 to 2023. Difference-in-differences estimates suggests that 5A tourist attraction designation is associated with higher corporate green total factor productivity in affected cities. This result is robust to relaxing the parallel trends assumption, using bounds based on imperfect instrumental variables, and applying estimators that accommodate heterogeneous treatment effects. Evidence on mechanisms points to greater green innovation, substantive improvements in environmental practices, and higher investment efficiency. The effects are larger for non-state-owned firms, downstream firms, and firms located in the Two Control Zones or in cities with more developed green finance. Double machine learning estimates further indicate that the designation strengthens green technology spillovers. These findings identify an environmental governance benefit of tourism-based place designations and show how such policies can promote sustainable development by reshaping local government and firm incentives. Full article

The intensification of Cannabis sativa cultivation has increased the need for effective and sustainable plant-health strategies. Pathogen control is particularly challenging because pesticide residues may compromise product safety and quality, while repeated chemical treatments can favour the emergence of fungicide-resistant populations. Microbial biological control agents (BCAs) represent a promising component of integrated disease management, although their discovery and validation remain largely empirical. This narrative review examines the current literature on the biological control of fungal and oomycete diseases of cannabis, with particular emphasis on Fusarium-associated syndromes, Golovinomyces-associated powdery mildew, grey mould caused by Botrytis cinerea and major oomycete root rots. Cannabis-specific research remains limited and heterogeneous regarding reproducible efficacy across host genotypes, pathogens, and environments; mechanisms of protection; and application-oriented assessment of biosafety, crop quality, and formulation performance. To address these gaps, available evidence is organised within a prospective multi-omics-guided framework combining host and pathogen genomic characterisation, microbiome profiling, targeted BCA isolation, strain-level genomic analysis, preliminary safety screening and comparative in planta evaluation. Transcriptomic, metabolomic, and microbiome analyses can complement these stages by identifying molecular and community-level patterns potentially related to direct antagonism, resource competition, host defence priming and microbiome-mediated protection. The relevance of these patterns to disease suppression requires functional validation, while the resulting evidence may inform the design and evaluation of synthetic microbial communities. Integrating omics across these stages could support more traceable and application-relevant BCA development by enabling mechanistic investigation while providing a structured roadmap for advancing biological control strategies against fungal and oomycete pathogens of cannabis. Full article

Introduction: Iron is essential for cerebral energy metabolism, neurotransmitter synthesis, myelination, and neural development. Iron deficiency may therefore impair brain function even before overt anemia develops. This systematic and mechanistic review synthesized EEG findings associated with iron deficiency across the lifespan and evaluated electrophysiological changes following iron treatment. Materials and Methods: PubMed/MEDLINE, Scopus, Web of Science, Embase, PsycINFO, and Google Scholar were searched from inception to July 2026. Human studies examining iron deficiency or iron-deficiency anemia using EEG, quantitative EEG, task-related oscillations, event-related potentials, or cortical-evoked potentials formed the core evidence base. Two additional studies of chronic kidney disease-related or mixed-etiology anemia were retained as contextual evidence to help distinguish iron-specific electrophysiological effects from abnormalities associated more generally with anemia severity and reduced oxygen-carrying capacity. Risk of bias was assessed using RoB 2 and ROBINS-I. Because of substantial heterogeneity, findings were synthesized narratively. Results: Thirty reports were retained for narrative synthesis, covering participants from the neonatal period to adulthood. Twenty-eight formed the core iron-specific evidence base, whereas two were analyzed separately as contextual anemia evidence. Iron deficiency was commonly associated with increased slow-wave activity, reduced alpha activity, delayed sensory and cognitive processing, prolonged P300 and N2 latencies, altered frontal alpha asymmetry, and impaired differentiation between relevant and irrelevant stimuli. Reductions in P300 amplitude were less consistent but were observed in severe anemia, demanding cognitive tasks, and after infantile iron-deficiency anemia. Iron supplementation improved several spectral and ERP outcomes, although recovery was variable and some abnormalities persisted after hematological correction. Interpretation was limited by heterogeneous diagnostic criteria, small samples, inconsistent EEG methods, residual confounding, variable risk of bias, and the partial non-independence of reports arising from overlapping longitudinal cohorts or parent trials. Findings from the contextual anemia studies were not interpreted as direct evidence of an effect of iron deficiency. Conclusions: Iron deficiency may disrupt the timing, synchronization, and maturation of neural activity through impaired energy metabolism, neurotransmission, myelination, and synaptic development. EEG may be useful for detecting functional brain alterations and monitoring treatment response, but no specific electrophysiological biomarker can currently be established. Full article

Acute kidney injury (AKI) is a severe complication of Eastern Russell’s viper (Daboia siamensis) envenoming, but species-specific mechanisms, treatment effects, and long-term outcomes remain uncertain. This review addressed four questions: the human renal evidence specific to D. siamensis; venom and host pathways contributing to AKI; conclusions supported for antivenom timing and thrombotic microangiopathy (TMA); and quantifiable long-term kidney risk. PubMed and OpenAlex were searched from inception through 3 August 2026. Species-authenticated human evidence was separated from mixed-species or D. russelii studies and from venom-analytical and experimental evidence. Referral cohorts show AKI and dialysis burdens, but heterogeneous ascertainment, definitions, and care preclude pooled incidence. Proteomic and experimental studies support interacting coagulopathic, endothelial, hemodynamic, pigment, inflammatory, and direct renal pathways; no human study quantifies their relative contribution, and no D. siamensis study localizes specific venom antigens within renal tissue. Observational data support prompt use of indicated, regionally appropriate antivenom but do not validate a universal two-hour renal-protection threshold. TMA and long-term outcome evidence remain largely indirect. Serial renal and coagulation surveillance is warranted irrespective of whether injury is direct or indirect. Prospective, species-authenticated studies linking venom kinetics and toxin profiles to standardized renal phenotypes and follow-up are required. Full article

Background/Objectives: Dental caries remains one of the most prevalent chronic diseases affecting children worldwide and continues to pose a substantial challenge to healthcare systems. Although the clinical consequences of paediatric dental caries are well documented, the associated economic burden has not been comprehensively synthesised. This systematic review aimed to evaluate and summarise the available evidence regarding the costs associated with dental caries in children and adolescents under 18 years of age. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420251138979). MEDLINE via PubMed, Scopus, and Dentistry & Oral Sciences Source (EBSCOhost) were searched for studies published between January 2012 and July 2025. The MEDLINE and Scopus searches were conducted on 22 July 2025, and an additional search of Dentistry & Oral Sciences Source (EBSCOhost) was conducted on 19 August 2026. Eligible studies included peer-reviewed cost-of-illness studies, economic evaluations, cost analyses, cross-sectional studies, retrospective studies, and randomised controlled trials reporting economic outcomes related to the prevention or management of dental caries in individuals under 18 years of age. Methodological quality was assessed using the Drummond 10-item checklist. Data were extracted on study characteristics, population demographics, cost components, study perspective, and key findings. Reported costs were categorised as direct, indirect, and intangible costs where applicable. Due to substantial methodological heterogeneity among studies, a narrative synthesis was performed. Results: Seventeen studies met the inclusion criteria. Most studies focused on direct medical costs associated with restorative treatment, hospital-based dental care, and emergency services. Direct costs were consistently substantial across different healthcare settings, particularly for cases requiring advanced treatment or general anaesthesia. Preventive interventions were generally reported to be more cost-effective than curative approaches. Indirect costs, including caregiver productivity losses, were infrequently assessed, while no study comprehensively evaluated intangible costs. Considerable variation in study design, costing perspective, and reporting methodology limited direct comparison across studies. Conclusions: Dental caries in individuals under 18 years of age imposes a considerable economic burden, driven primarily by direct treatment costs. Preventive oral health strategies appear to provide greater economic value than treatment-focused approaches. The limited assessment of indirect and intangible costs suggests that the overall societal burden of paediatric dental caries is likely underestimated. Future research should adopt standardised and comprehensive costing methodologies to better support policy development and resource allocation in paediatric oral healthcare. Full article

Monoclonal antibody-based therapies are widely used in chronic immune-mediated diseases, but their periodontal effects, dentoalveolar safety signals, and exposure characteristics remain incompletely characterized. This scoping review mapped periodontal clinical outcomes, biomarkers, microbiological and imaging findings, dentoalveolar safety, administration, treatment exposure, and pharmaceutical-context reporting. PubMed, Scopus, and Web of Science were searched in July 2026 without publication-year or language restrictions. Twenty-one reports representing 20 studies or cohort families were included. Evidence mainly concerned rheumatoid arthritis and therapies targeting tumor necrosis factor, interleukin-6 receptor, and cluster of differentiation 20. Evidence for interleukin-17A inhibition was insufficient and derived from one confounded five-patient case series. Tocilizumab showed the most consistent reductions in gingival inflammation and bleeding on probing, while structural changes were smaller and inconsistent. Tumor necrosis factor-directed findings were heterogeneous. Small rituximab studies showed favorable clinical or biomarker signals, whereas pharmacovigilance identified infectious and destructive dentoalveolar signals. Exposure reporting was incomplete, and no included periodontal study evaluated formulation stability, storage, cold-chain integrity, or handling deviations. This review integrates treatment-effect evidence, safety signals, and exposure variables across antibody targets and identifies a pharmaceutical–periodontal reporting gap requiring prospective investigation. Full article

Background: Adjuvant radiotherapy (RT) may improve in-field regional tumor control in melanoma following resection of lymph node macrometastases. However, no significant effect on recurrence-free survival or overall survival has been demonstrated. The approval of adjuvant systemic immune checkpoint inhibitors and targeted therapies has significantly impacted the role of adjuvant RT. Its use in clinical practice has decreased, with heterogeneous treatment indications and approaches observed across institutions and regions. Objectives: The aim of the present study was to characterize the population of melanoma patients still undergoing adjuvant RT in the era of modern adjuvant systemic treatments, and to outline potential clinical scenarios in which it may continue to play a role in the future. Patients and methods: Fifty-eight patients treated with adjuvant RT were identified in five participating Austrian and Swiss dermato-oncologic centers. Treatment timing, toxicity, recurrence patterns, and survival outcomes were analyzed, and compared to 88 stage-matched, non-irradiated patients from a German cohort of patients who met formal RT criteria. Results: The majority of irradiated patients (53.5%) received RT before systemic therapy. The concurrent administration of adjuvant systemic therapy and radiotherapy did not increase the frequency of RT-associated toxicities (77.8% vs. 74.2%, p = 0.456). No significant differences in recurrence-free survival or overall survival were observed between irradiated and non-irradiated patients (p = 0.725 and p = 0.986, respectively). Conclusions: Although still recommended in certain melanoma guidelines, adjuvant RT is infrequently performed in the era of modern systemic treatments. Due to its exclusively locoregional efficacy, the application of adjuvant RT should be limited to clearly defined scenarios where systemic treatment options are limited and locoregional control is most important. The concurrent administration of adjuvant RT and systemic therapy is safe and should be preferred if a combined treatment strategy is chosen. Full article

Background: Depression is a major health issue among older adults and is frequently accompanied by chronic physical conditions. Conventional care of depression in older adults is delivered through primary care settings and often fails to address the complex interactions between mental health, physical illness, and social determinants of health in this population. Integrated care models, characterized by coordinated, multidisciplinary, and patient-centered approaches, have emerged as a promising strategy for improving depression outcomes in late life. Objective: This scoping review aimed to characterize integrated care models for managing depression in older adults. The review examined the structure and implementation of these models and evaluated depression-related outcomes. Methods: A systematic literature search was conducted in PubMed and Google Scholar. Studies published in English between 2006 and February 2026 were considered. Eligible studies included randomized controlled trials (RCTs), cluster RCTs, and quasi-RCTs that evaluated integrated care interventions targeting depression in adults aged 65 years or older or mixed adult populations that included older adults. One reviewer conducted the search and initial screening, and four additional reviewers evaluated the eligibility of full-text reports and extracted data using a structured template. Results were synthesized descriptively. Results: Seventeen studies met the inclusion criteria. Integrated care interventions were implemented across primary care clinics, community health centers, and home healthcare programs in several countries. Participants commonly had depression alongside chronic medical conditions, including diabetes, hypertension, heart failure, or chronic obstructive pulmonary disease. Integrated care models varied in staffing, therapeutic components, specialist involvement, delivery intensity, and comparator conditions. Most interventions incorporated multidisciplinary care teams; structured symptom monitoring; care coordination; behavioral or psychological interventions; and, in some studies, chronic disease management, social support, or technology-supported follow-up. Thirteen studies reported a favorable depression-related finding at one or more assessment points; however, benefits were not always sustained, and some studies reported null- or comparator-favoring findings. Conclusions: Integrated care for depression in older adults encompasses heterogeneous models implemented across diverse healthcare contexts. Common themes included multidisciplinary collaboration, coordinated follow-up, structured psychological or behavioral treatment, symptom monitoring, and integration of mental and physical health management. Favorable outcomes were reported in most studies, but findings varied by population, setting, comparator, intervention intensity, and follow-up duration. These findings may inform future program design, although the effectiveness of the integrated care models and the independent contribution of individual components remain uncertain. Full article

Hypertension remains the leading modifiable cause of cardiovascular death, yet fewer than one in four treated adults achieves guideline-recommended blood pressure targets. Catheter-based renal denervation interrupts efferent and afferent renal sympathetic signalling and lowers blood pressure continuously and independently of medication adherence. After a decade of controversy following the neutral SYMPLICITY HTN-3 trial, a coherent body of second-generation sham-controlled randomised evidence, generated with radiofrequency, endovascular ultrasound, and perivascular alcohol platforms, has established a reproducible, modest, and durable antihypertensive effect with a favourable safety profile. Between 2024 and 2026, the field crossed three thresholds simultaneously: guideline endorsement on both sides of the Atlantic, including the first United States recommendation in the 2025 AHA/ACC guideline; a national coverage determination with coverage with evidence development; and the maturation of randomised and real-world follow-up to three years in cohorts exceeding 3000 patients. This state-of-the-art review synthesises the contemporary evidence base; quantifies the expected treatment effect and its heterogeneity; appraises safety across renal and vascular domains; examines emerging data in chronic kidney disease, diabetes, heart failure, and atrial fibrillation; and details the practical requirements for delivering renal denervation responsibly. We conclude by defining the research agenda that must now be addressed: the identification of responders, the development of an intraprocedural endpoint, a direct comparison with newly approved pharmacotherapy, and evidence of cardiovascular event reduction. Full article

Atopic dermatitis (AD) is a chronic, relapsing, and remitting condition that affects approximately 10% of the population. It is a multifactorial disease involving immune dysregulation, gene mutations, and environmental factors that ultimately disrupt skin barrier restoration, causing pruritic lesions. Given the marked heterogeneity of AD and the presence of multiple immune and clinical endotypes, no single therapeutic strategy is likely to be universally effective. Instead, a growing panel of distinct biomarkers offers an avenue for true precision medicine by enabling more accurate endotype classification, prediction of treatment response, and tailored treatments. In this context, ongoing research is increasingly focused on individualized, biomarker-informed strategies, as well as the evaluation of adjunctive approaches that can be integrated with standard therapies to optimize long-term disease control. Given the central role of systemic inflammation and barrier dysfunction in AD, the mechanistic focus of osteopathic manipulative medicine (OMM) on circulation, lymphatic drainage, and autonomic regulation offers another biological treatment to use alongside conventional therapies. This concise review examines the pathogenesis of AD, current treatments and their limitations, and the expanding role of biomarkers in refining diagnosis, prognosis, and therapeutic decision-making. It also explores the potential integration of OMM as a biologically plausible adjunct to support individualized, endotype-aware treatment strategies, while emphasizing the current lack of empirical evidence and the need for rigorous mechanistic and clinical studies. Full article

Philanthropic hospitals are key providers within Brazil’s public healthcare system and benefit from the Certification of Beneficent Social Assistance Entities in Health (CEBAS-Saúde), a tax relief program designed to incentivize service provision in underserved areas. We analyze a balanced panel of 1641 philanthropic general hospitals from 2005 to 2019, employing a conditional Difference-in-Differences (DiD) model with heterogeneous treatment exposure and entropy balancing to ensure comparability between certified and non-certified hospitals. The results show that certification significantly improved geographic access, mainly by reducing macro-regional patient evasion—the outflow of patients seeking care outside their designated health regions. This effect, most pronounced after ten years of certification, translated into an average annual reduction of approximately 8700 avoided hospitalizations between 2015 and 2019. The reduction was particularly concentrated in small hospitals and in the Northeast region, where access barriers are historically greater. These findings suggest that CEBAS-Saúde is an effective policy instrument for strengthening the regionalization of healthcare provision, reducing geographic inequities, and addressing service gaps in areas with limited healthcare supply. Full article