Search Results (806)

Thomas Jefferson, the Author of the Declaration of Independence and the Father of the University of Virginia, considered it a self-evident truth that our rights must be secured through government and that the people themselves are the only safe guardians of their liberty in a republican form of government. The civic education of the people is, therefore, imperative, in his view, if they are to be informed citizens. This article examines the ways that the first States sought to institute public universities, through both constitutional and legislative means, and highlights Jefferson’s vision for civic education against the activity of the States in establishing education. Surveying early State constitutions and university charters reveals, for those States instituting public education, a wide range of approaches, particularly with respect to three aspects: authorizing mode (constitutional or legislative mandates); civic rhetoric; and scope (tiered system or single institution). While several of the States recognize education as important to republican government, their commitments to public civic education vary. Against this backdrop, Jefferson’s views on education appear both comprehensive and constant, from his reform Bill for the More General Diffusion of Knowledge and Notes on the State of Virginia, which envision a three-tiered public system, to his efforts in retirement to pass education reform and establish a new university, with his purpose being explicitly civic. While his State never adopted his full system, Jefferson continued to advocate for ward republics and public instruction throughout his life. The founding of the University of Virginia in 1819 partially fulfilled this pursuit, embodying the keystone in his educational architecture. Yet Jefferson’s broader system—grounded in local participation and universal civic instruction—remained unrealized. This survey further reveals that statesmen in early America did not always agree with Jefferson that States must have an enduring institutional commitment to public civic education, as the best means to inform the people and to secure republican self-government. Full article

Restless legs syndrome (RLS) is a common yet underrecognized neurological disorder characterized by uncomfortable sensations and an irresistible urge to move he legs, typically following a circadian pattern. RLS frequently co-occurs with various other neurological diseases, raising questions about shared mechanisms and clinical consequences. This review synthesizes evidence on the prevalence, outcomes, and pathophysiology of RLS in various neurological disorders, including Parkinson’s disease, multiple sclerosis, migraine, dementia, stroke, epilepsy, and peripheral neuropathy. In Parkinson’s disease, RLS is linked to disease progression and dopaminergic therapy. In stroke and multiple sclerosis, RLS is associated with structural lesions at specific locations, such as the pons or spinal cord. In epilepsy, RLS is associated with refractory or nocturnal seizures. In neuropathies, disruption of small sensory fibers may contribute to RLS symptoms. In dementia, RLS adds diagnostic complexity. Overlapping mechanisms between RLS and its neurological comorbidities include altered sensorimotor processing, brainstem and spinal circuitry, and sleep/arousal regulation. RLS in neurological conditions often worsens sleep quality, mood, and fatigue, and contributes to reduced quality of life and worse outcomes. Future research should prioritize longitudinal designs, standardized diagnostic approaches, and mechanistically driven studies to clarify relationships between RLS and these neurological comorbidities. Full article

Type-1 ryanodine receptor (RyR1) is essential for skeletal muscle contraction. This Ca²⁺ release channel is expressed in cardiac myocytes; however, its function remains elusive. Cardiac-specific RyR1 overexpression (OE) mice were generated under the cardiac-specific Myh6 promoter. Cardiac hypertrophy (CH), cardiac functions, and mechanistic changes in RyR1 OE and control (wildtype, WT) mice were assessed using hematoxylin and eosin staining, echocardiography, electrocardiogram, quantitative RT-PCR, Western blotting, [³H]-ryanodine binding assay, confocal microscope, ROS dye Amplex Red and 2′,7′-dichlorofluorescein diacetate. RyR1 OE mice had increased whole heart, left ventricular weight, and left ventricular wall thickness, but decreased cardiac output and stroke volume, thereby presenting CH and heart failure (HF). CH markers like ANF, BNF, and aSKA mRNAs were increased in RyR1 OE heart. RyR1, but not RyR2 or RyR3, expression was increased in the RyR1 OE mouse heart. Similar results were found in mice with TAC-induced CH. RyR1, but not RyR2 mRNA, was increased in cardiac muscle from dogs and humans with CH and/or HF. Maximum [³H]-ryanodine binding was increased, whereas the binding dissociation constant decreased in left ventricular cardiomyocytes from RyR1 OE mice. RyR2-dependent Ca²⁺ sparks were increased, which was blocked by riluzole, a small molecule known to inhibit RyR2. Consistently, ROS was remarkably increased in RyR1 OE cardiac cells. We first generated cardiac-specific RyR1 OE mice; these mice had CH, HF, and increased RyR1 expression with no RyR2 or RyR3 alteration. Similar changes were observed in mice, dogs, and humans with CH and HF. Increased mitochondrial ROS-dependent RyR2 Ca²⁺ release was essential for RyR1-induced CH and HF. Full article

In quantum field theory, the vacuum is popularly considered to be a complex medium populated with virtual particle + antiparticle pairs. To an observer experiencing uniform acceleration, it is generally held that these virtual particles become real, appearing as a gas at a temperature that grows with the acceleration. This is the Unruh effect. However, it has been shown that vacuum complexity is an artifact produced by treating quantum field theory in a manner that does not manifestly enforce causality. Choosing a quantization approach that patently enforces causality, the quantum field theory vacuum is barren, bereft even of virtual particles. We show that acceleration has no effect on a trivial vacuum; hence, there is no Unruh effect in such a treatment of quantum field theory. Since the standard calculations suggesting an Unruh effect are formally consistent, insofar as they have been completed, there must be a canceling contribution that is omitted in the usual analyses. We argue that it is the dynamical action of conventional Lorentz transformations on the structure of an Unruh detector. Full article

Rare-earth-based permanent magnets have the unique ability to create Tesla-strength magnetic fields without the need for power supplies. Moreover, Halbach showed that the fields of assemblies of magnets can be calculated analytically, because the permeability of permanent magnets is very close to unity. But that only worked in the absence of materials with a non-unity permeability, which implies that numerical tools must be employed to account, for example, for materials used to shield stray fields. Here we employ the method of images to derive analytic expressions for the magnetic field of Halbach multipoles that are enclosed in infinite-permeability shielding. Full article

Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disabling conditions like cerebral palsy, epilepsy, and autism. It is well established that maternal infection and inflammation are significant risk factors for HIE but reasons for this increase in neurological risk to the offspring remain unknown. Inflammation or infection are associated with epigenetic changes and may contribute to the increased risk of neurodevelopmental disability in exposed offspring. Here, we analyzed and compared DNA methylation patterns in brain monocytes isolated from control, maternal immune activation (MIA), and an inflammation sensitized HIE (IS-HIE) CF-1 mouse model at postnatal day 7. We found that maternal inflammation induced significant methylation differences in neonates relative to control samples in both MIA and IS-HIE samples with no significant differences identified between the MIA and IS-HIE groups. MIA samples showed hypermethylation at loci involving craniofacial development and transcription factors important for regulating neurodevelopment and immune function. MIA samples also demonstrated significant hypermethylation at multiple mitochondrial genome CpGs. These findings suggest that maternal inflammation induces epigenetic alterations in fetal brain immune cells that are detectable in neonates. These changes may contribute to heightened neurodevelopmental risk in offspring following hypoxic injury, highlighting potential molecular pathways for future therapeutic targeting. Full article

Background/Objectives: This study aimed to assess the feasibility and acceptability of a 3-month health coaching intervention to promote PNF and healthy diet for men on ADT for PCa. Methods: The study was carried out via a two-armed randomized controlled trial including 40 patients with PCa at a medical center in Philadelphia. During the 3-month period, the intervention group (PNF+) received health coaching utilizing an interactive text message system, and the control group received healthy eating text messages for the same duration. The outcome variables were feasibility and acceptability. Results: The PNF+ group (n = 27) had high adherence to health coaching (82%), picture response (85%) and moderate adherence to the PNF window (69%). The intervention was rated highly acceptable with no reported A/E associated with the intervention, and most participants planning to continue in some capacity. At 3 months, the PNF+ group had numerically lower BMI (29.1) and body weight (195.2 lbs) compared to the control group (n = 13; BMI 31.6, weight 223.3 lbs). Improvements in patient-reported outcomes were observed in both groups. FACIT-F scores (higher scores indicate less fatigue) increased in the PNF+ group (43.6 to 45.2) and in the control group (42.5 to 45.5). FACT-P scores (higher scores indicate better quality of life) increased in the PNF+ group (121.3 to 125.5) but decreased slightly in the control group (121.1 to 119.8). Between-group comparisons of change from baseline showed no statistically significant differences across outcomes (all p > 0.05). Conclusions: The intervention demonstrated partial feasibility and high acceptability. It was associated with numerically lower BMI and body weight and favorable changes in patient-reported outcomes, particularly quality of life; however, no statistically significant differences were observed between groups. These findings should be interpreted cautiously given the small sample size and require confirmation in larger, adequately powered trials. Full article

Background/Objectives: Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a triplet repeat expansion in the Fmr1 gene leading to the loss of Fragile X Messenger Ribonucleoprotein (Fmr1 protein). The loss of Fmr1 protein modulates many cell biological processes and leads to the emergence of intellectual disability and autism. FXS is modeled in Fmr1-KO mice that display features consistent with human FXS, including hypersensitivity, cognitive and learning deficits, hyperactivity and audiogenic seizures. Here, we investigated the effect of auditory stimulation during a range of developmental stages on recognition memory and sociability deficits in Fmr1-KO mice. Methods: Fmr1-KO mice were subjected to auditory stimulation for 2 min three times a day at one-hour intervals for 5 days at the nursing, juvenile and adult stages. The animals were tested for social interaction and novel object recognition at 2 to 3 months old. Results: During auditory stimulation, the wild running phenotype was observed in the Fmr1-KO juvenile animals and two animals at the nursing stage experienced status epilepticus and died. Fmr1-KO animals showed social deficits compared to both the control and animals exposed to auditory stimulation at the juvenile stage. In the novel object recognition task, auditory stimulation was more effective at the nursing and juvenile stages. Conclusions: These data show that auditory stimulation may be an effective way to restore cognitive and social deficits in FXS. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable. Full article

Background: HIMALAYA demonstrated that STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) compared with sorafenib in participants with unresectable hepatocellular carcinoma (HCC). This retrospective, real-world cohort study evaluated outcomes with STRIDE in veterans with HCC. Methods: Patients diagnosed with HCC between 1 January 2008 and 28 February 2024 who received ≥1 dose of STRIDE for unresectable disease were included. Data were collected from the Veteran Affairs Corporate Data Warehouse. Safety and efficacy were evaluated overall and for subgroups of patients with Child–Pugh A versus Child–Pugh B cirrhosis, viral versus non-viral HCC, and those with versus without prior non-systemic therapies. Results: Overall, 107 patients (100.0% male) were included. Median (interquartile range) age was 72.2 (68.0–76.1) years. There were 22 Grade 3–4 adverse events reported (three in patients with Child–Pugh B cirrhosis). Median OS (95% CI) was 12.4 (9.1–22.1) months and 5.2 (1.5–9.3) months in patients with Child–Pugh A (n = 81; 75.7%) and Child–Pugh B cirrhosis (n = 26; 24.3%), respectively. In patients with viral (n = 64; 59.8%) versus non-viral etiology (n = 43; 40.2%), median OS (95% CI) was 10.5 (7.0–25.6) months versus 9.0 (4.6–16.0) months, respectively. In patients without (n = 30; 28.0%) versus with prior non-systemic therapies (n = 77; 72.0%), median OS (95% CI) was 7.7 (2.8–17.3) months versus 11.1 (7.6–17.6) months, respectively. Conclusions: These results suggest that STRIDE is well tolerated and may offer a survival benefit to a broad range of patients with unresectable HCC, representing populations that are more reflective of real-world clinical practice. Full article

Background: Fasting-based interventions are increasingly investigated as adjuncts to cancer treatment for the potential to reduce therapy-related toxicities, improve metabolic health, and enhance quality of life. However, clinical evidence regarding their efficacy, tolerability, and acceptability remains limited and fragmented. This scoping review aimed to systematically map the current evidence on fasting-based interventions in cancer patients and survivors. Methods: A literature search was conducted in PubMed, Scopus, Web of Science, and CINAHL up to 10 June 2025. Eligible interventional studies included cancer patients or survivors and evaluated fasting-based interventions, such as time-restricted eating, intermittent fasting, short-term fasting, or fasting-mimicking diets. Studies were categorized by fasting types and outcomes like fatigue, treatment toxicity, metabolic and hematologic parameters, weight, quality of life, adherence, acceptability, illness perception, and adverse events were assessed. Result: Twenty interventional studies of FMD, TRE, STF, IF, or fasting combined with altered dietary approaches conducted across 10 countries were included, comprising a total of 871 participants. Participant ages ranged from 28 to 75 years. Overall, 9 of 20 studies exclusively enrolled breast cancer patients or survivors, and chemotherapy was the most common treatment context in 11 studies. Five of six studies reported reductions in fatigue. Among the five studies assessing quality of life, one demonstrated improvement, three reported no change, and one yielded mixed results. Six of eight studies reported reductions in chemotherapy-related toxicity, and weight loss was observed in 10 of 12 studies. Reductions in IGF-1 and insulin levels were reported in six of seven and four of five studies, respectively. Hematologic changes were noted in six studies, and only one study assessed illness perceptions, reporting positive findings. Fasting-related adverse events, reported in nine studies, were generally mild and transient. High adherence and acceptability were observed across studies; however, findings were heterogeneous across intervention types and were largely derived from small or moderate-strength studies. A descriptive quality metric assessment indicated that most studies were of moderate methodological strength. More intensive fasting protocols, such as FMD and STF, appeared to demonstrate more consistent metabolic effects, whereas TRE showed higher adherence but more variable clinical outcomes. Conclusions: Fasting-based interventions have the potential to be feasible and well tolerated among cancer patients and survivors, with early evidence suggesting benefits in reducing fatigue, minimizing treatment-related toxicities, and favorable metabolic effects. Large, well-designed trials including diverse cancer populations are needed to confirm long-term outcomes and guide clinical integration. Full article

Background: Parents are children’s primary role models, are food and physical activity gatekeepers, and create the home structure/lifestyle environment. Thus, parents strongly influence children’s weight-related behaviors and have the opportunity to cultivate a “culture of health” within the home. Methods: The aim of the HomeStyles-2 (also called HomeStyles-Child) RCT was to determine whether this online, novel, age-appropriate, family intervention enabled and motivated the 131 systematically randomly assigned by computer parents of children in middle childhood (ages 6 to 11) in the experimental condition to shape home environments and healthy weight-related lifestyle practices to be more supportive of optimal health and reduced obesity risk in middle childhood youth more than the 134 counterparts assigned to the attention control condition. Results: This RCT demonstrated the feasibility of online delivery of a health promotion intervention to parents of children in middle childhood, which may inform the development of interventions targeting other age groups and health outcomes. Results indicate the HomeStyles-Child intervention improved healthy-weight-related behavior cognitions, which are predictors of behavior change, of the experimental group. Additionally, improvements in experimental parent and child health-related behaviors were observed. These improvements occurred during a time when families faced unprecedented and extraordinary economic and social stresses associated with the COVID-19 pandemic. Conclusions: HomeStyles-Child is one of the few interventions for families with middle childhood youth. It has the potential to help ameliorate obesity in middle childhood youth and, by extension, other family members. Full article

Effective rehabilitation tools are essential for improving language outcomes in chronic aphasia. Speech entrainment is a behavioral treatment that has shown promise in enhancing speech output in nonfluent aphasia, potentially by acting as an external mechanism to synchronize anterior and posterior language regions in the left hemisphere. Transcranial alternating current stimulation has been hypothesized to enhance functional connectivity between brain regions by amplifying endogenous oscillations. This proof-of-concept study explored whether high-definition tACS (HD-tACS) could improve speech fluency in nonfluent aphasia when paired with speech entrainment. In a double-blind, pseudorandomized study, 1 mA of HD-tACS at 7 Hz was applied to anterior and posterior left-hemisphere regions of individuals with nonfluent aphasia (N = 13). Stimulation was applied under three conditions: in-phase, anti-phase, and sham, and paired speech entrainment. Three outcome measures were examined: (1) number of words produced; (2) number of errors, and (3) ‘entrainment’ to the speech entrainment model. Group-level analyses for two of the three outcome measures reveal statistically significant differences between the experimental conditions. In-phase alternating current stimulation yielded more words and better entrainment to the audiovisual model than the sham condition. This study provides promising evidence that HD-tACS could improve speech production in individuals with nonfluent aphasia. These results contribute to growing evidence supporting the therapeutic potential of non-invasive brain stimulation approaches as an adjuvant to traditional behavioral speech-language therapy in stroke survivors. Full article

Background: Mitragynine pseudoindoxyl (MP) is a semi-synthetic kratom metabolite increasingly sold online and over-the-counter, marketed misleadingly as “kratom” or “7-OH,” despite lacking FDA approval and safety data in humans. Methods: This case report describes a 44-year-old male with polysubstance use history who developed opioid withdrawal symptoms after regular MP use (400 mg daily for pain management following neck injury). Vital signs, alcohol and opioid withdrawal scores and clinical outcomes were recorded. Results: The patient presented exhibiting symptoms of moderate opioid withdrawal in the absence of other opioid use. A buprenorphine macro-induction protocol was initiated. Following pre-treatment using chlorpromazine as an anti-emetic and diazepam to treat concomitant alcohol withdrawal, 32 mg buprenorphine were provided (16 mg × 2) on day one, with subsequent maintenance dosing and adjunctive medications. The patient demonstrated significant symptomatic improvement with decreased COWS scores and expressed interest in long-acting injectable buprenorphine maintenance therapy. Discussion: This represents the first documented case of suspected MP withdrawal successfully managed with buprenorphine macro-induction, demonstrating the potential efficacy of this approach for novel semi-synthetic kratom metabolites when standard withdrawal management protocols are insufficient. Further studies should evaluate long term outcomes and validate findings. Full article