Search Results (93)

This study aimed to investigate the physicochemical properties and composites of a novel cellulosic fiber extracted from Nerium oleander L. plant stem. Nerium oleander fibers (NOFs) were separated from mature oleander plants using a microbial degradation technique, and their composites (NOFCs) were fabricated using a compression molding technique. The chemical composition, physical and thermal behavior of NOFs, and mechanical and water absorption properties of NOFs and NOFCs were investigated. The findings show that NOFs have a cellulose content of 57%, hemicellulose content of 13%, lignin content of 16%, density of 1.46 g/cc, and crystallinity index (CI) of 57.14%. The results further revealed that NOFs had a tensile strength of 438 MPa and a strain rate of 1.8%, whereas NOFCs had a maximum tensile strength of 58.42 MPa. NOFs can withstand temperatures up to 357 °C, according to a thermogravimetric study, and the functional groups were analyzed using Fourier-transform infrared (FTIR) spectroscopy. Scanning electron microscopy (SEM) studies showed that the surface morphology and fractured surfaces of the NOFs and their composites were smooth and circular in cross-section. Full article

We propose a three-functional-layer decomposition framework for underwater acoustic (UWA) integrated sensing and communication (ISAC) preambles, instantiated as P5. Two spectrally separated chirp layers—hyperbolic frequency modulation (HFM) for wideband Doppler invariance and linear frequency modulation (LFM) for sub-meter ranging—are carried under a common constant-amplitude zero-autocorrelation (CAZAC) envelope that supplies cell identification and despreading against a root-blind attacker. Closed-form screening conditions constrain the layers to a near-orthogonal subspace, and direct cross-ambiguity measurement confirms the realized separation. In matched-filter Monte Carlo simulation, P5 meets the continuous-sensing target (range root mean square error ${\sigma }_R\le 1$ m at 10 dB signal-to-noise ratio) and has the smallest normalized matched-filter peak loss across twelve modeled UWA environments among four tested waveforms. Against four classical structure-aware attackers it stays below the strict $P_d\le 0.1$ low-probability-of-intercept target at 0 dB attacker-input SNR. A 10-seed, 11.2-million-parameter spectrogram ResNet-18 reaches $P_d=0.5$ against P5 at mean $+21.24$ dB total-energy SNR (95% CI $[+21.06,+21.42]$ dB) and $P_d=0.1$ at $+18.72$ dB ($[+18.45,+19.00]$ dB); these crossings are lower bounds on adversary capability, not a security guarantee. The integration also has explicit costs: composite peak-sidelobe level ($-7.60$ dB default, $-11.29$ dB optimized) remains inferior to equal-aperture single-waveform baselines, and sixteen-cell identification falls to ≤$0.07$ under a $+2$ dB near–far interferer. All-60-sounding WATERMARK replay further gives adverse P5^def–B5 losses of $-0.816$ dB on NOF1 (sounding-cluster 95% CI $[-1.021,-0.621]$ dB) and $-0.950$ dB on NCS1 ($[-0.977,-0.923]$ dB) after all waveforms are scaled into the same measured 8-kHz band. The evidence is therefore simulation dominant and supplemented by measured-channel replay of band-scaled variants; native-band transducer, pool, and sea-trial validation remain future work. Full article

This paper examines how the emergence of over-parameterized artificial intelligence models and the phenomenon of double descent challenge the classical assumption that simpler models generalize better. Traditional predictive analytics relied on parsimonious models grounded in the bias-variance trade-off, where increasing complexity was expected to produce overfitting. However, recent advances in deep learning demonstrate that highly over-parameterized models can achieve superior generalization after surpassing the interpolation threshold. This paradigm shift has enabled systems such as AlphaFold, Aurora, Delphi-2M, and recommenders to model complex, high-dimensional relationships through contextual attention rather than global feature selection. The paper argues that higher education analytics remains largely reductionist, relying on limited variables such as GPA, demographics, and course completion rates to identify “at-risk” students. While interpretable, these approaches often fail to capture the dynamic and multidimensional nature of student success. In response, this study proposes a transition toward over-parameterized personalization, where students’ academic and behavioral histories are modeled as longitudinal high-dimensional sequences. Drawing parallels to commercial recommendation systems such as Amazon, Netflix, and YouTube, the paper explores how higher education can move from generalized early-warning systems toward adaptive “n-of-1” interventions. Importantly, the paper is conceptual rather than empirical: it develops a research agenda and a set of testable propositions, and it identifies the evaluation designs—temporally valid prediction protocols and causal intervention studies—by which the promise of over-parameterized personalization in higher education should be assessed before any claim of superiority can be made. Full article

The association of atrial fibrillation (AF) and neck of femur fractures (NOF) are common in old people, creating a complex clinical scenario with significant implications for morbidity, mortality, and healthcare systems. This narrative review explores the bidirectional relationship between AF and NOF, focusing on shared risk factors, pathophysiological links, and challenges in clinical management, and also reviews the benefit of an orthogeriatric model. Advanced age, frailty, osteoporosis, polypharmacy, and cardiovascular comorbidities predispose patients to both conditions, while AF itself increases fall risk through haemodynamic instability, syncope, and adverse effects of rate- or rhythm-controlling medications. Importantly, the physiological stress of hip fracture and subsequent surgery can precipitate new-onset or worsening AF via inflammatory, neurohormonal, and metabolic mechanisms. The main challenge for ortho-geriatricians lies in anticoagulation management and preoperative and postoperative management. While anticoagulation reduces thromboembolic risk in AF, it increases perioperative bleeding risk in patients with NOF, often leading to delays in surgery that are independently associated with poorer outcomes. This review examines the current evidence regarding perioperative anticoagulation strategies, timing of surgery, and postoperative resumption of therapy. In addition, the review examines important outcome parameters such as mortality, stroke, bleeding, length of hospital stay, and functional recovery. This highlights the importance of not only improving multidisciplinary care involving orthopaedics, cardiology, geriatrics, and anaesthesia to optimise outcomes, but also enhancing risk stratification. Standardised perioperative pathways and integrated geriatric–cardiac assessment may help mitigate complications. Therefore, understanding how AF and NOF interact is key to delivering holistic, patient-centred care for an increasingly elderly population in orthogeriatric wards. Full article

Background: Hyponatraemia is the commonest electrolyte disturbance encountered in older adults admitted with neck of femur (NOF) fracture. It is now recognised both as associated with fragility fracture and as an independent prognostic indicator for adverse post-operative outcomes. Methods: Narrative review of the literature, with emphasis on cohort studies, meta-analyses and mechanistic investigations pertinent to hip fracture in adults. Results: Admission hyponatraemia affects approximately 13–20% of NOF patients, twice the prevalence observed in age-matched community-dwelling elders and broadly comparable to general geriatric inpatients. A further 20–30% develop in-hospital, predominantly post-operative, hyponatraemia. Mild hyponatraemia (130–135 mmol/L) accounts for 75–85% of cases. Pathophysiology is multifactorial: hypovolaemia from the fracture haematoma, fasting and pre-admission “long lie”; drug effects (thiazides, selective serotonin reuptake inhibitors (SSRIs), proton pump inhibitors, carbamazepine, opioids); and non-osmotic arginine vasopressin (AVP) release driven by pain, nausea and peri-operative stress. Chronic hyponatraemia is hypothesised to contribute to fracture risk through three convergent mechanisms, direct sodium-dependent stimulation of osteoclastogenesis with AVP-mediated bone resorption, subtle cerebral dysfunction producing gait and attention deficits, and sarcopenia, although much of this mechanistic evidence derives from animal and in vitro studies rather than from patients with hip fracture. Hyponatraemia is reproducibly associated with longer length of stay, delayed surgery, and an adjusted 30-day mortality hazard of approximately 1.15–1.40. A dose–response relationship with severity is demonstrable; pre-operative correction has not been shown to improve outcomes in any randomised trial. Conclusions: Hyponatraemia in NOF fracture is consistently a consequence of the acute event and, at minimum, a robust marker of frailty and adverse prognosis. Whether it also causally contributes to fracture risk remains unproven, since the supporting human evidence is entirely observational and mechanistic, each contributing study carries methodological weaknesses that warrant caution, and no interventional study has established causality. Where hyponatraemia is mild and isolated, current evidence does not support delaying surgery; moderate and severe hyponatraemia warrant individualised assessment, with cautious correction proceeding alongside surgical planning rather than postponing it. Given the absence of interventional evidence, no correction strategy can yet be recommended to improve fracture or surgical outcomes. Prospective trials of targeted correction strategies and rehabilitation outcomes are overdue. Full article

Background: Mucopolysaccharidosis type IIIB (MPSIIIB, Sanfilippo syndrome type B) is a rare lysosomal storage disease caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU) enzyme, leading to progressive accumulation of heparan sulfate and severe neurological decline. MPSIIIB’s significant genetic heterogeneity presents a major barrier to developing broadly effective treatments and suggests a need for personalized therapeutic strategies. Methods: We established a personalized drug repurposing platform using high-content imaging with lysotracker dye as an indirect functional readout of lysosomal dysfunction to screen compounds that correct lysosomal defects in patient-derived fibroblasts. We screened 2807 compounds on cells from an MPSIIIB patient with a homozygous NAGLU p.Arg297Ter mutation. Hits that reduced lysosomal accumulation by at least 25% with minimal cytotoxicity were validated and subsequently tested for efficacy in fibroblasts from a second patient with a different, compound heterozygous NAGLU genotype. Results: The primary screen yielded 72 hits (2.6% hit rate), with 10 confirmed in dose–response assays. Notably, four clinically approved drugs—baclofen, dextrose, epalrestat and moxifloxacin—reduced lysosomal accumulation in the index patient’s cells. However, none of these four drugs were effective in the second patient’s cells, demonstrating a profound patient-specific effect. Only one non-clinical compound, 6-chlorothymol, showed a trend toward activity in both cell lines. Conclusions: Our study demonstrates a feasible framework for conducting rapid, N-of-1 drug repurposing screens for rare diseases. While we identified four promising candidates for the index patient, the lack of efficacy in a second patient cell line underscores that genetic heterogeneity may preclude a “one-size-fits-all” approach for MPSIIIB. These findings support the integration of individualized drug screening as a potential precision-medicine strategy, offering a potential path toward patient-specific therapies for rare diseases rather than traditional drug development. Full article

Background and Objectives: Muscle symptoms are the most visible adverse event attributed to statins, but terminology is often imprecise. Most patients report myalgia or nonspecific aches, whereas objective myopathy, inflammatory or necrotizing myositis, rhabdomyolysis, and anti-HMGCR immune-mediated necrotizing myopathy are uncommon and clinically distinct entities. To provide a clinically oriented narrative synthesis of statin-associated muscle symptoms (SAMS) and severe statin-associated myotoxicity, and to propose a practical prevention, evaluation, and management algorithm. The classification of muscle events is used to standardize terminology and avoid diagnostic confusion, not to create a new formal taxonomy. Materials and Methods: A clinically oriented narrative review was performed using PubMed, Google Scholar, and major society documents published from January 2021 to April 2026. Eligible sources addressed SAMS, statin myopathy/myositis, rhabdomyolysis, anti-HMGCR immune-mediated necrotizing myopathy, nocebo/drucebo effects, pharmacogenetics, drug interactions, diagnosis, or management. The final evidence set comprised 55 verifiable sources, including blinded randomized or n-of-1/crossover evidence; meta-analyses; clinical statements and reviews; pharmacovigilance analyses; pharmacogenetic guidance; mechanism-focused reviews; anti-HMGCR series; and lipid-lowering guideline/treatment studies. Because the review was narrative, no pooled estimate or formal PRISMA screening log was generated. Results: Blinded evidence indicates only a small absolute excess of muscle pain with statins, concentrated mainly in the first year of therapy, and that most muscle symptoms reported during statin therapy are not pharmacologically caused by the statin. N-of-1 and crossover trials show that symptom intensity is often similar during statin and placebo periods, consistent with an important nocebo/drucebo contribution. Severe muscle toxicity can nevertheless occur, especially when systemic statin exposure is increased by a high dose, interacting drugs, frailty, renal or hepatic impairment, hypothyroidism, transporter or metabolic genotypes, or intense unaccustomed exercise. Statin choice matters chiefly through dose, pharmacokinetics, and interaction burden. Conclusions: SAMS are common as reported clinical problems, but confirmed statin-caused muscle injury is substantially less frequent than routine clinical attribution suggests. Permanent discontinuation should be reserved for carefully assessed cases. A structured approach—baseline risk assessment, selective CK measurement, exclusion of alternative causes, correction of modifiable risks, dechallenge/rechallenge, statin switching, dose reduction, and combination with non-statin therapy—preserves cardiovascular benefit while protecting the rare patient with genuine toxicity. Full article

Background/Objectives: Metastatic Prostate Cancer (mPCa) is generally treated with systemic therapy. Many of these treatments, particularly androgen ablation, are not curative and cause substantial morbidity. Oligometastasis is defined as a limited number of metastatic deposits, whose disease does not seem to progress to a widespread distribution of cancer. There have been some reports of trials of localized treatment of PCa oligometastatic disease with curative intent. We herein report a case of oligometastatic prostate cancer treated primarily with surgical removal of metastases, which has no evidence of active disease twenty years post-operatively. Methods: Extensive retrospective chart review, immunohistochemical staining, growth rate calculations, and imaging studies were performed to trace the progression of this patient’s disease course. Results: A detailed investigation of biochemical markers of recurrence revealed normal-low prostate specific antigen (PSA) despite advanced disease, early rather than metachronous dissemination of metastases to distant sites, and hypoxia-conditioned phenotypic plasticity and memory in disseminated tumor cells (DTCs). Conclusions: This rare outlier case of oligometastatic prostate adenocarcinoma challenges traditional linear models of metastatic progression and clinical reliance on PSA as a marker for PCa detection and treatment in advanced cases. By investigating key questions regarding the identity, timing, and trajectory of DTCs, we propose a biologically informed narrative of this patient’s disease progression and a reconsideration of metastases directed therapy (MDT) of oligometastases as primary therapy in select patients. Full article

Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype–phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies—customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches—including long-read sequencing, AI-driven oligo design, and improved delivery—promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases. Full article

Background: In biosimilar studies, assessing the switchability and interchangeability of biosimilars with their reference products is essential for ensuring reliable clinical evaluation. This study explores optimal trial design strategies incorporating balanced and uniform structures to enhance statistical efficiency in treatment effect under a carryover setting. Methods: Using a linear mixed-effect model for log-transformed responses, we conducted a theoretical variance-based evaluation of all possible two-treatment switching designs in three-period and four-period crossover trials, considering settings with and without carryover effects. A total of 247 distinct three-period designs and 65,519 distinct four-period designs were enumerated and classified according to structural properties, with particular attention to those incorporating a non-switching arm (NSA). Results: SBUwP-NSA (Strongly Balanced Uniform-within-Period designs with a Non-Switching Arm) consistently achieved the minimum variance for treatment effect estimation in both carryover and no-carryover settings. In the absence of carryover effects, UwP-NSA (Uniform-within-Period designs with a Non-Switching Arm) attained equivalent efficiency. In contrast, commonly used dedicated switching designs exhibited substantially lower relative efficiency, achieving as little as 50–55% of the efficiency of the optimal designs, depending on carryover assumptions. Conclusions: This comprehensive theoretical evaluation demonstrates that incorporating strong balance and uniformity properties can yield substantial efficiency gains in switching studies. The results provide quantitative guidance for selecting efficient crossover designs, enabling improved estimation precision while maintaining practical relevance for interchangeability and switching assessments in biosimilar research. Full article

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

Background/Objectives: Psychological stress is a common problem but hard to universally treat. Personalized (N-of-1) trials assess a participant’s response to multiple specific interventions. Though personalized (N-of-1) trials have been used in select interventions, no prior research has examined whether N-of-1 designs provide superior stress reduction relative to standard of care. Methods: Participants were randomized to personalized N-of-1 (N = 106) or standard-of-care (N = 106) arms for three stress-management interventions (mindfulness meditation; yoga; brisk walking). All participants completed ecological momentary assessments (EMA) of stress three times daily for 18 weeks (2-week baseline, 12-week intervention, 2-week assessment, and 2-week follow-up). After the intervention, participants in the N-of-1 arms received a personalized report identifying which intervention worked best for them. All participants chose one intervention to manage their stress during follow-up. The primary outcome was change in perceived stress between baseline and follow-up. Results: Participants in the personalized (N-of-1) arms did not report significantly reduced EMA stress levels relative to standard-of-care (p = 0.496), though the effect was stronger among N-of-1 participants who chose the stress-management intervention recommended by their report [B(SE) = −0.67(0.34); p = 0.049]. Conclusions: Results show the potential of personalized (N-of-1) trials to provide individuals with information unique to them to help identify interventions for stress management. However, many participants in the personalized trial arms did not choose the intervention recommended by their trial. Additional research is required to refine how personalized (N-of-1) trials are conducted and how trial results are reported to participants to ensure the maximal benefit of these trial designs. Full article

The role of the metal valence state on the surface properties of metal-loaded clay minerals in the adsorption/oxidative degradation of an antibiotic was investigated. Transitional metal cations and their zero-valent counterparts such as Fe⁰, Ni⁰, Co⁰ and Cu⁰ supported on montmorillonite were comparatively investigated for their interactions during adsorption and toxicity tests of antibiotic norfloxacin (NOF). UV-Vis spectrophotometric and Fourier transform infrared (FTIR) spectroscopic analyses confirmed the involvement of the hydroxyl and carboxyl groups and/or piperazinyl nitrogen of NOF in the complexation with metal cations. Ecotoxicological assessment using aquatic plants Lemna minor showed that the metal cations reduce the bioavailability of the organic pollutant and that the zero-valent metals display higher toxicity due to their specific interaction with NOF and clay mineral surface. This evaluation will provide insights into potential environmental impacts of the co-occurrence of antibiotics and metals and will certainly contribute to correlating the safety of the water treatment by assessing the residual toxicity and its fluctuations. Full article

Emergency Departments (EDs) are high-pressure environments that place significant psychological and physiological stress on both patients and healthcare staff. Despite increasing awareness of stress-related impacts, proactive stress management interventions have limited uptake in healthcare. This proof-of-concept study will evaluate WeCare: a 6-week, wearable-integrated, self-guided program grounded in a “Learn–Track–Act” framework to support stress regulation, resilience, and wellbeing. The study will examine four key aspects of implementing the program: (1) feasibility, (2) acceptability and usability, (3) preliminary clinical effectiveness (self-report and physiological outcomes), and (4) preliminary economic impacts. Using a mixed-methods, multiple-baseline N-of-1 design, the program will be trialled with up to 32 participants across four ED-exposed groups: patients with non-severe or severe injuries, patients with acute medical presentations, and ED staff. The intervention includes digital psychoeducation, continuous biofeedback via a smart ring, personalised guidance, and evidence-based self-regulation strategies. Assessments will include standardised questionnaires combined with continuous physiological monitoring via a smartwatch, and interviews. Quantitative outcomes include heart rate variability, sleep patterns, perceived stress, wellbeing, healthcare use, and time off work. Qualitative interviews will explore user experience, usability, and perceived barriers. The findings will inform the refinement of the intervention and co-design of a larger-scale trial, contributing valuable evidence to support low-cost, wearable-enabled proactive mental healthcare in high-stress healthcare environments. Full article

Background: To improve personalized behavioural interventions for people with stroke, it is crucial to understand which factors influence fluctuations in sedentary behaviour. This study aimed to explore the association between health and well-being determinants and daily variability in sedentary behaviour over time within community-dwelling people with stroke. Methods: An n-of-1 study design was conducted to examine the associations between determinants and sedentary behaviour during the RISE-intervention randomized multiple baseline study. The percentage of sedentary behaviour was measured daily with the ActivPAL activity monitor. The Visual Analogue Scale scores of the determinants were collected with diaries. Dynamic regression modelling (time-series analysis) was performed, starting with univariable and followed by multivariable linear regressions. Results: The analysis included twelve community-dwelling people with stroke (median age 65 years), with daily sedentary behaviour ranging from 55.5 to 81.4 percent. Objectively measured sleep length was positively associated with the percentage of sedentary behaviour in three participants (p = 0.001, p < 0.0001, and p = 0.045), and negatively associated in one participant (p = 0.002). Subjective sleep length (p = 0.016), fatigue (p = 0.013) and pain (p = 0.0098) were exclusively associated with the percentage of sedentary behaviour in one participant. No significant associations were found for sleep quality, happiness, stress or time pressure in five participants. Conclusions: The findings indicate inconsistent association patterns between health and well-being determinants and the day-to-day variability of sedentary behaviour across participants. This highlights the need for a personalized approach, as the determinants associated with the daily variability of sedentary behaviour in one individual may differ from those influencing another individual. Full article