Search Results (756)

The Ohon Continuous Casting is the main method for preparing single crystal copper wire, and it is also the research hotspot at present, but it is difficult to directly cast ultrafine single crystal copper wire (diameter < 0.05 mm). The copper wire obtained by continuous casting must be drawn and deformed before it can be used in practice, but this will bring a series of problems such as single crystal structure destruction and conductivity deterioration. Directional heat treatment technology can control the direction of heat flow at a low temperature, realize the directional migration of grain boundaries in the recrystallization process, and form columnar crystals or single crystals, which is of great significance for improving electrical conductivity. In this paper, the directional heat treatment method was used to investigate the microstructure evolution and influencing factors of pure copper wire, the process parameters were optimized, and the conductivity of pure copper wire was measured. It was found that the conductivity of pure copper wire increased by 5% when the heating temperature was 750 °C and the withdrawing velocity was 15 μm/s, which laid a foundation for the improvement of conductivity of pure copper wire. Full article

EEG remains the primary diagnostic tool for evaluating seizures in children, with interictal epileptiform discharges (IEDs) serving as key biomarkers of epileptogenic activity. However, not all IEDs have the same prognostic significance. Variations in IED topography, morphology, frequency, and timing influence outcomes in pediatric epilepsy. The developing brain’s maturation affects IED location and features, creating age-specific patterns with distinct implications. For example, occipital and midline IEDs are common in young children, with midline IEDs strongly linked to increased seizures and developmental delay than control patients. Morphological features provide additional prognostic stratification. While centrotemporal IEDs with tangential dipoles are well-established as favorable prognostic markers, IEDs exhibiting tangential dipoles in any brain region are associated with more benign clinical courses than control patients. Conversely, positive sharp waves persisting beyond the neonatal period signal less favorable prognosis, including developmental delay, abnormal neurological examination, and structural brain abnormalities. Additionally, IEDs occurring on ripples have been shown to serve as more reliable interictal biomarkers of the epileptogenic zone than IEDs or ripples alone. Topography, frequency and sleep-state dependence also carry clinical significance, as frequent IEDs during slow-wave sleep may impact cognition. Furthermore, the temporal context of IED occurrence during seizure onset, treatment, activation procedures, medication withdrawal, or after epilepsy surgery provides valuable prognostic information. Recognition of these nuanced electrophysiological distinctions enhances clinicians’ ability to predict clinical trajectories and optimize long-term management strategies. Full article

Background: Pyridoxine-dependent epilepsy (PDE) is a rare disorder characterized by seizures resistant to conventional treatments but responsive to pyridoxine therapy. Typically caused by biallelic variants in ALDH7A1, PNPO, or PLPBP, a few patients present a similar clinical phenotype but without confirmed molecular diagnoses. We report a child with a 13-year PDE diagnosis and normal intellectual development, whose seizures recurred after pyridoxine withdrawal but resolved with reintroduction, despite unremarkable whole-exome sequencing results. Methods: Following negative results from WES, optical genome mapping (OGM) and whole-genome sequencing (WGS) were performed to highlight any potential structural variants involving known PDE-associated genes. Results: OGM and WGS revealed a recurrent 16p11.2 BP4-5 duplication, inherited from his healthy father, along with a de novo chromothripsis-type unbalanced t(1;18)(p22.3;q12.3), affecting several genes not currently associated with epilepsy (RIT2, PIK3C3, COL24A1, LRRC8D, DIPK1A, and DPYD), with RIT2 being a plausible candidate for the neurological phenotype due to its neuron-specific expression along with a likely reshuffling of topologically associating domains (TADs) involving SYT4, an epilepsy-candidate gene. Discussion: While the molecular data do not pinpoint a single gene or locus as the cause of seizures in this case, a key aspect of our patient’s phenotype is true pyridoxine dependence, rather than just pyridoxine responsiveness. We propose that the genomic complexity associated with the chromothriptic t(1;18) and the 16p11.2 BP4-5 duplication may create a unique metabolic environment in which pyridoxine-dependent pathways are disrupted through unconventional mechanisms. The preservation of cognitive function in our case has been observed in small groups of PDE patients, especially those diagnosed and treated early. This may indicate a distinct phenotypic subgroup that warrants further genetic investigation. Full article

Purpose: The recurrence rate and related risk factors of infantile hemangiomas after treatment discontinuation remain concerns. We aim to evaluate the risk of recurrence after termination of oral propranolol for IHs and its associated risk factors. Methods: The Embase, PubMed, Web of Science, and Cochrane Central databases and clinicaltrials.gov were searched comprehensively for relevant studies from the inception of this study to November, 2024. Two independent reviewers conducted the data extraction and quality assessment. This review protocol was registered in the PROSPERO database (CRD42024589110). Results: A total of 1662 patients in 10 studies met the eligibility criteria, which was predominantly retrospective in design. All participants were infants diagnosed with infantile hemangiomas who received oral propranolol therapy; the majority of patients received propranolol treatment for at least six months. The results revealed that the pooled recurrence rate was 20% (95% CI: 15–24%), and 11% of patients required retreatment with propranolol (95% CI: 9–14%). Female sex (OR = 1.76, 95% CI: 1.20–2.59) and IHs located on the head and neck (OR = 2.40, 95% CI 1.59–3.63) increased the risk of recurrence. In contrast, IH type, lesion distribution, duration of therapy, and treatment initiation age showed no significant associations. Additionally, one trial included in this review reported that continued medication for one month after the lesion reaches its maximum degree of regression might increase the risk of recurrence as compared to three months of maintenance (OR = 1.86, 95% CI 0.98–3.5); however, the evidence is limited and preliminary. Conclusions: Female sex and IHs located on the neck or head contribute to the recurrence of IHs after termination of treatment. In addition, the type of IH and withdrawal criteria may influence recurrence risk, although evidence remains limited. Thus, optimizing treatment protocols, including individualized therapy duration and discontinuation strategies, may help reduce recurrence rates. Full article

Background/Objectives: The growing intersection between nyaope use and HIV infection constitutes a critical public health problem that undermines efforts to achieve universal access to HIV treatment in South Africa. Nyaope use is strongly associated with the increased risk of HIV of transmission. A significant amount of new HIV infections was linked to substance use through sharing of injectable needles. Despite significant progress made to increase public awareness and increase accessibility to HIV services, little is known about how addiction, stigma, and discrimination influence access to HIV treatment among homeless individuals who nyaope. This study explored the hurdles of accessing HIV treatment among people who use nyaope and are homeless in Mogale City, Gauteng Province. Methods: An exploratory descriptive qualitative research approach was employed among people who are homeless, living with HIV and using nyaope (PHHIVN) in Mogale City, between May and August 2024. Data were collected utilizing in- depth interviews in English, isiZulu and Setswana languages. Purposive sampling technique was followed to select participants, and a sample size of 25 participants was reached with a mean age of 32.28 and SD = ±5.54 years, of whom 21 (84%) were male, 3 (12%) were female and 1 (4%) identified as other. Audio recordings were transcribed, translated, and analyzed following inductive thematic analysis. Results: Social exclusion and fractured support system, prioritization of drug use, nyaope dependency, withdrawal symptoms, negative peer influence, socioeconomic factors and misconception about the interaction between nyaope and HIV treatment were reported as some of the main hurdles of accessing HIV treatment among PHHIVN in Mogale City, Gauteng Province. Conclusions: It is therefore concluded that access to HIV treatment among PHHIVN in Mogale City, Gauteng Province, remains a serious public health concern influenced by various hurdles. The development of tailored interventions to improve access and adherence to HIV treatment among this population group has potential to enhance the uptake of HIV treatment. Full article

Discontinuing active oncological treatment and initiating palliative care is a critical moment in cancer care, requiring oncologists to address complex clinical, ethical, and emotional challenges. This narrative review aims to provide clinicians with practical guidance for conducting conversations about treatment discontinuation and transitioning patients to palliative or hospice care. Drawing from current clinical guidelines, empirical research, and expert perspectives, the article reviews evidence-based communication strategies and frameworks, including the SPIKES protocol, Ask–Tell–Ask, the WHO model, and the disclosure model. The article also explores the clinical, functional, psychosocial, and ethical criteria relevant to treatment withdrawal decisions, as well as the timing and structure of end-of-life discussions. A practical algorithm is proposed, synthesizing key principles into a step-by-step guide for use in daily oncology practice. The algorithm supports clinicians in balancing medical indications with patient values and preferences, fostering shared decision-making and maintaining therapeutic relationships even in the most difficult circumstances. The review concludes that structured yet flexible communication enhances patient understanding, reduces unnecessary interventions, and improves the quality of end-of-life care. By promoting patient-centered care and timely palliative integration, this article offers oncologists a clear and adaptable approach to one of the most sensitive aspects of cancer care. Full article

Background: Childhood cancer survivors (CCSs) are at heightened risk of long-term neurocognitive and emotional difficulties that can affect educational attainment, social participation, and overall quality of life. These outcomes vary across developmental stages and are influenced by treatment modality, age at diagnosis, and central nervous system (CNS) involvement. Methods: A comprehensive literature search was conducted in PubMed, Scopus, PsycINFO, and Web of Science for articles published between January 2000 and June 2024. Search terms included combinations of “childhood cancer survivors,” “neurocognitive outcomes,” “executive function,” “emotional regulation,” and related MeSH terms. Inclusion criteria required peer-reviewed studies assessing CCS using standardized neuropsychological or emotional measures. Results: Evidence indicates persistent deficits in processing speed, working memory, and higher-order executive functions, with additional challenges in attention and memory. Emotional difficulties, including anxiety, depression, and social withdrawal, were prevalent and often co-occurred with cognitive impairments. Developmental timing of cancer and treatment was a key determinant of outcome. Family functioning, school reintegration support, and broader social environments emerged as important moderators of resilience. Conclusions: CCSs face complex, interrelated cognitive and emotional challenges that warrant early identification and ongoing, developmentally tailored intervention. Integrated approaches combining cognitive remediation and psychosocial support appear most effective. Future research should prioritize longitudinal designs, multi-informant assessments, and culturally sensitive frameworks to inform targeted prevention and rehabilitation strategies. Our synthesis highlights that deficits in processing speed and working memory are most pronounced following CNS-directed therapies during early developmental stages, whereas emotional vulnerabilities such as anxiety and social withdrawal often emerge later in adolescence. Interventions combining cognitive remediation, targeted psychosocial support, and structured school reintegration show the strongest evidence for improving adaptive outcomes. Coordinated survivorship care across healthcare, educational, and family systems is essential to sustain developmental recovery. Full article

The emergence of drug-resistant cytomegalovirus (CMV) complicates viral response to therapy. We present two cases of solid organ transplant (SOT) recipients, highlighting the reversion of UL97 mutations associated with val(ganciclovir) resistance. Patient 1, a heart transplant recipient, initially received pre-emptive treatment with val(ganciclovir), followed by foscarnet for recurrent CMV episodes. Mutations A594V in the UL97-kinase gene and V715M in the UL54-polymerase gene were detected. He developed CMV colitis and was then treated with maribavir. After discontinuing val(ganciclovir), genotyping revealed no resistance mutations. Following CMV DNA suppression, secondary prophylaxis with letermovir and val(ganciclovir) was initiated. Patient 2, a double-lung transplant recipient, experienced several CMV episodes. Initially treated with val(ganciclovir), he developed the L595S mutation in the UL97 kinase gene, conferring resistance. Therapy was then switched to foscarnet, which was suspended due to renal failure, and then to maribavir. Subsequently, the H411Y mutation in the UL97 was detected, conferring maribavir resistance, while val(ganciclovir) mutation was no longer detectable. He was then treated with val(ganciclovir) and letermovir, achieving undetectable CMV DNA, and then continued letermovir alone as prophylaxis. Detecting gene mutations that confer drug resistance is crucial for managing antiviral therapy when virological response is lacking. In our cases, the reversion of (va)ganciclovir-resistance mutations occurred after drug withdrawal, a previously unreported finding. Full article

Accurate understanding of a mental disorder’s symptomatology is essential for valid diagnosis, differential assessment, and treatment planning. It is therefore remarkable that failure to speak is defined as the only symptom in the diagnostic criteria of selective mutism (SM) in current classification systems. This narrow definition may not reflect the full range of difficulties experienced by affected children. This systematic review aimed to synthesize empirical findings on the broader symptomatology of SM across diverse study designs, informants, and assessment methods. Following PRISMA guidelines, we searched PubMed, Web of Science, and APA PsycNet, leading to 82 studies with participant samples (beyond single case reports) included in the final analysis. Results indicated that social and unspecific anxiety were the most frequently assessed and consistently identified symptoms. However, additional features—including withdrawal, depressive symptoms, social skill deficits, and, in qualitative accounts, externalizing and oppositional behaviors—were also documented. The observed symptom diversity varied notably across assessment methods and informants. Our findings support a multisymptomatic understanding of SM and suggest that failure to speak alone do not fully account for its clinical presentation. A more differentiated conceptualization may enhance diagnostic precision, inform individualized intervention strategies, and contribute to discussions on refining diagnostic frameworks. Full article

Background/Objectives: The drug development response to the unique pharmacology of fentanyl, which drives the current opioid epidemic, has primarily focused on increasing naloxone doses and employing longer-acting antidotes. While having lower withdrawal liability, the commonly perceived disadvantage of naloxone is its reduced effectiveness against re-narcotization or “fentanyl rebound,” due to a significant mismatch between its half-life (t_1/2) and that of fentanyl. Methods: We conducted a pharmacokinetic profile (PK) crossover study in fentanyl-sedated dogs to assess naloxone (NX) and its lipophilic prodrug (NX90) with regard to fentanyl PK and re-narcotization risk. Results: Our findings showed that naloxone redistributed fentanyl into the plasma, with correlating (R² = 0.9121) fentanyl and naloxone plasma levels when seven plasma samples per dog for each treatment (including placebo) were analyzed. This redistribution led to reductions in fentanyl’s volume of distribution at steady state (V_ss: 11.8 ± 1.7, 8.4 ± 2.4, and 8.7 ± 2.6 L/kg), mean residence time (MRT: 19.9 ± 1.8, 18.6 ± 7.2, and 16.2 ± 8.8 min), and half-life (t_1/2: 14.3 ± 1.9, 13.0 ± 4.9, and 11.2 ± 6.1 min) after the administration of a placebo, NX, and NX90, respectively. Additionally, we observed that the delay in the transient re-sedation (re-narcotization) of the dogs correlated (R² = 0.794) with naloxone’s exposure (AUC_inf). These data suggest that (i) the displacement of fentanyl into a metabolically active compartment and (ii) the delay in re-narcotization risk are both independent of naloxone’s half-life and are likely to be more effectively achieved with higher doses of naloxone. Conclusions: Combined with the lower risk of precipitating protracted withdrawal, these findings support the clinical use of higher-dose naloxone over longer-acting antidotes for reversing fentanyl-related overdoses. Full article

Progesterone (P4) withdrawal is the key trigger for labour onset. Labour is a sterile inflammatory process involving monocyte infiltration, differentiation into M1 or M2 macrophages (Macs) and contributing to the inflammatory milieu in the uterus. Premature leukocyte influx may lead to preterm birth. Inflammatory stimuli induce intracellular progesterone (P4) withdrawal in myometrial cells (MYOs) through activation of P4 metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase (20α-HSD). We hypothesized that (1) the pro-inflammatory M1-Macs induce 20α-HSD in MYO, which causes P4 withdrawal and MYO contractility, and (2) IL-1α produced by M1-Macs mediates the effect of M1-Macs on intracellular P4 withdrawal in MYO. Human myometrial biopsies from term pregnant women in labour (TL) and not in labour (TNL) revealed higher IL-1α in TL, with M1-Macs in TNL expressing more IL-1α than MYO. In vitro study shows (1) higher expression of IL-1α in M1-Macs compared to M2-Macs; (2) treatment of MYO with IL-1α or M1-Macs increased 20α-HSD and contractility; and (3) blockade of IL-1α, AP-1 transcription factors, or co-treatment with non-metabolizable progestin R5020 inhibit these effects. Our findings highlight the role of tissue-resident M1-Macs in regulating intracellular P4 metabolism and suggest that M1-Macs-derived IL-1α may facilitate P4-withdrawal and uterine contractility associated with labour onset. Full article

Objectives: Prolonged opioid use leads to tolerance and hyperalgesia in patients with chronic pain. Apart from an increase in pain, opioid use also leads to several other adverse effects. Nevertheless, the prevalence of opioid use as a treatment for chronic pain remains high, and opioid withdrawal interventions deserve more attention. This study evaluates the effects of a guideline for an opioid withdrawal intervention method that is nested in cognitive behavioral treatment (CBT) and is specifically for patients with a history of long-term opioid use and chronic pain. Methods: We conducted a clinical, exploratory, and mixed-methods study involving pre- and post-measurements on opioid use and health-related quality of life (SF-36), as well as a qualitative analysis of patient experiences (interviews) to evaluate the program. Results: A total of 29 patients were included in the study; 23 of these patients no longer used opioids, and some continued withdrawal under the guidance of their general practitioner. Quality of life improved in all domains, including the amount of pain experienced. No patients reported increased pain levels, and most experienced significantly fewer adverse side effects. Patient satisfaction was high, with no negative long-term side effects of the intervention reported. Conclusions: In light of the results of this study, it is important to address opioid use in patients with chronic pain. There are strong arguments in favor of motivating patients to withdraw from using opioids to treat chronic pain, which can be achieved in combination with CBT. Full article

Objectives: The purpose of this study was to analyze the effect of daily intake of cladribine tablets on the course of multiple sclerosis (MS) while monitoring for 1–4 years during and after the course in several neurological clinics from different regions of the Russian Federation. Materials and Methods: Information was collected on 235 patients from 12 neurological clinics and regional centers for MS, who were observed for an average of 3.4 years after starting treatment with cladribine. Results: An independent analysis of cases of prescription of cladribine in tablets showed that the reason for prescription of cladribine was highly active MS (HAMS) in 159 patients (67.7%), rapidly progressive MS (RPMS) in 20 patients (8.5%), active remitting MS in 50 patients (21.3%) and secondary progressive MS (SPMS) with exacerbations in 6 (2.5%). Among them, only 12 patients (5.1%) had not previously received DMTs, i.e., in these cases, the drug was prescribed as the first DMT. In total, 22 patients had previously received natalizumab, 5—ocrelizumab, and in 1 case—fingolimod. The remaining 207 patients were crossed over from the first-line DMTs. In all cases, there was a decrease in the frequency of exacerbations during and after the completion of the course of cladribine. Exacerbations between the first and second courses of cladribine were noted in 36 patients (15.3% of all treated), almost half of the cases—those who previously received natalizumab (17 exacerbations, or 47.2% of all exacerbations between the 1st and 2nd courses of cladribine), and in 3 cases—from ocrelizumab (in 60% of all patients crossed over from ocrelizumab). During 4 years of follow-up after a full course of cladribine, exacerbations were in 14 patients (6% of all patients included in the analysis), of which in 6 cases—after crossover from natalizumab. Discussion and Conclusions: The data obtained are generally consistent with the results of meta-analyses and reviews published recently, but high probability of exacerbations in patients who were crossed over from second-line drugs such as natalizumab and ocrelizumab were seen. The crossover from natalizumab is carried out more often due to the increased risk of developing progressive multifocal encephalopathy (PML). It is likely that the restoration of MS activity after the withdrawal of natalizumab is quite frequent, cladribine tablets were not able to fully prevent this. Such a crossover does not seem to be optimal, unlike the crossover from first-line DMTs. If such a crossover is still planned, it could be performed within 4 weeks after stopping natalizumab. Full article

Porcine extraintestinal pathogenic Escherichia coli (ExPEC) is a significant zoonotic pathogen with escalating antimicrobial resistance, underscoring the urgent need for novel therapeutics. This study aimed to investigate the therapeutic potential and mechanism of action of the antimicrobial peptide Protegrin-1 (PG-1) against a multidrug-resistant porcine ExPEC strain, PCN033. The minimal inhibitory concentration (MIC) was determined, and resistance stability was assessed through serial induction and withdrawal passages. Hemolytic activity was evaluated to gauge selectivity. A murine infection model was utilized to assess in vivo efficacy, bacterial load reduction, cytokine modulation, and histopathology. Comparative spleen transcriptomic analysis was performed to elucidate global host responses. PG-1 exhibited potent bactericidal activity (MIC = 32 μg/mL) and maintained its efficacy over multiple passages, demonstrating no induced resistance. It showed acceptable hemolytic activity and significantly improved survival, reduced bacterial loads in multiple organs, and mitigated tissue damage in mice. Transcriptomics revealed PG-1 treatment broadly tempered infection-induced hyperinflammatory responses, including NF-κB, MAPK, and TNF signaling pathways, and counteracted metabolic reprogramming. The findings conclude that PG-1 effectively integrates direct, resistance-resistant bactericidal activity with multimodal immunomodulation, representing a superior therapeutic strategy that simultaneously eliminates pathogens and restores immune homeostasis, offering a promising alternative to conventional antibiotics against MDR ExPEC infections. Full article

Medetomidine, a potent central acting α2 agonist, has emerged as a fentanyl adulterant in the non-medical opioid supply. Its use has been linked to a novel withdrawal syndrome that is often resistant to conventional treatment protocols. Four cases are presented exemplifying extreme, but increasingly common forms of this withdrawal syndrome. A literature review is provided demonstrating both the paucity of available literature as well as potential avenues for treatment and future research. As adulterants continue to proliferate in the illicit drug supply, clinicians should anticipate atypical withdrawal phenotypes and consider early intervention. Full article