Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Easily misdiagnosed X-linked adrenoleukodystrophy.

BACKGROUND: Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD. METHODS: We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics. RESULTS: Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum. CONCLUSIONS: Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

Clinical outcomes of multidrug-resistant tracheobronchial tuberculosis receiving anti-tuberculosis regimens containing bedaquiline or delamanid.

The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P < 0.001). Treatment with bedaquiline or delamanid were identified as independent predictors of culture conversion at 2 months (bedaquiline group: aOR = 13.417, 95% CI 4.067-44.260, delamanid group: aOR = 9.333, 95% CI 2.498-34.878) or 6 months (bedaquiline group: aOR = 13.333, 95% CI 3.379-52.610, delamanid group: aOR = 5.000, 95% CI 1.357-18.426) of treatment through multivariable logistic regression analyses. The delamanid group showed better improvement in lumen stenosis compared to bedaquiline. Regimens containing bedaquiline or delamanid may accelerate the culture conversion during the early treatment phase in multidrug-resistant tracheobronchial tuberculosis, and delamanid appears to have the potential to effectively improve airway stenosis.

Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy.

This was a single-arm, multicenter, open-label phase I trial. Lentiviral vectors (LV) carrying the ABCD1 gene (LV-ABCD1) was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy (CCALD), and multi-site injection was performed. The injection dose increased from 200 to 1600 µL (vector titer: 1×109 TU/mL), and the average dose per kilogram body weight ranges from 8 to 63.6 µL/kg. The primary endpoint was safety, dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein. A total of 7 patients participated in this phase I study and were followed for 1 year. No injection-related serious adverse event or death occurred. Common adverse events associated with the injection were irritability (71%, 5/7) and fever (37.2 â„ƒ-38.5 â„ƒ, 57%, 4/7). Adverse events were mild and self-limited, or resolved within 3 d of symptomatic treatment. The maximal tolerable dose is 1600 µL. In 5 cases (83.3%, 5/6), no lentivirus associated antibodies were detected. The overall survival at 1-year was 100%. The ABCD1 protein expression was detected in neutrophils, monocytes and lymphocytes. This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo; even the maximal dose did not increase the risk of adverse events. Furthermore, the direct LV-ABCD1 injection displayed low immunogenicity. In addition, the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed. This study has been registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, registration number: ChiCTR1900026649).

Exhaustive clinical examination of etiology and initial response to first-line treatment in 577 children with infantile epileptic spasm syndrome children: A 5-year retrospective observational study.

OBJECTIVE: Employing whole-exome sequencing (WES) technology to investigate the etiology of infantile epileptic spasm syndrome (IESS), and determining whether different etiologies exhibit phenotypic variations, while elucidating the potential associated factors, might improve short-term responses to first-line treatment. METHODS: We retrospectively evaluated patients with IESS admitted for treatment between January 2018 and June 2023. Clinical phenotypic differences among etiological classifications and clinical manifestations were analyzed. Variable selection using the best subset method was performed, followed by logistic regression analysis to identify the factors influencing treatment response. RESULTS: A total of 577 patients were included; 412 completed trio-WES. Magnetic resonance imaging abnormalities were detected in 387 patients (67.1%). Patients with etiology as structural abnormalities were likelier to have non-spasms at the initial seizure onset. A total of 532 patients completed the first-line treatment; 273 patients received it for the first time at our hospital (initial response rates: 30.1% and 42.1%, respectively). The response group had a lower proportion of early-onset seizures (≤3 months) than the no-response group (11.3% vs. 23.7%, p < 0.01 and 11.3% vs. 21.5%, p = 0.03, respectively). Logistic regression analysis indicated that earlier initiation of first-line treatment was associated with a higher likelihood of an initial response. However, the etiological classification did not have a significant impact on the initial response. INTERPRETATION: IESS patients with structural abnormalities are more likely to present with non-spasm seizures at initial onset. Early initiation of first-line treatment is crucial; however, initial responses may be less favorable when seizures occur in early infancy.

Efficient optimization of an accelerator neutron source for neutron capture therapy using genetic algorithms.

BACKGROUND: In recent years, genetic algorithms have been applied in the field of nuclear technology design, producing superior optimization results compared to traditional methods. They can be employed in the design and optimization of beam shaping assemblies (BSA) BSA to obtain the desired neutron beams. But it should be noted that the direct combination of Monte Carlo methods with genetic algorithms requires a significant amount of computational resources and time. PURPOSE: Design and optimize BSA more efficiently to achieve neutron beams that meet specified recommendations. METHODS: We propose an approach of NSGA II with crucial variables which are identified by multivariate statistical techniques. This approach significantly reduces the problem sizes, thus reducing the time required for optimization. We illustrate this methodology using the example of BSA design for AB-BNCT. RESULTS: The computational efficiency has tripled with crucial variables. By using NSGA II, we obtained optimized models conforming to both the new and old version IAEA BNCT guidelines through a single optimization process and subjected them to phantom analysis. The results demonstrate that models obtained through this method can meet the IAEA recommendations with deep advantage depth (AD) and high absorbed ratio (AR). CONCLUSION: The genetic algorithm with crucial variables displays tremendous potential in addressing BSA optimization challenges.

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1.

Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor. In experimental OA mice, miR-350-3p was increased in synovium and cartilage, while intra-articular injection of antagomir-350-3p inhibited the increase of miR-350-3p and alleviated cartilage degeneration and senescence. Further studies showed that macrophage-derived ectosomal miR-350-3p promoted OA progression by inhibiting nuclear receptor binding SET domain protein 1(NSD1) in chondrocytes and regulating histone H3 lysine 36(H3K36) methylation. This study demonstrated that the targeting of macrophage-derived ectosomal miRNAs was a potential therapeutic method for mechanical overload-induced OA.

The Brachypodium distachyon DREB transcription factor BdDREB-39 confers oxidative stress tolerance in transgenic tobacco.

Key message BdDREB-39 is a DREB/CBF transcription factor, localized in the nucleus with transactivation activity, and BdDREB-39-overexpressing transgenic yeasts and tobacco enhanced the tolerance to oxidative stress.Abstract The DREB/CBF transcription factors are generally recognized to play an important factor in plant growth, development and response to various abiotic stresses. However, the mechanism of DREB/CBFs in oxidative stress response is largely unknown. This study isolated a DREB/CBF gene BdDREB-39 from Brachypodium distachyon (B. distachyon). Multiple sequence alignment and phylogenetic analysis showed that BdDREB-39 was closely related to the DREB proteins of oats, barley, wheat and rye and therefore its study can provide a reference for the excavation and genetic improvement of BdDREB-39 or its homologs in its closely related species. The transcript levels of BdDREB-39 were significantly up-regulated under H2O2 stress. BdDREB-39 was localised in the nucleus and functioned as a transcriptional activator. Overexpression of BdDREB-39 enhanced H2O2 tolerance in yeast. Transgenic tobaccos with BdDREB-39 had higher germination rates, longer root, better growth status, lesser reactive oxygen species (ROS) and malondialdehyde (MDA), and higher superoxide dismutase (SOD) and peroxidase (POD) activities than wild type (WT). The expression levels of ROS-related and stress-related genes were improved by BdDREB-39. In summary, these results revealed that BdDREB-39 can improve the viability of tobacco by regulating the expression of ROS and stress-related genes, allowing transgenic tobacco to accumulate lower levels of ROS and reducing the damage caused by ROS to cells. The BdDREB-39 gene has the potential for developing plant varieties tolerant to stress.

Endovascular Repair Blunt Thoracic Aortic Injury in Adolescent: A Case Series.

BACKGROUND: Blunt traumatic aortic injury (BTAI) is a rare occurrence in adolescents, yet it is associated with a high mortality rate necessitating immediate treatment. Although endovascular repair has become the preferred treatment for such injuries in adults, its effectiveness in adolescents remains uncertain. CASE SUMMARY: Blunt traumatic aortic injury typically presents with concomitant injuries to other organs and carries a high perioperative mortality rate with operative repair (OR). In this report, we describe the treatment of 3 clinical cases of BTAI in adolescents using thoracic endovascular aortic repair (TEVAR). These cases contribute pertinent evidence supporting the efficacy of intravascular repair for BTAI. CONCLUSION: Operative repair (OR) remains the gold standard for treating BTAI in adolescents. Nevertheless, TEVAR therapy presents a viable alternative for patients with multiple injuries in whom anticoagulation is contraindicated. Further long-term observation is necessary to assess the lasting effects of TEVAR therapy. CLINICAL IMPACT: This study has provided insights into endovascular repair for adolescent BTAT, offering clinicians significant reference material for choosing treatment strategies for adolescent BTAT. The study aims to demonstrate the safety and effectiveness of endovascular repair treatments in a series of clinical cases involving adolescent BTAI.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

[Gly14]-humanin exerts a protective effect against D-galactose-induced primary ovarian insufficiency in mice.

RESEARCH QUESTION: Is there a protective effect of the humanin derivative [Gly14]-humanin (HNG) on a D-gal-induced mouse model of primary ovarian insufficiency (POI), and what is the underlying mechanism? DESIGN: D-gal (200 mg/kg/day) was injected subcutaneously for 6 weeks to induce the mouse POI model. Mice treated with HNG were injected intraperitoneally with different concentrations for 6 weeks. Ovarian morphology, function, levels of sex hormones and states of oxidative stress in the ovary and body were evaluated. RESULTS: Compared with the D-gal group, 10 mg/kg HNG improved the abnormal ovarian morphology and oestrous cycle (P = 0.0036), increased the number of ovarian follicles (P = 0.0016) and litters (P = 0.0127), and increased the levels of oestrogen (P = 0.0043) and AMH (P = 0.0147). Antioxidant indicators in the ovaries and serum of mice, including total antioxidant capacity (P = 0.0004 and P = 0.0032, respectively), catalase (P = 0.0173 and P = 0.0103, respectively) and glutathione (both P < 0.0001) were significantly increased. The oxidation indicator malondialdehyde decreased significantly (all P < 0.01). Apoptosis of ovarian granulosa cells was significantly reduced (P = 0.0140) as was the expression of senescence-related proteins p53, p21 and p16 (all P < 0.01). The level of autophagy in ovarian tissue of mice treated with high increased (significantly increased LC3 protein [P < 0.0001] and significantly reduced p62 protein [P = 0.0007]). CONCLUSIONS: HNG inhibited D-gal-induced oxidative stress, apoptosis and ovarian damage, promoting ovarian autophagy. HNG may be a potential prophylactic agent against POI.

Accelerated Course of Cerebral Adrenoleukodystrophy After Coronavirus Disease 2019 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can not only infect the respiratory system but also affect the nervous system through the release of inflammatory factors. Our study aimed to investigate the effect of COVID-19 infection on cerebral adrenoleukodystrophy (ALD). METHODS: Changes in the neurological symptoms of cerebral ALD after infection with COVID-19 from January 2022 to February 2023 were retrospectively analyzed. The primary assessment indicator was the Neurologic Function Scale (NFS) score. RESULTS: A total of 17 male patients with cerebral ALD were enrolled, with a median age of 101 months (80 to 151 months). Among them, 11 (11 of 17, 64.7%) developed an exacerbation of neurological symptoms after COVID-19 infection. Two patients with NFS = 0 started presenting with neurological symptoms after infection. Fifteen patients were in the advanced stage (NFS >1 and/or Loes score >9), of which nine did not progress to major functional disabilities (MFDs). Seven of the nine patients (77.8%) experienced an increase in NFS scores, ranging from 1 to 9 points, within two weeks of COVID-19 infection, with four of them experiencing MFDs. For the other six patients who had progressed to MFDs, there was not much room for further degeneration, so the NFS score did not increase after COVID-19 infection. No deaths related to COVID-19 infection occurred. CONCLUSIONS: COVID-19 infection may aggravate neurological symptoms of cerebral ALD, particularly among patients who have not yet progressed to MFDs. Therefore, COVID-19 may accelerate the course of cerebral ALD, so protecting patients from infection is essential for maintaining the stability of the disease.

Safety and efficacy of melatonin supplementation as an add-on treatment for infantile epileptic spasms syndrome: A randomized, placebo-controlled, double-blind trial.

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option.

Fluorene-9-bisphenol exposure damages the testis in mice through a novel mechanism of ferroptosis.

Fluorene-9-bisphenol (BHPF) is an emerging global endocrine-disrupting chemical found in numerous household products as a substitute of bisphenol A. Many studies have reported various toxicities associated with BHPF. However, the effect of BHPF on male reproduction, particularly on the structural integrity of the blood testis barrier (BTB) in mice, has not yet been extensively studied. Ferroptosis, a newly identified form of cell death, occurs in the testicular tissue following exposure to BPA, affecting male fertility. We investigated whether ferroptosis plays a role in BHPF-induced testicular damage. The findings indicated that BHPF exposure led decreases in serum testosterone (T) concentration and sperm concentration and motility in mice. Furthermore, BHPF disrupted the BTB by interfering with key BTB-related proteins, including Cx43, ß-catenin, and ZO-1. Moreover, BHPF induced ferroptosis through the induction of lipid peroxidation, iron overload, oxidative stress, and mitochondrial dysfunction in the testicular tissue. Inhibition of ferroptosis using Fer-1 mitigated the BHPF-induced damage to the BTB and ferroptosis in TM4 cells. Overall, our findings indicated the detrimental effects of BHPF on male reproductive function in mice, suggesting ferroptosis as a mechanism underlying testicular damage.

Adrenocorticotropic hormone combined with magnesium sulfate therapy for infantile epileptic spasms syndrome: a real-world study.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) is a serious disease in infants, and it usually evolves to other epilepsy types or syndromes, especially refractory or super-refractory focal epilepsies. Although adrenocorticotropic hormone (ACTH) is one of the first-line and effective treatment plans for IESS, it has serious side effects and is not sufficiently effective. METHODS: A retrospective study of the clinical outcomes of ACTH combined with magnesium sulfate (MgSO4) therapy for IESS in two hospital centers was conducted. The major outcome of the single and combined treatment was evaluated by changes in seizure frequency and improvements in hypsarrhythmia electroencephalography (EEG). To reduce the confounding bias between the two groups, we used SPSS for the propensity score matching (PSM) analysis. RESULTS: We initially recruited 1205 IESS patients from two Chinese hospitals and treated them with ACTH combined with MgSO4 and ACTH alone. Only 1005 patients were enrolled in the treatment (ACTH combined with MgSO4: 744, ACTH: 261), and both treatment plans had a more than 55% response rate. However, compared to patients treated with ACTH alone, those patients treated with ACTH combined with MgSO4 had better performance in terms of the seizure frequency and hypsarrhythmia EEG. After PSM, the two groups also showed significant differences in responder rate [70.8% (95% confidence interval, CI) = 66.7%-74.8%) vs. 53.8% (95% CI = 47.4%-60.2%), P < 0.001], seizure frequency (P < 0.001) and hypsarrhythmia EEG resolution (P < 0.001). Notably, multivariate analysis revealed that the lead time to treatment and the number of antiseizure medications taken before treatment were two factors that may affect the clinical outcome. Patients with less than 3 months of lead time responded to the treatment much better than those with > 3 months (P < 0.05). In addition, the overall incidence of adverse reactions in the ACTH combined with MgSO4 group was much lower than that in the ACTH group (31.4% vs. 63.1%, P < 0.001). During the treatment, only infection (P = 0.045) and hypertension (P = 0.025) were significantly different between the two groups, and no baby died. CONCLUSION: Our findings support that ACTH combined with MgSO4 is a more effective short-term treatment protocol for patients with IESS than ACTH alone, especially for those patients with short lead times to treatment. Video Abstract (MP4 533623 KB).

Case Report: Chronic inflammatory demyelinating polyradiculoneuropathy rather than hemophagocytic lymphohistiocytosis-the initial phenotype of PRF1 gene mutation.

Perforin is essentially involved in the granule-dependent killing activities of cytotoxic T lymphocytes and NK cells. Monoallelic PRF1 mutation increases the risk of autoimmune diseases, and biallelic PRF1 mutation causes familial hemophagocytic lymphohistiocytosis-2. Here, we report a case of a 12-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), followed by a rapidly progressive onset of hemophagocytic lymphohistiocytosis (HLH) 9 months later, alongside manifestations of demyelinating encephalopathy. Genetic sequencing revealed a heterozygous nonsense mutation in the PRF1 gene (c.984G>A; p.W328*) and a heterozygous missense mutation in the PRF1 gene (c.1349C>T; p.T450M). Eventually, she died because of no suitable allogeneic hematopoietic stem cell available in time. Our observations suggest that CIPD might represent the initial phenotype of biallelic PRF1 mutation and could serve as an early sign of subsequent HLH. A comprehensive understanding of this condition is paramount for timely diagnosis, treatment, and ultimately improved patient outcomes.

An education-based telehealth group improves the management and clinical outcomes of patients with inflammatory bowel disease in China (THEIM study).

BACKGROUND: Although poor medication adherence has a negative impact on disease prognosis in patients with inflammatory bowel disease (IBD), finding proven solutions remains a challenge. In this study, we developed a telehealth management model based on education and patient-centered medical care (PCEB) using the social media platform WeChat. OBJECTIVE: To investigate the effect of PCEB on adherence and clinical outcomes. METHODS: In this retrospective cohort, 543 IBD patients (274 in the PCEB group and 269 in the routine group) at the IBD center of Renmin Hospital (Wuhan University, Wuhan, China) were enrolled between January 2020 and September 2022. The routine group received routine follow-up and management, while for PCEB patients, a comprehensive IBD education program and PCEB were conducted. Medication adherence and clinical outcomes were also evaluated. RESULTS: There were no differences between the PCEB and routine groups in terms of patient demographics and clinical characteristics, including disease classification, duration, biological treatment, and educational background at baseline. Compared with routine treatment, PCEB greatly improved patient medication adherence, as assessed by compliance with oral medication, enteral nutrition, biological infusion, and scheduled endoscopic assessment. Clinical and endoscopic remission in patients with PCEB increased during short-term (month 4) and long-term (month 12) follow-ups, along with a decrease in relapse rates for CD (13.3% vs. 31.8%) and UC (19.8% vs. 37.2%). CONCLUSION: The telehealth model applied to the PCEB group improved medication adherence and clinical outcomes in patients with IBD. This is a new and powerful solution for the long-term management of this chronic and progressive disease.

Generation and characterization of induced pluripotent stem cell lines derived from skin fibroblasts of patients with adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We established two strains of iPSCs from skin fibroblasts of patients with childhood cerebral ALD and Addison's disease, respectively. CytoTune™2.0 Sendai reprogramming kit was used. The iPSC lines showed typical stem cell morphology, normal karyotype, and carrying ABCD1 variation. The iPSC lines express pluripotency markers, and have the capacity to differentiate into three germ layers. iPSCs can be used as an alternative cell source for ALD in vitro model to study its pathogenesis and therapeutic strategies.