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.

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.

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.

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.

[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.

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.

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.

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.

The humanin analogue (HNG) alleviates intrauterine adhesions by inhibiting endometrial epithelial cells ferroptosis: a rat model-based study.

STUDY QUESTION: Does a humanin analogue (HNG) have a therapeutic effect on intrauterine adhesions (IUAs) caused by uterine cavity surgery in a rat model? SUMMARY ANSWER: HNG supplementation attenuated the development of endometrial fibrosis and IUAs, improved fertility, and contributed to the regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs. WHAT IS KNOWN ALREADY: IUAs, which are characterized by endometrial fibrosis, are a common cause of female infertility. Humanin (rattin in rats) is a mitochondrial-derived peptide that is widely expressed in multiple tissues. S14G-humanin (HNG) is an HNG that has been reported to have a protective effect against myocardial fibrosis. STUDY DESIGN, SIZE, DURATION: Endometrial tissues from three patients with IUAs and three controls were tested for humanin expression. Two animal models were used to evaluate the modelling effect of IUAs and the preventive effect of HNG against IUAs. In the first model, 40 rats were equally randomized to control and Day 7, 14, and 21 groups to establish the IUA model. In the second model, 66 rats were equally randomized to the control, IUA, and IUA + humanin analogue (HNG) groups. Erastin was used to induce ferroptosis in the Ishikawa cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endometrium was scraped with a surgical spatula, combined with lipopolysaccharide treatment, to establish the rat model of IUAs. Rats were intraperitoneally injected with 5 mg/kg/day HNG for 21 consecutive days beginning from the day of operation to evaluate the therapeutic effect on IUAs. Haematoxylin-eosin and Masson's trichrome staining were used to assess endometrial morphology and evaluate fibrosis. Ferroptosis-related markers, namely nuclear factor E2-related factor 2 (Nrf2), acyl-CoA synthetase long-chain family member 4 (ACSL4), haeme oxygenase-1 (HO-1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and ferritin, were measured by immunohistochemistry and western blotting to determine whether ferroptosis was involved in the development of IUAs and to assess the attenuative effect of HNG on ferroptosis. Additionally, the female rats were mated with male rats with normal fertility to assess fertility. MAIN RESULTS AND THE ROLE OF CHANCE: Humanin was widely expressed in endometrial cells, including epithelial and stromal cells, in both humans and rats. Humanin expression levels were downregulated in the endometria of patients and rats with IUAs relative to the endometria of controls. Endometrial thickness and the number of glands were significantly decreased on Day 7, 14, and 21 after endometrial scraping when compared with the controls (all P < 0.05), whereas the fibrotic area was significantly increased (P < 0.05). Among the tested ferroptosis markers, the expression levels of Nrf2, SLC7A11, and GPX4 were significantly downregulated and those of ACSL4, HO-1, and ferritin were significantly upregulated after endometrial scraping relative to their expression levels in controls (all P < 0.05). The mating rates in the control, IUA, and IUA + HNG groups were 100% (10/10), 40% (4/10), and 80% (8/10), respectively. The number of embryos in rats with IUAs (mean ± SD: 1.6 ± 2.1) was significantly less than the number in the controls (11.8 ± 1.5). HNG supplementation significantly attenuated this decrease in the number of implanted embryos (6.3 ± 4.5) (P < 0.01). Further results showed that HNG significantly attenuated the altered expression levels of proteins involved in ferroptosis in the endometria of rats with IUAs. Moreover, in vitro experiments showed that HNG significantly attenuated the erastin-induced decrease in the viability of the Ishikawa cell line and also attenuated the increase in reactive oxygen species production and the downregulation of GPX4. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The findings of this study showed that HNG inhibited ferroptosis and reduced fibrosis in a rat model of IUAs. However, we could not establish a causal relationship between ferroptosis and the development of IUAs. WIDER IMPLICATIONS OF THE FINDINGS: HNG may be effective at alleviating fibrosis during the development of IUAs, and the inhibition of ferroptosis is a promising new strategy for IUA therapy. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (No. 82171647); the '1000 Talent Plan' of Yunnan Province (No. RLQN20200001); and the Basic Research Project of the Yunnan Province-Outstanding Youth Foundation (No. 202101AW070018). The authors declare no competing financial interests.

KRT15 in early breast cancer screening and correlation with HER2 positivity, pathological grade and N stage.

Objective: This study was designed to explore KRT15 dysregulation and its correlation with clinical characteristics among ductal carcinoma in situ (DCIS), DCIS with microinvasion (DCIS-MI) and invasive breast cancer (IBC) patients. Methods: KRT15 from lesion samples of 50 DCIS patients, 48 DCIS-MI patients and 50 IBC patients was detected by immunohistochemistry. Results: KRT15 discriminated IBC patients from DCIS patients (area under the curve [AUC] = 0.895; 95% CI = 0.836-0.954) and DCIS-MI patients (AUC = 0.707; 95% CI = 0.606-0.808). In DCIS patients, KRT15 was negatively correlated with pathological grade (p = 0.015). In DCIS-MI patients, KRT15 was positively related to estrogen receptor positivity but negatively associated with Ki-67 (both p < 0.05). In IBC patients, KRT15 was negatively linked to HER2 positivity, histological grade, N stage and tumor node metastasis stage (all p < 0.05). Conclusion: KRT15 assessment may help with early breast cancer screening.

Sirolimus can promote the disappearance of renal angiomyolipoma associated with tuberous sclerosis complex: a prospective cohort study.

BACKGROUND: Renal angiomyolipoma (RAML) is the most common kidney lesion in patients with tuberous sclerosis complex (TSC), affecting about 80% of patients. It is a benign tumor that grows over time, usually bilaterally, and can easily lead to kidney complications such as acute hemorrhage. Herein, we investigated the efficacy and safety of sirolimus in children with TSC-associated RAML and explored the factors affecting tumor disappearance under sirolimus treatment through subgroup analysis. METHODS: A prospective cohort study was conducted. Sirolimus was initiated at 1 mg/(m2 × day), and dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5-10 ng/mL. The disappearance of RAML in children after sirolimus treatment was observed, and Cox regression was used to screen the factors affecting tumor disappearance. RESULTS: One hundred and twenty-six patients who met the criteria were analyzed. After 3 months, 6 months, 12 months, and 24 months of follow-up, tumors disappeared in 18 (14.3%), 30 (23.8%), 39 (31.0%), and 42 (33.3%) children, respectively. Tumors disappeared in 50 (39.7%) children by the last visit of each individual, and 30 (60%) of them occurred within 6 months. The multivariate Cox regression analysis showed that patients with a smaller maximum tumor diameter at baseline had a higher tumor disappearance rate. Thirty-six (29%) patients had stomatitis during the entire treatment period, and no serious adverse reactions were observed. CONCLUSIONS: Sirolimus could promote the disappearance of TSC-related RAML. The disappearance rate was correlated with the maximum diameter at baseline, and the smaller the tumor was, the higher the disappearance rate. It is well tolerated in the treatment of RAML associated with TSC.

Challenges in the Management of Children and Adolescents With Epilepsy in China During the COVID-19 Pandemic: An Online Survey-Based Study.

INTRODUCTION: To investigate the challenges in the management of children and adolescents with epilepsy in China during the coronavirus disease (COVID-19) pandemic. METHODS: We conducted a cross-sectional survey among 845 patients with epilepsy using an online-based questionnaire. The questionnaire focused on sociodemographic characteristics, epilepsy-related conditions, health care access, COVID-19 vaccination, and the mental health of caregivers. Depression was assessed using Patient Health Questionnaire-9. RESULTS: During the pandemic, 24.73% of the patients had increased seizures. The majority of patients (68.89%) experienced difficulty obtaining antiseizure medications. In addition, 94.79% of the patients had difficulty consulting a doctor. A total of 52.78% of the patients selected telemedicine services, and most found these services to be helpful. Moreover, 76.11% of the patients failed to complete the COVID-19 vaccination. More than half of the caregivers had anxiety and depressive symptoms. The risk factors for depression comprised irregularity in taking antiseizure medications, difficulty in obtaining antiseizure medications, and failure to consult a doctor on time. CONCLUSIONS: The COVID-19 pandemic presented a great challenge in the management of children and adolescents with epilepsy in China. The findings highlight the importance of improving health care systems and medication management and the mental health of their caregivers.

Efficacy of Ustekinumab Optimization by 2 Initial Intravenous Doses in Adult Patients With Severe Crohn's Disease.

BACKGROUND: Although increasing studies have reported that dose escalation can improve treatment response to ustekinumab in patients with Crohn's disease (CD), their strategies mainly focus on maintenance regimen. Evidence of ustekinumab dose escalation in induction regimen, particularly in severe CD, remains limited. This study evaluated the efficacy and safety of intravenous ustekinumab with 2 initial doses in patients with severely active CD. METHODS: A retrospective observational study of 99 adult patients with severe CD treated with ustekinumab from 3 IBD centers included 48 patients with standard and 51 with optimized induction treatment. Clinical outcomes, inflammatory biomarkers including fecal calprotectin (FC) normalization, and endoscopic outcomes were evaluated at weeks 16 and 48. Adverse events and treatment decisions after initial induction were also collected. RESULTS: Compared with the standard group, 2 initial intravenous injections of ustekinumab achieved higher clinical response (92.2%, 47 of 51, P = .656), clinical remission (88.2%, 45 of 51, P = .221), endoscopic response (75.8%, 25 of 33, P = .125), and FC normalization (70.6%, 36 of 51, P = .138) at week 16. The mucosal healing rate at week 16 (63.6%, P = .022) was statistically higher in the optimization group. At week 48, patients with optimized treatment achieved higher clinical response (80.4%, 41 of 51, P = .003), clinical remission (70.6%, 36 of 51, P = .007), FC normalization (66.7%, 34 of 51, P = .031), endoscopic response (72.7%, 24 of 33, P = .006), and mucosal healing (57.6%, 19 of 33, P = .004). At the last follow-up, 82.4% of optimally treated patients adhered to continued treatment with ustekinumab (P < .001). CONCLUSIONS: Optimization of ustekinumab by 2 initial intravenous inductions is more effective than standard therapy for adult patients with severe CD.

This study used an optimization strategy in severe adult Crohn's disease with 2 initial intravenous doses of ustekinumab. This new strategy proved to be effective and safe.

Differences in epidemiological and clinical features between adult and pediatric tracheobronchial tuberculosis patients in Southwest China.

Background: Tracheobronchial tuberculosis (TBTB) is a common form of extrapulmonary tuberculosis that affects the tracheobronchial tree. However, the mechanism has not been fully elucidated. Comparisons of clinical characteristics in various age groups can aid in the understanding of TBTB. Methods: This retrospective study was conducted at the Public Health Clinical Center of Chengdu between July 2017 and December 2021, including adults and children with TBTB. Clinical data were extracted from medical records. T/T' test, Mann-Whitney U test, Chi-square test, or Fisher's exact test were used in this study. Results: This study enrolled 347 patients with TBTB (175 adults and 172 children). Adult females were more susceptible to TBTB, whereas gender-based differences were not observed in children. Children had a higher occurrence of irritant dry cough and fever, and acute hematogenous disseminated PTB, and specific types of EPTB, but a shorter interval before diagnosis, and lower diagnostic yields compared to adults (P < 0.05). Adults presented more extensive lung lesions and cavitations as compared to children. Granulation hyperplasia and lymph fistula were more frequently observed in children, as well as airway stenosis, but less severe. Conclusions: The study revealed important variations exist in multiple respects between adults and children with TBTB.