Advancing randomized controlled trials of vascular anomalies: an analysis of trial waste.

A series of randomized controlled trials (RCTs) have advanced the therapeutic approaches for vascular anomalies (VA). However, a notable obstacle in applying the findings of these trials to real-world patient care is trial waste (TW). To date, the extent of TW in RCTs for VA is not clear. In June 2024, we searched the ClinicalTrials database using the entity names defined by ISSVA classification as search terms. We documented the data available and then explored PubMed and Scopus for the publication status. Reporting adequacy was evaluated using the CONSORT checklist. Design limitations were analyzed based on bias risk and whether the article referenced a relevant systematic review. One hundred fifty-nine RCTs met the inclusion criteria. The majority of RCTs focused on benign VA (81.1%) and utilized pharmacotherapy (79.9%). Over 90% of these trials were conducted in North America, Europe, and Asia as single-center studies (68.6%), with funding primarily from official institutions (83.7%). The analysis of TW excluded 61 RCTs completed after June 2020 that remained unpublished. Among the remaining 98 RCTs, 53 were published, 41 had adequate reporting, and 16 had design limitations. In total, 67 RCTs exhibited at least one characteristic of TW. The 31 RCTs without waste tended to enroll more participants (P = 0.014) and conduct studies across multiple centers (P < 0.001) and countries (P = 0.022). Multicenter participation (P = 0.028) emerged as an independent protective factor against TW. CONCLUSION: We delineated the features of 159 VA RCTs and revealed that 68.4% of them exhibited TW. The diverse traits of the different TW indicators identified could serve as valuable insights for conducting future VA RCTs more rationally and efficiently. WHAT IS KNOWN: • Currently, a number of RCTs have been conducted on vascular anomalies (VA). However, there has been no study analyzing the situation of trial waste in VA-related RCTs. WHAT IS NEW: • This study is the first to describe the characteristics of VA-related RCTs globally over the past 20 years and has identified a high burden of trial waste in this field. Multicenter participation was an independent protective factor against trial waste.

meta-C-H functionalization of phenylethyl and benzylic alcohol derivatives via Pd/NBE relay catalysis.

The transition metal-catalyzed meta-C-H functionalization of alcohols and their hydroxylamine derivatives remains underdeveloped. Herein, we report an efficient meta-C-H arylation of both phenylethyl and benzylic alcohols and their hydroxylamine derivatives using a readily removable oxime ether directing group. Using electronically activated 2-carbomethoxynorbornene as the transient mediator and 3-trifluoromethyl-2-pyridone as the enabling ligand, this reaction features a broad substrate scope and good functional group tolerance. More importantly, with this oxime-directed meta-C-H functionalization, this method provides a dual approach for efficient access to both meta-substituted alcohols and hydroxylamines using two sets of simple deprotection conditions. This protocol leads to the efficient synthesis of bioactive compounds possessing promising reactivities for the treatment of pulmonary fibrosis.

Increasing trends of non-tuberculous mycobacteria clinical isolates in Guangzhou, China.

Non-tuberculous mycobacteria (NTM) are one of major public health concern. The current study aimed to find the prevalence trends of NTM in Guangzhou, China from January 2018 to December 2023. A total of 26,716 positive mycobacterial cultures were collected. Thirty-six specimens with incomplete personal information were excluded. The remaining 26,680 specimens were identified using a gene chip method. 16,709 isolates were Mycobacterium tuberculosis (MTB) (62.63 %), and 9,971 were NTM (37.37 %). 43.43 % (4,330/9,971) of NTM isolates were male, and 56.57 % (5,641/9,971) were female (χ2 = 24.36, P < 0.05), a male to female ratio of approximately 1:1.30. Infections in individuals with aged 40 years and above was higher (77.63 %) than below 40 years (22.37 %) (χ2 = 4.94, P = 0.026). The annual NTM isolation rates from 2018 to 2023 were 32.03 %, 34.00 %, 36.27 %, 38.58 %, 38.99 %, and 43.24 %, respectively, showing an increasing trend (χ2 for trend = 0.097, P < 0.05) (R = 0.097, P < 0.05). Out of 9,971 NTM isolates, 8,881 cases include only five common NTM species (MAC, M. abscessus/M. chelonae, M. kansasii, M. fortuitum, and M. gordonae). The overall NTM isolation rate was 37.37 %. The NTM isolation rate was significantly higher than the national average, showing an increasing trend over the last six years.

PIK3CA mutations enhance the adipogenesis of ADSCs in facial infiltrating lipomatosis through TRPV1.

Facial infiltrating lipomatosis (FIL) is a congenital disorder. The pathogenesis of FIL is associated with PIK3CA mutations, but the underlying mechanisms remain undetermined. We found that the adipose tissue in FIL demonstrated adipocytes hypertrophy and increased lipid accumulation. All adipose-derived mesenchymal stem cells from FIL (FIL-ADSCs) harbored PIK3CA mutations. Moreover, FIL-ADSCs exhibited a greater capacity for adipogenesis. Knockdown of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA sequencing (RNA-seq) revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression or activation of TRPV1 both inhibited adipogenesis. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and this effect was achieved by suppressing TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.

A clinically used anti-human papilloma virus agent (3-hydroxyphthalic anhydride-modified bovine ß-lactoglobulin) has a potential for topical application to prevent sexual transmission of monkeypox virus.

A global outbreak of monkeypox (mpox) caused by the mpox virus (MPXV) has posed a serious threat to public health worldwide, thus calling for the urgent development of antivirals and vaccines to curb its further spread. In this study, we screened 41 anhydride-modified proteins and found that 3-hydroxyphthalic anhydride-modified ß-lactoglobulin (3HP-ß-LG), a clinically used anti-HPV agent, was highly effective in inhibiting infection of vaccinia virus Tiantan strain (VACV-VTT) and MPXV. Mechanistic studies demonstrated that 3HP-ß-LG bound to the virus, not the host cell, by targeting the early stage of virus entry, possibly through the interaction between the amino acids with negatively charges in 3HP-ß-LG and the key amino acids with positive charges in the target region of A29L, a key surface protein of MPXV. A synergistic effect was observed when 3HP-ß-LG was combined with tecovirimat, a small-molecule antiviral drug approved by the United States Food and Drug Administration and the European Medicine Agency for the treatment of smallpox and mpox. Because of its clinically proven safety and stability, 3HP-ß-LG shows promise for further development as a prophylactic agent to prevent the sexual transmission of MPXV.

Lysophosphatidylcholine Impairs the Mitochondria Homeostasis Leading to Trophoblast Dysfunction in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a common pregnancy disorder associated with an increased risk of pre-eclampsia and macrosomia. Recent research has shown that the buildup of excess lipids within the placental trophoblast impairs mitochondrial function. However, the exact lipids that impact the placental trophoblast and the underlying mechanism remain unclear. GDM cases and healthy controls were recruited at Kaohsiung Medical University Hospital. The placenta and cord blood were taken during birth. Confocal and electron microscopy were utilized to examine the morphology of the placenta and mitochondria. We determined the lipid composition using liquid chromatography-mass spectrometry in data-independent analysis mode (LC/MSE). In vitro studies were carried out on choriocarcinoma cells (JEG3) to investigate the mechanism of trophoblast mitochondrial dysfunction. Results showed that the GDM placenta was distinguished by increased syncytial knots, chorangiosis, lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) overexpression, and mitochondrial dysfunction. Lysophosphatidylcholine (LPC) 16:0 was significantly elevated in the cord blood LDL of GDM patients. In vitro, we demonstrated that LPC dose-dependently disrupts mitochondrial function by increasing reactive oxygen species (ROS) levels and HIF-1α signaling. In conclusion, highly elevated LPC in cord blood plays a pivotal role in GDM, contributing to trophoblast impairment and pregnancy complications.

Evaluating research waste and traits among randomized controlled trials of scars over the past 20 years: a cross-sectional study.

PURPOSE: To analyze the changes in the characteristics of randomized controlled trials (RCTs) in the field of scarring over the last two decades, unveil the components of research waste (RW) within these RCTs, and identify targets for improvement. METHODS: A search was conducted on ClinicalTrials.gov for RCTs registered from January 2000 to December 2023, using "scar" as the keyword. The search was carried out in January 2024. RESULTS: 391 RCTs were included in this analysis. The global registration of RCTs in scarring has exhibited a consistent increase annually, with the proportion in Asia gradually rising, while the shares in North America and Europe have demonstrated a declining trend. In the analysis of RW, 232 RCTs were included, of which 96 (41.4%) have been published. Among the published RCTs, 56 (58.3%) were evaluated to have sufficient reporting, while 47 RCTs (48.9%) were identified as having avoidable design flaws. Ultimately, 183 RCTs (78.9%) exhibited at least one form of RW. Multicenter design (OR: 3.324, 95%CI: 1.385-7.975, P = 0.018), non-pharmacological interventions (OR: 2.61, 95%CI: 1.253-5.435, P = 0.010), the absence of external funding (OR: 0.325, 95%CI: 0.144-0.732, P = 0.031), and participant numbers exceeding 50 (OR: 3.269, 95%CI: 1.573-6.794, P = 0.002) were identified as independent protective factors against waste. CONCLUSIONS: This study delineates the changes in the characteristics of scar RCTs globally over the past two decades, uncovering a substantial burden of RW in scarring research. It provides an evidential reference for more rational planning of future scar-related RCTs and for minimizing RW.

Single-cell sequencing of facial adipose tissue unveils FKBP5 as a therapeutic target for facial infiltrating lipomatosis.

BACKGROUND: Facial infiltrating lipomatosis is characterized by excessive growth of adipose tissue. Its etiology is associated with somatic phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) variants, but the specific mechanisms are not yet fully understood. METHODS: We collected facial adipose tissue from both FIL patients and non-FIL individuals, isolated the stromal vascular fraction (SVF) and performed single-cell transcriptome sequencing on these samples. RESULTS: We mapped out the cellular landscape within the SVF, with a specific focus on a deeper analysis of fibro-adipogenic precursor cells (FAPs). Our analysis revealed that FAPs from FIL patients (FIL-FAPs) significantly overexpressed FK506 binding protein 51 (FKBP5) compared to FAPs from individuals without FIL. Further experiments indicated that FKBP5 is regulated by the PI3K-AKT signaling pathway. The overactivation of this pathway led to an increase in FKBP5 expression. In vitro experiments demonstrated that FKBP5 promoted adipogenic differentiation of FAPs, a process that could be hindered by FKBP5 knockdown or inhibition. Additionally, in vivo assessments confirmed FKBP5's role in adipogenesis. CONCLUSIONS: These insights into the pathogenesis of FIL underscore FKBP5 as a promising target for developing non-surgical interventions to manage the excessive adipose tissue growth in FIL.

Delineation of the phenotypes and genotypes of PIK3CA-related overgrowth spectrum in East asians.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.

Aesthetic Reconstruction of the Sequelae of Large Facial Involuted Infantile Hemangioma with Tissue Expanders.

BACKGROUND: Large involuted infantile hemangioma remains a challenge in facial reconstruction. The characteristic fibrofatty residuum and multiple subunits/tissues involvement contribute significantly to the difficulty of surgical management. Tissue expander plays an important role in facial reconstruction, allowing plastic surgeons to repair skin damaged by both congenital and acquired defects. METHODS: Between 2009 and 2021, 30 patients who underwent tissue expansion surgery were reviewed in a single hospital. The demographic data, lesion characteristics, surgical approaches, complication rate, and aesthetic outcomes were analyzed. RESULTS: Thirty patients (5 men and 25 women) with a mean age of 14.03 ± 7.25 years (range, 4-33 years) were included. The mean follow-up is 35.92 months, ranging from 9 to 75 months. Tissue expansion-related complications include closed infection, 2/30 (6.67%); skin ischemia, 2/30 (6.67%); hematoma, 1/30 (3.33%); flap necrosis, 1/30 (3.33%). CONCLUSION: Large facial involuted infantile hemangiomas have variable patterns of presentation and necessitate tailored therapy. Tissue expansion is a reproducible approach to achieving aesthetic reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas.

Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.

Characteristics and Research Waste of Randomized Clinical Trials in Melanoma.

BACKGROUND: Numerous large-scale RCTs have propelled the melanoma treatment strategies. Research waste (RW) presents a significant challenge in translating the outcomes of RCTs into clinical practice. Currently, RW has not yet reported in the melanoma-related RCTs. METHODS: In January 2024, we searched ClinicalTrials.gov for phase 3/4 RCTs registered from January 2000 to December 2023 using "melanoma" as a keyword. We recorded the information listed on the website and searched PubMed and Scopus for the publication and citation status of the RCTs. A completed RCT required at least 47 months of preparation time for publication, hence RCTs completed after December 2019 but not yet published were excluded in the analysis of publication status. RESULTS: A total of 165 RCTs were included in the analysis. Melanoma RCTs primarily studied pharmacological interventions, with the registrations for immunotherapy increasing annually. In the analysis of RW, 103 RCTs were included, of which 41 RCTs (41/103, 39.8%) were unpublished. Of the 62 published RCTs, 19 (19/62, 30.6%) reported insufficiently, and 19 had avoidable design flaws (19/62, 30.6%). Ultimately, 64 (64/103, 62.1%) RCTs were judged to have RW. Registration after 2010, conducting studies in multiple countries, using multiple drug interventions, and having survival as primary outcomes were independent protective factors against RW. Thirty-four RCTs (34/62, 54.8%) were cited by guidelines, and 21 RCTs (21/62, 33.9%) reused their prospective data. CONCLUSIONS: We describe the characteristics of phase III/IV RCTs related to melanoma conducted over the past two decades and identify a substantial degree of RW. The protective factors against RW revealed in this study can provide references for the rational and efficient conduct of new RCTs in the future.

Design of Ultrasound-Driven Charge Interference Therapy for Wound Infection.

Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.

FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Risk predictors of glycaemic control in children and adolescents with type 1 diabetes: A systematic review and meta-analysis.

OBJECTIVES: To conduct systematic evaluation of the risk predictors of glycaemic control in children and adolescents with type 1 diabetes mellitus. METHODS: Cohort studies on risk predictors of glycaemic control in children and adolescents with type 1 diabetes were retrieved from CNKI, PubMed, Web of Science, Embase databases, etc. from the construction of the repository to 3 February 2023. Literature screening was conducted according to inclusion and exclusion criteria, then data extraction of region, sample size, age, follow-up time, risk predictors, outcome indicators, etc., and quality evaluation of The Newcastle-Ottawa Scale were conducted by two researchers while the third researcher makes decisions if there are disagreements. Finally, Revman5.4 and StataMP17 were used for meta-analysis. RESULTS: A total of 29 studies were included, and the results showed that insulin pump [Weighed mean difference (WMD) = -.48, 95% CI (-.73, -.24), p < .01], high-frequency sensor monitoring, early use of insulin pumps, prospective follow-up male, white race, large body mass index-standardised scoring, conscientiousness, agreeableness of mothers, eicosapentaenoic acid, leucine and protein (p < .05) were beneficial for reducing HbA1c levels in children and adolescents with diabetes. Ketoacidosis [WMD = .39, 95% CI (.28, .50), p < .01], selective admission, higher HbA1c level at one time (p < .01), higher glutamate decarboxylase antibody at 1 month after diagnosis, lower socio-economic status, non-living with biological parents, non-two-parent family, family disorder, family history of diabetes and high carbohydrate intake (p < .05) increased HbA1c levels in children and adolescents with diabetes. CONCLUSION: For children and adolescents with type 1 diabetes mellitus, the use of insulin pump, high-frequency sensor monitoring, prospective follow-up, good family support and reasonable diet are conducive to blood glucose control, while selective admission and DKA are not. Disease characteristics and demographic characteristics of children are closely related to subsequent blood glucose control, and the relationship between diagnosis age and blood glucose control needs to be further explored.

Association of Serum Uric Acid with Non-Valvular Atrial Fibrillation: A Retrospective Study in China.

Purpose: The association between serum uric acid (SUA) and atrial fibrillation (AF) has been widely focused on and studied in recent years. However, the exact association between SUA and AF is unclear, and the effect of gender on the association between SUA levels and AF has been controversial. This study aimed to investigate the association between SUA levels and non-valvular AF (NVAF) and the potential effect of gender on it. Patients and Methods: A total of 866 NVAF patients (463 males, age 69.44 ± 8.07 years) and 646 sex-matched control patients in sinus rhythm, with no history of arrhythmia were included in this study. t-test, ANOVA, and chi-square test were used for baseline data analysis. The receiver operating characteristic curve, logistic regression and Pearson correlation analysis were used for correlation analysis. Results: Compared to controls, NVAF patients exhibited higher SUA (P<0.001). After adjusting for confounders of NVAF, SUA remained significantly associated with NVAF, regardless of gender (OR= 1.31, 95% CI 1.18-1.43, P<0.001). SUA demonstrated higher predictability and sensitivity in predicting the occurrence of female NVAF compared to male (area under the curve was 0.68 (95% CI 0.64-0.72, P<0.001), sensitivity 87.3%), with the optimal cut-off point identified as 5.72 mg/dL. Furthermore, SUA levels correlated with APOA1, Scr and NT-proBNP in NVAF patients. SUA levels varied significantly among NVAF subtypes. Conclusion: High SUA levels were independently associated with NVAF, regardless of gender. SUA exhibited higher predictability and sensitivity in predicting the occurrence of NVAF in females compared to males. High SUA levels may affect other NVAF-related factors and participate in the pathophysiological process of NVAF.