Inhibition of Sesn2 has negative regulatory effects on the myogenic differentiation of C2C12 myoblasts.

Sestrin2 (Sesn2) has been previously confirmed to be a stress-response molecule. However, the influence of Sesn2 on myogenic differentiation remains elusive. This study was conducted to analyze the role of Sesn2 in the myogenic differentiation of C2C12 myoblasts and related aspects in mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Our results showed that knockdown of Sesn2 reduced the myogenic differentiation capacity of C2C12 myoblasts. Predictive analysis from two databases suggested that miR-182-5p is a potential regulator of Sesn2. Further experimental validation revealed that overexpression of miR-182-5p decreased both the protein and mRNA levels of Sesn2 and inhibited myogenesis of C2C12 myoblasts. These findings suggest that miR-182-5p negatively regulates myogenesis by repressing Sesn2 expression. Extending to an in vivo model of DMD, knockdown of Sesn2 led to decreased Myogenin (Myog) expression and increased Pax7 expression, while its overexpression upregulated Myog levels and enhanced the proportion of slow-switch myofibers. These findings indicate the crucial role of Sesn2 in promoting myogenic differentiation and skeletal muscle regeneration, providing potential therapeutic targets for muscular dystrophy.

Efficacy and Safety of Early Treatment with Glibenclamide in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized Controlled Trial.

BACKGROUND: This study aims to investigate the efficacy and safety of glibenclamide treatment in patients with acute aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The randomized controlled trial was conducted from October 2021 to May 2023 at two university-affiliated hospitals in Beijing, China. The study included patients with aSAH within 48 h of onset, of whom were divided into the intervention group and the control group according to the random number table method. Patients in the intervention group received glibenclamide tablet 3.75 mg/day for 7 days. The primary end points were the levels of serum neuron-specific enolase (NSE) and soluble protein 100B (S100B) between the two groups. Secondary end points included evaluating changes in the midline shift and the gray matter-white matter ratio, as well as assessing the modified Rankin Scale scores during follow-up. The trial was registered at ClinicalTrials.gov (identifier NCT05137678). RESULTS: A total of 111 study participants completed the study. The median age was 55 years, and 52% were women. The mean admission Glasgow Coma Scale was 10, and 58% of the Hunt-Hess grades were no less than grade III. The baseline characteristics of the two groups were similar. On days 3 and 7, there were no statistically significant differences observed in serum NSE and S100B levels between the two groups (P > 0.05). The computer tomography (CT) values of gray matter and white matter in the basal ganglia were low on admission, indicating early brain edema. However, there were no significant differences found in midline shift and gray matter-white matter ratio (P > 0.05) between the two groups. More than half of the patients had a beneficial outcome (modified Rankin Scale scores 0-2), and there were no statistically significant differences between the two groups. The incidence of hypoglycemia in the two groups were 4% and 9%, respectively (P = 0.439). CONCLUSIONS: Treating patients with early aSAH with oral glibenclamide did not decrease levels of serum NSE and S100B and did not improve the poor 90-day neurological outcome. In the intervention group, there was a visible decreasing trend in cases of delayed cerebral ischemia, but no statistically significant difference was observed. The incidence of hypoglycemia did not differ significantly between the two groups.

Good learning environment of medical schools is an independent predictor for medical students' study engagement.

Background: Study engagement is regarded important to medical students' physical and mental wellbeing. However, the relationship between learning environment of medical schools and the study engagement of medical students was still unclear. This study was aimed to ascertain the positive effect of learning environment in study engagement. Methods: We collected 10,901 valid questionnaires from 12 medical universities in China, and UWES-S was utilized to assess the study engagement levels. Then Pearson Chi-Square test and Welch's ANOVA test were conducted to find the relationship between study engagement and learning environment, and subgroup analysis was used to eradicate possible influence of confounding factors. After that, a multivariate analysis was performed to prove learning environment was an independent factor, and we constructed a nomogram as a predictive model. Results: With Pearson Chi-Square test (p < 0.001) and Welch's ANOVA test (p < 0.001), it proved that a good learning environment contributed to a higher mean of UWES scores. Subgroup analysis also showed statistical significance (p < 0.001). In the multivariate analysis, we could find that, taking "Good" as reference, "Excellent" (OR = 0.329, 95%CI = 0.295-0.366, p < 0.001) learning environment was conducive to one's study engagement, while "Common" (OR = 2.206, 95%CI = 1.989-2.446, p < 0.001), "Bad" (OR = 2.349, 95%CI = 1.597-3.454, p < 0.001), and "Terrible" (OR = 1.696, 95%CI = 1.015-2.834, p = 0.044) learning environment only resulted into relatively bad study engagement. Depending on the result, a nomogram was drawn, which had predictive discrimination and accuracy (AUC = 0.680). Conclusion: We concluded that learning environment of school was an independent factor of medical student's study engagement. A higher level of learning environment of medical school came with a higher level of medical students' study engagement. The nomogram could serve as a predictive reference for the educators and researchers.

Identification of genetic susceptibility for Chinese migraine with depression using machine learning.

Background: Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. Objective: The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. Methods: In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. Results: In univariate analysis, ANKDD1B rs904743 showed significant differences in genotype and allele distribution between migraineurs and controls. Furthermore, a machine learning approach was used to perform multivariate analysis. The results of the Random Forest algorithm indicated that ANKDD1B rs904743 was a significant risk factor for migraine susceptibility in China. Additionally, subgroup analysis by the Boruta algorithm showed a significant association between this SNP and migraine comorbid depression. Migraineurs with depression have been observed to have worse scores on the Beck Anxiety Inventory (BAI) and the Migraine Disability Assessment Scale (MIDAS). Conclusion: The study indicates that there is an association between ANKDD1B rs904743 and susceptibility to migraine with and without depression in Chinese patients.

Genome-wide identification of gap junction gene family and their expression profiles under low temperature stress in noble scallop Chlamys nobilis.

Gap junctions, formed by gap junction proteins (GJ), play crucial roles in cell signaling and immune responses. The structure and function of the GJ from vertebrates (called connexins) have been extensively studied. However, little is known about the proteins forming gap junctions in invertebrates (called innexins). In this study, 14 GJ genes of Chlamys nobilis were identified. GJ proteins are mainly distributed on the plasma membrane, and all proteins are hydrophilic Phylogenetic tree analysis showed that the GJ proteins in C. nobilis were distantly related to those in vertebrates but closely related to those in invertebrates. Conserved motifs analysis of these GJ proteins in C. nobilis identified to have 10 conserved motifs, similar to gap junction proteins in other bivalves. Moreover, expression profiles of CnGJ genes under chronic and acute low temperature stress were also investigated. Results showed that chronic low temperature stress had a significant effect on the expression levels of CnGJ genes, and the expression profiles of CnGJ genes showed significantly variation under acute low temperature stress. All these results indicated that CnGJ genes play important roles in environmental adaptation in scallops. The present study initially elucidated the function of gap junction genes in noble scallop C. nobilis, which provides new insights into the GJ genes in mollusks and will help us better understand their roles in environmental stress in scallops.

A multicenter cross-sectional study in China revealing the intrinsic relationship between medical students' grade and their perceptions of the learning environment.

BACKGROUND: Medical school learning environment (MSLE) has a holistic impact on students' psychosomatic health, academic achievements, and personal development. Students in different grades perceive MSLE in different ways. Thus, it is essential to investigate the specific role of student's grade in the perception of MSLE. METHODS: Using the Johns Hopkins Learning Environment Scale (JHLES) as a quantification instrument for the perception level of MSLE, 10,901 medical students in 12 universities in China were categorized into low or high JHLES group according to their questionnaires. We investigated the relationship between student's grade and JHLES category by univariate analysis employing Pearson Chi-square test and Welch's ANOVA. Then multivariable logistic regression analysis confirmed the predictive efficacy of student's grade. A nomogram concerning the prediction of low JHLES score probability in medical students was also constructed. RESULTS: A significant difference between two JHLES categories among students in different grades was observed (p < 0.001), with the proportion of the high JHLES group dominating in grade 1, 5, and the graduate subgroups (p < 0.001). The mean JHLES score declined especially in the third and fourth graders compared to freshmen (p < 0.001), while the mean score among the fifth graders had a remarkable rebound from the third graders (p < 0.001). Most imperatively, identified by multivariable logistic regression analysis, students in grade 3 (OR = 1.470, 95% CI = 1.265-1.709, p < 0.001) and 4 (OR = 1.578, 95% CI = 1.326-1.878, p < 0.001) perceived more negatively than freshmen. The constructed nomogram provided a promising prediction model for student's low JHLES score probability, with accuracy, accordance, and discrimination (area under the curve (AUC) = 0.627). CONCLUSION: The student's grade was a significant influencing factor in medical students' perception of MSLE. The perceptions among the third and fourth graders got worse, probably due to the worrying changes in various aspects of MSLE during that period. The relevant and appropriate interventions to improve medical students' perceptions are urgently needed.

Molecular Crystal Structure Simulations and Structure-Magnetic Properties of LiFePO4 Composite Particles Optimized by La.

In this study LiFePO4/C composite particles were synthesized using five different carbon sources via a one-step sol-gel method. La-doped LiFePO4 was also synthesized using the sol-gel method. The XRD pattern of LixLayFePO4 (x = 0.9~1.0, y = 0~0.1) after being calcined at 700 °C for 10 h indicates that as the doping ratio increased, the sample's cell volume first increased then decreased, reaching a maximum value of 293.36 Å3 (x = 0.94, y = 0.06). The XRD patterns of Li0.92La0.08FePO4 after being calcined at different temperatures for 10 h indicate that with increasing calcination temperature, the (311) diffraction peak drifted toward a smaller diffraction angle. Similarly, the XRD patterns of Li0.92La0.08FePO4 after being calcined at 700 °C for different durations indicate that with increasing calcination times, the (311) diffraction peak drifted toward a larger diffraction angle. The infrared spectrum pattern of LixLayFePO4 (x = 0.9~1.0, y = 0~0.1) after being calcined at 700 °C for 10 h shows absorption peaks corresponding to the vibrations of the Li-O bond and PO43- group. An SEM analysis of LixLayFePO4 (x = 1, y = 0; x = 0.96, y = 0.04; x = 0.92, y = 0.08) after being calcined at 700 °C for 10 h indicates that the particles were irregular in shape and of uniform size. The hysteresis loops of Li0.92La0.08FePO4 after being calcined at 600 °C, 700 °C, or 800 °C for 10 h indicate that with increasing calcination temperature, the Ms gradually increased, while the Mr and Hc decreased, with minimum values of 0.08 emu/g and 58.21 Oe, respectively. The Mössbauer spectra of LixLayFePO4 (x = 1, y = 0; x = 0.96, y = 0.04; x = 0.92, y = 0.08) after being calcined at 700 °C for 10 h indicate that all samples contained Doublet(1) and Doublet(2) peaks, dominated by Fe2+ compounds. The proportions of Fe2+ were 85.5% (x = 1, y = 0), 89.9% (x = 0.96, y = 0.04), and 96.0% (x = 0.92, y = 0.08). The maximum IS and QS of Doublet(1) for the three samples were 1.224 mm/s and 2.956 mm/s, respectively.

Molecular detection, subtyping of Blastocystis sp. in migratory birds from nature reserves in northeastern China.

Migratory birds play an important role in the cross-regional transmission of zoonotic pathogens. Assessing the presence of zoonotic pathogens carried by migratory birds is critical for disease control. However, information about Blastocystis infection in the migratory birds is very limited. Thus, we conducted this study with the aim to explore the occurrence, prevalence and subtyping of Blastocystis in four breeds of migratory birds in northeastern China. From October 2022 to April 2023, a total of 427 fresh fecal samples were obtained from four breeds of migratory birds in five nature reserves in northeastern China, and screened for Blastocystis by PCR amplification. Twenty-one (4.92 %) of the studied samples were confirmed Blastocystis-positive, and two known zoonotic subtypes ST6 and ST7 were founded, with ST7 being the major subtype. Until now, we firstly reported the infection status and subtyping of Blastocystis in the migratory Greater White-Fronted Goose, White Stork, Oriental White Stork and Bean Goose in China. More importantly, these findings present further data on the genetic diversity and transmission routes of Blastocystis and further arouse public health concerns about this organism.

Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis.

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases.

Selection and Genetic Analysis of High Polysaccharide-Producing Mutants in Inonotus obliquus.

Inonotus obliquus, a medicinal fungus, has garnered significant attention in scientific research and medical applications. In this study, protoplasts of the I. obliquus HS819 strain were prepared using an enzymatic method and achieved a regeneration rate of 5.83%. To enhance polysaccharide production of I. obliquus HS819, atmospheric and room temperature plasma (ARTP) technology was employed for mutagenesis of the protoplasts. Through liquid fermentation, 32 mutant strains exhibiting diverse characteristics in morphology, color of the fermentation broth, mycelial pellet size, and biomass were screened. Secondary screening identified mutant strain A27, which showed a significant increase in polysaccharide production up to 1.67 g/L and a mycelial dry weight of 17.6 g/L, representing 137.67% and 15% increases compared to the HS819 strain, respectively. Furthermore, the fermentation period was reduced by 2 days, and subsequent subculture cultivation demonstrated stable polysaccharide production and mycelial dry weight. The genome resequencing analysis of the HS819 strain and mutant strain A27 revealed 3790 InDel sites and mutations affecting 612 functional genes associated with polysaccharide synthesis. We predict that our findings will be helpful for high polysaccharide production through genetic engineering of I. obliquus.

Predictive factors of postoperative complications related to free flap reconstruction in head and neck cancer patients admitted to intensive care unit: a retrospective cohort study.

BACKGROUND: The epidemiology and risk factors for postoperative complications related to free flap reconstruction in head and neck cancer patients admitted to the Intensive Care Unit (ICU) are unknown. METHODS: We performed a retrospective cohort study of patients with free flap reconstruction of head and neck cancer between September 2015 and April 2023 admitted to the ICU of Beijing Tongren Hospital. The univariate and multivariate analyses were used to explore the risk factors for postoperative complications related to free flap reconstruction admitted to ICU, including flap necrosis, bleeding, fistula, and infection. RESULTS: A total of 239 patients were included in this study, and 38 (15.9%) patients had postoperative complications related to free flap reconstruction. The median length of ICU stay was 1 day (interquartile range, 1-2 days). Multivariate analysis found that low BMI (P < 0.001), high postoperative CRP (P = 0.005), low hemoglobin (P = 0.012), and inadequate fluid intake (P < 0.05) were independent risk factors for complications. CONCLUSIONS: Postoperative complications related to free flap reconstruction were common in this ICU population. Careful fluid management and monitoring of CRP and hemoglobin levels may reduce complications.

Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models.

Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)-dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.

The output of cataract surgery performed by trained non-ophthalmologist physicians in rural areas: study of cataract outcomes and up-take of services report 7.

BACKGROUND: Cataract is the leading cause of blindness worldwide and surgery can restore vision in most patients. Some patients have little access to surgical services due to lack of cataract surgeons and the unaffordable costs. In 2005 we built a service model that trained rural non-ophthalmologist physicians to perform cataract surgeries in rural China. This study evaluates the long-term impacts of this model. METHODS: We conducted a retrospective cohort study to analyze patients' hand-written medical records and electronic outpatient record between January 2005 and December 2019 at two rural health clinics in Southern China. RESULTS: In total, 34,601 patients (49,942 eyes) underwent cataract surgery by non-ophthalmologist physicians from 2005 to 2019.Visual acuity was clearly documented in 38,251 eyes. Before surgery, the unaided distance visual acuity (UDVA) of 60.7% (23,205/38,251) eyes was less than 0.05 decimal. On the first day after surgery, the percentage of UDVA < 0.05 eyes was reduced to 6.0%, and 96.7% (36,980/38,251) of the eyes achieved a better UDVA compared to pre-operation. Surgical-related complications occurred in 218 eyes. The most common complication was posterior capsule rupture (114, 0.23%). 44.3% (15,341/34,601) of the patients chose to have a second eye cataract surgery (SECS) in the same clinic. At one of the outpatient clinics, 21,595 patients received basic eye care apart from cataract surgery between 2018 and 2020. CONCLUSIONS: Non-ophthalmologist physicians trained for cataract surgeries in rural clinics can improve cataract related visual acuity and basic eye care to the local population.

Therapeutically Fine-Tuning Autonomic Nervous System to Treat Sepsis: A New Perspective on the Immunomodulatory Effects of Acupuncture.

Recent studies have highlighted the immunomodulatory effects of acupuncture on sepsis and proposed novel non-pharmacological or bioelectronic approaches to managing inflammatory illnesses. Establishing rules for selectively activating sympathetic or vagal nerve-mediated anti-inflammatory pathways using acupuncture has valuable clinical applications. Over the years, studies have revealed the segmental modulatory role of acupuncture in regulating visceral function by targeting the autonomic nervous system (ANS). In this review, we aim to summarize recent findings on acupuncture in treating sepsis, focusing on the underlying ANS mechanism, as well as the rules of acupoint specificity, intensity, frequency, and other parameters utilized in these studies. Mechanistically, the immunomodulatory properties of the sympathetic nervous system have been highlighted. Furthermore, we explore the immunotherapeutic benefits of acupuncture in treating sepsis. A better understanding of the immunoregulatory mechanism of sympathetic nervous system may offer novel approaches for the development of therapeutics to treat or prevent a variety of inflammatory diseases.

Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.

Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

Targeted quantitative metabolomic and flavor objective quantification technique reveal the impact mechanism of shaking on black tea quality and non-volatile metabolites.

Shaking constitutes a pivotal technique for enhancing black tea quality; nevertheless, its impact on the transformation mechanism of non-volatile metabolites (NVMs) in black tea remains obscure. The present study aimed to investigate the impact of shaking-withering methods (SWM) and traditional-withering methods (TWM) on black tea quality and NVMs conversion. A total of 57 NVMs and 14 objective quantitative indicators were obtained. SWM enhanced sweetness and umami taste, as well as appearance and liquor color brightness of black tea. Eight key differential NVMs were identified by multivariate statistical and dose over threshold value analysis. Metabolic pathway and evolution law analysis revealed that SWM enhanced the oxidation of catechins and flavonol glycosides, promoted the decarboxylation of glutamic acid, then facilitated the formation of theaflavin-3,3'-digallate, finally enhanced the taste and color quality of black tea. This study offers theoretical guidance and technical support for the targeted processing of high-quality black tea.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Human birth tissue products as a non-opioid medicine to inhibit post-surgical pain.

Pain after surgery causes significant suffering. Opioid analgesics cause severe side effects and accidental death. Therefore, there is an urgent need to develop non-opioid therapies for managing post-surgical pain. Local application of Clarix Flo (FLO), a human amniotic membrane (AM) product, attenuated established post-surgical pain hypersensitivity without exhibiting known side effects of opioid use in mice. This effect was achieved through direct inhibition of nociceptive dorsal root ganglion (DRG) neurons via CD44-dependent pathways. We further purified the major matrix component, the heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM that has greater purity and water solubility than FLO. HC-HA/PTX3 replicated FLO-induced neuronal and pain inhibition. Mechanistically, HC-HA/PTX3 induced cytoskeleton rearrangements to inhibit sodium current and high-voltage activated calcium current on nociceptive neurons, suggesting it is a key bioactive component mediating pain relief. Collectively, our findings highlight the potential of naturally derived biologics from human birth tissues as an effective non-opioid treatment for post-surgical pain. Moreover, we unravel the underlying mechanisms of pain inhibition induced by FLO and HC-HA/PTX3.