Activatable Heavy-Atom-Free Photosensitizer with Large Stokes Shift and a NIR-II Emission Harnessing Rhodamine Ring-Opening Strategy.

Activatable photosensitizers (PSs) generating 1O2 only under specific conditions can minimize concomitant injury to normal tissues. Heavy-atom-free PSs hold the merits of low dark toxicity, long triplet-state lifetimes, good photostability, and relatively low cost. PSs with emission in the second near-infrared (NIR-II) window are highly valuable for deep-tissue, high-contrast imaging. Herein, we have designed and synthesized a series of heavy-atom-free PSs by a one-step reaction between an easily accessible rhodamine derivative and commercially available thiophene aldehydes. One of the as-prepared PSs, 2b-3T, exhibits emission maxima at 810 nm and tails to the NIR-II region at 1140 nm, together with large Stokes shift (178 nm). Importantly, the newly developed PSs, featuring functional carboxylic acid groups, present promising opportunities as versatile platforms for creating activatable PSs. To validate our concept, we developed Cu2+/pH-activatable PSs using the spirocyclization mechanism of rhodamine. Ultimately, we showcased the effectiveness of these innovative PSs in photodynamic therapy through in vitro experiments.

An NIR Type I Photosensitizer Based on a Cyclometalated Ir(III)-Rhodamine Complex for a Photodynamic Antibacterial Effect toward Both Gram-Positive and Gram-Negative Bacteria.

Type I photosensitizers offer an advantage in photodynamic therapy (PDT) due to their diminished reliance on oxygen levels, thus circumventing the challenge of hypoxia commonly encountered in PDT. In this study, we present the synthesis and comprehensive characterization of a novel type I photosensitizer derived from a cyclometalated Ir(III)-rhodamine complex. Remarkably, the complex exhibits a shift in absorption and fluorescence, transitioning from "off" to "on" states in aprotic and protic solvents, respectively, contrary to initial expectations. Upon exposure to light, the complex demonstrates the effective generation of O2- and ·OH radicals via the type I mechanism. Additionally, it exhibits notable photodynamic antibacterial activity against both Gram-positive and Gram-negative bacteria, demonstrated through in vitro and in vivo experiments. This research offers valuable insights for the development of novel type I photosensitizers.

The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA.

Sirtuins are pro-longevity genes with chromatin modulation potential, but how these properties are connected is not well understood. Here, we generated a panel of isogeneic human stem cell lines with SIRT1-SIRT7 knockouts and found that any sirtuin deficiency leads to accelerated cellular senescence. Through large-scale epigenomic analyses, we show how sirtuin deficiency alters genome organization and that genomic regions sensitive to sirtuin deficiency are preferentially enriched in active enhancers, thereby promoting interactions within topologically associated domains and the formation of de novo enhancer-promoter loops. In all sirtuin-deficient human stem cell lines, we found that chromatin contacts are rewired to promote aberrant activation of the placenta-specific gene PAPPA, which controls the pro-senescence effects associated with sirtuin deficiency and serves as a potential aging biomarker. Based on our survey of the 3D chromatin architecture, we established connections between sirtuins and potential target genes, thereby informing the development of strategies for aging interventions.

Diffusion kurtosis imaging and diffusion tensor imaging parameters applied to white matter and gray matter of patients with anti-N-methyl-D-aspartate receptor encephalitis.

Objectives: To compare parameters of diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) to evaluate which can better describe the microstructural changes of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients and to characterize the non-Gaussian diffusion patterns of the whole brain and their correlation with neuropsychological impairments in these patients. Materials and methods: DTI and DKI parameters were measured in 57 patients with anti-NMDAR encephalitis and 42 healthy controls. Voxel-based analysis was used to evaluate group differences between white matter and gray matter separately. The modified Rankin Scale (mRS) was used to evaluate the severity of the neurofunctional recovery of patients, the Montreal Cognitive Assessment (MoCA) was used to assess global cognitive performance, and the Hamilton Depression Scale (HAMD) and fatigue severity scale (FSS) were used to evaluate depressive and fatigue states. Results: Patients with anti-NMDAR encephalitis showed significantly decreased radial kurtosis (RK) in the right extranucleus in white matter (P < 0.001) and notably decreased kurtosis fractional anisotropy (KFA) in the right precuneus, the right superior parietal gyrus (SPG), the left precuneus, left middle occipital gyrus, and left superior occipital gyrus in gray matter (P < 0.001). Gray matter regions with decreased KFA overlapped with those with decreased RK in the left middle temporal gyrus, superior temporal gyrus (STG), supramarginal gyrus (SMG), postcentral gyrus (POCG), inferior parietal but supramarginal gyrus, angular gyrus (IPL) and angular gyrus (ANG) (P < 0.001). The KFA and RK in the left ANG, IPL and POCG correlated positively with MoCA scores. KFA and RK in the left ANG, IPL, POCG and SMG correlated negatively with mRS scores. KFA in the left precuneus and right SPG as well as RK in the left STG correlated negatively with mRS scores. No significant correlation between KFA and RK in the abnormal brain regions and HAMD and FSS scores was found. Conclusion: The microstructural changes in gray matter were much more extensive than those in white matter in patients with anti-NMDAR encephalitis. The brain damage reflected by DKI parameters, which have higher sensitivity than parameters of DTI, correlated with cognitive impairment and the severity of the neurofunctional recovery.

RGMa Participates in the Blood-Brain Barrier Dysfunction Through BMP/BMPR/YAP Signaling in Multiple Sclerosis.

The infiltration of inflammatory cells into the central nervous system (CNS) through the dysfunctional blood-brain barrier (BBB) was critical in the early stages of MS. However, the mechanisms underlying BBB dysfunction remain unknown. Repulsive guidance molecule-a (RGMa) is involved in the pathogenesis of multiple sclerosis (MS), but its role needs to be further explored. This study aimed to evaluate whether RMGa regulates BBB permeability in endothelial cells and MS, and if so, what mechanism may be involved. We created an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice and a human brain microvascular endothelial cell (HBMEC) culture. The permeability of the BBB is measured in response to various interventions. Our results showed that RGMa is expressed in the endothelial cells in HBMECs and EAE mice. RGMa and its signaling counterpart, bone morphogenetic protein 2 (BMP2)/bone morphogenetic protein receptor type II (BMPRII), were gradually increased as the disease progressed. Moreover, as EAE progressed and the BBB was disrupted, the downstream effector, yes-associated protein (YAP), as well as the tight junctional proteins zonula occludens 1 (ZO-1) and claudin-5, decreased significantly. The permeability assay revealed that lentivirus-induced RGMa overexpression in HBMECs caused a significant breakdown of the BBB, whereas RGMa knockdown significantly strengthens the integrity of the BBB. Furthermore, specifically activating BMPR II or inhibiting YAP based on RGMa knockdown results in a significant decrease of ZO-1 and claudin-5 in vitro. On the contrary, inhibition of BMPR II or activation of YAP after upregulating RGMa prevents the downregulation of ZO-1 and claudin-5 in HBMECs. In addition, serum-soluble RGMa (sRGMa) levels were significantly higher in MS patients, particularly in MS patients with Gd+ lesions, indicating that the BBB has been disrupted. In conclusion, this study shows that RGMa causes BBB dysfunction in endothelial cells via BMP2/BMPR II/YAP, resulting in BBB integrity disruption in MS and that it could be a novel therapeutic target for BBB permeability in MS.

Clinical Variables, Deep Learning and Radiomics Features Help Predict the Prognosis of Adult Anti-N-methyl-D-aspartate Receptor Encephalitis Early: A Two-Center Study in Southwest China.

Objective: To develop a fusion model combining clinical variables, deep learning (DL), and radiomics features to predict the functional outcomes early in patients with adult anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in Southwest China. Methods: From January 2012, a two-center study of anti-NMDAR encephalitis was initiated to collect clinical and MRI data from acute patients in Southwest China. Two experienced neurologists independently assessed the patients' prognosis at 24 moths based on the modified Rankin Scale (mRS) (good outcome defined as mRS 0-2; bad outcome defined as mRS 3-6). Risk factors influencing the prognosis of patients with acute anti-NMDAR encephalitis were investigated using clinical data. Five DL and radiomics models trained with four single or combined four MRI sequences (T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery imaging and diffusion weighted imaging) and a clinical model were developed to predict the prognosis of anti-NMDAR encephalitis. A fusion model combing a clinical model and two machine learning-based models was built. The performances of the fusion model, clinical model, DL-based models and radiomics-based models were compared using the area under the receiver operating characteristic curve (AUC) and accuracy and then assessed by paired t-tests (P < 0.05 was considered significant). Results: The fusion model achieved the significantly greatest predictive performance in the internal test dataset with an AUC of 0.963 [95% CI: (0.874-0.999)], and also significantly exhibited an equally good performance in the external validation dataset, with an AUC of 0.927 [95% CI: (0.688-0.975)]. The radiomics_combined model (AUC: 0.889; accuracy: 0.857) provided significantly superior predictive performance than the DL_combined (AUC: 0.845; accuracy: 0.857) and clinical models (AUC: 0.840; accuracy: 0.905), whereas the clinical model showed significantly higher accuracy. Compared with all single-sequence models, the DL_combined model and the radiomics_combined model had significantly greater AUCs and accuracies. Conclusions: The fusion model combining clinical variables and machine learning-based models may have early predictive value for poor outcomes associated with anti-NMDAR encephalitis.

Deep Learning-Enabled Identification of Autoimmune Encephalitis on 3D Multi-Sequence MRI.

BACKGROUND: Autoimmune encephalitis (AE) is a noninfectious emergency with severe clinical attacks. It is difficult for the earlier diagnosis of acute AE due to the lack of antibody detection resources. PURPOSE: To construct a deep learning (DL) algorithm using multi-sequence magnetic resonance imaging (MRI) for the identification of acute AE. STUDY TYPE: Retrospective. POPULATION: One hundred and sixty AE patients (90 women; median age 36), 177 herpes simplex virus encephalitis (HSVE) (89 women; median age 39), and 184 healthy controls (HC) (95 women; median age 39) were included. Fifty-two patients from another site were enrolled for external validation. FIELD STRENGTH/SEQUENCE: 3.0 T; fast spin-echo (T1 WI, T2 WI, fluid attenuated inversion recovery imaging) and spin-echo echo-planar diffusion weighted imaging. ASSESSMENT: Five DL models based on individual or combined four MRI sequences to classify the datasets as AE, HSVE, or HC. Reader experiment was further carried out by radiologists. STATISTICAL TESTS: The discriminative performance of different models was assessed using the area under the receiver operating characteristic curve (AUC). The optimal threshold cut-off was identified when sensitivity and specificity were maximized (sensitivity + specificity - 1) in the validation set. Classification performance using confusion matrices was reported to evaluate the diagnostic value of the models and the radiologists' assessments before being assessed by the paired t-test (P < 0.05 was considered significant). RESULTS: In the internal test set, the fusion model achieved the significantly greatest diagnostic performance than single-sequence DL models with AUCs of 0.828, 0.884, and 0.899 for AE, HSVE, and HC, respectively. The model demonstrated a consistently high performance in the external validation set with AUCs of 0.831 (AE), 0.882 (HSVE), and 0.892 (HC). The fusion model also demonstrated significantly higher performance than all radiologists in identifying AE (accuracy between the fuse model vs. average radiologist: 83% vs. 72%). DATA CONCLUSION: The proposed DL algorithm derived from multi-sequence MRI provided desirable identification and classification of acute AE. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

A case report of early application of veno-arterial extracorporeal membrane oxygenation in amniotic fluid embolism.

RATIONALE: Amniotic fluid embolism (AFE) is a rare obstetrical complication and is a leading cause of maternal death in developed countries. Despite the development of supportive therapeutic measures, the mortality rate remains high. PATIENT CONCERNS: A 38-year-old nulliparous pregnant woman, who underwent in vitro fertilization-embryo transfer, was admitted for labor at 37 weeks' gestation. Approximately 30 minutes after delivery of the placenta, the puerpera developed postpartum hemorrhage with uterine atony. Soon after, the patient experienced hypotension, repeated cardiac arrest, refectory hypoxia, and disseminated intravascular coagulopathy. DIAGNOSIS: AFE is diagnosed clinically. The pregnant woman in this case fulfilled the diagnostic criteria for AFE: acute hypotension, cardiac arrest, acute hypoxia, and coagulation disorders within approximately 30 minutes after delivery of the placenta. INTERVENTIONS: The patient was intubated, connected to a ventilator, and was administered a high dose of vasoactive drugs to maintain blood pressure and underwent an emergency hysterectomy. Considering the risk for recurrent cardiac arrest and severe refractory hypoxia, venoarterial extracorporeal membrane oxygenation was initiated and discontinued as soon as cardiac function was restored based on serial bedside ultrasound assessment. OUTCOMES: The patient stabilized on day 7 in the intensive care unit and was transferred to the obstetrics ward and, 1 week later, was discharged with no complications. Two months later, follow-up revealed that the patient was in good condition. LESSON: Serial bedside ultrasound was crucial for assessing cardiac function and optimal weaning. Timely application of venoarterial extracorporeal membrane oxygenation and weaning was significant to avoid the occurrence of complications and improve long-term outcomes.

Prediction of unenhanced lesion evolution in multiple sclerosis using radiomics-based models: a machine learning approach.

BACKGROUND: The volume change of multiple sclerosis (MS) lesion is related to its activity and can be used to assess disease progression. Therefore, the purpose of this study was to develop radiomics models for predicting the evolution of unenhanced MS lesions by using different kinds of machine learning algorithms and explore the optimal model. METHODS: In this prospective observation, 45 follow-up MR images obtained in 36 patients with MS (mean age 32.53±10.91; 23 women, 13 men) were evaluated. The lesions will be defined as interval activity and interval inactivity, respectively, based on the percentage of enlargement or reduction of the lesion >20% in the follow-up MR images. We extracted radiomic features of lesions on FLAIR images, and used recursive feature elimination (RFE), ReliefF algorithm and least absolute shrinkage and selection operator (LASSO) for feature selection, then three classification models including logistic regression, random forest and support vector machine (SVM) were used to build predictive models. The performance of the models were evaluated based on the sensitivity, specificity, precision, negative predictive value (NPV) and receiver operating characteristic curve (ROC) curves analyses. RESULTS: 135 interval inactivity lesions and 110 interval activity lesions were registered in our study. A total of 972 radiomics features were extracted, of which 265 were robust. The consistency and effectiveness of model performance were compared and verified by different combinations of feature selection and machine learning methods in different K-fold cross-validation strategies where K ranges from 5 to 10, thus demonstrating the stability and robustness. SVM classifier with ReliefF algorithm had the best prediction performance with an average accuracy of 0.827, sensitivity of 0.809, specificity of 0.841, precision of 0.921, NPV of 0.948 and the areas under the ROC curves (AUC) of 0.857 (95% CI: 0.812-0.902) in the cohorts. CONCLUSION: The results demonstrated that the radiomics-based machine learning model has potential in predicting the evolution of MS lesions.

Individualized Study of Posterior Hemivertebra Excision and Short-Segment Pedicle Screw Fixation for the Treatment of Congenital Scoliosis.

OBJECTIVES: To compare the surgical effect of children with symmetrical screw fixation and asymmetric screw fixation during posterior hemivertebra excision and short-segment pedicle screw fixation for the treatment of congenital scoliosis (CS). METHODS: A total of 30 children with CS who underwent posterior hemivertebra excision and short-segment bilateral pedicle screw fixation in our hospital from 2012 to 2018 were retrospectively included and were divided into two groups: symmetric fixation group (n = 18) and asymmetric fixation group (n = 12). The total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, coronal balance, and apical vertebra translation were measured in the coronal plane. The segmental kyphosis, thoracic kyphosis, lumbar lordosis, and sagittal balance were measured in the sagittal plane. RESULTS: Of the 30 children, 28 hemivertebrae were resected. Twenty-two children had one hemivertebra, three had two hemivertebrae, and five were rib deformities. The average operation time was 268 min (180-420 min). The average blood loss was 291 mL (150-550 mL). The average follow-up was 21.1 months (12-47 months). For symmetric fixation group and there were significant differences among postoperative and follow-up parameters including the total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, apical vertebra translation and segmental kyphosis compared with those of preoperative parameters (P < 0.05). The postoperative coronal balance was significantly lower than preoperative coronal balance (P < 0.05). The follow-up thoracic kyphosis was significantly higher than preoperative and postoperative thoracic kyphosis (P < 0.05). For asymmetric fixation group, the postoperative and follow-up parameters including the total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, apical vertebra translation, and segmental kyphosis had statistical differences compared with those of preoperative parameters (P < 0.05). The postoperative sagittal balance was significantly higher than preoperative postoperative (P < 0.05). There were no significant differences in the postoperative and follow-up correction rate and correction loss between the two groups (P > 0.05). There were three complications in 30 children in our study, including two cases who had poor wound healing, and the wound healed smoothly after half a month of sterile dressing change. Postoperative curve progression occurred in one case after T12 and L3 hemivertebra resection and thoracic hemivertebra resection was planned again. CONCLUSION: For pedicles which were difficult for screw fixation, adjacent segments can be chosen for screw fixation and it is safe and effective for vertebral pedicles ≤3 without internal fixation.

miRNA-214 Protects Sepsis-Induced Myocardial Injury.

Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. The underlying mechanisms associated with sepsis-induced myocardial injury (SIMI) include impaired cardiac contractility, excessive cardiac inflammation, oxidative stress, cardiomyocyte apoptosis, and so on. SIMI is usually accompanied with dynamic changes of microRNAs (miRNAs) expression. And previous studies have shown that miR-214 plays a vital role in the protection of cardiomyocyte subjected to oxidative stress. In this study, we aimed to test whether miRNA-214 plays any roles in sepsis-induced myocardial injury. We performed quantitative real-time polymerase chain reaction in the septic mouse model induced by cecal ligation and puncture (CLP) and found the expression of miR-214 was upregulated. Then we transfected with the miRNA-214 precursor (pre-miR-214) to upregulate miR-214 expression and with the miR-214 inhibitor (anti-miR-214) to downregulate miR-214 expression respectively. Pre-miR-214 mouse model, anti-miR-214 mouse model, and wild-type mice were subjected to CLP or sham surgery. We observed that compared with control wild types, cardiac function, inflammatory response, the degree of myocardial injury, and myocyte apoptosis were remarkably alleviated in CLP-treated pre-miR-214 mice and aggravated in CLP-treated anti-miR-214 mice. Taken together, our study reveals that miR-214 has a protective effect in SIMI and thereby may provide a potential novel approach to treat SIMI.

Surgical versus Nonsurgical Treatments of Acute Primary Patellar Dislocation with Special Emphasis on the MPFL Injury Patterns.

The objective of the present study was to compare the clinical results of the surgical versus nonsurgical treatments of acute primary patellar dislocations with a medial patellofemoral ligament (MPFL) injury in the nonoverlap region with the vastus medialis oblique. In this study, 62 patients with an acute patellar dislocation and a concurrent MPFL injury in the nonoverlap region were randomly divided into two groups based on their birth years (even vs. odd years) and received either surgical or nonsurgical treatment. Of the 62 eligible patients, 30 were in the nonsurgical treatment group (Group 1) and 32 were in the surgical group (Group 2). Patellar stability tests and the Kujala knee questionnaire were performed, and radiographs were evaluated for patellar tilt and the lateral shift ratio by two blinded investigators. An osteochondral injury was noted in six (23.1%) patients from Group 1 and five (16.7%) patients from Group 2, with no statistical difference between the two groups. The mean Kujala score was 80.19 ± 5.07 and 93.57 ± 4.03 (p < 0.001) between the surgical and nonsurgical groups, respectively. The mean patellar tilt was 8.96 ± 1.64 and 6.83 ± 1.44 degrees (p < 0.001) and the lateral shift ratio was 11.08 ± 1.99 and 9.23 ± 1.96 (p = 0.001) between the surgical and nonsurgical groups, respectively. This study showed that the surgical treatment of MPFL injuries in the nonoverlap region achieved better clinical outcomes and improved subjective knee function compared with conservative therapy. Surgery should therefore be considered as the treatment of choice for these specific injuries.

Improved ACL reconstruction outcome using double-layer BPTB allograft compared to that using four-strand hamstring tendon allograft.

BACKGROUND: This study compared the clinical outcomes of anterior cruciate ligament reconstruction using double-layer bone-patellar tendon-bone (DBPTB) allografts and four-strand hamstring (4SHS) grafts. METHODS: This prospective randomized controlled trial included 101 patients. Of these, 50 patients received DBPTB allografts, and 51 received 4SHS grafts. Evaluations included KT-1000 arthrometer measurements, Lachman tests, pivot-shift tests, the International Knee Documentation Committee (IKDC) classification and Lysholm scores at three year postoperative follow-up. RESULTS: Two DBPTB patients (four percent) and nine 4SHS patients (17.6%) had graft failures, which was significantly different (P=0.028). The DBPTB group had significantly better Lachman test, IKDC knee score and Lysholm score results than the 4SHS group (P<0.05). However, these differences were below the threshold for clinical significance. CONCLUSIONS: DBPTB allografts had fewer graft failures at three years than 4SHS grafts for anterior cruciate ligament reconstruction; and there were statistically significant differences but not clinically significant differences between DBPTB and 4SHS grafts in terms of the KT1000 test, IKDC and Lysholm scores.