Recent advances in the synthesis of chiral α-tertiary amines via transition-metal catalysis.

The significance of chiral α-tertiary amines in medicinal chemistry and drug development has been unquestionably established in the last few decades. α-Tertiary amines are attractive structural motifs for natural products, bioactive molecules and pharmaceuticals and are preclinical candidates. Their syntheses have been the focus of intensive research, and the development of new methods has continued to attract more and more attention. In this review, we present the progress in the last decade in the development of synthetic methods for the assembly of chiral ATAs via transition-metal catalysis. To date, the effective approaches in this area could be categorized into three strategies: enantioselective direct and indirect Mannich addition to ketimines; umpolung asymmetric alkylation of imine derivatives; and asymmetric C-N cross-coupling of tertiary alkyl electrophiles. Several related developing strategies for the synthesis of ATAs, such as hydroamination of alkenes, HAT amination approaches and the C-C coupling of α-aminoalkyl fragments, are also described in this article. These strategies have emerged as attractive C-C and C-N bond-forming protocols for enantioselective construction of chiral α-tertiary amines, and to some extent are complementary to each other, showing the prospect of application in medicinal chemistry and chemical biology.

Relationship between self-reported sleep and cognitive function: a specification curve analysis.

The relationship between self-reported sleep and cognitive function is complex; it is unclear whether self-reported sleep is a robust correlate of people's cognitive function. We address this gap by using a comprehensive large-scale dataset (N = 1054) coupled with a novel modeling approach, specification curve analysis (SCA), to test the association between self-reported sleep and cognitive function. The results of the SCA showed robust correlations between self-reported sleep and cognitive function, with poorer sleep associated with worse cognitive function. Furthermore, the correlations between sleep components and cognitive function were heterogeneous, with differences emerging across cognitive measures and domains. Specifically, daytime dysfunction was associated with the strongest effect on subjective cognitive function, whereas sleep duration and sleep efficiency had the strongest effect on objective cognitive function. Therefore, the relationship between self-reported sleep and cognition depends largely on what and how cognitive function is measured. Our findings guide measurement and domain selection for future research on the role of sleep in cognitive function.

Brønsted Acid Promoted Facile Synthesis of Benzoacridines from Aromatic Aldehydes and N-Phenyl Naphthylamines.

A facile method for the rapid synthesis of benzoacridines has been described. This protocol promoted by p-toluenesulfonic acid starts from aromatic aldehydes and N-phenyl naphthylamines, affording a variety of benzoacridines in 30-90 % yields under metal-free conditions. The present approach involves a cascade of condensation, Friedel-Crafts alkylation, annulation and dehydroaromatization in one pot.

Jaggeds/Notches promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Nanosensor-Driven Detection of Neuron-Derived Exosomal Aß42 with Graphene Electrolyte-Gated Transistor for Alzheimer's Disease Diagnosis.

Blood-based tests have sparked tremendous attention in non-invasive early diagnosis of Alzheimer's disease (AD), a most prevalent neurodegenerative malady worldwide. Despite significant progress in the methodologies for detecting AD core biomarkers such as Aß42 from serum/plasma, there remains cautious optimism going forward due to its controversial diagnostic value and disease relevance. Here, a graphene electrolyte-gated transistor biosensor is reported for the detection of serum neuron-derived exosomal Aß42 (NDE-Aß42), which is an emerging, compelling trove of blood biomarker for AD. Assisted by the antifouling strategy with the dual-blocking process, the noise against complex biological background was considerably reduced, forging an impressive sensitivity gain with a limit of detection of 447 ag/mL. An accurate detection of SH-SY5Y-derived exosomal Aß42 was also achieved with highly conformable enzyme-linked immunosorbent assay results. Importantly, the clinical analysis for 27 subjects revealed the immense diagnostic value of NDE-Aß42, which can outclass that of serum Aß42. The developed electronic assay demonstrates, for the first time, nanosensor-driven NDE-Aß42 detection, which enables a reliable discrimination of AD patients from non-AD individuals and even the differential diagnosis between AD and vascular dementia patients, with an accuracy of 100% and a Youden index of 1. This NDE-Aß42 biosensor defines a robust approach for blood-based confident AD ascertain.

HER2 Expression Associated with Clinical Characteristics and Prognosis of Urothelial Carcinoma in a Chinese Population.

BACKGROUND: The frequency of HER2 overexpression in bladder cancer is reported as 9%-61%. HER2 alteration correlates with aggressive disease in bladder cancer. Traditional anti-HER2 targeted therapy has failed to show clinical benefits in patients with advanced urothelial carcinoma . METHODS: The information on pathologically proven patients with urothelial carcinoma with detected HER2 status was collected from the database of Peking University Cancer Hospital. The HER2 expression, as well as its association with clinical characteristics and prognosis, was analyzed. RESULTS: A total of 284 consecutive patients with urothelial carcinoma were enrolled. HER2 was positive (IHC 2+/3+) in 44% of urothelial carcinoma. HER2 positivity was found more frequent in UCB than in UTUC (51% vs. 38%). Stage, radical surgery, and histological variant were associated with survival (P < .05). For metastatic patients, multivariate analysis shows that 3 indicators, including liver metastasis, the number of involved organs, and anemia, are independent risk factors of prognosis. Receiving immunotherapy or disitamab vedotin (DV) treatment is an independent protecting factor. The survival of patients with low HER2 expression was also significantly improved by the treatment of DV (P < .001). HER2 expression (IHC 1+, 2+, 3+) was associated with a better prognosis in this population. CONCLUSION: DV has improved the survival of patients with urothelial carcinoma in the real world. With the new-generation anti-HER2 ADC treatment, HER2 expression is no longer a poor prognostic factor.

An automatic FreshRib fracture detection and positioning system using deep learning.

OBJECTIVE: To evaluate the performance and robustness of a deep learning-basedautomatic freshrib fracture detection and positioningsystem (FRF-DPS). METHODS: CT scans of 18,172 participants admitted to eighthospitals from 2009.06 to 2019.03 were retrospectively collected. Patients were divided into development set (14,241), multi center internal test set (1,612), and external test set (2,319). In internal test set, sensitivity, false-positives (FPs) and specificity were used to assess fresh rib fracture detection performance at the lesion- and examination-levels. In external test set, the performance of detecting fresh rib fractures by radiologist and FRF-DPS were evaluated at lesion, rib, and examinationlevels. Additionally, the accuracy of FRF-DPS in rib positioning was investigated by the ground-truth labeling. RESULTS: In multicenter internal test set, FRF-DPS showed excellent performance at the lesion- (sensitivity: 0.933 [95%CI, 0.916-0.949], FPs: 0.50 [95%CI, 0.397-0.583]) and examination-level. In external test set, the sensitivity and FPs at the lesion-level of FRF-DPS (0.909 [95%CI, 0.883-0.926], p < 0.001; 0.379 [95%CI, 0.303-0.422], p = 0.001) were better than the radiologist (0.789 [95%CI, 0.766-0.807]; 0.496 [95%CI, 0.383-0.571]), so were the rib-and patient-levels. In subgroup analysis of CT parameters, FRF-DPS were robust (0.894-0.927). Finally, FRF-DPS(0.997 [95%CI, 0.992-1.000], p < 0.001) is more accurate than radiologist(0.981 [95%CI, 0.969-0.996]) in rib positioning and takes 20 times less time. CONCLUSION: FRF-DPS achieved high detection rate of fresh rib fractures with low FP values, and precise positioning of ribs, thus can be used in clinical practiceto improve the detection rate and work efficiency. ADVANCES IN KNOWLEDGE: Wedeveloped the FRF-DPS system which can detect fresh rib fractures and rib position, andevaluatedbyalarge amount of multicenter data.

Synchronous multiple primary malignant neoplasms in breast, kidney, and bilateral thyroid: A case report.

BACKGROUND: Multiple primary malignant neoplasms (MPMNs) are rare, while synchronous MPMNs (SMPMNs) are even less common. Owing to the progression of medical technology and the extension of life expectancy, its incidence is gradually increasing. CASE SUMMARY: Although reports of breast and thyroid dual cancers are common, cases of an additional diagnosis of kidney primary cancer within the same individual are rare. CONCLUSION: We present a case of simultaneous MPMN of three endocrine organs, reviewing the relevant literature to enhance our understanding of SMPMNs while emphasizing the increasingly important need for accurate diagnosis and multidisciplinary management whenever this challenging situation arises.

Iron, Ferroptosis, and Ischemic Stroke.

Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment of post-ischemic stroke remains a critical challenge. Recently, iron has emerged as a crucial factor in post-reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development.

Intestinal Knockout of Peroxisome Proliferator-activated Receptor-alpha Affects Structural Adaptation but not Liver Injury Following Massive Enterectomy.

BACKGROUND: Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of intestinal lipid transport and metabolism whose expression is selectively increased after SBR. Here we asked if attenuating intestinal PPARα signaling would prevent steatosis and liver injury after SBR. METHODS: Pparα was deleted selectively in adult mouse intestine using a tamoxifen-inducible Cre-LoxP breeding schema. Mice underwent 50% SBR. At 10 weeks post-operatively, metabolic phenotyping, body composition analysis, in vivo assessment of lipid absorption and intestinal permeability, and assessment of adaptation and liver injury was completed. RESULTS: Pparα intestinal knockout and littermate control mice were phenotypically similar in terms of weight trends and body composition after SBR. All mice demonstrated intestinal adaptation with increased villus height and crypt depth; however, Pparα intestinal knockout mice exhibited decreased villus growth at 10 weeks compared to littermate controls. Liver injury and fibrosis were similar between groups as assessed by serum AST and ALT levels, Sirius Red staining, and hepatic expression of Col1a1 and Acta2. CONCLUSIONS: Inducible intestinal deletion of Pparα influences structural adaptation but does not mitigate liver injury after SBR. These findings suggest that enterocyte PPARα signaling in adult mice is dispensable for resection-induced liver injury. The results are critical for understanding the contribution of intestinal lipid metabolic signaling pathways to the pathogenesis of hepatic injury associated with short bowel syndrome.

Simultaneous determination of twenty-nine active compounds in fuzhengjiedu granules by HPLC-QQQ-MS/MS.

As an empirical medicine of traditional Chinese medicine, Fuzhengjiedu Granules have shown an effect against COVID-19 in clinical and inflammatory animal models. It is formulated with eight herbs, including Aconiti Lateralis Radix Praeparata, Zingiberis Rhizoma, Glycyrrhizae Radix Et Rhizoma, Lonicerae Japonicae Flos, Gleditsiae Spina, Fici Radix, Pogostemonis Herba, and Citri Reticulatae Pericarpium. This study established a high-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS) method by simultaneously determining 29 active compounds in the granules with significant content differences. Separation by gradient elution using acetonitrile and water (0.1% formic acid) as mobile phases was performed on a Waters Acquilty UPLC T3 column (2.1 mm × 100 mm, 1.7 µm). A triple quadrupole mass spectrometer, operating in positive and negative ionization modes, was used for multiple reaction monitoring to detect the 29 compounds. All calibration curves showed good linear regression (r2 > 0.998). RSDs of precision, reproducibility, and stability of active compounds were all lower than 5.0%. The recovery rates were 95.4-104.9%, with RSDs< 5.0%. This method was successfully used to analyze the samples, and the results showed that 26 representative active components from 8 herbs were detected in the granules. While aconitine, mesaconitine, and hypaconitine were not detected, indicating that the existing samples were safe. The granules had the maximum and minimum content of hesperidin (27.3 ± 0.375 mg/g) and benzoylaconine (38.2 ± 0.759 ng/g). To conclude, a fast, accurate, sensitive, and reliable HPLC-QQQ-MS/MS method was established, which can simultaneously detect 29 active compounds that have a considerable difference in the content of Fuzhengjiedu Granules. This study can be used to control the quality and safety of Fuzhengjiedu Granules and provide a basis and guarantee for further experimental research and clinical application.

Anti-HER2 scFv-nCytc-Modified Lipid-Encapsulated Oxygen Nanobubbles Prepared with Bulk Nanobubble Water for Inducing Apoptosis and Improving Photodynamic Therapy.

Bulk nanobubbles fascinate scientists because of their stability over long periods of time and their ability to carry gases, leading to numerous potential applications. Considering the hypoxic tumor microenvironment and the advantages of bulk nanobubbles, lipid-encapsulated oxygen nanobubbles are prepared from free bulk oxygen nanobubbles in this study. The obtained carrier is then modified with a protein fused with the single-chain antibody of human epidermal growth factor receptor 2 (anti-HER2 scFv) and tandem-repeat cytochrome c (anti-HER2 scFv-nCytc) to enhance tumor targeting and induce tumor apoptosis. Copper phthalocyanine is used as the photosensitizer to demonstrate how the oxygen in the nanobubbles affects the efficiency of photodynamic therapy (PDT). The combination of anti-HER2 scFv-nCytc and PDT synergistically improves the therapeutic effect and alleviates hypoxia in tumors in vivo while causing little inflammatory response. Based on the findings, bulk nanobubble water shows promise in the targeted delivery of oxygen and can be combined with antibody therapy to enhance the efficiency of PDT.

Recent progress in targeted therapy for non-small cell lung cancer.

The high morbidity and mortality of non-small cell lung cancer (NSCLC) have always been major threats to people's health. With the identification of carcinogenic drivers in non-small cell lung cancer and the clinical application of targeted drugs, the prognosis of non-small cell lung cancer patients has greatly improved. However, in a large number of non-small cell lung cancer cases, the carcinogenic driver is unknown. Identifying genetic alterations is critical for effective individualized therapy in NSCLC. Moreover, targeted drugs are difficult to apply in the clinic. Cancer drug resistance is an unavoidable obstacle limiting the efficacy and application of targeted drugs. This review describes the mechanisms of targeted-drug resistance and newly identified non-small cell lung cancer targets (e.g., KRAS G12C, NGRs, DDRs, CLIP1-LTK, PELP1, STK11/LKB1, NFE2L2/KEAP1, RICTOR, PTEN, RASGRF1, LINE-1, and SphK1). Research into these mechanisms and targets will drive individualized treatment of non-small cell lung cancer to generate better outcomes.

Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury.

BACKGROUND: Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites. METHODS: Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice to determine the effect of jejunal (proximal SBR) versus ileocecal resection (distal SBR) on bile acid metabolism and liver injury. Tissues were harvested at 2 and 10-week postoperative timepoints. RESULTS: When compared with 50% proximal SBR, mice that underwent distal SBR exhibited less hepatic oxidative stress as verified by decreased mRNA expression of tumor necrosis factor-α (TNFα, p ≤ 0.0001), nicotinamide adenine dinucleotide phosphate oxidase (NOX, p ≤ 0.0001), and glutathione synthetase (GSS, p ≤ 0.05). Distal SBR mice also exhibited a more hydrophilic bile acid profile with reduced abundance of insoluble bile acids (cholic acid (CA), taurodeoxycholic acid (TCA), and taurolithocholic acid (TLCA)), and increased abundance of soluble bile acids (tauroursodeoxycholic acid (TUDCA)). In contrast with proximal SBR, ileocecal resection alters enterohepatic circulation leading to reduced oxidative stress and promotes physiological bile acid metabolism. CONCLUSION: These findings challenge the notion that preservation of the ileocecal region is beneficial in patients with short bowel syndrome. Administration of selected bile acids may present potential therapy to mitigate resection-associated liver injury. LEVEL OF EVIDENCE: III-Case-Control Study.

Laparoscopic total colectomy with ileorectal anastomosis and subtotal colectomy with antiperistaltic cecorectal anastomosis for slow transit constipation.

To investigate the clinical efficacy of laparoscopic total colectomy with ileorectal anastomosis (TC-IRA) and laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis (SC-ACRA) on adults with slow transit constipation (STC). One hundred and three patients with STC were assigned to the TC-IRA group (n = 53) and the SC-ACRA group (n = 50). The clinical data were analyzed. The surgery was successful in all patients (100%). Significantly (P = 0.03) more patients took anti-laxatives during hospitalization in the TC-IRA than the SC-ACRA group (39.62% vs. 20.00%). Abdominal pain and distension was present in 33.96% and 32.00% patients in the TC-IRA and SC-ACRA group, respectively, which decreased insignificantly (P > 0.05) to 18.87% and 18.00% 24 months after surgery, respectively. The postoperative Wexner and gastrointestinal quality of life (GIQLI) scores were not significantly different (P > 0.05) at all times after surgery in both groups. The defecation frequency decreased in both groups, and the average defecation frequency was significantly (P < 0.05) higher in the TC-IRA than the SC-ACRA group (3.91 ± 1.23 vs. 3.14 ± 1.15 times/day) at 3 months. Three months after surgery, significantly (P < 0.05) fewer patients were satisfied with defecation frequency in the TC-IRA than the SC-ACRA group (29 vs. 37 patients), whereas the number of patients who were willing to choose the same procedure again was not significantly (P > 0.05) different between the two groups. The WIS score of patients was significantly (P = 0.035) higher in the TC-IRA than the SC-ACRA group (6 vs. 5) 3 months later. TC-IRA and SC-ACRA are both safe and effective for adult slow transit constipation, and can significantly improve the quality of life of patients. Even though SC-ACRA has better early defecation frequency, postoperative antidiarrheal application and satisfaction, the long-term follow-up effects are similar.

Apatinib combined with camrelizumab in advanced acral melanoma patients: An open-label, single-arm phase 2 trial.

BACKGROUND: At present, immune monotherapy and combination therapy has not shown satisfactory effects on acral melanoma, and still no standard treatment is available for advanced acral melanoma. Here, a phase II trial was performed to explore the safety and efficacy of apatinib combined with camrelizumab in advanced acral melanoma patients as first-line therapy (NCT03955354). METHODS: Patients with pathologically confirmed, locally unresectable or metastatic treatment native acral melanoma received 250 mg apatinib once daily and camrelizumab 200 mg once every two weeks intravenously every 28-day cycle. The primary end-point was objective response rate and the secondary end-points were disease control rate, overall survival, progression-free survival and safety. RESULTS: Thirty patients were recruited between January 2015 and January 2022. Among them, 21 (70.0%) had stage IV, and a median tumour burden was 50 mm (range: 11-187). Objective response rate was 24.1%, and 7 of 29 patients had an anti-tumour response, including partial response (n = 5) and complete response (n = 2). Disease control rate was 82.8%, median progression-free survival was 7.39 months (confidence interval: 3.65-9.92), and median overall survival was 13.4 months (confidence interval: 1.9-25.0). Grade 3-4 treatment-related toxicity (grade 3 50.5%; grade 4 3.3%) included transaminase elevations, proteinuria, leukocytopenia, vomiting, diarrhea and drug-induced liver injury. No treatment-related mortality occurred. The mutations of TTN, MUC16, VPS13D, ALPK2 and SCUBE1 showed significant alterations with survival outcome. CONCLUSIONS: Apatinib combined with camrelizumab showed manageable safety profile and reasonable anti-tumour activity in advanced acral melanoma patients as first-line therapy.

Clinical applications of deep learning in breast MRI.

Deep learning (DL) is one of the most powerful data-driven machine-learning techniques in artificial intelligence (AI). It can automatically learn from raw data without manual feature selection. DL models have led to remarkable advances in data extraction and analysis for medical imaging. Magnetic resonance imaging (MRI) has proven useful in delineating the characteristics and extent of breast lesions and tumors. This review summarizes the current state-of-the-art applications of DL models in breast MRI. Many recent DL models were examined in this field, along with several advanced learning approaches and methods for data normalization and breast and lesion segmentation. For clinical applications, DL-based breast MRI models were proven useful in five aspects: diagnosis of breast cancer, classification of molecular types, classification of histopathological types, prediction of neoadjuvant chemotherapy response, and prediction of lymph node metastasis. For subsequent studies, further improvement in data acquisition and preprocessing is necessary, additional DL techniques in breast MRI should be investigated, and wider clinical applications need to be explored.

Intravenous Polymyxin B as Adjunctive Therapy to High-Dose Tigecycline for the Treatment of Nosocomial Pneumonia Due to Carbapenem-Resistant Acinetobacter baumannii and Klebsiella pneumoniae: A Propensity Score-Matched Cohort Study.

Although the combination of polymyxin and tigecycline is widely used in treating carbapenem-resistant bacterial infections, the benefit of this combination is still uncertain. To assess whether adding polymyxin B to the high-dose tigecycline regimen would result in better clinical outcomes than the high-dose tigecycline therapy in patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, we conducted a propensity score-matched cohort study in a single center between July 2019 and December 2021. Of the 162 eligible patients, 102 were included in the 1:1 matched cohort. The overall 14-day mortality in the matched cohort was 24.5%. Compared with high-dose tigecycline, the combination therapy was not associated with better clinical outcomes, and showed similar 14-day mortality (OR, 0.72, 95% CI 0.27-1.83, p = 0.486), clinical cure (OR, 1.09, 95% CI 0.48-2.54, p = 0.823), microbiological cure (OR, 0.96, 95% CI 0.39-2.53, p = 0.928) and rate of nephrotoxicity (OR 0.85, 95% CI 0.36-1.99, p = 0.712). Subgroup analyses also did not demonstrate any statistical differences. Based on these results, it is reasonable to recommend against adding polymyxin B to the high-dose tigecycline regimen in treating pneumonia caused by carbapenem-resistant K. pneumoniae and A. baumannii.

From Waterloo to the Great Wall: A retrospective, multicenter study on the clinical practice and cultural attitudes in the management of premature ejaculation, in China.

Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting selective serotonin reuptake inhibitor approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine Public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: Although the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study-the largest in the field-shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies.

A ratiometric luminescence sensing platform based on lanthanide-based silica nanoparticles for selective and sensitive detection of Fe3+ and Cu2+ ions.

Detection of Fe(III) and Cu(II) in water is highly desirable because their abnormal levels can cause serious harm to human health and environmental safety. In this work, a ratiometric luminescence sensing platform based on lanthanide-based silica nanoparticles was constructed for the detection of Fe3+ and Cu2+ ions. The terbium-silica nanoparticles (named SiO2@Tb) with dual-emission signals were successfully prepared by grafting Tb3+ ions onto trimellitic anhydride (TMA) functionalized silica nanospheres. It can serve as a ratiometric fluorescent probe for the detection of Fe3+ and Cu2+ ions in water with the green emission of Tb3+ ions as a response signal and the blue emission of silica nanospheres as the reference signal. Significantly, an easy-to-differentiate color change for visual detection was also realized. SiO2@Tb shows high sensitivity even in very low concentration regions towards the sensing of Fe3+ and Cu2+ with low detection limits of 0.75 µM and 0.91 µM, respectively. Moreover, the mechanism for the luminescence quenching of SiO2@Tb was systematically investigated, and was attributed to the synergetic effect of the absorption competition quenching (ACQ) mechanism and cation exchange. This study demonstrates that SiO2@Tb can be employed as a promising fluorescent probe for the detection of Fe3+ and Cu2+ ions, and the combination of lanthanide ions with silica nanoparticles is an effective strategy to construct a ratiometric fluorescent sensing platform for the determination of analytes in environmental detection.