Identification and validation of a novel cuproptosis signature for stratifying different prognostic, immune, metabolic, and therapeutic landscapes in pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic adenocarcinoma (PAAD) is a highly malignant cancer that urgently needs more effective therapeutic strategies. The discovery of cuproptosis brings great inspiration for the treatment and clinical assessment of cancers. MATERIALS AND METHODS: A novel cuproptosis-related (CR) risk signature was constructed using the Lasso regression analysis. Its prognostic value was assessed via a series of survival analyses and validated in four GEO cohorts. The effects of CR risk signature on tumor immune microenvironment (TIM) were explored through CIBERSORT, ESTIMATE, and ssGSEA algorithms. Using GESA, we investigated its associations with various patterns of programmed cell death (PCD) and the metabolism process. The somatic mutation features of each CR-risk group were also probed using 'maftools' R package and cBioPortal database. The potential linkages between CR risk score and the efficacy of multiple therapeutic approaches were elucidated using tumor mutation burden, the expressions of immune checkpoints, the TIDE score, and the GDSC database. Finally, we ascertained the biofunctions of LIPT1 (Lipoyltransferase 1) in pancreatic cancer (PC) cells through immunohistochemistry, qPCR (quantitative polymerase chain reaction), colony formation, and Transwell assays. RESULTS: LIPT1, LIAS (lipoyl synthase), PDP1 (Pyruvate dehydrogenase phosphatase1), and GCSH (Glycine cleavage system H protein) constituted the CR risk signature. The CR risk signature possessed a high prognostic value and could improve the traditional prognostic model. Moreover, the CR risk score was indicative of the changes in infiltration levels of CD8+T cells and macrophages, whereas it was not associated with the enrichment of various PCD patterns and multiple metabolic processes. As for therapeutic correlation, CR risk score was a potential biomarker for predicting the efficacy of ICBs but failed in targeted drugs and chemotherapeutic agents. Through qPCR and immunohistochemistry detection in clinical samples, we confirmed that LIPT1 was significantly downregulated in pancreatic adenocarcinoma (PAAD) samples. Experiments in vitro revealed that silencing LIPT1 promoted the proliferation, migration, and invasion of PANC-1 and SW1990 cells. CONCLUSIONS: The novel CR risk signature contributed to the risk stratification of PAAD patients. Cuproptosis regulatory genes, well represented by LIPT1, provided new insights into PAAD treatment and assessment.

[Diagnostic value of rapid antigen testing for the detection of SARS-CoV-2 infection].

Objective: To investigate the diagnostic value of rapid antigen test based on colloidal gold immunochromatographic assay for the detection of SARS-CoV-2 infection in symptomatic patients. Methods: From May 20 to June 5 2022, 76 hospitalized children and their 55 accompanying family members with confirmed SARS-CoV-2 infection in the COVID-19 isolation unit of the Children's Hospital of Fudan University (designated referral hospital for SARS-CoV-2 infection in Shanghai) enrolled. Their nasopharyngeal swab specimens were consecutively collected. The samples were tested for SARS-CoV-2 nucleic acid by real-time quantitative. SARS-CoV-2 antigen was tested by immunochromatography. The correlation between the antigen detection results and the change of the cycle threshold (Ct) values were evaluated, as well as the sensitivity and specificity of SARS-CoV-2 antigen detection at different periods after the onset of the disease. Kappa consistency test was conducted to investigate the consistency between the 2 diagnostic methods. Results: Of the enrolled SARS-CoV-2 symptomatic infections, 76 were children, including 41 males and 35 females, with an age of 5 (2, 9) years; 55 were accompanying families, including 8 males and 47 females, with an age of 38 (32, 41) years. All 478 samples were simultaneously tested for SARS-CoV-2 antigen and nucleic acid. In any period from disease onset to negative conversion of viral nucleic acid, the overall sensitivity of the rapid antigen test was 48.2% (119/247), the specificity was 98.3% (227/231), and antigen test and nucleic acid test showed moderate consistency (κ=0.46, P<0.05). The sensitivity of antigen test was 100% (82/82) when the Ct value was ≤25. And the sensitivity of antigen test was 8/10, 4/15 and 8.3% (3/36) when the Ct value was 26, 30 and 35, respectively. All antigen tests were negative when Ct value was >35. During the period of 1-2 days, 3-5 days, 6-7 days, 8-10 days and >10 days after onset, the sensitivity and specificity of SARS-CoV-2 antigen test were 5/8 and 5/5, 90.2% (37/41) and 5/5, 88.9% (24/27) and 2/5, 45.0% (36/80) and 94.1% (32/34), 18.7% (17/91) and 98.9% (183/185) respectively. The Ct values of nasopharyngeal swabs were<26 during 2 to 7 days after onset, 28.7±5.0 on day 8, 34.5±2.9 on day 13 and > 35 after 14 days, respectively. Conclusion: SARS-CoV-2 antigen test in the patients with SARS-CoV-2 infection shows acceptable sensitivity and specificity within 7 days after onset of disease, and the sensitivity was positively correlated with viral load and negatively correlated with onset time.

[Clinical analysis of liver chemistries in children and adolescent with 2019-nCoV infection].

Objective: To describe the clinical features of liver involvement in children and adolescent with 2019-nCoV infection. Methods: The clinical data of 77 hospitalized cases admitted to the Children's Hospital of Fudan University were collected from January 19 to November 28, 2020. The characteristics and risk factors of abnormal liver chemistries in children with laboratory-confirmed 2019-nCoV infection were analyzed. Results: Of the 77 cases, 44 were male (57.1%) and 33 were female (42.9%), with a median age of 10 years. 27(35.1%) were asymptomatic, 28(36.4%) had mild illness, 22(28.6%)had non-severe pneumonia. Hydroxychloroquine was used in 7 cases. Of the 75 children without underlying diseases, alanine aminotransferase was elevated in 1 case (1.5%, during hydroxychloroquine therapy), aspartate aminotransferase was elevated in 7 cases (10.3%), alkaline phosphatase was elevated in 7 cases (28%), and total bilirubin, direct bilirubin, albumin, international normalized ratio were in normal range. There was no statistical difference between the pneumonia group and the non-pneumonia group in term of liver chemistries (P > 0.05), same as between the elevated erythrocyte sedimentation rate group and the normal group. There was no aggravation of liver injury in the child with biliary atresia. The child with epilepsy showed no abnormal liver chemistries after infection. Conclusion: Children with 2019-nCoV infection had mild clinical symptoms with few cases of liver injury. The abnormal liver chemistries in children with COVID-19 infection may be related to the underlying disease and the use of antiviral drugs.

A dominant strain of Elizabethkingia anophelis emerged from a hospital water system to cause a three-year outbreak in a respiratory care center.

BACKGROUND: Elizabethkingia species are ubiquitous bacteria but uncommonly cause human infection. An outbreak of Elizabethkingia anophelis bacteraemia was observed in a respiratory care center of a tertiary hospital in Taiwan from 2015 to 2018. METHODS: Clinical and environmental isolates were collected for the outbreak investigation. Pulsed-field gel electrophoresis (PFGE) and complete-genome sequencing were conducted to elucidate the mechanism of transmission. FINDINGS: The three-year outbreak involved 26 patients with E. anophelis bacteraemia and the incidence significantly increased during the outbreak period compared with that observed from 2010 to 2014 (P<0.05). All 26 clinical isolates during the outbreak period belonged to a cluster by PFGE analysis. In contrast, the PFGE pattern was heterogeneous among comparative historical strains. Hospital tap water was highly contaminated by Elizabethkingia species (18/34, 52.9%); among that, five E. anophelis belonged to the outbreak cluster (5/18, 27.8%). As for the inanimate surface survey, 3.4% sites (4/117) revealed positive growth of E. anophelis including two from feeding tubes/bags and two from sputum suction regulators. All four isolates belonged to the outbreak clone. The outbreak strain had no apparent relationship to currently known E. anophelis strains worldwide through complete-genome sequencing analysis. Specific infection control strategies aimed at water source control and environmental disinfection were implemented subsequently and the outbreak ended in mid-2018. CONCLUSIONS: A specific E. anophelis strain was identified from a three-year outbreak. The elucidation of the mechanism of dominance and intra-hospital transmission is crucial for development of corresponsive infection control policies and outbreak control.

Defining Ischemic Core in Acute Ischemic Stroke Using CT Perfusion: A Multiparametric Bayesian-Based Model.

BACKGROUND AND PURPOSE: The Bayesian probabilistic method has shown promising results to offset noise-related variability in perfusion analysis. Using CTP, we aimed to find optimal Bayesian-estimated thresholds based on multiparametric voxel-level models to estimate the ischemic core in patients with acute ischemic stroke. MATERIALS AND METHODS: Patients with anterior circulation acute ischemic stroke who had baseline CTP and achieved successful recanalization were included. In a subset of patients, multiparametric voxel-based models were constructed between Bayesian-processed CTP maps and follow-up MRIs to identify pretreatment CTP parameters that were predictive of infarction using robust logistic regression. Subsequently CTP-estimated ischemic core volumes from our Bayesian model were compared against routine clinical practice oscillation singular value decomposition-relative cerebral blood flow <30%, and the volumetric accuracy was assessed against final infarct volume. RESULTS: In the constructed multivariate voxel-based model, 4 variables were identified as independent predictors of infarction: TTP, relative CBF, differential arterial tissue delay, and differential mean transit time. At an optimal cutoff point of 0.109, this model identified infarcted voxels with nearly 80% accuracy. The limits of agreement between CTP-estimated ischemic core and final infarct volume ranged from -25 to 27 mL for the Bayesian model, compared with -61 to 52 mL for oscillation singular value decomposition-relative CBF. CONCLUSIONS: We established thresholds for the Bayesian model to estimate the ischemic core. The described multiparametric Bayesian-based model improved consistency in CTP estimation of the ischemic core compared with the methodology used in current clinical routine.

MiR-30c exerts tumor suppressive functions in colorectal carcinoma by directly targeting BCL9.

OBJECTIVE: Colorectal carcinoma (CRC) remains a leading health threat worldwide due to its high mortality. MicroRNA (miR-30c) is an important tumor suppressor in various cancers. B cell lymphoma 9 (BCL9) is one of the candidate genes for cancers. The synergistic effects of miR-30c and BCL9 in CRC progression remain to be carefully elucidated. PATIENTS AND METHODS: Fifty pairs of CRC samples and matched adjacent non-tumor tissues were collected from Yantai Yuhuangding Hospital between 2015 and 2017. MiR-30c and BCL9 expression levels were measured by quantitative Real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cell lines. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the influence of miR-30c on the proliferation ability of CRC cells. Target Scan was used to predict the potential target of miR-30c. Then, luciferase assay was performed to confirm the prediction. In addition, we also investigated the biological influence of BCL9 on miR-30c-mediated functions in CRC. RESULTS: We found that miR-30c was significantly decreased in CRC tissues and cell lines while the BCL9 expression level was prominently increased in CRC tissues and cells. Additionally, the miR-30c expression was negatively correlated with BCL9 expressions in CRC tissues. Furthermore, the findings of this study also showed that BCL9 was a direct target of miR-30c in CRC and miR-30c could inhibit the CRC proliferation by binding to its 3'-UTR. CONCLUSIONS: This study showed that miR-30c overexpression inhibited CRC proliferation via the regulation of BCL9, suggesting that miR-30c may be a new molecular therapeutic target for CRC.

Bariatric surgery is associated with increased risk of new-onset inflammatory bowel disease: case series and national database study.

BACKGROUND: Case series suggest a possible association between bariatric surgery and incident IBD. AIM: The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD. METHODS: We first conducted a multi-institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC. RESULTS: A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en-Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52). CONCLUSION: New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.

Antibiotic strategies and clinical outcomes in critically ill patients with pneumonia caused by carbapenem-resistant Acinetobacter baumannii.

OBJECTIVES: This study aimed to investigate antibiotic prescribing patterns and effectiveness of different anti-carbapenem-resistant Acinetobacter baumannii (CRAB) strategies for CRAB pneumonia. METHODS: We conducted a multicentre, retrospective study in three hospitals. During 2010-2015, adult ICU patients with CRAB pneumonia treated with at least one antimicrobial agent covering the CRAB isolate in vitro for more than 2 days were included. We used multivariate logistic regression to analyse the associations of anti-CRAB strategies with ICU mortality and other clinical outcomes. RESULTS: Among 238 patients with CRAB pneumonia, tigecycline monotherapy (84, 35.3%) was the most common antibiotic strategy, followed by tigecycline with colistin (43, 18.1%), colistin monotherapy (34, 14.3%), colistin combination without tigecycline (33, 13.9%), tigecycline combination without colistin (32, 13.4%), and sulbactam-based therapy without tigecycline and colistin (12, 5.0%). In multivariate analysis, tigecycline-based therapy was associated with higher ICU mortality than non-tigecycline therapy (adjusted OR 2.30, 95% CI 1.19-4.46). There was no difference between colistin-based therapy and non-colistin therapy. Compared with tigecycline monotherapy, colistin monotherapy was associated with lower ICU mortality (aOR 0.30, 95% CI 0.10-0.88). Treatment failure analyses showed similar trends. Tigecycline-based therapy was associated with higher treatment failure rate than non-tigecycline therapy (aOR 2.51, 95% CI 1.39-4.54), whereas colistin-based therapy was associated with lower treatment failure rate than non-colistin-based therapy (aOR 0.48, 95% CI 0.27-0.86). CONCLUSIONS: Tigecycline was commonly prescribed for CRAB pneumonia. However, tigecycline-based therapy was associated with higher ICU mortality and treatment failure. Our study suggests that colistin monotherapy may be a better antibiotic strategy for CRAB pneumonia.

[Clinical epidemiology and antimicrobial resistance of nontyphoidal Salmonella enteric infections in children: 2012-2014].

OBJECTIVE: To understand the clinical epidemiology and manifestation of nontyphoidal Salmonella (NTS)enteric infections and serotypes and antibiotic resistance patterns of NTS in children. METHOD: All cases with probable acute bacterial inflammatory diarrhea were included into this study from the Children's Hospital of Fudan University during January 2012 through December 2014. Salmonella species and other major enteric bacteria were routinely isolated from the fresh stool sample of the enrolled patients at their first visit to the enteric clinic. Salmonella isolates were serotyped and tested for antimicrobial susceptibility testing using Kirby-Bauer method at the reference laboratory of Shanghai Municipal Center for Disease Control and Prevention. All enrolled cases had clinical records. The enumeration data were described by constituent ratio. RESULT: Of the enrolled 3 143 patients, 742 (23.6%) were confirmed to have Salmonella infections, and NTS was identified in 738 (23.5%) cases and Salmonella Paratyphi B was identified in 4 (0.1%) cases, respectively. The isolation rate of NTS exceeded diarrheagenic Escherichia coli (6.7%, 182/2 727), Campylobacter (4.1%, 129/3 143) and Shigella (2.4%, 77/3 143). Nine serogroups and 41 serovars were identified in 742 salmonella isolates. Salmonella Enteritidis and Salmonella Typhimurium were the most common serovars, representing 42.6% (316/742) and 28.2% (209/742) of isolates, respectively.NTS infections were prevalent year-round with a seasonal peak from May to October. The common symptoms included fever (57.5%, 424/738) and blood-in-stool (31.0%, 229/738). Antimicrobial susceptibility showed only 8 (1.1%) of 742 isolates sensitive to 16 tested antibiotics.Resistance to the current first-line antibiotics such as the third-generation and(or) fourth-generation cephalosporins (cefotaxime and cefepime), ciprofloxacin was detected in 10.0%(74/738), 8.1%(60/738) and 1.1%(8/738), respectively. CONCLUSION: NTS is the leading causative agent responsible for bacterial inflammatory diarrhea in Shanghainese children. The prevalence of NTS enteric infections show an increasing trend year by year. It is essential to continuously monitor the antimicrobial resistance of NTS and trace the source of infection to prevent and treat NTS infections in Shanghai.

Alendronate and risk of lower limb ischemic vascular events: a population-based cohort study.

UNLABELLED: While alendronate inhibits atherosclerosis experimentally, its effect on lower limb ischemia risk is unknown. Our results suggest that alendronate reduces the risk of lower limb ischemic vascular events requiring surgical interventions, including amputation. Our results are relevant for patients at risk of lower limb ischemia undergoing fragility fracture treatment. INTRODUCTION: This study aimed to determine the association between alendronate therapy and the risk of lower limb ischemic vascular events (i.e., bypass surgery, endovascular stenting, and major lower limb amputation for lower limb ischemia). METHODS: We used a nationwide population-based cohort of patients aged over 50 years diagnosed with a vertebral or hip fracture between January 1999 and June 2010. We compared the risk of lower limb ischemic vascular events between patients undergoing treatment with alendronate (n = 3,731) and an age- and sex-matched comparison group (n = 7,462) over 5 years of follow-up. Hazard ratios (HR) were estimated using Cox proportional regression analysis with adjustment for treatment status, comorbidities, and other variables. RESULTS: Ten patients (0.3 %) in the alendronate treatment group had a lower limb ischemic vascular event compared with 51 patients (0.7 %) in the comparison group. The incidence of lower limb ischemic vascular events was 8.4 (95 % CI, 4.0-15.5) per 10,000 person-years in the alendronate group and 21.8 (95 % CI, 16.2-28.7) per 10,000 person-years in the comparison group. The risk of a lower limb ischemic vascular event in the alendronate treatment group was lower (adjusted HR, 0.41; 95 % CI, 0.21-0.82). CONCLUSION: Alendronate treatment was associated with a reduced risk of lower limb ischemic vascular events among hip or vertebral fragility fracture patients.

Efficient high-peak-power AlGaInAs eye-safe wavelength disk laser with optical in-well pumping.

We have demonstrated an efficient high-peak-power AlGaInAs eye-safe wavelength disk laser at 1555 nm. The quantum defect and the thermal load are significantly reduced by pumping the quantum well directly. The overall conversion efficiency is enhanced over three times compared with the barrier pumping method. With a pump peak power of 3.7 kW, an output peak power of 0.52 kW is generated at a pulse repetition rate of 20 kHz.

High-efficiency Q-switched dual-wavelength emission at 1176 and 559 nm with intracavity Raman and sum-frequency generation.

An efficient Q-switched dual-wavelength laser with self-frequency Raman conversion in composite Nd:YVO(4) and intracavity sum-frequency generation in BBO is reported. With an input pump power of 17.5 W, average power of 0.53 W at the first-Stokes 1176 nm and average power of 1.67 W at the sum-frequency mixed 559 nm are simultaneously generated at a pulse repetition rate of 100 kHz, corresponding to a total conversion efficiency of 12.5%.

Compact efficient Q-switched eye-safe laser at 1525 nm with a double-end diffusion-bonded Nd:YVO4 crystal as a self-Raman medium.

We report on an efficient Q-switched eye-safe laser at 1525 nm with a double-end diffusion-bonded Nd:YVO(4) crystal as a self-Raman gain medium. A diffusion-bonded crystal not only reduces the thermal effects but also increase the interaction length for the stimulated Raman scattering. With an input pump power of 17.2 W, average power of 2.23 W at the first- Stokes wavelength of 1525 nm is generated at a pulse repetition rate of 40 kHz, corresponding to a conversion efficiency of 13%.

Subnanosecond mJ eye-safe laser with an intracavity optical parametric oscillator in a shared resonator.

We theoretically verify that the threshold of an intracavity optical parametric oscillator pumped by a passively Q-switched laser is entirely controlled by the bleach of the saturable absorber not by the signal output reflectivity. We use a series of different output couplers to optimize the output performance. With a signal output reflectivity of 15%, we experimentally achieve an efficient subnanosecond eye-safe laser with 3.3 mJ pulse energy and 1.5 MW peak power.

Passive Q switching of Er-Yb fiber laser with semiconductor saturable absorber.

A high-performance AlGaInAs quantum-well saturable absorber is developed for passively Q-switched Er-Yb double-clad fiber lasers at 1560 nm. With an incident pump power of 13.5 W, an average output power of 1.26 W with a pulse repetition rate of 12 kHz is obtained. The maximum peak power is greater than 500 W.

The cost-effectiveness of syndromic management for male sexually transmitted disease patients with urethral discharge symptoms and genital ulcer disease in Taiwan.

OBJECTIVE: To assess the cost-effectiveness of syndromic management for the treatment of sexually transmitted diseases (STD) in comparison with the strategies currently used in STD clinics in Taiwan. METHODS: Between July 2004 and June 2005, all male patients with genitourinary symptoms attending two hospitals were included in this study. Current clinical procedures (presumptive treatment and laboratory tests), aetiological diagnosis and syndromic management were compared in terms of diagnostic accuracy, treatment appropriateness, costs and effectiveness. RESULTS: 473 patients met the inclusion criteria and were enrolled in the study. 335 patients (71%) had urethral symptoms (discharge, dysuria or painful urination) and 138 (29%) had genital ulcers, sores and skin rashes. For the current approach, the sensitivity, specificity and positive predictive value (PPV) for the detection of chlamydial, gonococcal and combined forms of infection were 100%, 40.0% and 60.4%, respectively. In contrast, the sensitivity, specificity and PPV for the detection of syphilis were 100%, 86.7% and 70.2%, respectively. For syndromic management, the sensitivity, specificity and PPV detection of chlamydial, gonococcal and combined forms of infection were 85.0%, 40.0% and 56.4%, respectively. In contrast, the sensitivity, specificity and PPV for the detection of syphilis were 78.8%, 18.1% and 23.2%, respectively. The average cost of implementing a correct treatment using the current approach was US$54.27 and US$30.74 for urethritis and syphilis, respectively. For the aetiological approach, the average cost of implementing a correct treatment was US$32.83 and US$21.58 for urethritis and syphilis, respectively. For the syndromic approach, the average cost for a correct treatment was US$3.86 and US$14.30 for urethritis and syphilis, respectively. CONCLUSIONS: In this sample of patients attending STD clinics in Taiwan, syndromic management was found to be a more cost-effective protocol in terms of cost per treated STD patient compared with the current and aetiological protocols for STD.