A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting.

N-methyl-D-aspartate receptors (NMDARs) are crucial for neuronal development and synaptic plasticity. Dysfunction of NMDARs is associated with multiple neurodevelopmental disorders, including epilepsy, autism spectrum disorder, and intellectual disability. Understanding the impact of genetic variants of NMDAR subunits can shed light on the mechanisms of disease. Here, we characterized the functional implications of a de novo mutation of the GluN2A subunit (P1199Rfs*32) resulting in the truncation of the C-terminal domain. The variant was identified in a male patient with epileptic encephalopathy, multiple seizure types, severe aphasia, and neurobehavioral changes. Given the known role of the CTD in NMDAR trafficking, we examined changes in receptor localization and abundance at the postsynaptic membrane using a combination of molecular assays in heterologous cells and rat primary neuronal cultures. We observed that the GluN2A P1199Rfs*32-containing receptors traffic efficiently to the postsynaptic membrane but have increased extra-synaptic expression relative to WT GluN2A-containing NMDARs. Using in silico predictions, we hypothesized that the mutant would lose all PDZ interactions, except for the recycling protein Scribble1. Indeed, we observed impaired binding to the scaffolding protein postsynaptic protein-95 (PSD-95); however, we found the mutant interacts with Scribble1, which facilitates the recycling of both the mutant and the WT GluN2A. Finally, we found that neurons expressing GluN2A P1199Rfs*32 have fewer synapses and decreased spine density, indicating compromised synaptic transmission in these neurons. Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function variant with altered membrane localization in neurons and provide mechanistic insight into disease etiology.

Assessing Left Ventricular Systolic Function in Patients with Pregnancy-Induced Hypertension Using Three-Dimensional Speckle Tracking Technology.

Objective: This study investigates the clinical utility of three-dimensional speckle tracking technology in assessing left ventricular systolic function in pregnancy-induced hypertension syndrome (PIH). Methods: We retrospectively enrolled 70 patients with diagnosed PIH treated at our institution between July 2019 and August 2021 as the study group. A total of 70 healthy pregnant women undergoing routine antenatal examinations at the same institution during the same period were included in the control group. Two-dimensional conventional echocardiography measured left ventricular parameters in both groups. Three-dimensional speckle tracking technology analyzed Left Ventricular Global Longitudinal Peak Strain (LVGLS), Left Ventricular Global Radial Peak Strain (LVGRS), and Left Ventricular Global Circumferential Peak Strain (LVGCS). Differences in left ventricular systolic function and pregnancy outcomes were compared. Results: In the study group, LVEDD, LVPWTd, and IVSTd (47.67±4.88, 10.68±1.21, 11.24±1.03) exceeded those in the control group (45.21±5.65, 8.17±0.98, 8.91±0.37). LVEF (62.12±5.63) was lower than the control group (65.25±5.17) (all P < .05). LVGLS, LVGCS, and LVGAS in the study group (-15.66±1.07, -20.17±2.89, -23.17±3.43) were higher than the control group (-20.14±1.27, -25.17±1.36, -37.68±3.29), while LVGRS (30.29±3.61) was lower than the control group (34.18±4.08) (all P < .05). The study group had 72.86% natural deliveries and 27.14% cesarean sections; the control group had 31.43% natural deliveries and 68.57% cesarean sections (all P < .05). Weeks of delivery and birth weight in the study group (36.87±1.23, 2.71±0.41) were lower than the control group (38.96±1.54, 3.41±0.78) (both P < .05). Conclusions: Compared to traditional methods, three-dimensional speckle tracking technology more sensitively detects left ventricular strain and rotation in PIH patients. It holds clinical relevance in early left ventricular dysfunction detection, effectively mitigating adverse pregnancy outcomes and warranting clinical adoption and application.

Integrated metabolic and transcriptional analysis reveals the role of carotenoid cleavage dioxygenase 4 (IbCCD4) in carotenoid accumulation in sweetpotato tuberous roots.

BACKGROUND: Plant carotenoids are essential for human health, having wide uses in dietary supplements, food colorants, animal feed additives, and cosmetics. With the increasing demand for natural carotenoids, plant carotenoids have gained great interest in both academic and industry research worldwide. Orange-fleshed sweetpotato (Ipomoea batatas) enriched with carotenoids is an ideal feedstock for producing natural carotenoids. However, limited information is available regarding the molecular mechanism responsible for carotenoid metabolism in sweetpotato tuberous roots. RESULTS: In this study, metabolic profiling of carotenoids and gene expression analysis were conducted at six tuberous root developmental stages of three sweetpotato varieties with different flesh colors. The correlations between the expression of carotenoid metabolic genes and carotenoid levels suggested that the carotenoid cleavage dioxygenase 4 (IbCCD4) and 9-cis-epoxycarotenoid cleavage dioxygenases 3 (IbNCED3) play important roles in the regulation of carotenoid contents in sweetpotato. Transgenic experiments confirmed that the total carotenoid content decreased in the tuberous roots of IbCCD4-overexpressing sweetpotato. In addition, IbCCD4 may be regulated by two stress-related transcription factors, IbWRKY20 and IbCBF2, implying that the carotenoid accumulation in sweeetpotato is possibly fine-tuned in responses to stress signals. CONCLUSIONS: A set of key genes were revealed to be responsible for carotenoid accumulation in sweetpotato, with IbCCD4 acts as a crucial player. Our findings provided new insights into carotenoid metabolism in sweetpotato tuberous roots and insinuated IbCCD4 to be a target gene in the development of new sweetpotato varieties with high carotenoid production.

Patient outcomes following thyroid surgery for thyrotoxicosis.

OBJECTIVE: Total thyroidectomy can be used as a definitive treatment modality for thyrotoxicosis. This study assessed the outcomes of patients treated with surgery at a single secondary care site. METHOD: A retrospective cohort study was conducted analysing consecutive patients who underwent thyroid surgery for thyrotoxicosis between 24 November 2000 and 26 April 2019 (n = 595). RESULTS: Total thyroidectomy was performed in 95.4 per cent of patients. Two-thirds of patients had Graves' disease histology. Of patients, 22.8 per cent became transiently hypothyroid whilst on levothyroxine (thyroid hormone replacement therapy). Transient and persistent hypocalcaemia was present in 23.3 per cent and 2.8 per cent of patients respectively. Recurrent laryngeal nerve palsy was transient and persistent in 3.6 per cent and 0.3 per cent respectively. Of patients, 2.5 per cent developed post-operative haematomas that required surgical evacuation in the operating theatre. CONCLUSION: The overall complication rate for thyroid surgery is higher in thyrotoxic than in euthyroid patients. Compared to other treatment modalities, total thyroidectomy appears to be the most effective, definitive means of managing Graves' disease.

Physiologically Based Pharmacokinetic Modeling To Guide Management of Drug Interactions between Elexacaftor-Tezacaftor-Ivacaftor and Antibiotics for the Treatment of Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing. The CYP3A-mediated DDIs between ETI and the NTM therapies rifabutin, clarithromycin, and clofazimine were evaluated using physiologically based pharmacokinetic (PBPK) modeling by incorporating demographic and physiological "system" data with drug physicochemical and in vitro parameters. Models were verified and then applied to predict untested scenarios to guide continuation of ETI during antibiotic treatment, using ivacaftor as the most sensitive CYP3A4 substrate. The predicted area under the concentration-time curve (AUC) ratios of ivacaftor when coadministered with rifabutin, clofazimine, or clarithromycin were 0.31, 2.98, and 9.64, respectively, suggesting moderate and strong interactions. The simulation predicted adjusted dosing regimens of ETI administered concomitantly with NTM treatments, which required delayed resumption of the standard dose of ETI once the NTM treatments were completed. The dosing transitions were determined based on the characteristics of the perpetrator drugs, including the mechanism of CYP3A modulation and their elimination half-lives. This study suggests increased doses of elexacaftor/tezacaftor/ivacaftor 200/100/450 mg in the morning and 100/50/375 mg in the evening when ETI is coadministered with rifabutin and reduced doses of elexacaftor/tezacaftor 200/100 mg every 48 h (q48h) and ivacaftor 150 mg daily or a dose of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg q72h when coadministered with clofazimine or clarithromycin, respectively. Importantly, the PBPK simulations provide evidence in support of the use of treatments for NTM in pwCF receiving concomitant dose-adjusted ETI therapy.

Accurate staging of non-metastatic colon cancer with CT: the importance of training and practice for experienced radiologists and analysis of incorrectly staged cases.

PURPOSE: To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists. METHODS: Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls. RESULTS: Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3-4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part. CONCLUSION: The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.

Markers of Iron Metabolism and Stroke Risk: Cross-Sectional and Longitudinal Findings from the China Health and Nutrition Survey (CHNS).

BACKGROUND: The association of iron metabolism or status with the stroke risk remains unclear. We aimed to examine the associations between markers of iron metabolism or status and stroke risk using data from the China Health and Nutrition Survey (CHNS). METHODS: Overall, 8589 in the CHNS in 2009, and 7290 participants between 2009 and 2015 were included in the cross-sectional and longitudinal analyses, respectively. Markers included hemoglobin, ferritin (FET), transferrin (TRF), soluble transferrin receptor (sTRF-R), and ratio of sTRF-R/log FET (sTfR-F index). Multivariable logistic regression and Cox proportional hazards models were used to analyze the associations between those markers and risk of stroke. Age, gender, high-sensitivity CRP (hsCRP), body mass index (BMI), current smoking, drinking status, diabetes and hypertension were included as potential confounding factors. RESULTS: We observed longitudinal associations of hemoglobin (HR: 1.54, 95% CI: 1.15 - 2.06, P = 0.004), and sTfR-F index (HR: 0.68, 95% CI: 0.46 - 0.99, P = 0.044) with stroke risk among the participants whose BMI ≤ 23 kg/m2. In addition, FET levels were significantly associated with stroke risk among female (HR: 1.45, 95% CI: 1.00 - 2.09, P = 0.049) after a median of 6.1 years follow-up. Hemoglobin, FET, TRF, sTRF-R, and sTfR-F index were not associated with the risk of stroke in overall analyses. CONCLUSION: FET among female, hemoglobin and sTfR-F index among those BMI ≤ 23 kg/m2 may be contributing factors for stroke.

Combined diagnosis of ultrasonic elastography and BI-RADS classification increases diagnostic value in female patients with breast neoplasms.

OBJECTIVE: This study was designed to investigate the clinical value of ultrasonic elastography combined with the Breast Imaging Reporting and Data System (BI-RADS) classification in patients with breast neoplasms. METHODS: A retrospective observational study was conducted on 89 patients with breast neoplasms hospitalized from June 2017 to June 2018. All the enrolled patients had received ultrasound examinations. The diagnostic value of ultrasonic elastography, BI-RADS classification, and the combined diagnosis for breast neoplasms was analyzed. RESULTS: The postoperative pathological examination showed 51 cases of benign lesions and 38 cases of malignant lesions among the 89 cases. The detection of the focal zone revealed 75 benign and 44 malignant lesions. Ultrasonic elastography misdiagnosed 8 malignant lesions as benign and 17 benign lesions as malignant; BI-RADS classification misdiagnosed 7 malignant lesions as benign and 15 benign lesions as malignant; The combined diagnosis misdiagnosed 2 malignant lesions as benign and 4 benign lesions as malignant. The sensitivity of the combined diagnosis was higher than that of ultrasonic elastography (P<0.05). The specificity and positive- and negative predictive values of the combined diagnosis were all higher than those of ultrasonic elastography and BI-RADS classification (all P<0.05). CONCLUSION: Ultrasonic elastography combined with BI-RADS classification has high clinical application value in the diagnosis of breast neoplasms, especially the sensitivity to benign and malignant lesions. And compared with the mono-detection of either ultrasonic elastography or BI-RADS classification, the combined detection yields significantly higher diagnostic accuracy.

Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

Research progress of brain injuries in patients with small cell lung cancer caused by prophylactic cranial irradiation / 国际肿瘤学杂志

Small cell lung cancer (SCLC), as a pathological type with high malignancy, presents a high risk of early brain metastasis. Prophylactic cranial irradiation (PCI) can reduce the risk of brain metastasis in patients with SCLC, however, the incidence of brain structural and functional damage caused by PCI is high, and their clinical symptoms are not typical. The existing treatment methods can relieve some clinical symptoms, but can not effectively reverse the process of brain injury, which reduces the survival benefit of patients. In-depth understanding the mechanisms of PCI neurotoxicity and exploring effective strategies for ptevention and treatment are of great value in improving prognosis of SCLC.

[Extraction and Separation of Sinapine from Rapeseed Cake and the Mode of Action of Melanin Production Inhibition].

Brassica campestris L. is the important oil-bearing crop in China. Rapeseed cake is the main byproduct of rapeseed oil extraction. As the main active ingredient in rapeseed cake, sinapine has several important biological activities. Therefore, the inhibitory activity of sinapine on tyrosinase in vitro and its free radical-scavenging rate were determined. Tyrosinase activity in A-375 human melanocytes was also investigated and the effects of sinapine on the melanin content and its antioxidant effects on melanin biosynthesis were studied. The results showed that sinapine had significant antioxidant activity. Sinapine significantly inhibited A-375 human melanocytes in a dose-dependent manner. Sinapine inhibited melanin synthesis in A-375 cells by downregulating the mRNA and protein expression of TRP-1, TRP-2, and MITF factors. The results showed that rapeseed cake sinapine inhibited melanin production and could be used as a potential active ingredient in the development of whitening agents.

Targeting Delivery Nanocarriers for (+)-Terrein to Enhance Its Anticancer Effects.

As a compound from marine fungi, (+)-terrein showed significant anticancer activity. In this study, (+)-terrein was extracted from the marine-derived fungus and showed significant cytotoxicity against cancer cells, especially in A549 cells. To enhance its anticancer effects, redox-responsive nanocarriers based on folic acid-chitosan decorating the mesoporous silica nanoparticles were designed to control (+)-terrein target delivery into cancer cells. (+)-Terrein was loaded in the holes, and folic acid-chitosan worked as a gatekeeper by disulfide linkage controlling (+)-terrein release in the tumor microenvironment. The (+)-terrein drug delivery systems exhibited cytotoxicity toward A549 cells through induction of apoptosis. The apoptosis effect was confirmed by the increase in the expression of cleaved caspase-3, caspase-9, and PARP. Taken together, this work evaluates for the first time the (+)-terrein delivery system and provides a promising nanomedicine platform for (+)-terrein.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Diabetic nephropathy produces alterations in the tissue expression profile of the orphan receptors GPR149, GPR153, GPR176, TAAR3, TAAR5 and TAAR9 in Wistar rats.

Diabetes mellitus is a debilitating health care problem affecting 382 million people around the world and one of the most common complications is diabetic nephropathy. For this reason, it is important to try to identify new mechanisms that could be involved in diabetes. A new class of receptors has been reported, called orphan receptors because the associated ligand and signaling cascades are unknown. These receptors could be an important source of targets for the treatment of many diseases such as diabetes and its associated complications like diabetic nephropathy. Therefore, the aim of this work was to study expression of the orphan receptors GPR149, GPR153, GPR176, TAAR3, TAAR5 and TAAR9 in the kidney of diabetic rats. We used male Wistar rats at 10-12 weeks of age. Diabetes was induced by a single dose of streptozotocin (60 mg/kg i.p.). After 4 weeks, tissues were obtained, and the expression of the mRNAs was measured by RT-PCR. Our results showed that the orphan receptors are expressed in a different way in the kidney. In conclusion, we suggest that orphan receptors could be involved in the development of diabetic nephropathy.

Impact of immunogenicity on efficacy and tolerability of tumour necrosis factor inhibitors: pooled analysis of biosimilar studies in rheumatoid arthritis.

Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).

The incidence and survival of melanoma and nonmelanoma skin cancer in patients with vitiligo: a nationwide population-based matched cohort study in Korea.

BACKGROUND: While studies report a lower incidence of skin cancer in white patients with vitiligo compared with controls, the skin cancer incidence in Asian patients with vitiligo is unknown. OBJECTIVES: To quantify the incidence of melanoma and nonmelanoma skin cancer (NMSC) in Korean patients with vitiligo and compare it with matched nonvitiligo controls. METHODS: A retrospective matched cohort study was performed with 131 245 incident vitiligo cases and 2 624 900 age- and sex-matched (1 : 20) controls at index date, who were selected from the Korean National Health Insurance database between January 2005 and December 2017. Stratified Cox proportional hazards regression (stratified by sex, birth year and index year) was used to calculate the hazard ratio (HR) of skin cancer in patients with vitiligo. RESULTS: Patients with vitiligo were followed up for a mean duration of 6·34 years compared with a follow-up period of 6·27 years for matched controls. Ultraviolet (UV) treatment-adjusted HR for melanoma in patients with vitiligo was 3·32 [95% confidence interval (CI) 2·29-4·81] and 1·29 (95% CI 1·06-1·56) for NMSC. The HRs for melanoma and NMSC in the vitiligo population without a history of UV treatment were 3·37 (95% CI 2·32-4·90) and 1·35 (95% CI 1·11-1·64), respectively. CONCLUSIONS: In contrast to white patients with vitiligo, the risk of skin cancer was increased in the Korean vitiligo population. However, it is noteworthy that the skin cancer incidence in Korean patients with vitiligo was lower than that of their white counterparts. Owing to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted for race. What's already known about this topic? Prior studies have reported a lower incidence of melanoma and nonmelanoma skin cancer (NMSC) in white patients with vitiligo compared with nonvitiligo controls. The skin cancer incidence in Asian patients with vitiligo is unknown. What does this study add? In contrast to white patients, the risk of both melanoma and NMSC was increased in Korean patients with vitiligo compared with controls. Owing to possible ethnic differences in susceptibility to skin cancer, skin cancer surveillance in the vitiligo population should be adjusted for race.

Cluster of serogroup W invasive meningococcal disease in a university campus.

INTRODUCTION: In France, the expansion of an hypervirulent strain causing serogroup W invasive meningococcal disease (MenW) has been observed since 2015/16. We describe a cluster of three MenW cases, causing two deaths, at the end of 2016 in a university campus, and the vaccination campaign which was consequently organized. METHODS: Epidemiological and microbiological analyses led a multidisciplinary expertise group to recommend the organization of a mass vaccination campaign using ACWY vaccine targeting more than 30,000 students and staff in the university campus. Individual data on vaccination was collected using the lists of students and staff registered at the university to estimate vaccine coverage. RESULTS: Three MenW cases occurred within a 2-month period among students in different academic courses. All three isolates were identical and belonged to the "UK-2013 strain" phylogenetic branch. The attack rate was 10.8/100,000 students. The vaccination campaign was organized only 15 days after the third case occurred. In total, 13,198 persons were vaccinated. Vaccine coverage was estimated at 41% for students of the university and 35% for university staff. CONCLUSION: Timely notification of cases to health authorities was essential for the detection of the cluster and the rapid implementation of the vaccination campaign. No further cases occurred in the campus in the year following the vaccination campaign. This episode is the second cluster of MenW caused by the "UK-2013 strain" in a university since 2016.

Scutellarin Exerts Anti-Inflammatory Effects in Activated Microglia/Brain Macrophage in Cerebral Ischemia and in Activated BV-2 Microglia Through Regulation of MAPKs Signaling Pathway.

BACKGROUND: Scutellarin, an herbal compound, can effectively suppress the inflammatory response in activated microglia/brain macrophage(AM/BM) in experimentally induced cerebral ischemia; however, the underlying mechanism for this has not been fully clarified. We sought to elucidate if scutellarin would exert its anti-inflammatory effects on AM/BM through the MAPKs pathway. MATERIALS AND METHODS: Western blot and immunofluorescence labeling were used to determine the expression of the MAPKs pathway in AM/BM in rats subjected to middle cerebral artery occlusion (MCAO) also in lipopolysaccharide (LPS)-activated BV-2 microglia in vitro. Furthermore, expression of p-p38 along with that of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta(IL-1ß), and inducible nitric oxide synthase (iNOS) in LPS-activated microglia subjected to pretreatment with p38 inhibitor SB203580, p38 activator sc-201214, scutellarin, or a combination of them was evaluated. FINDINGS: Scutellarin markedly attenuated the expression of p-p38, p-JNK in AM/BM in MCAO rats and in vitro. Conversely, p-ERK1/2 expression level was significantly increased by scutellarin. Meanwhile, scutellarin suppressed the expression of proinflammatory mediators including iNOS, TNF-α, and IL-1ß in AM/BM. More importantly, SB203580 suppressed p-p38 protein expression level in LPS-activated BV-2 microglia that was coupled with decreased expression of proinflammatory mediators (TNF-α, iNOS) in LPS-activated BV-2 microglia. However, p38 activator sc-201214 increased expression of proinflammatory mediators TNF-α, iNOS, and IL-1ß. Interestingly, the decreased expression of both proinflammatory markers by p38 MAPK inhibitor and increased expression of proinflammatory markers by p38 MAPK activator were compatible with that in BV-2-activated microglia pretreated with scutellarin. CONCLUSIONS: The results suggest that scutellarin down-regulates the expression of proinflammatory mediators in AM/BM through suppressing the p-JNK and p-p38 MAPKs. Of note, the anti-inflammatory effect of p38 MAPK inhibitor and scutellarin is comparable. Besides, p38 MAPKs activator reverses the effect of scutellarin. Additionally, scutellarin increases p-ERK1/2 expression that may be neuroprotective.

Phenotypic and genotypic characterization of meningococcal isolates in Tunis, Tunisia: High diversity and impact on vaccination strategies.

OBJECTIVES: The aim of this study was to characterize Neisseria meningitidis (Men) isolates in Tunisian paediatric patients with invasive meningococcal disease (IMD) in order to target therapeutic and preventive strategies. METHODS: Fifty-nine isolates of Men and four cerebrospinal fluid samples that were culture-negative but Men-positive by PCR (NC-MenPPCR) (2009-2016) were collected from IMD patients. Isolates were analysed for their antimicrobial susceptibility. Whole-genome sequencing (WGS) was used to characterize isolates and multilocus sequence typing for NC-MenPPCR. Coverage of Men serogroup B (MenB) was determined by Genetic Meningococcal Antigen Typing System (gMATS) and fHbp expression by ELISA. RESULTS: MenB was the predominant type (88.9%). The majority of isolates (81%) had reduced susceptibility to penicillin G with altered penA alleles. The clonal complex CC461 (27.1%) was the most frequent. Among the MenB vaccine targets neisserial heparin binding antigen (NHBA) and fHbp, the predominant variants were NHBA118 (30.8%) and fHbp peptide 47 (25%), respectively. The nadA gene was present in 17.3% of isolates. Using gMATS, 36.5% of MenB were predicted to be covered by the 4CMenB vaccine. ELISA showed that 92.4% of the MenB were expected to be killed by anti-fHbp antibodies. CONCLUSIONS: MenB was the leading serogroup in IMD, and more than 90% had a sufficient level of fHbp expression for vaccine coverage. The study results will be useful for the Tunisian vaccination programme.