bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma
Authors: Haakensen Vilde Drageset , Nowak Anna K. , Ellingsen Espen Basmo , Farooqi Saima Jamil , Bjaanæs Maria Moksnes , Horndalsveen Henrik , Mcculloch Tine , Grundberg Oscar , Cedres Susana M. , Helland Åslaug 
Published: June 2021

Abstract
Background
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients.

Methods
NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy.

Discussion
Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.
Trial registration: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1.
The effect of revascularization on recovery of mitochondrial respiration in peripheral artery disease: a case control study
Authors: Gratl Alexandra , Pesta Dominik , Gruber Leonhard , Speichinger Fiona , Raude Ben , Omran Safwan , Greiner Andreas , Frese Jan Paul 
Published: June 2021

Abstract
Background
Peripheral arterial disease (PAD) is accompanied by myopathy characterized by mitochondrial dysfunction. The aim of this experimental study was to investigate the effect of revascularization procedures on mitochondrial function in ischemic and non-ischemic muscle.

Methods
Muscle biopsies from patients with symptomatic stage IIB/III PAD caused by isolated pathologies of the superficial femoral artery were obtained from muscle regions within the chronic ischemic muscle (gastrocnemius) and from non-ischemic muscle (vastus lateralis) before and 6 weeks after invasive revascularization. High-resolution respirometry was used to investigate mitochondrial function and results were normalized to citrate synthase activity (CSA). Results are given in absolute values and fold over basal (FOB).

Results
Respiratory states (OXPHOS (P) and electron transfer (E) capacity) normalized to CSA decreased while CSA was increased in chronic ischemic muscle after revascularization. There were no changes in in non-ischemic muscle. The FOB of chronic ischemic muscle was significantly higher for CSA (chronic ischemic 1.37 (IQR 1.10–1.64) vs. non-ischemic 0.93 (IQR 0.69–1.16) p = 0.020) and significantly lower for respiratory states normalized to CSA when compared to the non-ischemic muscle (P per CSA chronic ischemic 0.64 (IQR 0.46–0.82) vs non-ischemic 1.16 (IQR 0.77–1.54) p = 0.011; E per CSA chronic ischemic 0.61 (IQR 0.47–0.76) vs. non-ischemic 1.02 (IQR 0.64–1.40) p = 0.010).

Conclusions
Regeneration of mitochondrial content and function following revascularization procedures only occur in muscle regions affected by malperfusion. This indicates that the restoration of blood and oxygen supply are important mediators aiding mitochondrial recovery.
Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature
Authors: Yokoi Kyoko , Minamiguchi Sachiko , Honda Yoshitaka , Kobayashi Mizuho , Kobayashi Satoru , Nishikomori Ryuta 
Published: June 2021

Abstract
Background
Cryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1β and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination.

Case presentation
The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis.

Conclusions
The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.
Impact of COVID-19 pandemic on HIV viremia: a single-center cohort study in northern Italy
Authors: Izzo Ilaria , Carriero Canio , Gardini Giulia , Fumarola Benedetta , Chiari Erika , Castelli Francesco , Quiros-Roldan Eugenia 
Published: June 2021

Abstract
Background
Brescia Province, northern Italy, was one of the worst epicenters of the COVID-19 pandemic. The division of infectious diseases of ASST (Azienda Socio Sanitaria Territoriale) Spedali Civili Hospital of Brescia had to face a great number of inpatients with severe COVID-19 infection and to ensure the continuum of care for almost 4000 outpatients with HIV infection actively followed by us. In a recent manuscript we described the impact of the pandemic on continuum of care in our HIV cohort expressed as number of missed visits, number of new HIV diagnosis, drop in ART (antiretroviral therapy) dispensation and number of hospitalized HIV patients due to SARS-CoV-2 infection. In this short communication, we completed the previous article with data of HIV plasmatic viremia of the same cohort before and during pandemic.

Methods
We considered all HIV-patients in stable ART for at least 6 months and with at least 1 available HIV viremia in the time window March 01–November 30, 2019, and another group of HIV patients with the same two requisites but in different time windows of the COVID-19 period (March 01–May 31, 2020, and June 01–November 30, 2020). For patients with positive viremia (PV) during COVID-19 period, we reported also the values of viral load (VL) just before and after PV. Results: the percentage of patients with PV during COVID-19 period was lower than the previous year (2.8% vs 7%). Only 1% of our outpatients surely suffered from pandemic in term of loss of previous viral suppression.

Conclusions
Our efforts to limit the impact of pandemic on our HIV outpatients were effective to ensure HIV continuum of care.
Lymphocyte–monocyte–neutrophil index: a predictor of severity of coronavirus disease 2019 patients produced by sparse principal component analysis
Authors: Qi Yingjie , Jia Jian-an , Li Huiming , Wan Nagen , Zhang Shuqin , Ma Xiaoling 
Published: June 2021

Abstract
Background
It is important to recognize the coronavirus disease 2019 (COVID-19) patients in severe conditions from moderate ones, thus more effective predictors should be developed.

Methods
Clinical indicators of COVID-19 patients from two independent cohorts (Training data: Hefei Cohort, 82 patients; Validation data: Nanchang Cohort, 169 patients) were retrospected. Sparse principal component analysis (SPCA) using Hefei Cohort was performed and prediction models were deduced. Prediction results were evaluated by receiver operator characteristic curve and decision curve analysis (DCA) in above two cohorts.

Results
SPCA using Hefei Cohort revealed that the first 13 principal components (PCs) account for 80.8% of the total variance of original data. The PC1 and PC12 were significantly associated with disease severity with odds ratio of 4.049 and 3.318, respectively. They were used to construct prediction model, named Model-A. In disease severity prediction, Model-A gave the best prediction efficiency with area under curve (AUC) of 0.867 and 0.835 in Hefei and Nanchang Cohort, respectively. Model-A’s simplified version, named as LMN index, gave comparable prediction efficiency as classical clinical markers with AUC of 0.837 and 0.800 in training and validation cohort, respectively. According to DCA, Model-A gave slightly better performance than others and LMN index showed similar performance as albumin or neutrophil-to-lymphocyte ratio.

Conclusions
Prediction models produced by SPCA showed robust disease severity prediction efficiency for COVID-19 patients and have the potential for clinical application.
Lithium inhibits NF-κB nuclear translocation and modulate inflammation profiles in Rift valley fever virus-infected Raw 264.7 macrophages
Authors: Makola Raymond Tshepiso , Kgaladi Joe , More Garland Kgosi , Jansen van Vuren Petrus , Paweska Janusz Tadeusz , Matsebatlela Thabe Moses 
Published: June 2021

Abstract
Introduction
Rift Valley fever virus (RVFV) is a zoonotic life-threatening viral infection endemic across sub-Saharan African countries and the Arabian Peninsula; however, there is a growing panic of its spread to non-endemic regions. This viral infection triggers a wide spectrum of symptoms that span from fibril illnesses to more severe symptoms such as haemorrhagic fever and encephalitis. These severe symptoms have been associated with dysregulated immune response propagated by the virulence factor, non-structural protein (NSs). Thus, this study investigates the effects of lithium on NF-κB translocation and RFVF-induced inflammation in Raw 264.7 macrophages.

Methods
The supernatant from RVFV-infected Raw 264.7 cells, treated with lithium, was examined using an ELISA assay kit to measure levels of cytokines and chemokines. The H2DCF-DA and DAF-2 DA florigenic assays were used to determine the levels of ROS and RNS by measuring the cellular fluorescence intensity post RVFV-infection and lithium treatment. Western blot and immunocytochemistry assays were used to measure expression levels of the inflammatory proteins and cellular location of the NF-κB, respectively.

Results
Lithium was shown to stimulate interferon-gamma (IFN-γ) production as early as 3 h pi. Production of the secondary pro-inflammatory cytokine and chemokine, interleukin-6 (IL-6) and regulated on activation, normal T cell expressed and secreted (RANTES), were elevated as early as 12 h pi. Treatment with lithium stimulated increase of production of tumor necrosis factor-alpha (TNF-α) and Interleukin-10 (IL-10) in RVFV-infected and uninfected macrophages as early as 3 h pi. The RVFV-infected cells treated with lithium displayed lower ROS and RNS production as opposed to lithium-free RVFV-infected control cells. Western blot analyses demonstrated that lithium inhibited iNOS expression while stimulating expression of heme oxygenase (HO) and IκB in RVFV-infected Raw 264.7 macrophages. Results from immunocytochemistry and Western blot assays revealed that lithium inhibits NF-κB nuclear translocation in RVFV-infected cells compared to lithium-free RVFV-infected cells and 5 mg/mL LPS controls.

Conclusion
This study demonstrates that lithium inhibits NF-kB nuclear translocation and modulate inflammation profiles in RVFV-infected Raw 264.7 macrophage cells.
Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction
Authors: Wang Jiajia , Yang Xinjing , Li Yongsheng , Huang Jian-an , Jiang Junhong , Su Nan 
Published: June 2021

Abstract
Background
To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD.

Methods
The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD.

Results
The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time.

Conclusions
The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.
Massive hemothorax caused by intercostal artery pseudoaneurysm:a case report
Authors: Liu Caiyang , Ran Ran , Li Xiaoliang , Liu Gaohua , Wang Chuanxi , Li Ji 
Published: June 2021

Abstract
Background
Intercostal artery pseudoaneurysm is rare and at the risk of rupture. The aetiology is always reported to be iatrogenic and traumatic injury. Embolisation is the most common therapeutic method. Here, we report a case of spontaneous intercostal artery pseudoaneurysm and cured by combining covered stent grafting and surgical management.

Case presentation
A 60-year-old man complained of acute right back pain for 5 h. Computed tomography showed right massive hemothorax and a giant mass with distinct feeding vessel originated from the thoracic aorta within the right hemithorax. Thoracocentesis was performed, and then a covered stent was positioned across the origin of the feeding vessel. The patient was diagnosed with intercostal artery pseudoaneurysm. Finally, we successfully resected the pseudoaneurysm and ligated the proximal part of the artery. Histologic examination have proved the diagnosis. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. There is no recurrence reported during follow-up.

Conclusions
Spontaneous intercostal artery pseudoaneurysm is extremly rare. Delayed hemothorax due to rupture of the pseudoaneurysm may occur years after the formation. Early diagnosis is important and a combined treatment of endovascular intervention and surgical management is feasible, especially for the case of ruptured large tumour-like mass presentation of the pseudoaneurysm.
Lidocaine for postoperative pain after cardiac surgery: a systematic review
Authors: Boswell Michael R. , Moman Rajat N. , Burtoft Melissa , Gerdes Harrison , Martinez Jacob , Gerberi Danielle J. , Wittwer Erica , Murad M. Hassan , Hooten W. Michael 
Published: June 2021

AbstractObjectiveLidocaine is one of the most widely used local anesthetics with well-known pharmacological properties. The purpose of this systematic review is to investigate the effects of lidocaine on postoperative pain scores and recovery after cardiac surgery.MethodsA comprehensive database search was conducted by a reference librarian for randomized clinical trials (RCT) from January 1, 1980 to September 1, 2019. Eligible study designs included randomized controlled trials of lidocaine for postoperative pain management in adults undergoing cardiac surgery. After removal of duplicates, 947 records were screened for eligibility and 3 RCTs met inclusion criteria.ResultsSources of bias were identified in 2 of 3 RCTs. Lidocaine was administered intravenously, topically, and intrapleurally. Key findings included [1] 2% lidocaine placed topically on chest tube prior to intraoperative insertion was associated with significantly lower pain scores and lower cumulative doses of fentanyl; and [2] 2% lidocaine administered intrapleurally was associated with significantly lower pain scores and significant improvements in pulmonary mechanics. Lidocaine infusions were not associated with significant changes in pain scores or measures of recovery. No significant associations were observed between lidocaine and overall mortality, hospital length of stay or ICU length of stay. No data were reported for postoperative nausea and vomiting or arrhythmias.ConclusionsDue to the favorable risk profile of topical lidocaine and the need for further advancements in the postoperative care of adults after cardiac surgery, topically administered lidocaine could be considered for incorporation into established postoperative recovery protocols.
Identification of anti-inflammatory compounds from Zhongjing formulae by knowledge mining and high-content screening in a zebrafish model of inflammatory bowel diseases
Authors: Yu Yunru , Chen Jing , Zhang Xiaohui , Wang Yingchao , Wang Shufang , Zhao Lu , Wang Yi 
Published: June 2021

AbstractBackgroundInflammatory bowel diseases (IBD) are chronic relapsing intestinal inflammations with increasing global incidence, and new drug development remains in urgent demand for IBD management. To identify effective traditional Chinese medicine (TCM) formulae and compounds in IBD treatment, we innovatively combined the techniques of knowledge mining, high-content screening and high-resolution mass spectrometry, to conduct a systematic screening in Zhongjing formulae, which is a large collection of TCM prescriptions with most abundant clinical evidences.MethodsUsing Word2vec-based text learning, the correlations between 248 Zhongjing formulae and IBD typical symptoms were analyzed. Next, from the top three formulae with predicted relationship with IBD, TCM fractions were prepared and screened on a transgenic zebrafish IBD model for their therapeutic effects. Subsequently, the chemical compositions of the fraction hits were analyzed by mass spectrometry, and the major compounds were further studied for their anti-IBD effects and potential mechanisms.ResultsThrough knowledge mining, Peach Blossom Decoction, Pulsatilla Decoction, and Gegen Qinlian Decoction were predicted to be the three Zhongjing formulae mostly related to symptoms typical of IBD. Seventy-four fractions were prepared from the three formulae and screened in TNBS-induced zebrafish IBD model by high-content analysis, with the inhibition on the intestinal neutrophil accumulation and ROS level quantified as the screening criteria. Six herbal fractions showed significant effects on both pathological processes, which were subsequently analyzed by mass spectrometry to determine their chemical composition. Based on the major compounds identified by mass spectrometry, a second-round screen was conducted and six compounds (palmatine, daidzin, oroxyloside, chlorogenic acid, baicalin, aesculin) showed strong inhibitory effects on the intestinal inflammation phenotypes. The expression of multiple inflammatory factors, includingil1β,clcx8a,mmpandtnfα, were increased in TNBS-treated fish, which were variously inhibited by the compounds, with aesculin showing the most potent effects. Moreover, aesculin and daidzin also upregulatede-cadherin’sexpression.ConclusionTaken together, we demonstrated the regulatory effects of several TCM formulae and their active compounds in the treatment of IBD, through a highly efficient research strategy, which can be applied in the discovery of effective TCM formulae and components in other diseases.Graphic abstract