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Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus.Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n = 143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p = 0.21). Most patients required drug withdrawal treatment (n = 113, 74%) and can achieve a recovered-resolved state (n = 72, 46%). All ICIs were significantly associated with ileus (ROR = 4.27, 95%Cl: 3.75-4.85; IC = 2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n = 164, ROR = 3.83, 95%Cl: 3.28-4.48; IC = 1.90, 95%Cl: 1.62-2.21).This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.

It is well known that preferences are formed through choices, known as choice-induced preference change (CIPC). However, whether value learned through externally provided rewards influences the preferences formed through CIPC remains unclear. To address this issue, we used tasks for decision-making guided by reward provided by the external environment (externally guided decision-making; EDM) and for decision-making guided by one’s internal preference (internally guided decision-making; IDM). In the IDM task, we presented stimuli with learned value in the EDM and novel stimuli to examine whether the value in the EDM affects preferences. Stimuli reinforced by rewards given in the EDM were reflected in the IDM’s initial preference and further increased through CIPC in the IDM. However, such stimuli were not as strongly preferred as the most preferred novel stimulus in the IDM, indicating the superiority of intrinsically learned values (SIV). The underlying process of this phenomenon is discussed in terms of the fundamental self-hypothesis.Author SummaryWe make decisions based on internal value criteria, which are individual preferences, or based on external value criteria, which are the values learned from the external environment. Although it is known that values are learned in both types of decisions, is there a difference in the nature of these values? Our study uses simulation and fits human behavioral data to address this question. The results showed that stimuli that were learned to be highly valued because of external feedback became preferred in subsequent preference judgments. However, it is interesting to note that such stimuli were not chosen as much as stimuli that were preferred without influence from the external environment. This finding suggests that values formed through one’s own criteria have characteristics distinct from those formed through external environmental influence. Our findings promote an integrated understanding of the decision-making process.

Background Several risk factors of immune checkpoint inhibitors (ICIs)-associated acute kidney injury (AKI) have been reported sporadically. To identify the risk factors of ICIs-associated AKI in a large-scale population, therefore we conducted a systematic review and a real-world retrospective study. Methods We search literature concerning risk factors of ICIs-associated AKI in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to January 2022. Meta-analysis was performed by using odds ratios (ORs) with 95%CIs. In a separate retrospective pharmacovigilance study by extracting data from US FDA Adverse Event Reporting System (FAERS) database, disproportionality was analyzed using the reporting odds ratio (ROR). Results A total of 9 studies (5927 patients) were included in the meta-analysis. The following factors were associated with increased risk of ICIs-associated AKI, including proton pump inhibitors(PPIs) (OR = 2.07, 95%CI 1.78–2.42), angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (OR = 1.56, 95%CI 1.24–1.95), nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 1.29, 95%CI 1.01–1.65), diuretics (OR = 2.00, 95%CI 1.38–2.89), diabetes mellitus (OR = 1.28, 95%CI 1.04–1.57), genitourinary cancer (OR = 1.46, 95%CI 1.15–1.85), combination therapy of ICIs (OR = 1.93, 95%CI 1.25–2.97) and extrarenal immune-related adverse events(irAEs) (OR = 2.51, 95%CI 1.96–3.20). Furthermore, analysis from FAERS database verified that concurrent exposures of PPIs (ROR = 2.10, 95%CI 1.91–2.31), ACEIs/ARBs (ROR = 3.25, 95%CI 2.95–3.57), NSAIDs (ROR = 3.06, 95%CI 2.81–3.32) or diuretics (ROR = 2.82, 95%CI 2.50–3.19) were observed significant signals associated with AKI in ICIs-treated patients. Conclusions Concurrent exposures of PPIs, ACEIs/ARBs, NSAIDs or diuretics, diabetes mellitus, genitourinary cancer, combination therapy, and extrarenal irAEs seem to increase the risk of AKI in ICIs-treated patients.

To evaluate the effects of adjuvant chemotherapy (CT) and radiotherapy (RT) on the survival of uterine carcinosarcoma (UCS) patients.We analyzed 3207 patients with uterine carcinosarcoma without distant metastasis after surgery from 2004 to 2015 by utilizing data from the Surveillance, Epidemiology, and End Results database. Generally, cancer-specific survival (CSS) and overall survival (OS) outcomes were analyzed by Kaplan-Meier and Cox proportional hazards regression models. Further subgroup survival analysis was performed for those receiving RT and chemoradiotherapy (CRT).In general, both univariate and multivariate analyses showed that age, race, marital status, stage, lymph node metastasis, lymphadenectomy (LND), RT, and chemotherapy (CT) were associated with improved CSS and OS (P 0.05). Further subgroup analysis showed that CRT exhibited a survival advantage over RT or CT alone in different groups. Various RT modalities, including brachytherapy (BT), external radiotherapy (EBRT), and EBRT + BT, were correlated with improved survival for patients aged 60-69 years with stage III-IV disease and lymph node metastasis. Patients with stage I-II disease aged 70 years seemed to gain survival benefits from brachytherapy (BT) alone. BT with or without external radiotherapy was associated with improved survival for those who did not undergo lymphadenectomy.For UCS without distant metastasis after surgery, CRT should be considered. Regarding RT, BT alone is efficient in improving survival, especially for patients with stage I-II disease aged 70 years old. EBRT alone does not show results in survival improvement for patients who did not undergo LND and those with lymph node metastasis. However, considering the limitation of SEER database, further studies with more large sample size and strict study design are needed to confirm it.

Thrombosis is the second leading cause of mortality in cancer patients. This study aimed to investigate the association between cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and thrombosis. A retrospective pharmacovigilance analysis based on real-world data combined with a systematic review was used to explore the thrombotic risk profiles of CDK4/6i. The study has been registered with Prospero (CRD42021284218). In the pharmacovigilance analysis, CDK4/6i showed a higher rate of reported venous thromboembolism (VTE) (ROR = 2.78, 95% CI = 2.64–2.92), with the highest signal for trilaciclib (ROR = 27.55, 95% CI = 13.43–56.52) but only 9 cases, followed by abemaciclib (ROR = 3.73, 95% CI = 3.19–4.37). For arterial thromboembolism (ATE), only ribociclib increased the reporting rate (ROR = 2.14, 95% CI = 1.91–2.41). In the meta-analysis, palbociclib, abemaciclib, and trilaciclib all increased the risk of VTE (OR = 2.23, 3.17, and 3.90). In the subgroup analysis, only abemaciclib increased the risk of ATE (OR = 2.11, 95% CI = 1.12–3.99) . CDK4/6i had different profiles of thromboembolism. Palbociclib, abemaciclib, or trilaciclib increased the risk of VTE. Ribociclib and abemaciclib showed a weak association with the risk of ATE.

Purpose Immune checkpoint inhibitors (ICIs) have favorable anti-tumor effects but can cause severe autoimmune toxicities. The number of cases of previous studies about the risk of Sjogren's syndrome (SS) induced by ICIs is low. This pharmacovigilance study is to reassess the relationship between SS and ICIs in the FDA Adverse Event Reporting System (FAERS). Methods Case reports of SS after ICIs were extracted from 2013 Q1 to 2020 Q4 in FAERS. the clinical features of the cases were described. The disproportionality analysis, reporting odds ratio (ROR) and information component (IC), was used to estimate the correlation between SS and ICIs. The clinical features of ICI-SS were described. Results In total, 160 cases of ICI-related SS were screened out. The median age was 63.5 years, more than half of were men (59%). The median latency of SS was 45 days. 13% of SS resolved after ICIs discontinuation or dose reduction. SS was significantly associated with ICIs (ROR = 11.19, 95%CI: 9.53–13.14; IC = 3.34, 95%CI: 2.85–3.93). The signal was also observed in anti-PD-1 (ROR025 = 9.20, IC025 = 2.75), anti-PD-L1 (ROR025 = 3.34, IC025 = 1.33), and combination therapy (ROR025 = 14.49, IC025 = 2.89). Conclusions This study suggested that ICIs significantly increased the risk of SS. This association was stronger in combination therapy.

Background Drug-induced liver injury (DILI) has become one of the most common and serious adverse drug reactions owing to its high morbidity and leading cause of hepatic failures, which had attracted great attentions worldwide in the past two decades. A need therefore exists to conduct a bibliometric and visualized analysis of the global research trends on DILI with the aim of identifying the status of current research and prioritize the future research areas. Methods Publications related to DILI from 1999 to 2019 were extracted through an electronic search of the Web of Science (WoS) and PubMed databases. VOSviewer software was used to perform visualized analysis of bibliographic coupling, co-authorship, co-citation and co-occurrence, and to assess the global trends. Results Totally of 6,563 publications were identified based on the inclusion criteria. It is noted that the global trends of literatures on DILI showed a significant increase over time and more importantly predict the relevant publications will rise continuously in the coming decades. The United States led in terms of publication numbers with the most citations (the highest h-index). Hepatology made great contributions to the highest h-index and the most citations of publications. University of North Carolina was regarded as the most contributive institution. Notably, after conducting co-occurrence and cluster analysis of keywords and citation networks, it is shown that the pathogenesis, clinical manifestations, diagnosis and risk factors of this field will become the most prominent research hotspots. Conclusions The mapping results provides global development trends of publications on DILI from 1999 to 2019. Future studies focused on the diagnosis and predisposing factors of this field will be encouraged.

Kidney transplant recipients with cancer are at higher risk of kidney transplant rejection (KTR), and the safety of immune checkpoint inhibitors (ICIs) is unclear. The present study investigates the relationship between ICIs and KTR using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).Case reports of KTR inducted by ICIs in FAERS from 1 January 2011, to 30 June 2021, were collected, and a disproportionate analysis was performed to assess the correlation between ICIs and KTR.A total of 99 cases of ICI-related KTR were reported in the FAERS database. Most of them were male patients (n = 63, 84.0%), and more than half of patients suffered from malignant melanoma (n = 46, 52.9%). The median onset time after the medication was 22 days, the withdrawal rates of ICIs were 78.0%, and the overall death rate was 29.3%. In general, there was a significant relevance between ICIs and KTR (ROR = 3.92[3.21-4.79] IC025 = 1.56), of which PD-1 was the most prominent (n = 81 ROR = 5.26[4.22-6.57] IC025 = 1.86).ICIs may increase the risk of KTR in organ transplant recipients with cancer.

Aim: To evaluate the cost–effectiveness of ribociclib plus fulvestrant versus fulvestrant in hormone receptor-positive/human EGF receptor 2-negative advanced breast cancer. Materials & methods: A three-state Markov model was developed to evaluate the costs and effectiveness over 10 years. Direct costs and utility values were obtained from previously published studies. We calculated incremental cost–effectiveness ratio to evaluate the cost–effectiveness at a willingness-to-pay threshold of $150,000 per additional quality-adjusted life year. Results: The incremental cost–effectiveness ratio was $1,073,526 per quality-adjusted life year of ribociclib plus fulvestrant versus fulvestrant. Conclusions: Ribociclib plus fulvestrant is not cost-effective versus fulvestrant in the treatment of advanced hormone receptor-positive/human EGF receptor 2-negative breast cancer. When ribociclib is at 10% of the full price, ribociclib plus fulvestrant could be cost-effective.

After multi-stage volume hydraulic fracturing in a shale oil reservoir, massive amounts of water can be imbibed into the matrix pores. One of the key imbibition characteristics of a shale reservoir is the imbibition water and its height distribution. Based on high pressure mercury injection (HPMI) experiments and nuclear magnetic resonance (NMR) analyses, this study quantitatively evaluated the pore-size distribution of Chang 7 continental shale oil reservoirs in Yanchang Formation, Ordos Basin. The pores could be divided into three types as micropores (≤0.1 μm), mesopores (0.1–1.0 μm), and macropores (>1.0 μm), while the volume of micropores and mesopores accounted for more than 90%. This demonstrated that there were strong heterogeneity and micro–nano characteristics. According to the spontaneous imbibition (SI) experiments, the cumulative proportion of imbibition water content was the largest in micropores, exceeding 43%, followed by mesopores around 30%, and that of macropores was the lowest, and basically less than 20%. The negative values of stage water content in the macropore or mesopore indicated that these pores became a water supply channel for other dominant imbibition pores. Additionally, combining the fractal theory with the NMR T2 spectrum, the relative imbibition water and actual height were calculated in different pores, while the height distribution varied with cores and shale oil. The shorter the core, the higher was the relative height, while the radius of macropores filled with imbibition water was reduced. This indicates that the height distribution was affected by the pore structure, oil viscosity, and core length.

ObjectiveTo evaluate the risk of interstitial lung disease associated with poly (ADP-ribose) polymerase inhibitors (PARPi) and characterize its clinical features.MethodsWe systematically reviewed phase III randomized clinical trials of interstitial lung disease related to PARPi and calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting cases of PARPi-related interstitial lung disease from the FDA Adverse Events Reporting System and assessing disproportionalities by reporting ORs and information components.ResultsA total of five randomized clinical trials involving 2980 patients were included. Although PARPi showed a tendency to increase the risk of interstitial lung disease compared with controls, this difference was not significant (Peto OR: 4.92; 95% CI: 0.92 to 26.35). A total of 170 cases of interstitial lung disease related to PARPi were included, with a median latency of 99 days. PARPi had a significantly increased reporting of interstitial lung disease (reporting OR: 2.86; 95% CI: 2.46 to 3.33; information component (IC): 1.49; 95% CI: 1.28 to 1.74). Our sensitivity analyses showed strong robustness of the disproportionalities between PARPi as a class, olaparib, and interstitial lung disease. Some 91.9% of patients experienced discontinuation, 51.6% achieved remission, and no deaths were reported.ConclusionOur pharmacovigilance study suggested increased reporting of interstitial lung disease related to PARPi particularly olaparib.

Zebrafish represent an economical alternative to rodents for developmental neurotoxicity (DNT) testing. Mechanistic understanding is the key to successfully translating zebrafish findings to humans. In the present study, we used a well-known dopaminergic (DA) neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model chemical to uncover the molecular pathways for observed DNT effects. To enhance the specificity of potential molecular targets, we restricted our exposure to a concentration that is nonteratogenic yet exhibits high DNT effects and an exposure window sensitive to MPTP. Our DNT assessment based on a battery of motor and social behavioral tests revealed an effective concentration of 1 μM and a sensitive window of 48-96 h postfertilization (hpf) for MPTP-induced hypoactivity. It is worth noting that this hypoactivity persisted into later larval development until 28 dpf. We observed increased cell apoptosis, oxidative stress, and decreased ATP levels in larvae immediately after exposure at 96 hpf. Significant reductions of DA neurons were found in the retina at 72, 96, and 120 hpf. No visible deformity was found in motoneurons at 72, 96, and 120 hpf. Transcriptome analysis uncovered a novel pathway manifested by significant upregulation of genes enriched with erythropoiesis. Sensitive window exposure of MPTP and other DA neurotoxins rotenone and paraquat exhibited a concentration-dependent effect on transcriptional changes of embryonic hemoglobins and anemia. Given that anemia is a significant risk factor for Parkinson's disease and MPTP is known to cause parkinsonism in humans, we concluded that anemia resulting from dysregulation of primitive erythropoiesis during embryonic development might serve as a common mechanism underlying DA neurotoxin-induced DNT effects between zebrafish and humans.

Ischemic stroke is a very common cerebrovascular accident that occurred in adults and causes higher risk of neural deficits. After ischemic stroke, patients are often left with severe neurological deficits. Therapeutic strategies for ischemic stroke might mitigate neuronal loss due to delayed neural cell death in the penumbra or seek to replace dead neural cells in the ischemic core. Currently, stem cell therapy is the most promising approach for inducing neurogenesis for neural repair after ischemic stroke. Stem cell treatments include transplantation of exogenous stem cells but also stimulating endogenous neural stem cells (NSCs) proliferation and differentiation into neural cells. In this review, we will discuss endogenous NSCs-induced neurogenesis after ischemic stroke and provide perspectives for the therapeutic effects of endogenous NSCs in ischemic stroke. Our review would inform future therapeutic development not only for patients with ischemic stroke but also with other neurological deficits.

Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood–brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca2+ level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.

Acute kidney injury (AKI) is a rare but severe adverse event of immune checkpoint inhibitors (ICIs). With the increasing reports of ICIs, it's necessary to put new insights into ICIs-related AKI. We conducted a systematic review of randomized controlled trials(RCTs) and a real-world study by extracting data from the US FDA Adverse Event Reporting System (FAERS) database.We explored ICIs-related AKI events in RCTs available in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to August 2021. Meta-analysis was performed by using risk ratios (RRs) with 95 %CIs. In a separate retrospective pharmacovigilance study of FAERs, disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC).A total of 79 RCTs (500,09 patients) were included, and ICIs were associated with increased risk of all-grade (RR = 1.37, 95 %CI:1.14-1.65) and high-grade AKI (RR = 1.60, 95 %CI:1.16-2.20). Results of subgroup analysis indicated that RR of ICI-related AKI did not vary significantly by cancer type, treatment regimen (monotherapy or combination of ICIs), study design (double-blind or open-label), individual ICIs and publication status (published or unpublished). FAERS pharmacovigilance data identified 1918 cases of AKI related to ICIs therapy. ICIs were significantly associated with over-reporting frequencies of AKI (ROR = 2.38, 95 %CI:2.27-2.49; IC = 1.22, 95 %CI:1.16-1.27). The median onset time of AKI was 48 days, 77.5 % of patients discontinued the use of ICIs, and 15.9 % of patients resulted in death.These data suggest that ICIs were significantly associated with increased risk of AKI in both trial settings and clinical practice.

ObjectiveTo our knowledge, the impact of area-level socioeconomic status (SES) has not yet been described in primary central nervous system lymphomas (PCNSLs). Current study sought to explore the association of socioeconomic deprivation, measured using the Area Deprivation Index (ADI), with PCNSL outcomes.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify PCNSL patients diagnosed between 2006 and 2015 for our analyses. The impact of ADI on overall survival (OS) and cancer-specific survival (CSS) were investigated. Survival analyses were conducted using Kaplan-Meier method with log-rank tests. The Inverse Probability Weighting (IPW) analysis and multivariate cox proportional hazards regression analysis were employed to make covariate adjustments. Multiple mediation analysis (MMA) was performed to estimate the mediating effects.ResultsA total of 3159 PCNSL patients classified into low and high ADI subgroups according to the median ADI score were studied. The Kaplan-Meier analyses showed that low ADI was significantly associated with higher OS rates (HR 1.15, 95%CI 1.06-1.26, Pvia IPW and multivariate cox methods. Subgroup analyses revealed that ADI could remain a prognostic indictor among different subsets. MMA revealed that several factors including chemotherapy and HIV status making up about 40% of the overall effect, mediated PCNSL survival disparities related to the ADI. Finally, multivariable logistic regression analysis showed that ADI as well as several other factors were independently related to receipt of chemotherapy.ConclusionsOur study highlights the role of area-level SES in prognosis of PCNSLs. And several factors including chemotherapy and HIV status of PCNSL patents contributed to the CSS disparities between ADI subgroups were uncovered by MMA. Such relationships would highlight the importance of policies development to enhance healthcare delivery and promote awareness of HIV prevention and treatment in low-resource neighborhoods.

While supercapacitors can deliver high electrical power, their low energy density limits their application. Here, we designed and fabricated a facile asymmetric supercapacitor (ASC) with excellent ...

Objective Following brain injury, the neurogenic niche provides a permissive cue for iatrogenesis rather than neurogenesis; reactive astrocytes play essential roles in orchestrating this process, markedly forming a glial scar around the area of damaged brain tissue. The objective of this study was to alter the neurogenic niche at the injured cortex and study its impact on neurogenesis. Methods We constructed a stromal cell-derived factor 1 (SDF-1) gradient matrix to attract reactive astrocytes to the glial scar core. Results SDF-1 reacted with the astrocytes in the injured site. By changing the neurogenic niche of the injured part of the brain after traumatic brain injury (TBI), SDF-1 downregulated thrombospondin 4 (Thbs4) promoting neuronal cell regeneration and playing a beneficial role in nerve function recovery after brain injury. Discussion The matrix we created in this study could attract and interact with reactive glial cells and, thus, we called it a glial pump. Using the glial pump, we identified a new mechanism of brain injury repair and neuronal regeneration after TBI, which relied on Thbs4 downregulation after the altered neurogenic niche promoted neuronal regeneration and functional recovery.

Summary Background Considering the global burden of diabetes and associated cardiovascular disease, an urgent need exists for the best treatment, which should be based on the best available evidence. We examined the association between glucose-lowering medications and a broad range of cardiovascular outcomes, and assessed the strength of evidence for these associations. Methods For this umbrella review we searched PubMed, Embase, and the Cochrane Library to identify systematic reviews and meta-analyses of randomised controlled trials examining the cardiovascular safety of glucose-lowering medications. Cardiovascular outcomes examined included major adverse cardiovascular events, cardiovascular death, myocardial infarction, stroke, heart failure, unstable angina, and atrial fibrillation. For each meta-analysis, we estimated the relative risk (RR) and 95% CI. We also created an evidence map showing the plausible benefits or harms of each intervention and the certainty of the evidence. Findings We examined 232 meta-analyses evaluating ten classes of diabetes drugs. We identified six risk and 38 protective associations showing a high strength of evidence. Six associations increased the risk of cardiovascular disease, including glimepiride (stroke [RR 2·01; 95% CI 1·02–3·98]), rosiglitazone (myocardial infarction [1·28; 1·02–1·62] and heart failure [1·72, 1·31–2·27]), and pioglitazone (heart failure [1·40; 1·16–1·69]). 38 associations decreased the risk of cardiovascular disease, including glucagon-like peptide-1 receptor agonists as a class (major adverse cardiovascular events [RR 0·88; 95% CI 0·84–0·92], death from cardiovascular disease [0·87; 0·81–0·94], myocardial infarction [0·92; 0·86–0·99], stroke [0·84; 0·77–0·93], and heart failure [0·90; 0·83–0·99]), albiglutide (major adverse cardiovascular events [0·81; 0·68–0·96], myocardial infarction [0·77; 0·64–0·92], and heart failure [0·71; 0·55–0·93]), dulaglutide (stroke [0·78; 0·64–0·96]), exenatide (major adverse cardiovascular events [0·91; 0·83–1·00]), liraglutide (major adverse cardiovascular events [0·86; 0·77–0·96]), semaglutide (major adverse cardiovascular events [0·76; 0·62–0·92] and stroke [0·67; 0·45–1·00]), sodium-glucose co-transporter-2 inhibitors as a class (major adverse cardiovascular events [0·87; 0·82–0·93], death from cardiovascular disease [0·82; 0·75–0·90], myocardial infarction [0·86; 0·78–0·94], and heart failure [0·68; 0·63–0·73]), canagliflozin (major adverse cardiovascular events [0·84; 0·75–0·93], death from cardiovascular disease [0·82; 0·71–0·96], and heart failure [0·65; 0·54–0·78]), dapagliflozin (heart failure [0·70; 0·60–0·82]), empagliflozin (major adverse cardiovascular events [0·85; 0·77–0·94], death from cardiovascular disease [0·62; 0·50–0·78], and heart failure [0·64; 0·53–0·77]), and pioglitazone (major adverse cardiovascular events [0·84; 0·74–0·96], myocardial infarction [0·80; 0·67–0·95], and stroke [0·79; 0·65–0·95]). Interpretation We found varied levels of evidence for the associations between diabetes drugs and cardiovascular outcomes; some drugs raised the risk of cardiovascular disease, whereas others showed benefit. Funding None.

As a chronic musculoskeletal degeneration disease, intervertebral disc degeneration (IVDD) has been identified as a crucial cause for low back pain. This condition has a prevalence of 80% among adults without effective preventative therapy. Procyanidin B3 (Pro‐B3) is a procyanidin dimer, which is widely present in the human diet and has multiple functions, such as preventing inflammation. But the inhibiting effect of Pro‐B3 in IVDD development is still no known. Thus, our study aimed to demonstrate the therapeutical effect of Pro‐B3 in IVDD and explain the underlying mechanism. In vitro studies, human nucleus pulposus (NP) cells were isolated and exposed in lipopolysaccharide (LPS) to simulate IVDD development. Pro‐B3 pre‐treatment inhibited LPS‐induced production of inflammation correlated factors such as tumour necrosis factor α (TNF‐α), interleukin‐6 (IL‐6), prostaglandin E2 (PGE2) and Nitric oxide (NO). On the other hand, LPS‐medicated extracellular matrix (ECM) breakdown was blocked in Pro‐B3 treated NP cells. Additionally, Pro‐B3 treatment blocked the activation of NF‐κB/toll‐like receptor 4 pathway in LPS‐exposed NP cells. Mechanistically, Pro‐B3 could occupy MD‐2's hydrophobic pocket exhibiting high affinity for LPS to intervene LPS/TLR4/MD‐2 complex formation. In vivo, Pro‐B3 treatment prevented the loss of gelatin NP cells and structural damage of annulus fibrosus in rat IVDD model. In brief, Pro‐B3 is considered to be a treatment agent for IVDD.

Crystalline iron oxides/hydroxides are generally preferred as supercapacitor electrode materials instead of the low-crystalline structure, despite the fact that an amorphous phase could have a comprehensive electrochemical performance owing to its structural disorder. Herein, we present a facile and scalable method for preparing amorphous FeOOH nanoflowers@multi-walled carbon nanotubes (FeOOH NFs@MWCNTs) composites. The resulting hybrid nanoflowers hold a distinctive heterostructure composed of a self-assembled amorphous FeOOH nanofilm on the MWCNTs surface. The low-crystalline 1FeOOH NFs@1MWCNTs composites at pH 8 exhibit a high comprehensive capacitive performance, which may be attributed to the advantageous structural features. In a −0.85 to 0 V vs Ag/AgCl potential window, the prepared hybrid electrode delivers a high specific capacitance of 345 F g–1 at a current density of 1 A g–1, good cycling stability (76.4% capacity retention over 5000 consecutive cycles), and outstanding rate performance (167 F g–1 at 11.4 A g–1). This work may trigger the possibilities of these nanomaterials for further application in supercapacitor electrodes, specifically low-crystalline oxide/hydroxide-based electrode materials.

To estimate the risk of type 1 diabetes associated with immune checkpoint inhibitor (ICI-T1DM), and to describe its clinical features.ICI-T1DM events in randomized clinical trials (RCTs) available in electronic databases were systematically reviewed. The primary outcome was the summary risk of T1DM related to ICIs, a meta-analysis was conducted to obtain Peto odds ratios (ORs) with 95 % CIs. In pharmacovigilance study, ICI-T1DM cases were extracted from FAERs. Disproportionality analyses were performed by calculating reporting odds ratio (ROR) and information components (IC).A total of 29 RCTs (20,234 patients) were included, treatment with ICIs significantly increased the risk of all-grade ICI-T1DM (OR: 4.54, 95 % CI: 2.66-7.72), and high-grade (grade 3 or above) ICI-T1DM (OR: 4.26, 95 % CI: 2.12-8.58). No significant differences among subgroup analyses were observed: ICIs treatment schedule, tumor type, case of events (T1DM vs F-T1DM), study design (double blind vs open label) or median PFS (PFS favours ICIs vs PFS favours Control). A total of 978 case reports form FAERS was extracted, treatment with ICIs significantly increased the reporting of ICI-T1DM (n = 978; ROR = 38.45, 95 %CI:35.70-41.41; IC = 4.77, 95 %CI:4.43-5.14). In cases with available data, the median latency period was 10.4 weeks, drug interruption was recorded in 82.3 % of cases, with a positive dechallenge in 76 % of cases, and death was recorded as outcome in 3.6 % of reports.Both data from clinical trials and postmarketing suggested that ICIs was associated with increased risk of ICI-T1DM. As ICIs gain greater clinical use, practitioners must be aware of ICI-T1DM events.

Zebrafish is an economical alternative model for developmental neurotoxicity (DNT) testing. DNT studies in zebrafish have been focused on acute effects; few studies explore enduring neurotoxicity in adults. More recently, gut microbiome has emerged as an important modulator between chemical exposure and neurotoxicity, rendering its necessity to be included in DNT testing. The present study used a well-known dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model chemical to explore long-lasting neurotoxicity in adults after transient exposure during early development. We demonstrated that transient MPTP exposure at 1 μM during a sensitive developmental window of 48-96 h post-fertilization (hpf) altered gut microbiome and led to male-biased locomotion and behavioral deficits in adult fish. The locomotion deficit was manifested as hypoactivity observed in adult males under light conditions or specifically the reduction of fast swim bouts. The social behavioral deficits were characterized by the reduced number of times fish crossed the mirror zone in the mirror response assay and the reduced percent time fish spent at the area proximal to conspecific fish shoal in the social preference test. Gut microbiome analysis revealed that transient MPTP exposure during early development might render fish more susceptible to the colonization of the pathogenic Vibrio. In conclusion, our study revealed that transient MPTP exposure during early development could lead to long-lasting neurotoxicity in adult fish and cause altered gut microbiome composition in both larval and adult fish.

Ischemic stroke, with its high morbidity and mortality, is the most common cerebrovascular accident and results in severe neurological deficits. Despite advances in medical and surgical intervention, post-stroke therapies remain scarce, which seriously affects the quality of life of patients. Over the past decades, stem cell transplantation has been recognized as very promising therapy for neurological diseases. Neural stem cell (NSC) transplantation is the optimal choice for ischemic stroke as NSCs inherently reside in the brain and can potentially differentiate into a variety of cell types within the central nervous system. Recent research has demonstrated that NSC transplantation can facilitate neural recovery after ischemic stroke, but the mechanisms still remain unclear, and basic/clinical studies of NSC transplantation for ischemic stroke have not yet been thoroughly elucidated. We thus, in this review, provide a futher understanding of the therapeutic role of NSCs for ischemic stroke, and evaluate their prospects for future application in clinical patients of ischemic stroke.

The technology of radial-well-assisted hydraulic fracturing is applied in the stimulation of low-permeability hydrocarbon reservoirs where commercial production cannot be achieved by the conventional fracturing method. Here, a study on the reservoir stimulation effect and the fracture propagation pattern of radial-well-assisted deflagration fracturing was carried out. Based on smooth particle hydrodynamics (SPH), rock mechanics theory, and finite element theory, a numerical model of radial-well-assisted deflagration fracturing was established by integrating the JWL state equation. Research on the effects of the deflagration position, radial well azimuth and horizontal principal stress difference on the fracture propagation was carried out. The results show that the deflagration position, radial well azimuth and horizontal principal stress difference have significant effects on the fracture area in deflagration fracturing. The closer distance from the deflagration position is, the larger the radial well azimuth and the smaller the horizontal stress difference are, leading to a larger fracture area, which is conducive to reservoir stimulation. During fracturing, both shear fractures and tensile fractures are formed. The formation and conversion of shear fractures and tensile fractures are related to the deflagration position, radial well azimuth, horizontal principal stress difference, etc.

Carbon materials have been used as negative electrodes for supercapacitor applications; nevertheless, owing to the low capacitance, they have limited ability to enhance the supercapacitor electrochemical properties. Here, we employ a facile chemical precipitation method for preparing a squirrel cage structure Fe

Background Colorectal poorly differentiated adenocarcinoma is rarely founded, especially in early-stage. Endoscopic features of early poorly differentiated colorectal cancer in magnifying endoscopy and chromoendoscopy haven’t been clarified. Case presentation A 49-year-old man was referred to our hospital for endoscopic treatment of a lateral spread tumor located in the rectum. We performed pre-resection endoscopic examination for the patient. In magnifying endoscopy with crystal violet staining, the lesion showed irregular microvessels and turned out to be poorly stained with predominantly non-structural pit pattern and a few roundish pits scattered on the surface. The histology revealed a poorly differentiated adenocarcinoma of the rectum invading the deep submucosal layer with negative lymphovascular invasion. Conclusions In this case report, we presented a case of poorly differentiated colorectal adenocarcinoma detected at an early stage, showing interesting endoscopic findings in magnifying endoscopy with crystal violet staining.

Background: Stress-related obesity might be related to the suppression of the hypothalamic-pituitary- adrenocortical axis and dysregulation of the metabolic system. Chronic stress also induces the dysregulation of the reward system and increases the risk of food addiction, according to recent clinical findings. However, few studies have tested the effect of chronic stress on food addiction in animal models. Purpose: The objective of this study was to identify whether chronic stress promotes food addiction or not and explore the possible mechanisms. Method: We applied adaily 2 hrsflashing LED irradiation stress to mice fed chow or palatable food to mimic the effect of chronic stress on feeding. After 1 month of chronic stress exposure, we tested their binge eating behaviors, cravings for palatable food, responses for palatable food, and compulsive eating behaviors to evaluate the effect of chronic stress on food addiction-like behaviors. We detected changes in the levels of various genes and proteins in the nucleus accumbens (NAc), ventral tegmental area (VTA) and lateral hypothalamus using qPCR and immunofluorescence staining, respectively. Results: Behaviors results indicated chronic stress obviously increased food addiction score (FAS) in the palatable food feeding mice. Moreover, the FAS had astrong relationship with the extent of the increase in body weight. Chronic stress increased the expression of corticotropin-releasing factor receptor 1(CRFR1) was increased in the NAc shell and core but decreased in the VTA of the mice fed with palatable food. Chronic stress also increased expression of both dopamine receptor 2 (DR2) and mu-opioid receptor (MOR) in the NAc. Conclusion: Chronic stress aggravates the FAS and contributed to the development of stress-related obesity. Chronic stress drives the dysregulation of the CRF signaling pathway in the reward system and increases the expression of DR2 and MOR in the nucleus accumbens.

Hypertension is associated with increased risk of stroke and bleeding in patients with atrial fibrillation (AF). In the present study, we aimed to investigate the influence of hypertension status in patients with AF receiving treatment with non-vitamin K antagonist oral anticoagulants (NOACs). PubMed, Embase, and Cochrane Library were searched from the inception of each database to November 2017. Randomized controlled trials (RCTs) that evaluated NOACs versus warfarin in patients with AF and hypertension were identified. A meta-analysis was performed using random- or fixed-effects models according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five trials (72,967 patients, including 51,378 patients with hypertension) were enrolled. NOACs significantly reduced the risk of stroke and systemic embolism (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.81–0.94, n = 51,378 patients), hemorrhagic stroke (HR 0.55, 95% CI 0.41–0.74, n = 28,818 patients), death from any cause (HR 0.91, 95% CI 0.85–0.97, n = 43,101 patients), major bleeding (HR 0.78, 95% CI 0.74–0.83, n = 51,378 patients) and intracranial bleeding (HR 0.50, 95% CI 0.38–0.67, n = 27,185 patients). The benefits of NOACs in comparison with warfarin were consistent in AF patients with or without hypertension (Pinteraction for all outcomes > 0.05). Our findings suggest that NOACs can be recommended for the prevention of stroke or systemic embolism in patients with AF and hypertension.

Flower-like metallic nanocrystals are generally used for applications in analytical science, but so far there have been few reports of ‘nanoflowers’ made of protein components. Herein, we report a novel electrochemical sensor based on copper ions–crosslinked bovine serum albumin nanoflower networks (Cu/CBSA NFNs). Due to the positive synergistic effects between the protein and copper ions, the new modified GCE delivers enhanced catalytic activity toward the electro-oxidation of nitrite ions. Through differential pulse voltammetry (DPV) the fabricated sensor is found to exhibit good analytical performance. Features include a wide dynamic linear range (0.5 to 500 μM, R2 = 0.999), a highly reproducible response (R.S.D. of 2.47%), and a low detection limit (0.1 μM, S/N = 3). Furthermore, the versatility of the proposed GCE can be demonstrated by the distinguished selectivity in the presence of some interfering agents and the electrode can also be utilized to determine nitrite in mineral water samples.

We examined case reports of immune checkpoint inhibitors (ICIs) associated pulmonary tuberculosis (PT) using data from the Food and Drug Administration Adverse Event Reporting System database. Disproportionality analysis was performed by using the reporting OR (ROR) with relevant 95% CI. A total of 74 cases of PT related to ICIs therapy were identified. ICIs were significantly associated with over-reporting frequencies of PT (ROR=3.16, 95% CI: 2.51 to 3.98), while the signal was differed between anti-programmed death-1/ligand-1 and anti-cytotoxic T lymphocyte antigen-4 agents. Most indications were lung cancer (64.9%), the median onset age was 70 years, the median time to onset of PT was 70 days, ICIs were discontinued in most cases (85.2%).

Background Anaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10–15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC. Methods The GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter. Results. After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC. Conclusion This study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.

BackgroundAnaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10-15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC.MethodsThe GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter.Results.After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC.ConclusionThis study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.

Multimodal 3D medical images have the characteristics of huge operational data and multi degrees of freedom in geometric transformation. However, there are some difficulties in multimodal medical image registration, such as low registration efficiency and speed. In order to meet the clinical needs, a feature sphere constrained registration algorithm based on conformal geometric algebra is proposed in this paper. Firstly, 3D contour point clouds are extracted from multimodal medical images. Then, the spatial conformal sphere is constructed, and the feature points are calculated based on the spatial projection constraint from the point cloud to the conformal sphere. Finally, rotation operators are constructed by feature points to realize fast 3D medical image registration. Experimental results indicate that the registration algorithm based on geometric feature constraints in this paper is more effective for registration of multimodal 3D medical images, with high accuracy, anti-noise ability, rapid calculation, and strong universality.