Robust prognostic model based on immune infiltration‐related genes and clinical information in ovarian cancer

Immune infiltration of ovarian cancer (OV) is a critical factor in determining patient''s prognosis. Using data from TCGA and GTEx database combined with WGCNA and ESTIMATE methods, 46 genes related to OV occurrence and immune infiltration were identified. Lasso and multivariate Cox regression were applied to define a prognostic score (IGCI score) based on 3 immune genes and 3 types of clinical information. The IGCI score has been verified by K‐M curves, ROC curves and C‐index on test set. In test set, IGCI score (C‐index = 0.630) is significantly better than AJCC stage (C‐index = 0.541, p < 0.05) and CIN25 (C‐index = 0.571, p < 0.05). In addition, we identified key mutations to analyse prognosis of patients and the process related to immunity. Chi‐squared tests revealed that 6 mutations are significantly (p < 0.05) related to immune infiltration: BRCA1, ZNF462, VWF, RBAK, RB1 and ADGRV1. According to mutation survival analysis, we found 5 key mutations significantly related to patient prognosis (p < 0.05): CSMD3, FLG2, HMCN1, TOP2A and TRRAP. RB1 and CSMD3 mutations had small p‐value (p < 0.1) in both chi‐squared tests and survival analysis. The drug sensitivity analysis of key mutation showed when RB1 mutation occurs, the efficacy of six anti‐tumour drugs has changed significantly (p < 0.05).     

Tumour microenvironment‐based molecular profiling reveals ideal candidates for high‐grade serous ovarian cancer immunotherapy

ObjectiveDue to limited immunological profiles of high‐grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists.Materials and MethodsA training cohort of 418 HGSOC samples from TCGA was analysed by consensus non‐negative matrix factorization. We correlated the expression patterns with the presence of immune cell infiltrates, immune regulatory molecules and other genomic or epigenetic features. Two independent cohorts containing 482 HGSOCs and in vitro experiments were used for validation.ResultsWe identified immune and non‐immune groups where the former was enriched in signatures that reflect immune cells, infiltration and PD‐1 signalling (all, P < 0.001), and presented with a lower chromosomal aberrations but increased neoantigens, tumour mutation burden, and microsatellite instability (all, P < 0.05); this group was further refined into two microenvironment‐based subtypes characterized by either immunoactivation or carcinoma‐associated fibroblasts (CAFs) and distinct prognosis. CAFs‐immune subtype was enriched for factors that mediate immunosuppression and promote tumour progression, including highly expressed stromal signature, TGF‐β signalling, epithelial‐mesenchymal transition and tumour‐associated M2‐polarized macrophages (all, P < 0.001). Robustness of these immune‐specific subtypes was verified in validation cohorts, and in vitro experiments indicated that activated‐immune subtype may benefit from anti‐PD1 antibody therapy (P < 0.05).ConclusionOur findings revealed two immune subtypes with different responses to immunotherapy and indicated that some HGSOCs may be susceptible to immunotherapies or combination therapies.     

Phospholipase D1 promotes cervical cancer progression by activating the RAS pathway

This study aimed to further investigate the effect of PLD1 on the biological characteristics of human cervical cancer (CC) cell line, CASKI and the potential related molecular mechanism. CRISPR/Cas9 genome editing technology was used to knock out the PLD1 gene in CASKI cells. Cell function assays were performed to evaluate the effect of PLD1 on the biological function of CASKI cells in vivo and in vitro. A PLD1‐overexpression rescue experiment in these knockout cells was performed to further confirm its function. Two PLD1‐knockout CASKI cell lines (named PC‐11 and PC‐40, which carried the ins1/del4 mutation and del1/del2/ins1 mutation, respectively), were constructed by CRISPR/Cas9. PLD1 was overexpressed in these knockout cells (named PC11‐PLD1 and PC40‐PLD1 cells), which rescued the expression of PLD1 by approximately 71.33% and 74.54%, respectively. In vivo, the cell function assay results revealed that compared with wild‐type (WT)‐CASKI cells, the ability of PC‐11 and PC‐40 cells to proliferate, invade and migrate was significantly inhibited. The expression of H‐Ras and phosphorylation of Erk1/2 (p‐Erk1/2) was decreased in PC‐11 and PC‐40 cells compared with WT‐CASKI cells. PC‐11 and PC‐40 cells could sensitize CASKI cells to cisplatin. More importantly, the proliferation, migration and invasion of PC11‐PLD1 and PC40‐PLD1 cells with PLD1 overexpression were significantly improved compared with those of the two types of PLD1 knockout cells. The sensitivity to cisplatin was decreased in PC11‐PLD1 and PC40‐PLD1 cells compared with PC‐11 and PC‐40 cells. In vivo, in the PC‐11 and PC‐40 tumour groups, tumour growth was significantly inhibited and tumour weight (0.95 ± 0.27 g and 0.66 ± 0.43 g vs. 1.59 ± 0.67 g, p = 0.0313 and 0.0108) and volume (1069.41 ± 393.84 and 1077.72 mm³ ± 815.07 vs. 2142.94 ± 577.37 mm³, p = 0.0153 and 0.0128) were significantly reduced compared to those in the WT‐CASKI group. Tumour differentiation of the PC‐11 and PC40 cells was significantly better than that of the WT‐CASKI cells. The immunohistochemistry results confirmed that the expression of H‐Ras and p‐Erk1/2 was decreased in PC‐11 and PC‐40 tumour tissues compared with WT‐CASKI tumour tissues. PLD1 promotes CC progression by activating the RAS pathway. Inhibition of PLD1 may serve as an attractive therapeutic modality for CC.     

An alternative miRISC targets a cancer‐associated coding sequence mutation in FOXL2

The authors note that P values presented in the original Fig 1A and Appendix Fig S1A were not assessed using a proper statistical analysis method. In contrast to the initially employed two‐group t‐test, a one‐sample one‐tailed t‐test is appropriate here, as the basic null hypothesis is that the proportion of MT FOXL2 mRNA in each AGCT patient is lower than WT {H ₀: WT(%) > MT(%) }. New p values are presented in the corrected Fig 1A and Appendix Fig S1A, which are P < 0.00001 and P < 0.05, respectively. These revised P values did not affect the conclusion drawn.     

A comparative study of the ability of recombinant oncolytic adenovirus,doxorubicin and tamoxifen to inhibit the proliferation of breast cancer cells

In this study, we compared the inhibitory effects of recombinant oncolytic adenovirus (Ad‐apoptin‐hTERTp‐E1a, Ad‐VT) with that of doxorubicin (DOX), a first‐line chemotherapy drug, and tamoxifen (TAM), an endocrine therapy drug, on the proliferation of breast cancer cells. We found that Ad‐VT could effectively inhibit the proliferation of breast cancer cells (p < 0.01); the inhibition rate of Ad‐VT on normal mammary epithelial MCF‐10A cells was less than 20%. DOX can effectively inhibit the proliferation of breast cancer cells and also has a strong inhibitory effect on MCF‐10A cells (p < 0.01). TAM also has a strong inhibitory effect on breast cancer cells, among which the oestrogen‐dependent MCF‐7 cell inhibition was stronger (p < 0.01), At higher concentrations, TAM also had a high rate of inhibition (>70%) on the proliferation of MCF‐10A cells. We also found that both recombinant adenovirus and both drugs could successfully induce tumour cell apoptosis. Further Western blot results showed that the recombinant adenovirus killed breast cancer cells through the endogenous apoptotic pathway. Analysis of the nude mouse subcutaneous breast cancer model showed that Ad‐VT significantly inhibited tumour growth (the luminescence rate of cancer cells was reduced by more than 90%) and improved the survival rate of tumour‐bearing mice (p < 0.01). Compared with DOX and TAM, Ad‐VT has a significant inhibitory effect on breast cancer cells, but almost no inhibitory effect on normal breast epithelial cells, and this inhibitory effect is mainly through the endogenous apoptotic pathway. These results indicate that Ad‐VT has significant potential as a drug for the treatment of breast cancer.     

Clinical characteristics and outcomes of newly diagnosed patients with HIV‐associated aggressive B‐cell NHL in China

Little is known about the incidence, clinical characteristics and prognostic factors in HIV associated lymphoma as these are less common than HIV‐negative lymphoma in China. Currently, there are no standard guidelines for treatment of these patients. Therefore, we performed a study to analyse the clinical characteristics and outcomes of newly diagnosed HIV‐associated aggressive B‐cell non‐Hodgkin''s lymphoma (NHL) patients in Chongqing University Cancer Hospital (CUCH). Totally 86 newly diagnosed HIV‐associated aggressive B‐cell NHL patients in CUCH, southwest China, from July 2008 to August 2021, were analysed. In the entire cohort, median age was 48 years (range, 23–87 years), and more patients were male (87.2%). Most patients had elevated lactate dehydrogenase (LDH) (82.6%), advanced ann arbor stage (80.2%) and high IPI score (IPI score, 3–5) (62.7%) at diagnosis. Median CD4+ T‐cell count at diagnosis was 191/μl (range, 4–1022), 84 patients (97.7%) were on combination antiretroviral therapy (cART) at lymphoma diagnosis. In DLBCL patients, cox multivariate analysis showed that age ≥ 60 (HR = 2.251, 95%CI 1.122–4.516; p = 0.012), elevated LDH (HR = 4.452, 95%CI 1.027–19.297; p = 0.041) and received less than two cycles of chemotherapy (HR = 0.629, 95%CI 0.589–1.071; p = 0.012) were independent risk factors for adverse prognosis based on PFS. Age ≥ 60 (HR = 3.162, 95%CI 1.500–6.665; p = 0.002) and received less than two cycles of chemotherapy (HR = 0.524, 95%CI 0.347–0.791; p = 0.002) were also independent risk factor for adverse prognosis based on OS. In BL patients, cox multivariate analysis showed that elevated LDH and received less than two cycles of chemotherapy were independent risk factors for adverse prognosis. In the DLBCL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 12 months, respectively (p = 0.006). Median OS times were not reached and 36 months, respectively (p = 0.021). In the BL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 4.8 months, respectively (p = 0.046). Median OS times were not reached and 10.1 months, respectively (p = 0.035). Overall, these data indicated that standardized anti‐lymphoma therapy and rituximab administration were significantly associated with improved outcomes in patients with HIV‐associated DLBCL and BL.     

Tetrahedral DNA nanostructure improves transport efficiency and anti‐fungal effect of histatin 5 against Candida albicans

ObjectivesAnti‐microbial peptides (AMPs) have been comprehensively investigated as a novel alternative to traditional antibiotics against microorganisms. Meanwhile, Tetrahedral DNA nanostructures (TDNs) have gained attention in the field of biomedicine for their premium biological effects and transportation efficiency as delivery vehicles. Hence, in this study, TDN/Histatin 5 (His‐5) was synthesized and the transport efficiency and anti‐fungal effect were measured to evaluate the promotion of His‐5 modified by TDNs.Materials and MethodsTetrahedral DNA nanostructures/His‐5 complex was prepared via electrostatic attraction and characterized by transmission electron microscopy (TEM), polyacrylamide gel electrophoresis (PAGE), dynamic light scattering (DLS) and electrophoretic light scattering (ELS). The anti‐fungal effect of the TDN/His‐5 complex was evaluated by determining the growth curve and colony‐forming units of C. albicans. The morphological transformation of C. albicans was observed by light microscope and scanning electron microscope (SEM). Immunofluorescence was performed, and potassium efflux was detected to mechanistically demonstrate the efficacy of TDN/His‐5.ResultsThe results showed that Histatin 5 modified by TDNs had preferable stability in serum and was effectively transported into C. albicans, leading to the increased formation of intracellular reactive oxygen species, higher potassium efflux and enhanced anti‐fungal effect against C. albicans.ConclusionsOur study showed that TDN/His‐5 was synthesized successfully. And by the modification of TDNs, His‐5 showed increased transport efficiency and improved anti‐fungal effect.     

Kinetics and persistence of cellular and humoral immune responses to SARS‐CoV‐2 vaccine in healthcare workers with or without prior COVID‐19

SARS‐CoV‐2 vaccines are highly efficient against severe forms of the disease, hospitalization and death. Nevertheless, insufficient protection against several circulating viral variants might suggest waning immunity and the need for an additional vaccine dose. We conducted a longitudinal study on the kinetics and persistence of immune responses in healthcare workers vaccinated with two doses of BNT162b2 mRNA vaccine with or without prior SARS‐CoV‐2 infection. No new infections were diagnosed during follow‐up. At 6 months, post‐vaccination or post‐infection, despite a downward trend in the level of anti‐S IgG antibodies, the neutralizing activity does not decrease significantly, remaining higher than 75% (85.14% for subjects with natural infection, 88.82% for vaccinated after prior infection and 78.37% for vaccinated only). In a live‐virus neutralization assay, the highest neutralization titres were present at baseline and at 6 months follow‐up in persons vaccinated after prior infection. Anti‐S IgA levels showed a significant descending trend in vaccinated subjects (p < 0.05) after 14 weeks. Cellular immune responses are present even in vaccinated participants with declining antibody levels (index ratio 1.1–3) or low neutralizing activity (30%–40%) at 6 months, although with lower T‐cell stimulation index (p = 0.046) and IFN‐γ secretion (p = 0.0007) compared to those with preserved humoral responses.     

Oral intake of Lactobacillus plantarum L‐14 extract alleviates TLR2‐ and AMPK‐mediated obesity‐associated disorders in high‐fat‐diet‐induced obese C57BL/6J mice

ObjectivesWhether periodic oral intake of postbiotics positively affects weight regulation and prevents obesity‐associated diseases in vivo is unclear. This study evaluated the action mechanism of Lactobacillus plantarum L‐14 (KTCT13497BP) extract and the effects of its periodic oral intake in a high‐fat‐diet (HFD) mouse model.Materials and methodsMouse pre‐adipocyte 3T3‐L1 cells and human bone marrow mesenchymal stem cells (hBM‐MSC) were treated with L‐14 extract every 2 days during adipogenic differentiation, and the mechanism underlying anti‐adipogenic effects was analysed at cellular and molecular levels. L‐14 extract was orally administrated to HFD‐feeding C57BL/6J mice every 2 days for 7 weeks. White adipose tissue was collected and weighed, and liver and blood serum were analysed. The anti‐adipogenic mechanism of exopolysaccharide (EPS) isolated from L‐14 extract was also analysed using Toll‐like receptor 2 (TLR2) inhibitor C29.ResultsL‐14 extract inhibited 3T3‐L1 and hBM‐MSC differentiation into mature adipocytes by upregulating AMPK signalling pathway in the early stage of adipogenic differentiation. The weight of the HFD + L‐14 group (31.51 ± 1.96 g) was significantly different from that of the HFD group (35.14 ± 3.18 g). L‐14 extract also significantly decreased the serum triacylglycerol/high‐density lipoprotein cholesterol ratio (an insulin resistance marker) and steatohepatitis. In addition, EPS activated the AMPK signalling pathway by interacting with TLR2, consequently inhibiting adipogenesis.ConclusionsEPS from L‐14 extract inhibits adipogenesis via TLR2 and AMPK signalling pathways, and oral intake of L‐14 extract improves obesity and obesity‐associated diseases in vivo. Therefore, EPS can be used to prevent and treat obesity and metabolic disorders.     

High‐fat diet‐induced obesity augments the deleterious effects of estrogen deficiency on bone: Evidence from ovariectomized mice

Several epidemiological studies have suggested that obesity complicated with insulin resistance and type 2 diabetes exerts deleterious effects on the skeleton. While obesity coexists with estrogen deficiency in postmenopausal women, their combined effects on the skeleton are poorly studied. Thus, we investigated the impact of high‐fat diet (HFD) on bone and metabolism of ovariectomized (OVX) female mice (C57BL/6J). OVX or sham operated mice were fed either HFD (60%fat) or normal diet (10%fat) for 12 weeks. HFD‐OVX group exhibited pronounced increase in body weight (~86% in HFD and ~122% in HFD‐OVX, p < 0.0005) and impaired glucose tolerance. Bone microCT‐scanning revealed a pronounced decrease in trabecular bone volume/total volume (BV/TV) (−15.6 ± 0.48% in HFD and −37.5 ± 0.235% in HFD‐OVX, p < 0.005) and expansion of bone marrow adipose tissue (BMAT; +60.7 ± 9.9% in HFD vs. +79.5 ± 5.86% in HFD‐OVX, p < 0.005). Mechanistically, HFD‐OVX treatment led to upregulation of genes markers of senescence, bone resorption, adipogenesis, inflammation, downregulation of gene markers of bone formation and bone development. Similarly, HFD‐OVX treatment resulted in significant changes in bone tissue levels of purine/pyrimidine and Glutamate metabolisms, known to play a regulatory role in bone metabolism. Obesity and estrogen deficiency exert combined deleterious effects on bone resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass. Our results suggest that obesity may increase bone fragility in postmenopausal women.     

Hepatoprotective effect of nanoniosome loaded Myristica fragrans phenolic compounds in mice‐induced hepatotoxicity

In this study, nanoniosome‐loaded Myristica fragrans'' (MF) phenolic compounds (NLMP) were synthesized and characterized for their physical properties, and hepatoprotective effects on mice with liver toxicity induced by L‐asparaginase (LA) injection. According to the results, NLMP has a spherical shape with a 263 nm diameter, a zeta potential of −26.55 mV and a polydispersity index (PDI) of 0.192. The weight and feed intake of mice induced with hepatotoxicity were significantly (p ≤ 0.05) increased after they were treated with NLMP (2.5 mg/kg body weight of mice). In addition, the blood levels of triglyceride (TG), cholesterol (Chol), liver enzymes (aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP)) and total bilirubin were significantly (p ≤ 0.05) decreased. A significant increase (p ≤ 0.05) in the blood levels of the antioxidant defence system (glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT)) were also reported after NLMP treatment. NLMP was also led to a significant decrease (p ≤ 0.05) in inflammatory‐related gene expression of inducible nitric oxide synthase (iNOS) and Interferon‐gamma (IFN‐γ) in the liver, as well as a meaningful (p ≤ 0.05) increase in the expression of SOD as an antioxidant status biomarker. Consequently, the NLMP is recommended as a potential dietary supplement to alleviate the symptoms of LA‐induced hepatotoxicity.     

Effect of dexamethasone prodrug on inflamed temporomandibular joints in juvenile rats

IntroductionJuvenile idiopathic arthritis (JIA) often causes inflammation of the temporomandibular joint (TMJ) and has been treated with both systemic and intra-articular steroids, with concerns about effects on growing bones. In this study, we evaluated the impact of a macromolecular prodrug of dexamethasone (P-DEX) with inflammation-targeting potential applied systemically or directly to the TMJ.MethodsJoint inflammation was initiated by injecting two doses of complete Freund’s adjuvant (CFA) at 1-month intervals into the right TMJs of 24 growing Sprague–Dawley male rats (controls on left side). Four additional rats were not manipulated. With the second CFA injection, animals received (1) 5 mg of P-DEX intra-articularly (n = 9), (2) 15 mg of P-DEX into the tail vein (n = 7), or (3) nothing in addition to CFA (n = 8). The rats were killed 28 days later and measured by radiography for ramus height (condylar superior to gonion inferior [CsGoInf]), by micro-computed tomography for condylar width (CW) and bone volume/standardized condylar volume (BV/CV), and by histology for retrodiscal inflammatory cells. Inflammation targeting of systemic P-DEX was confirmed by IVIS infrared dye imaging. Inflammation and bone growth were compared between groups using analysis of variance and Pearson’s correlations.ResultsCFA caused a significant reduction in CsGoInf (p < 0.05), but neither route of P-DEX administration had an effect on CsGoInf or CW at CFA injection sites. BV/CV was significantly reduced in both inflamed and control condyles as a result of either steroid application (p < 0.05). The inflammatory infiltrate was overwhelmingly lymphocytic, comprising 16.4 ± 1.3 % of the field in CFA alone vs. <0.01 % lymphocytes in contralateral controls (p < 0.0001). Both P-DEX TMJ (10.1 ± 1.2 %) and systemic P-DEX (8.9 ± 1.7 %) reduced lymphocytes (p < 0.002). The total area of inflammatory infiltrate was significantly less in the systemic injection group than in the group that received CFA injections alone (2.6 ± 1.5 mm² vs. 8.0 ± 1.3 mm²; p = 0.009), but not in the group that received intra-articular P-DEX (8.8 ± 1.2 mm²).ConclusionsHigh-dose systemic administration of inflammation-targeting P-DEX is more effective than an intra-articular injection in reducing TMJ inflammation, but both routes may affect TMJ bone density.     

Characteristics of chest pain in COVID-19 patients in the emergency department

IntroductionPatients with coronavirus disease 2019 (COVID-19) can present with chest pain. However, the characteristics of this chest pain are unknown. We performed a single-centre observational study to review and summarise chest pain characteristics in COVID-19 patients at first presentation to the emergency department (ED).MethodsWe collected data on characteristics of ‘chest pain’ reported by COVID-19 patients who attended the ED of Bernhoven Hospital, the Netherlands from 4 through 30 March 2020.ResultsWe included 497 COVID-19 patients, of whom 83 (17%) reported chest pain upon presentation to the ED. Chest pain characteristics were: present since disease onset (88%), retrosternal location (43%), experienced as compressing/pressure pain (61%), no radiation (61%) and linked to heavy coughing (39%). Patients who reported chest pain were younger than those without chest pain (61 vs 73 years; p < 0.001). Patients with syncope were older (75 vs 72 years; p = 0.017), had a shorter duration of symptoms (5 vs 7 days; p < 0.001) and reported fewer respiratory complaints (68% vs 90%; p < 0.001) than those without syncope. Patients with new-onset atrial arrhythmias presented with a shorter duration of symptoms (5 vs 7 days; p = 0.013), experienced fewer respiratory complaints (72% vs 89%; p = 0.012) and more frequently had a history of cardiovascular disease (79% vs 50%; p = 0.003) than patients who presented without arrythmias.ConclusionChest pain and other cardiac symptoms were frequently observed in COVID-19 patients. Treating physicians should be aware that chest pain, arrhythmias and syncope can be presenting symptoms of COVID-19.Supplementary InformationThe online version of this article (10.1007/s12471-022-01730-7) contains supplementary material, which is available to authorized users.     

Transition metal cation inhibition of Mycobacterium tuberculosis esterase RV0045C

Mycobacterium tuberculosis virulence is highly metal‐dependent with metal availability modulating the shift from the dormant to active states of M. tuberculosis infection. Rv0045c from M. tuberculosis is a proposed metabolic serine hydrolase whose folded stability is dependent on divalent metal concentration. Herein, we measured the divalent metal inhibition profile of the enzymatic activity of Rv0045c and found specific divalent transition metal cations (Cu²⁺ ≥ Zn²⁺ > Ni²⁺ > Co²⁺) strongly inhibited its enzymatic activity. The metal cations bind allosterically, largely affecting values for k _cat rather than K _M. Removal of the artificial N‐terminal 6xHis‐tag did not change the metal‐dependent inhibition, indicating that the allosteric inhibition site is native to Rv0045c. To isolate the site of this allosteric regulation in Rv0045c, the structures of Rv0045c were determined at 1.8 Å and 2.0 Å resolution in the presence and absence of Zn²⁺ with each structure containing a previously unresolved dynamic loop spanning the binding pocket. Through the combination of structural analysis with and without zinc and targeted mutagenesis, this metal‐dependent inhibition was traced to multiple chelating residues (H202A/E204A) on a flexible loop, suggesting dynamic allosteric regulation of Rv0045c by divalent metals. Although serine hydrolases like Rv0045c are a large and diverse enzyme superfamily, this is the first structural confirmation of allosteric regulation of their enzymatic activity by divalent metals.     

Conservative initial postoperative anticoagulation strategy after HeartMate 3 left ventricular assist device implantation

IntroductionAlthough anticoagulation therapy is mandated after implantation of a left ventricular assist device (LVAD), postoperative bleedings and reoperations occur relatively frequently and are associated with worse outcomes. We evaluated the use of a conservative postoperative anticoagulation protocol in patients implanted with a HeartMate 3 (HM3) LVAD.MethodsIn a single-centre retrospective analysis of postoperative outcomes after HM3 LVAD implantation, a standard (old) anticoagulation protocol (i.e. early, full-dose anticoagulation with low-molecular weight heparin and overlapping vitamin K antagonist) was compared with a new conservative anticoagulation protocol (i.e. slow initiation of vitamin K antagonists without overlapping heparin). Main outcomes were changes in international normalised ratio (INR), lactate dehydrogenase (LDH), bleeding and/or tamponade events requiring reoperation, length of stay and adverse events.ResultsIn total, 73 patients (48 in old vs 25 in new protocol group) were evaluated. Mean age was 56 years (standard deviation 13) and most patients (78%) were males. Changes in INR and LDH in the first 14 days were similar in both groups (p = 0.50 and p = 0.997 for interaction, respectively). Number of bleeding/tamponade events requiring reoperation was lower in the new than in the old protocol group (4% vs 33%, p = 0.005). Postoperative 30-day mortality was similar, and we observed no thromboembolic events. Median (25th–75th percentiles) total length of postoperative hospital stay (27 (25–41) vs 21 (19–27) days, p < 0.001) and length of intensive care unit stay (5 (2–9) vs 2 (2–5) days, p = 0.022) were significantly shorter in the new protocol group.ConclusionThese retrospective data suggest that conservative slow initiation of anticoagulation therapy after HM3 LVAD implantation is associated with less bleeding/tamponade events requiring reoperation, a similar safety profile and a shorter duration of stay than the currently advised standard anticoagulation protocol.Supplementary InformationThe online version of this article (10.1007/s12471-022-01671-1) contains supplementary material, which is available to authorized users.     

Prognostic significance of incident atrial fibrillation following STEMI depends on the timing of atrial fibrillation

Atrial fibrillation (AF) is associated with short-term mortality after ST-elevation myocardial infarction (STEMI), but there is limited data on the temporal association between AF and mortality after STEMI. A total of 830 patients were included (age: 62 ± 12 years, 76 % male). Patients with new-onset AF < 30 days after STEMI were divided among three subgroups: AF on the day of admission, AF 24–72 h and AF > 72 h after admission. Thirty-day mortality was assessed by telephone and via the municipal population registry. Twenty patients died < 30 days after admission. In 41 patients, AF was detected on the day of admission, in 14 patients 24–72 h after admission and in 18 patients > 72 h after admission. Mortality was higher in patients with AF on the day of admission (7.3 vs 2.2 %, p = 0.036) and 24–72 h after admission (14.3 vs 1.4 %, p < 0.001), but not in patients with AF > 72 h after admission (0 vs 1.1 %, p > 0.999). Age (odds ratio (OR) 1.123, p < 0.001), Killip class (adjusted OR 8.341, p < 0.001), AF on the day of admission (OR 3.585, p = 0.049) and 24–72 h after admission (OR 11.515, p = 0.003) were, amongst other variables, associated with an increased 30-day mortality. In conclusion, only new-onset incident AF during the first 72 h after admission was associated with 30-day mortality in STEMI patients.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-015-0709-2) contains supplementary material, which is available to authorized users.     

Coronary CT angiography for suspected acute coronary syndrome: sex-associated differences

AimThe optimal diagnostic test in the work-up of suspected acute coronary syndrome (ACS) may differ between men and women. The aim of this study was to compare sex-associated differences between using a diagnostic strategy including early coronary computed tomography angiography (CCTA) and standard of care (SOC).MethodsIn total, 500 patients who presented with symptoms suggestive of ACS at the emergency department were randomised between a diagnostic strategy supplemented with early CCTA and SOC.ResultsWomen were generally older than men (mean ± standard deviation 56 ± 10 vs 53 ± 10 years, p < 0.01) and were less often admitted to hospital (33% vs 44%, p = 0.02). Obstructive coronary artery disease on CCTA (> 50% luminal narrowing) was less frequently seen in women (14% vs 26%, p = 0.02), and ACS was diagnosed less often in women (5% vs 10%, p = 0.03). Women underwent less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS (p = 0.008).ConclusionWomen had a lower incidence of obstructive CAD on CCTA and were less often admitted to hospital than men. They were subjected to less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS.Supplementary InformationThe online version of this article (10.1007/s12471-021-01607-1) contains supplementary material, which is available to authorized users.     

Outcome of transcatheter aortic valve replacement in patients over 85 years of age versus patients aged 85 and younger

IntroductionThe Dutch general population is aging rapidly. Many of these patient are fit and eligible for TAVR. However, studies on outcome in older versus younger patients are scant.Material and methodsA single-centre retrospective study comparing patients older and younger than age 85 on outcome.Results190 patients underwent TAVR: 136 were aged 85 or younger (U85), 54 were older than 85 (O85). The U85 group had more men (U85: 71 [52.2%] vs O85: 19 [35.2%]; p = 0.034), a higher incidence of diabetes (U85: 36 [26.5%] vs O85: 3 [5.6%]; p = 0.001) and atrial fibrillation (U85: 35 [25.7%] vs O85: 5 [9.3%]; p = 0.03) and a higher body mass index (U85: 27.5 [± 5.24] vs O85: 26 [± 3.78]; p = 0.027). In the O85 group there was a lower estimated glomerular filtration rate (O85: 50.28 [± 15.32] ml/min vs U85: 65.25 [± 29.97] ml/min; p = 0.012). There was no difference in 30-day mortality (U85: 6 [4.4%] vs O85: 3 [5.6%]) and 1‑year mortality (U85 9 [6.6%] vs O85 3 [5.6%]) (p = 0.521). There was an equal amount of new onset permanent left bundle branch block (U85: 38 [27.9%] vs O85: 14 [25.9%]; p = 0.896) and permanent pacemaker implantation (U85: 28 [20.6%] vs O85: 28 [20.6%]; p = 0.748). There was no difference in bleeding events (p = 0.469), vascular complications (p = 0.195) or moderate/severe regurgitation (p = 0.972). The U85 group had a slightly longer admission duration (U85 6.29 [± 5.289] days vs O85 5.98 [± 3.328] days (p = 0.037)).ConclusionTAVR in patients over 85 years of age has excellent outcome, comparable to those aged 85 and younger.     

A novel multikinase inhibitor SKLB‐YTH‐60 ameliorates inflammation and fibrosis in bleomycin‐induced lung fibrosis mouse models

ObjectivesIdiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis.Materials and MethodsSKLB‐YTH‐60 was developed through computer‐aided drug design, de novo synthesis and high‐throughput screening. We employed the bleomycin (BLM)‐induced lung fibrosis animal models and used TGF‐β₁ to induce the epithelial‐mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α‐smooth muscle actin (α‐SMA), E‐cadherin, p‐FGFR1, p‐PLCγ, p‐Smad2/3 and p‐Erk1/2 was detected by western blot.ResultsYTH‐60 has obvious anti‐proliferative activity on fibroblasts and A549 cells. Moreover, YTH‐60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF‐β/Smad‐dependent pathways. Intraperitoneal administration of preventive YTH‐60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH‐60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH‐60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half‐life time (T _1/2 = 8.03 hours).ConclusionsTaken together, these preclinical evaluations suggested that YTH‐60 could be a promising drug candidate for treating IPF.     

Impact of COVID-19 outbreak on hospital admissions and outcome of acute coronary syndromes in a single high-volume centre in southeastern Europe

BackgroundAs coronavirus disease 2019 (COVID-19) has reached pandemic status, authors from the most severely affected countries have reported reduced rates of hospital admissions for patients with acute coronary syndrome (ACS).AimThe aim of the present study was to investigate the influence of the COVID-19 outbreak on hospital admissions and outcomes in ACS patients in a single high-volume centre in southeastern Europe.MethodsThis retrospective observational study aimed to investigate the number of hospital admissions for ACS, clinical findings at admission, length of hospitalisation, major complications and in-hospital mortality during the COVID-19 outbreak and to compare the data with the same parameters during an equivalent time frame in 2019. For the ST-elevated myocardial infarction (STEMI) subgroup of patients, changes in ischaemic times were analysed as well.ResultsThere was a significant reduction of 44.3% in the number of patients admitted for ACS during the COVID-19 outbreak when compared with the same period in 2019 (151 vs 271; 95% confidence interval 38.4–50.2, p < 0.01) with a higher mortality rate (13.2% vs 7.2%, p = 0.03). In 2020, patients with non-ST-elevated myocardial infarction presented more often with acute heart failure (3.3% vs 0.7%, p = 0.04). During the COVID-19 outbreak, we observed increases in the total ischaemic time (303 ± 163.4 vs 200.8 ± 156.8 min, p < 0.05) and door-to-balloon time (69.2 ± 58.4 vs 50.5 ± 31.3 min, p < 0.01) in STEMI patients.ConclusionsThese findings should increase the awareness of morbidity and mortality related to missed or delayed treatment of ACS among the public and the healthcare services.