Unfavorable Clinical Outcome Research Articles

Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance.

In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival. This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.

Prognostic Potential of Pulmonary Hypertension in Patients with Hematologic Malignancy.

Cardiovascular diseases present a great burden for survivors of hematologic malignancy (HM). However, the effect of pulmonary hypertension (PH) on the clinical outcome of patients with HM remains unknown. This study aims to evaluate the prognostic potential of PH in patients with HM and explore the related clinical determinants. This retrospective study included 220 patients with HM and PH and 220 controls without PH, the case-matching cohort analysis was performed based on age, sex, the year of diagnosis and disease type. The baseline characteristics and overall survival (OS) of the patients with HM with or without PH were compared. The cumulative overall survival was analyzed using the Kaplan-Meier curves and the log-rank test. Multivariate Cox proportional hazard models were conducted to identify the predictors of OS. PH was found in 11.98% (302/2520) of the patients with HM. The PH group had lower levels of hemoglobin, platelet, albumin, fibrinogen and Bcell count; whereas the levels of lactate dehydrogenase, N terminal pro B type natriuretic peptide, D-dimer, fibrinogen degradation products and C-reactive protein were higher. Additionally, the PH group had a higher prevalence of atrial fibrillation. Survival analysis revealed that the PH group had an inferior OS compared to the non-PH group (16.9 vs. 37.6months, p = 0.002). Further subgroup analysis revealed that the severe PH group had the worst OS, followed by the moderate and the mild PH groups (8.7 vs. 14.7 vs. 23.7months, p < 0.001). Multivariate analysis showed that PH was an independent predictor for unfavorable clinical outcomes. Coexisting PH was associated with inferior clinical outcomes in patients with HM, and the severe PH group had the worst prognosis. The study may provide additional risk stratification for patients with HM.

Case report of metastatic colorectal cancer associated with &lt;i&gt;KRAS&lt;/i&gt; A146V and A59G mutations

In colorectal cancer (CRC) in addition to the most common mutations in the second exon of KRAS, there are rarer mutations that are not well understood as prognostic markers.Description of cases. We describe two clinical cases of moderately differentiated adenocarcinoma (low-grade, G2), which manifested a complicated course in a 67-year-old woman – intestinal obstruction (case 1) and in a 62-year-old man – paratumorous abscess (case 2). Both cases were characterized by the development of regional and distant metastases (liver, brain) and a short relapse-free period. We found rare sporadic mutations of KRAS A146V and A59G with microsatellite stability and no mutation in the V600 BRAF site.Discussion. In the presented case 1, the KRAS A146V mutation was detected, the frequency of its detection in our practice of testing 2103 cases of CRC was 0.48%. Case 2 shows the extremely rare A59G mutation. Among the patients with CRC we studied, we found mutations in codon 59 in only two, which amounted to 0.095%. Both rare mutations represent separate molecular subgroups of CRC, characterized by an unfavorable clinical outcome and requiring the development of special treatment regimens.

Prognostic values of geriatric nutrition risk index on elderly patients after spinal tuberculosis surgery.

Spinal tuberculosis (STB) is a significant public health concern, especially in elderly patients, due to its chronic and debilitating nature. Nutritional status is a critical factor affecting the prognosis of STB patients. The geriatric nutritional risk index (GNRI) has been established as a reliable predictor of adverse outcomes in various diseases, but its correlation with surgical outcomes in elderly STB patients has not been studied. The study aimed to assess the prognostic value of the GNRI in elderly patients with STB who underwent surgery. We conducted a retrospective analysis of medical records of elderly patients (65 years or older) diagnosed with active STB who underwent surgical treatment. Data collection included patient demographics, comorbidities, clinical history, laboratory testing, and surgical factors. GNRI was calculated using serum albumin levels and body weight. Postoperative complications were observed and recorded. The patients were followed up for at least 1 year, and their clinical cure status was assessed based on predefined criteria. A total of 91 patients were included in the study. We found that a GNRI value of <98.63 g/dL was a cutoff value for predicting unfavorable clinical prognosis in elderly STB patients undergoing surgery. Patients with a low GNRI had higher Charlson Comorbidity Index scores, were more likely to receive red blood cell transfusions, and had a higher prevalence of overall complications, particularly pneumonia. The unfavorable clinical prognosis group had lower GNRI scores compared to the favorable prognosis group. Multivariate analysis showed that lower GNRI independently predicted unfavorable clinical outcomes in elderly STB patients. The study concluded that the GNRI is a valuable biomarker for predicting prognosis in elderly STB patients undergoing surgical intervention. Patients with lower GNRI scores had worse outcomes and a higher incidence of complications.

Using Radiomics and Convolutional Neural Networks for the Prediction of Hematoma Expansion After Intracerebral Hemorrhage.

Hematoma enlargement (HE) is a common complication following acute intracerebral hemorrhage (ICH) and is associated with early deterioration and unfavorable clinical outcomes. This study aimed to evaluate the predictive performance of a computed tomography (CT) based model that utilizes deep learning features in identifying HE. A total of 408 patients were retrospectively enrolled between January 2015 and December 2020 from our institution. We designed an automatic model that could mask the hematoma area and fusion features of radiomics, clinical data, and convolutional neural network (CNN) in a hybrid model. We assessed the model's performance by using confusion matrix metrics (CM), the area under the receiver operating characteristics curve (AUC), and other statistical indicators. After automated masking, 408 patients were randomly divided into two cohorts with 204 patients in the training set and 204 patients in the validation set. The first cohort trained the CNN model, from which we then extracted radiomics, clinical data, and CNN features for the second validation cohort. After feature selection by K-highest score, a support vector machines (SVM) model classification was used to predict HE. Our hybrid model exhibited a high AUC of 0.949, and 0.95 of precision, 0.83 of recall, and 0.94 of average precision (AP). The CM found that only 5 cases were misidentified by the model. The automatic hybrid model we developed is an end-to-end method and can assist in clinical decision-making, thereby facilitating personalized treatment for patients with ICH.

The impact of the distance traveled between residence and gestational trophoblastic neoplasia reference center and clinical outcomes in Brazilian women

ObjectiveTo relate the distance traveled from the patient's residence to the gestational trophoblastic neoplasia (GTN) reference center (RC) and the occurrence of unfavorable clinical outcomes, as well as to estimate the possible association between this distance and the risk of metastatic disease at presentation, the need for multiagent chemotherapy to achieve remission and loss to follow-up before remission. Study designRetrospective historical cohort study of patients with GTN followed at 8 Brazilian GTN-RC, from January 1st, 2000 - December 31st, 2017. ResultsEvaluating 1055 cases of GTN, and using a receiver operating characteristic curve, we found a distance of 56 km (km) from the residence to the GTN-RC (sensitivity = 0.57, specificity = 0.61) best predicted the occurrence of at least one of the following outcomes: occurrence of metastatic disease, need for multiagent chemotherapy to achieve remission, or loss to follow-up during chemotherapy. Multivariate logistic regression adjusted by age, ethnicity, marital status and the reference center location showed that when the distance between residence and GTN-RC was ≥56 km, there was an increase in the occurrence of metastatic disease (relative risk - RR:3.27; 95%CI:2.20–4.85), need for multiagent chemotherapy (RR:1.36; 95%CI:1.05–1.76), loss to follow-up during chemotherapy (RR:4.52; 95CI:1.93–10.63), occurrence of chemoresistance (RR:4.61; 95%CI:3.07–6.93), relapse (RR:10.27; 95%CI:3.08–34.28) and death due to GTN (RR:3.62; 95%CI:1.51–8.67). ConclusionsThe distance between the patient's residence and the GTN-RC is a risk factor for unfavorable outcomes, including death from this disease. It is crucial to guarantee these patients get prompt access to the GTN-RC and receive follow-up support.

Prognostic value of spinal cord lesion measures in early relapsing-remitting multiple sclerosis

BackgroundSpinal cord (SC) lesions have been associated with unfavourable clinical outcomes in multiple sclerosis (MS). However, the relation of whole SC lesion number (SCLN) and volume (SCLV) to the future...

Impact of C3 laminectomy on cervical sagittal alignment in cervical laminoplasty: a prospective, randomized controlled trial comparing clinical and radiological outcomes between C3 laminectomy with C4–C6 laminoplasty and C3–C6 laminoplasty

Background ContextC3 laminectomy in cervical laminoplasty is a modified laminoplasty technique that can preserve the semispinalis cervicis muscle attached to the C2 spinous process. Several previous studies have shown that this technique can lead to better outcomes of postoperative axial neck pain and C2–C3 range of motion (ROM) than conventional cervical laminoplasty. However, there is still a lack of understanding of total and proportional postoperative cervical sagittal alignment outcomes. PurposeTo assess the effects of C3 laminectomy in cervical laminoplasty on postoperative cervical alignment and clinical outcomes. DesignA single-center, patient-blinded, randomized controlled trial. Patient SampleWe included consecutive 126 patients diagnosed with cervical spondylotic myelopathy (CSM) or ossification of posterior longitudinal ligament (OPLL) who were scheduled for cervical laminoplasty from March 2017 to January 2020. Outcome MeasuresThe primary outcome measures were C2–C7 Cobb angle (CA) and neck disability index (NDI). Secondary outcomes measures included other clinical outcomes and radiographic parameters including segmental Cobb angle and presence of C2–C3 interlaminar fusion. MethodsPatients were randomly allocated to either the C3 laminectomy with C4–C6 laminoplasty group (LN group) or the C3–C6 laminoplasty group (LP group) at a 1:1 ratio. Laminoplasty was performed using a unilateral open-door technique and stabilized with titanium mini plates. A linear mixed model analysis was employed to examine the longitudinal data from postoperative 1-year through 3-year. Additional analysis between three types of cervical sagittal alignment morphology was done. ResultsAmong 122 patients who were randomly allocated to one of two groups (LN group, n=61; LP group, n=61), modified intent-to-treat analysis was done for 109 patients (LN group, n=51, LP group, n=58) who had available at least a year of postoperative data. Postoperative C2–C7 CA was not significantly different between the two groups. However, NDI was significantly different between the two groups (12.8±1.0 in the LN group vs 8.6±1.0 in LP group, p=.005), which exceeded the minimum clinically important difference (MCID). The postoperative C2–C3 CA was significantly greater in the LN group (7.1±0.5° in LN group vs 3.2±0.5° in LP group, p<.001) while C4–C7 CA was significantly smaller in the LN group (3.9±0.8° in LN group vs 7.7±0.7° in LP group, p<.001) with greater cSVA in the LN group (31.6±1.4 mm in LN group vs 25.5±1.3 mm in LP group at postoperative 3-year, p=.002). Postoperative Euro-Quality of Life-5 Dimension (EQ-5D), numerical rating scores for neck pain (NRS-N) were significantly better in the LP group than in the LN group (all p<.05) and only EQ-5D surpassed the MCID. The C2-C3 fusion rate was significantly different between the LN group (9.8%) and the LP group (44.8%) (p<.001). The LN group showed a higher prevalence of a specific cervical alignment morphology characterized by a sigmoid shape with proximal lordosis and distal kyphosis (S curve). This S curve demonstrated significantly unfavorable outcomes across multiple outcome variables. ConclusionThe impact of C3 laminectomy in cervical laminoplasty on postoperative kyphosis among patients with CSM or OPLL did not significantly differ from that of C3–C6 laminoplasty. However, C3 laminectomy in cervical laminoplasty might result in an unfavorable clinical outcome with an unbalanced cervical sagittal alignment characterized by a sigmoid shape with proximal lordosis and distal kyphosis.

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis.

Introduction: Clear cell renal cell carcinoma (ccRCC) is associated with unfavorable clinical outcomes. To identify viable therapeutic targets, a comprehensive understanding of intratumoral heterogeneity is crucial. In this study, we conducted bioinformatic analysis to scrutinize single-cell RNA sequencing data of ccRCC tumor and para-tumor samples, aiming to elucidate the intratumoral heterogeneity in the ccRCC tumor microenvironment (TME). Methods: A total of 51,780 single cells from seven ccRCC tumors and five para-tumor samples were identified and grouped into 11 cell lineages using bioinformatic analysis. These lineages included tumor cells, myeloid cells, T-cells, fibroblasts, and endothelial cells, indicating a high degree of heterogeneity in the TME. Copy number variation (CNV) analysis was performed to compare CNV frequencies between tumor and normal cells. The myeloid cell population was further re-clustered into three major subgroups: monocytes, macrophages, and dendritic cells. Differential expression analysis, gene ontology, and gene set enrichment analysis were employed to assess inter-cluster and intra-cluster functional heterogeneity within the ccRCC TME. Results: Our findings revealed that immune cells in the TME predominantly adopted an inflammatory suppression state, promoting tumor cell growth and immune evasion. Additionally, tumor cells exhibited higher CNV frequencies compared to normal cells. The myeloid cell subgroups demonstrated distinct functional properties, with monocytes, macrophages, and dendritic cells displaying diverse roles in the TME. Certain immune cells exhibited pro-tumor and immunosuppressive effects, while others demonstrated antitumor and immunostimulatory properties. Conclusion: This study contributes to the understanding of intratumoral heterogeneity in the ccRCC TME and provides potential therapeutic targets for ccRCC treatment. The findings emphasize the importance of considering the diverse functional roles of immune cells in the TME for effective therapeutic interventions.

Increased preanalytical errors during Covid-19 Pandemic

The clinical laboratories worldwide have faced numerous obstacles due to the COVID-19 pandemic. In the midst of this outbreak, mistakes that occur during the preanalytical phase of sample collection, transportation, and processing can result in unfavorable clinical outcomes. Therefore, the aim of this investigation was to ascertain and contrast the rate at which blood specimens are rejected by a clinical laboratory and to analyze and compare the types of preanalytical errors during the pre-pandemic and pandemic periods. The present retrospective study was done in Chhatrapati Shivaji Subharti Hospital; India. Information was gathered from two distinct time periods - the pre-pandemic phase, which spanned from December 30th, 2019 to March 22, 2020, and the pandemic phase, which ran from March 23th to November 30, 2020. The rate of rejection for blood samples was established by determining the percentage of blood collection tubes containing preanalytical mistakes out of the total number of tubes received. A total of 102,000 blood samples were examined, out of which 40,800 (40%) were collected during the pandemic. The pandemic phase witnessed a significantly higher rate of rejection of blood samples (4%) as compared to the pre-pandemic phase (1%) (P &amp;#60; 0.001). In both phases, the most common preanalytical error was the clotting of samples. There was a significant increase in improperly labeled samples during the pandemic, while there was a notable decrease in hemolyzed samples. Given the prevailing situation of the Corona pandemic, altered logistics have led to a significant surge in preanalytical errors and consequent rejection of blood specimens in clinical laboratories. Therefore, it is imperative to take corrective measures at different levels to minimize preanalytical errors, which would ultimately enhance patient care and optimize the utilization of resources.

Chorionicity-associated variation in metabolic phenotype of cord blood in twin

BackgroundMonochorionic (MC) twins present a higher incidence of unfavorable clinical perinatal outcomes than dichorionic (DC) twins, often in association with placental vascular anastomosis. In this study, we profiled the umbilical cord plasma metabolomes of uncomplicated MC and DC twin pregnancies and related these to several offspring outcomes, previously associated with birthweight.MethodsUmbilical vein blood samples were collected at birth from 25 pairs of uncomplicated MC twins and 24 pairs of uncomplicated DC twins. The samples were subjected to gas chromatography-mass spectrometry-based metabolomics. 152 metabolites were identified from the cord plasma samples of MC and DC twins. Partial least squares discriminant analysis and pathway analysis were performed to compare within DC/MC twin pairs and between DC and MC twins. A generalized estimating equation (GEE) model was utilized to explore the correlation between metabolic differences and birthweight discordance within and between twin pairs.ResultsOur study revealed clear differences between the metabolite profiles of umbilical cord plasma of MC and DC twins. Metabolite profiles in MC within twin pairs and DC within twin pairs were characterized by the differences in 2 − hydroxyglutaramic acid levels and nicotinamide levels, respectively. The metabolic pathways of GSH, tryptophan, and fatty acid metabolism, were significantly downregulated in MC twins compared to DC twins. In addition, the concentration of caffeine and decamethyl-cyclopentasiloxane (D5) was positively correlated with birthweight in MC and DC twins.ConclusionThis study demonstrated that the altered metabolites in umbilical plasma made contributions to the different chorionicities between uncomplicated MC twins and DC twins. The chorionicity of twins seems to affect the metabolic cross-talk between co-twin pairs and be related to birthweight discordance of twins.

Two approaches to modeling the risk of progressive atherosclerosis

Progressive or accelerated atherosclerosis is accompanied by unfavorable clinical outcomes. Studying and understanding this process and creating a personalized method for assessing the risk and prognosis of this disease are necessary to optimize approaches to treatment and prevention.Aim: To compare two approaches to the creation of prognostic risk model of progressive atherosclerosis: non-linear regression model of logistic type and free cross-platform visual programming system Orange method.Material and Methods. The retrospective cohort study included 202 patients with confirmed coronary heart disease: 147 men and 55 women. The mean age of the patients was 53.3 ± 7.16 years. Group 1 included patients with myocardial infarction or unstable stenocardia, emergency arterial stenting, stroke, peripheral arterial thrombosis, critical ischemia and lower extremity amputation within 2 years before inclusion in the study. Patients in the comparison group did not have these events. Predictive models of the influence of different studied parameters on the probability of rapid progression of atherosclerosis were built using factor and correlation analysis and free cross-platform Orange visual programming system.Results. The authors’ suggested approaches to the evaluation of the risk of progressive atherosclerosis have a good prognostic accuracy (sensitivity 94.1, specificity 97.0 and accuracy 95.5 coefficients, respectively) for the regression model and 0,950 (95,0%) for the machine learning model. However, the construction of the regression model is a more complex procedure compared to the second approach, where the choice of informative indicators for the prediction model is made by Orange. Nevertheless, the above two approaches can successfully complement each other, allowing to build more accurate predictive risk models.Conclusion. The proposed authors’ approaches to assessing the risk of progressive atherosclerosis have a good prognostic accuracy.

Glycolysis induces Th2 cell infiltration and significantly affects prognosis and immunotherapy response to lung adenocarcinoma.

Glycolysis has a major role in cancer progression and can affect the tumor immune microenvironment, while its specific role in lung adenocarcinoma (LUAD) remains poorly studied. We obtained publicly available data from The Cancer Genome Atlas and Gene Expression Omnibus databases and used R software to analyze the specific role of glycolysis in LUAD. The Single Sample Gene Set Enrichment Analysis (ssGSEA) indicated a correlation between glycolysis and unfavorable clinical outcome, as well as a repression effect on the immunotherapy response of LUAD patients. Pathway enrichment analysis revealed a significant enrichment of MYC targets, epithelial-mesenchymal transition (EMT), hypoxia, G2M checkpoint, and mTORC1 signaling pathways in patients with higher activity of glycolysis. Immune infiltration analysis showed a higher infiltration of M0 and M1 macrophages in patients with elevated activity of glycolysis. Moreover, we developed a prognosis model based on six glycolysis-related genes, including DLGAP5, TOP2A, KIF20A, OIP5, HJURP, and ANLN. Both the training and validation cohorts demonstrated the high efficiency of prognostic prediction in this model, which identified that patients with high risk may have a poorer prognosis and lower sensitivity to immunotherapy. Additionally, we also found that Th2 cell infiltration may predict poorer survival and resistance to immunotherapy. The study indicated that glycolysis is significantly associated with poor prognosis in patients with LUAD and immunotherapy resistance, which might be partly dependent on the Th2 cell infiltration. Additionally, the signature comprised of six genes related to glycolysis showed promising predictive value for LUAD prognosis.

Persistent poverty impacts access to minimally invasive surgery among patients with hepatopancreatobiliary cancer.

Minimally invasive surgery (MIS) has been successfully adopted in hepatopancreatobiliary (HPB) cancer, and has been associated with improved perioperative and comparable oncological outcomes. We sought to define the impact of county-level duration of poverty on access to MIS and clinical outcomes among patients with HPB cancer undergoing surgical treatment. Data on patients diagnosed with HPB cancer were obtained from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2010-2016). County-level poverty data wereobtained from the American Community Survey and the U.S. Department of Agriculture, and categorized into three groups: never high poverty (NHP), intermittent high poverty (IHP), and persistent poverty (PP). Multivariable regression was used to assess the relationship between PP and MIS. Among 8098 patients, 82% (n = 664) resided in regions with NHP, 13.6% (n = 1104) resided in regions with IHP, and 4.4% (n = 350) resided in regions with PP. Median age at the diagnosis was 71 years (interquartile range [IQR]: 67-77). Patients from IHP and PP counties had lower odds of undergoing MIS (IHP/PP vs. NHP,odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.36-0.96, p = 0.034) and being discharged home (IHP/PP vs.NHP, OR: 0.64, 95% CI: 0.43-0.99, p = 0.043), as well as a higher risk of 1-year mortality (IHP/PP vs. NHP, HR: 1.51, 95% CI: 1.036-2.209, p = 0.032) compared with patients residing in NHP counties. Duration of county-level poverty was associated with lower receipt of MIS and unfavorable clinical and survival outcomes among patients with HPB cancer. There is a need to improve access to modern surgical treatment options among vulnerable, PP populations.

Integrated bioinformatics analysis and experimental validation reveal ISG20 as a novel prognostic indicator expressed on M2 macrophage in glioma

BackgroundGlioma is the most common malignant primary brain tumor and is characterized by a poor prognosis and limited therapeutic options. ISG20 expression is induced by interferons or double-stranded RNA and is associated with poor prognosis in several malignant tumors. Nevertheless, the expression of ISG20 in gliomas, its impact on patient prognosis, and its role in the tumor immune microenvironment have not been fully elucidated.MethodsUsing bioinformatics, we comprehensively illustrated the potential function of ISG20, its predictive value in stratifying clinical prognosis, and its association with immunological characteristics in gliomas. We also confirmed the expression pattern of ISG20 in glioma patient samples by immunohistochemistry and immunofluorescence staining.ResultsISG20 mRNA expression was higher in glioma tissues than in normal tissues. Data-driven results showed that a high level of ISG20 expression predicted an unfavorable clinical outcome in glioma patients, and revealed that ISG20 was possibly expressed on tumor-associated macrophages and was significantly associated with immune regulatory processes, as evidenced by its positive correlation with the infiltration of regulatory immune cells (e.g., M2 macrophages and regulatory T cells), expression of immune checkpoint molecules, and effectiveness of immune checkpoint blockade therapy. Furthermore, immunohistochemistry staining confirmed the enhanced expression of ISG20 in glioma tissues with a higher WHO grade, and immunofluorescence assay verified its cellular localization on M2 macrophages.ConclusionsISG20 is expressed on M2 macrophages, and can serve as a novel indicator for predicting the malignant phenotype and clinical prognosis in glioma patients.

Absolute Monocyte Count as Early and Safe Marker for Antibiotic Cessation in Febrile Neutropenia Without Etiology in Pediatric Oncology Patients.

There is no practice standard regarding antibiotic duration in children with cancer and unexplained febrile neutropenia (FN). We hypothesized that absolute monocyte count (AMC) and absolute phagocyte count (APC= ANC + AMC + bands) are more sensitive, earlier, and safe markers of antibiotic cessation compared with absolute neutrophil count (ANC). A retrospective review of FN episodes (FNEs) in pediatric oncology patients was conducted between 2009 and 2016. Included patients were afebrile for 24 hours and without an identified infectious source at antibiotic cessation. Primary endpoints, including recurrent fever, readmission, bloodstream infection, microbiologically documented infection, and adverse outcomes, were assessed 10 days after antibiotic cessation and compared among different bone marrow recovery parameters (ANC, AMC, APC). Secondary endpoints included length of FN stay, antibiotic-free days, and cost. Three hundred ninety-one FNEs in 235 patients were included. Three groups were compared based on ANC (cells/μL) at the time of antibiotic cessation: < 200 in 102 (26%), 200 to 500 in 111 (28%), and >500 in 178 (46%). No statistically significant differences in primary endpoints were identified among the 3 ANC groups; however, a trend toward unfavorable outcomes in the ANC ≤200 cells/μL group compared with the ANC >200 cells/μL was observed. Primary endpoints based on AMC >100 cells/μL at the time of antibiotic cessation showed statistically significant favorable outcomes compared AMC ≤100 cells/μL (80%, 88%, 90%, 89%, and 93% risk reduction in recurrent fever, readmission, new bloodstream infection, new microbiologically documented infection, and adverse events, respectively). Similar favorable results were seen when APC >300 cells/μL was used as a threshold for antibiotic cessation. The median length of stay for FN if discharged when AMC >100 cells/μL was 3 days shorter and associated with fewer unfavorable outcomes, thus resulting in fewer hospital days, fewer antibiotic days, and decreased cost. Our results suggest that AMC >100 cells/μL (regardless of ANC) or APC >300 cells/μL may be safe thresholds for empiric antibiotic cessation and result in reduced unfavorable clinical outcomes within 10 days postdischarge, reduced antibiotic days of therapy and reduced health care costs. Further prospective studies are needed to validate AMC as an accurate surrogate marker for antibiotic cessation in FNEs in children with cancer.

Expansion of healthcare-associated hypervirulent KPC-2-producing Klebsiella pneumoniae ST11/KL64 beyond hospital settings

The spread of carbapenemase-producing Klebsiella pneumoniae beyond hospital settings is a global critical issue within a public health and One Health perspective. Another worrisome concern is the convergence of virulence and resistance in healthcare-associated lineages of K. pneumoniae leading to unfavorable clinical outcomes. During a surveillance study of WHO critical priority pathogens circulating in an impacted urban river in São Paulo, Brazil, we isolate two hypermucoviscous and multidrug-resistant K. pneumoniae strains (PINH-4250 and PINH-4900) from two different locations near to medical centers. Genomic investigation revealed that both strains belonged to the global high-risk sequence type (ST) ST11, carrying the blaKPC-2 carbapenemase gene, besides other medically important antimicrobial resistance determinants. A broad virulome was predicted and associated with hypervirulent behavior in the Galleria mellonella infection model. Comparative phylogenomic analysis of PINH-4250 and PINH-4900 along to an international collection of publicly available genomes of K. pneumoniae ST11 revealed that both environmental strains were closely related to hospital-associated K. pneumoniae strains recovered from clinical samples between 2006 and 2018, in São Paulo city. Our findings support that healthcare-associated KPC-2-positive K. pneumoniae of ST11 clone has successfully expanded beyond hospital settings. In summary, aquatic environments can become potential sources of international clones of K. pneumoniae displaying carbapenem resistance and hypervirulent behaviors, which is a critical issue within a One Health perspective.

Increased plasma levels of circPTP4A2 and circTLK2 are associated with stroke injury.

Accumulating studies have shown that circulating circular RNAs (circRNAs) represent novel biomarkers for many human diseases. We investigated whether plasma circPTP4A2 and circTLK2 levels are associated with stroke severity, infarct volume, stroke etiology, and functional outcome in acute ischemic stroke (AIS) patients. We applied quantitative real-time PCR (qPCR) to measure plasma circPTP4A2 and circTLK2 levels of 236 AIS patients within 72 h of symptoms onset and 136 healthy controls. We further assessed the National Institutes of Health Stroke Scale (NIHSS), infarct size, the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification and the 90-day modified Rankin scale (mRS) for each patient. At admission, plasma circPTP4A2 and circTLK2 levels in patients with moderate to severe stroke were significantly higher compared to those with mild stroke. Logistic regression and receiver-operating characteristic (ROC) curve analyses indicated that they might function as predictive biomarkers for moderate to severe stroke. We also observed a medium positive correlation between these two circRNAs and NIHSS. Plasma circPTP4A2 and circTLK2 levels were slight positively correlated with cerebral infarct volume only in anterior circulation infarction (ACI) patients. Levels of both circPTP4A2 and circTLK2 were closely related with large artery atherosclerosis (LAA) stroke. Moreover, changes within 7 days after admission in circPTP4A2 and circTLK2 were able to predict unfavorable clinical outcome 90 days after AIS. These results demonstrate that plasma circPTP4A2 and circTLK2 strongly correlated with severity, subtypes and prognosis of AIS, and they could serve as promising biomarkers.

The Dark Side of Nosocomial Infections in Critically Ill COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is a potentially serious acute respiratory infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the World Health Organization (WHO) declared COVID-19 a global pandemic, the virus has spread to more than 200 countries with more than 500 million cases and more than 6 million deaths reported globally. It has long been known that viral respiratory tract infections predispose patients to bacterial infections and that these co-infections often have an unfavourable clinical outcome. Moreover, nosocomial infections, also known as healthcare-associated infections (HAIs), are those infections that are absent at the time of admission and acquired after hospitalization. However, the impact of coinfections or secondary infections on the progression of COVID-19 disease and its lethal outcome is still debated. The aim of this review was to assess the literature on the incidence of bacterial co-infections and superinfections in patients with COVID-19. The review also highlights the importance of the rational use of antibiotics in patients with COVID-19 and the need to implement antimicrobial stewardship principles to prevent the transmission of drug-resistant organisms in healthcare settings. Finally, alternative antimicrobial agents to counter the emergence of multidrug-resistant bacteria causing healthcare-associated infections in COVID-19 patients will also be discussed.

Longitudinal Study of the Association between Antenatal Nephrourinary Ultrasonographic Findings with Unfavorable Clinical Outcomes during Postnatal Period, Childhood and Adolescence, in Patients with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Longitudinal Study of the Association between Antenatal Nephrourinary Ultrasonographic Findings with Unfavorable Clinical Outcomes during Postnatal Period, Childhood and Adolescence, in Patients with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)