Strong Predictor Of Poor Outcome Research Articles

Lactate Is a Strong Predictor of Poor Outcomes in Patients with Severe Traumatic Brain Injury

Background: Lactate is a byproduct of glycolysis, often linked to oxygen deprivation. This study aimed to examine how lactate levels (LLs) affect clinical outcomes in patients with severe TBI, hypothesizing that higher LLs would correlate with worse outcomes. Methods: This is a level 1 single-center, retrospective study of patients with severe TBI between 1 January 2020 and 31 December 2023, inclusive. Results: Single-factor ANOVA indicated a significant decrease in LLs with increasing age. Linear regression models showed the same for hospital admission, Intensive Care Unit (ICU) admission LLs, and death LLs. Prognostic scores such as Injury Severity Scores (ISS) and Glasgow Coma Score (GCS) showed a strong correlation with both Hospital admission and ICU admission LLs. ANOVA indicated higher LLs with increasing ISS and increasing LLs with decreasing GCS. Linear regressions revealed a strong positive correlation between ISS and LLs. On linear regression, the LL measured at hospital admission and ICU admission was positively associated with the length of stay (LOS) in the hospital, LOS in the ICU, ventilator days, and mortality. Linear regression models showed that a decreased delta LL during ICU admission led to an increased LOS at the hospital and the ICU, as well as a higher number of days on a ventilator. Discussion: We discovered that high LLs were linked to higher AIS and GCS scores, longer stays in the hospital and ICU, more days requiring a ventilator, and higher mortality rates in patients with severe TBI. Conclusions: LLs can be considered a strong predictor of poor clinical outcomes in patients with severe TBI.

Osteosarcopenia in patients with cancer: A systematic review and meta-analysis.

Osteosarcopenia is frequent, and the relative risk of fracture is higher among patients with sarcopenia. It is a strong predictor of poor outcomes in older adults undergoing cancer treatment, suggesting that osteosarcopenia is important in an aging society. This study aimed to evaluate the overall survival (OS) and disease-free survival (DFS) of patients with cancer with and without osteosarcopenia. Five electronic databases-Embase, PubMed, Web of Science, Scopus, and CINAHL-were searched for relevant articles published before February 2024. Studies that met the criteria were used to evaluate the OS and DFS of patients with cancer with and without osteosarcopenia. From the 603 initially identified articles, 8 involving 1608 participants were included in the meta-analysis. We observed that patients with cancer diagnosed with osteopenia, sarcopenia, or osteosarcopenia had worse DFS than those without these conditions. Specifically, osteopenia (pooled hazard ratio [HR] = 1.70, P = .01) and osteosarcopenia (pooled HR = 2.17, P = .0001) emerged as independent predictors of DFS. However, sarcopenia was significantly associated with DFS. The quality of the included studies was generally good, and no publication bias was detected among them for either OS or DFS. These meta-analysis results suggest that osteopenia and osteosarcopenia are associated with worse DFS among patients with cancer. The use of different case definitions appeared to be a major source of heterogeneity among studies. Further studies are warranted to confirm our findings, especially those regarding OS and DFS.

Entinostat as a combinatorial therapeutic for rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).

Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10–7.67, Cox P = 2.63e−05) and PFS (HR = 3.72, 95% CI 2.06–6.73, Cox P = 1.38e−05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24–6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16–3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2–3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08–3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH.

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer.

Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an "innate checkpoint", reminiscent of the function of "classical" adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.

Early prognosis prediction in acute myeloid and acute lymphoid leukemia patients using cell-free DNA concentration ratios.

Background: Cell-free DNA (cfDNA) is a promising biomarker for disease prediction in many cancers, including acute leukemia (acute myeloid leukemia [AML] and acute lymphoblastic leukemia [ALL]). This study investigated the role of cfDNA in predicting relapse or unfavorable outcomes in acute leukemia patients upon initial diagnosis. Methods: Paired peripheral blood samples of 25 patients with ALL and AML were compared at baseline and induction/follow-up and clinically correlated with clinicopathological and outcome variables according to the risk category. cfDNA was isolated using commercial cfDNA extraction kits. The probability of poor outcomes in high-risk groups and a cut-off value for risk stratification minimal residual disease (MRD) positivity and outcome prediction were derived. Results: Twenty-five patients diagnosed with AML and ALL were risk-stratified based on NCI risk stratification, and of these 25 patients, 4 patients were of standard risk (SR) and 1 patient was of intermediate risk (IR), while a majority of patients (80%) were of high risk (HR). Of these, four HR patients passed away. The ratio of cfDNA reduction at baseline and the end of induction was a strong predictor of poor outcomes in high-risk patients, regardless of the MRD status. A cfDNA ratio score of 2.6 or higher at diagnosis/remission predicted poor outcomes, with higher accuracy than conventional MRD detection by flow cytometry. Conclusion: A higher cfDNA ratio at diagnosis/remission or at baseline predicts poor outcomes in acute leukemia patients. This pilot study suggests that cfDNA ratio scoring may be a useful tool for predicting prognosis in acute leukemia patients, regardless of the MRD status.

Early and recurrent cerebral vasospasms after aneurysmal subarachnoid hemorrhage: The impact of age.

Cerebral vasospasms remain a strong predictor of poor outcome after aneurysmal SAH. The aim of this study was to describe the time course of relevant vasospasms after aneurysmal SAH and to determine the variables associated with early-onset or prolonged and recurrent vasospasms. We conducted a retrospective, single-center study of consecutive adult patients with aneurysmal SAH admitted between 2016 and 2022 at our tertiary stroke center. Relevant vasospasms, defined as vessel narrowing detected in DSA in combination with clinical deterioration or new perfusion deficit, were detected according to our in-house algorithm and eventually treated endovascularly. The primary endpoint was the diagnosis of relevant vasospasms. As secondary endpoints, the time from hemorrhage to the onset of vasospasms and the time from the first to the last endovascular intervention were measured. Of 368 patients with aneurysmal SAH, 135 (41.0%) developed relevant vasospasms. The median time between ictus and detection of vasospasms was 8 days (IQR: 6-10). Patients with early-onset vasospasms were significantly younger (mean 52.7 ± 11.2 years vs 58.7 ± 11.5 years, p = 0.003) and presented more frequently vasospasm-related infarctions at discharge (58.8% vs 38.7%, p = 0.03). In 74 patients (54.8%), recurrent relevant vasospasms were observed despite endovascular treatment. Younger age and early onset were significantly associated with longer duration of relevant vasospasms (both p < 0.05). Younger age was associated with early-onset and longer duration of relevant vasospasms in this study. More frequent clinical and diagnostic follow-up should be considered in this subgroup of patients that are at risk for poor outcomes.

Rotational Thromboelastometry (ROTEM®) in Relation to Inflammatory Biomarkers and Clinical Outcome in COVID-19 Patients.

Background: The pathogenesis of hypercoagulability in COVID-19 patients is complex and not fully understood. Rotational thromboelastometry (ROTEM®) is a viscoelastic method that allows the definition of a patient's hemostatic profile. This study aimed to assess the relationship between ROTEM® parameters, the profile of inflammatory cytokines, and clinical outcomes in COVID-19 patients. Methods: A total of 63 participants (n = 29 symptomatic non-ICU COVID-19 patients, and n = 34 healthy controls) were prospectively included in the study. We assessed the relationship between the parameters of three ROTEM® tests (NATEM®, EXTEM®, and FIBTEM®) and levels of CRP, interleukin-8, interleukin-1β, interleukin-6, interleukin-10, tumor necrosis factor, interleukin 12p70, and clinical outcomes. Results: ROTEM® indicated hypercoagulability in COVID-19 patients in all the tests performed. The levels of all inflammatory cytokines were significantly higher in COVID-19 patients. NATEM more frequently detected hypercoagulability in COVID-19 patients compared to EXTEM. The strongest correlations with inflammatory biomarkers and CT severity score were with FIBTEM parameters. The elevated maximum clot elasticity (MCE) in FIBTEM was the strongest predictor of poor outcomes. Conclusions: Increased FIBTEM MCE may be associated with greater severity of COVID-19. Non-activated ROTEM (NATEM test) seems to be more valuable for detecting hypercoagulability in COVID-19 patients compared to the tissue factor activated test (EXTEM).

Abstract 3763: microRNAs associated with metastatic potential in salivary gland mucoepidermoid carcinoma

Abstract Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Metastatic spread occurs in up to 80% of high-grade tumors and it is a strong predictor of poor outcome, however, the mechanisms underlying this process are largely unknown. Large-scale microRNA expression profiling studies of human cancers have demonstrated that dysregulation of miRNA is frequently associated with many cancer types. The aim of this study was to investigate the microRNA profile in metastatic versus non-metastatic MECs. Using Real Time RT-PCR (qPCR) we have analyzed the expression of 384 miRNAs and controls in 4 non-metastatic MECs, 3 MECs with lymph node metastasis, 3 MECs with distant metastasis, and 2 non-neoplastic human salivary gland samples. The microRNA profile was able to discriminate between non-neoplastic and tumor samples and between metastatic and non-metastatic tumors. Considering non-neoplastic samples and non-metastatic MECs, 12 microRNAs were differentially expressed. The non-neoplastic versus lymph node metastasis MEC analysis demonstrated that 10 microRNAs were differentially expressed. Considering non-neoplastic versus distant metastasis MECs, 3 microRNAs were differentially expressed: 1 down-regulated and 2 up-regulated. Comparing non-metastatic MECs versus lymph node metastasis MECs we observed 17 up-regulated microRNAs. Considering non-metastatic MECs versus distant metastasis MECs, 2 microRNAs were up-regulated. One microRNA is differentially expressed between lymph node metastasis MECs and distant metastasis MECs. Our results suggest that microRNA profiles could discriminate the metastatic potential of salivary MECs and might be helpful in diagnostic and prognostic evaluation of patients. Citation Format: Maria Eduarda S. Trevizani, Katia K. Oliveira, Fabio A. Marchi, Daniela Bizinelli, Fernanda V. Mariano, Cibele P. Nagano, Felipe A. Costa, Clóvis A. Pinto, Luiz P. Kowalski, Silvia V. Lourenço, Cláudia M. Coutinho-Camillo. microRNAs associated with metastatic potential in salivary gland mucoepidermoid carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3763.

Prognostic significance of osteosarcopenia in older adults with colorectal cancer.

Osteopenia and sarcopenia, features of the aging process, are recognized as major health problems in an aging society. This study investigated the prognostic impact of osteosarcopenia, the coexistence of osteopenia and sarcopenia, in older adults undergoing curative resection for colorectal cancer. We retrospectively reviewed data of older adults aged 65-98 y who had undergone curative resection for colorectal cancer. Osteopenia was evaluated by bone mineral density measurement in the midvertebral core of the 11th thoracic vertebra on preoperative computed tomography images. Sarcopenia was evaluated by measuring the skeletal muscle cross-sectional area at the third lumbar vertebra level. Osteosarcopenia was defined as the coexistence of osteopenia and sarcopenia. We explored the relationship of preoperative osteosarcopenia with the disease-free and overall survival after curative resection. Among the 325 patients included, those with osteosarcopenia had significantly lower overall survival rates than those with osteopenia or sarcopenia alone (P <0.01). In the multivariate analysis, male sex (P =0.045), C-reactive protein-to-albumin ratio (P <0.01), osteosarcopenia (P <0.01), pathological T4 stage (P =0.023), and pathological N1/N2 stage (P <0.01) were independent predictors of disease-free survival, while age (P <0.01), male sex (P =0.049), C-reactive protein-to-albumin ratio (P <0.01), osteosarcopenia (P <0.01), pathological T4 stage (P =0.036), pathological N1/N2 stage (P <0.01), and carbohydrate antigen 19-9 (P =0.041) were independent predictors of overall survival. Osteosarcopenia was a strong predictor of poor outcomes in older adults undergoing curative resection for colorectal cancer, suggesting an important role of osteosarcopenia in an aging society.

ALL-237 Bortezomib and Rituximab in De Novo Adolescent/Adult CD20-Positive, Ph-Negative Pre-B-Cell Acute Lymphoblastic Leukaemia: Updated 3-Year Results

CD20 expression in B-cell precursor acute lymphoblastic leukemia (B-ALL) is associated with inferior outcomes. Treatment approaches involve the incorporation of rituximab (variable doses and scheduling between trials), intensification of chemotherapy, and allogeneic stem cell transplant in patients who continue to remain MRD- positive post-induction. Treatment intensification with chemotherapy or allogeneic stem cell transplantation for EOI MRD-positive patients is limited in resource constraint areas due to cost and infection-related morbidity and mortality. Hence, there is an unmet need to identify active and safe drugs to improve EOI MRD negative rates which can reduce the need for transplant and chemotherapy intensification. To test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20 positive, Philadelphia-negative precursor B-ALL. Here we present updated results with longer follow up. Single-center, phase 2, nonrandomized open-label trial (Simon's two-stage design) conducted between December 2017 and August 2019. The primary endpoint of the study was the rate of (end of induction) EOI BM-MRD negativity. Secondary endpoints were EFS and OS. A total of 35 patients were enrolled between December 2017 and August 2019. EOI MRD negative rates were 70.1% compared with 51.7% in a historical cohort treated with chemotherapy. On longer follow up (median follow up 38months), 3-year EFS and OS rates were 75.6% (95% CI 62.3-91.9%), and 75.6% (95% CI 62.3-91.9%) respectively. 3-year rates of EFS based on post-induction (week 4) MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. 3-year rates of OS based on EOI MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. The median OS for patients who attained CR was not reached versus 8 months in patients who fail to achieve CR. On longer follow-up, the activity of the combination of bortezomib and rituximab is maintained without any new safety concerns. EOI MRD positivity and lack of complete remission post-induction are strong predictors of poor outcomes.

Association of congestion with worsening renal function in acute decompensated heart failure according to age.

Acute decompensated heart failure (ADHF) is a frequent cause of hospitalization for patients with heart disease, and ADHF patients are at high risk of heart failure (HF) re-hospitalization. Residual congestion at discharge is also a strong predictor of poor outcomes and re-hospitalization for ADHF patients. However, the impact of residual congestion at discharge on worsening renal function (WRF) in both high-aged and older patients remains uncertain because previous studies of WRF in ADHF patients were conducted for older patients. We therefore designed and conducted a retrospective, population-based study using the Kobe University Heart Failure Registry in Awaji Medical Center (KUNIUMI) Registry to investigate the association of residual congestion at discharge with WRF in ADHF patients according to age. We studied 966 hospitalized ADHF patients with a mean age of 80.2±11.4years from among 1971 listed in the KUNIUMI Registry. WRF was defined as an increase of ≥0.3mg/dL in the serum creatinine level during the hospital stay compared with the value on admission. The primary endpoint was defined as cardiovascular death or HF re-hospitalization after discharge over a mean follow-up period of 2.0±0.1years. The primary endpoint was recorded for 369 patients (38.2%). As expected, patients with both WRF and residual congestion at discharge had significantly less favourable outcomes compared with those without one of them, and patients without either of these two characteristics had the most favourable outcomes, whereas those with residual congestion and with WRF had the least favourable outcomes. Moreover, WRF was significantly associated with worse outcomes for high-aged patients ≥80years old, but not for those <80years old if decongested. Multivariable Cox regression analysis showed that both residual congestion at discharge and WRF were the independent predictors of outcomes for high-aged patients, but residual congestion at discharge, not WRF, was the independent predictor of outcomes for older patients. Association of residual congestion at discharge with WRF for hospitalized ADHF patients can differ according to age. Our findings showed the importance of WRF and residual congestion at discharge for high-aged ADHF patients and of aggressive diuresis to alleviate congestion for older ADHF patients for better management of such patients in a rapidly ageing society.

Egyptian recommendations for treating to target of lupus nephritis: an evidence-based consensus on clinical practice recommendations for the management of lupus nephritis and pregnancy

BackgroundNephritis is known to be one of the most serious complications of lupus and a strong predictor of poor outcome. This study was carried out aiming at setting up an up-to-date recommendation for the management of women living with lupus nephritis and planning for a family throughout conception, pregnancy, and the postpartum period.Ten key clinical questions were identified by the scientific committee according to the Patient/Population, Intervention, Comparison, Outcomes and Timing (PICOT) approach. The literature review team performed a systematic review to summarise evidence advocating the benefits and harms of available pharmacologic and nonpharmacologic therapies for women living with lupus nephritis (LN) and planning for a family. Subsequently, recommendations were formulated. The level of evidence was determined for each section using the Oxford Centre for Evidence-Based Medicine (CEBM) system. A 2-round Delphi process was conducted with 24 experts. All rounds were conducted online. A consensus was achieved on the direction and the strength of the recommendations.ResultsAn online questionnaire was sent to an expert panel who participated in the two rounds (response rate 100%). At the end of round 2, a total of 20 recommendation items, categorised into 10 domains to address the main LN with pregnancy categories, were obtained. The percentage of those who agreed with the recommendations (rank 7–9) ranged from 88.5 to 100%. On the phrasing of all the clinical standards defined by the scientific committee, a consensus was reached (i.e., 75% of respondents strongly agreed or agreed). An algorithm for the management of LN with pregnancy has been suggested.ConclusionThese recommendations provide an updated consensus on the pharmacological treatment of LN with pregnancy and strategies to reach optimal outcomes for both the mother and newborn in common clinical scenarios, based on a combination of evidence and expert opinion. Best treatment decisions should be tailored to each individual patient’s situation.

Analysis of changes in location before hospital admission, discharge destination and prognostic factors for the survival in hospitals with chronic-phase inpatients

To clarify changes in location before hospital admission and discharge destination over the 10-year period of 2010 to 2020 and to identify prognostic factors associated with the survival in hospitals with chronic-phase inpatients. The subjects were patients newly admitted to 12 hospitals in 2010 and 2020. The age, sex, location before hospital admission, outcomes at 90 days after admission, discharge destination, and results of 6 biochemical tests at admission were evaluated. A survival analysis was performed for the age, sex, and biochemical tests at admission. We analyzed 8007 newly hospitalized patients. Compared with 2010, there were more hospital admissions from acute-care hospitals and fewer admissions from long-term-care facilities in 2020. In addition, relative to 2010, regarding the outcomes at 90 days after admission, there were more discharges to home and residential facilities in 2020, fewer discharges to long-term-care facilities, and lower mortality rates. In the survival analysis, a multivariate analysis revealed that an elderly age, male sex, low albumin, high total cholesterol, high urea nitrogen, and low serum sodium were poor prognostic factors. These five variables were consistently poor prognostic factors in both 2010 and 2020, and Kaplan-Meier curves showed that the scores were dose-dependent prognostic factors for a poor survival. The present analysis of pre-admission location and discharge destination in hospitals with chronic-phase patients revealed an elderly age, male sex, high urea nitrogen, low serum sodium, and low albumin at the time of admission to be strong predictors of poor outcomes in these patients.

Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC

BackgroundNeurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.MethodsIn the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.ResultsOf the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients.ConclusionsBased on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis.

Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC.

Admission Hyperglycemia in COVID-19 as Outcome Predictor: A Single Centre Study

Background: Hyperglycemia on admission among COVID-19 may affect the patient outcome. Objective: To determine the effect of admission hyperglycemia on outcome among COVID-19 patients. Methodology: It was a cross-sectional analytical study in which 421 COVID-19 patients were admitted with high blood sugar levels (BSR&gt;180mg/dl) to the High Dependency Unit, Sir Sadiq Abbasi Hospital, Bahawalpur, from April to May 2021 were included. Preexisting diabetes status was confirmed on the basis of history taken from the patients. Patients were divided into two groups on basis of BSR, moderate hyperglycemia (180-299mg/dl) and severe hyperglycemia (300-450mg/dl). The primary outcome was taken as an increase in oxygen demand leading to shifting of the patient to ICU for Non-Invasive Ventilator (NIV) support or a decrease in oxygen demand leading to discharge home. Results: Among 421 COVID-19 patients; 349 (83%) patients had moderate hyperglycemia and among them, 172 (49.4%) were shifted to NIV, and 177 (50.6%) patients were discharged after improving. Seventy-two patients came out to have severe hyperglycemia out of which 61 (84.3%) were shifted to NIV and 11 (15.3%) patients were discharged home (p-value = 0.01). Among 83 patients who were shifted to NIV, 22 (26.5%) were diabetic and 61 (73.5%) were non-diabetic and had risk factors other than diabetes. Conclusion: Hyperglycemia on admission is a strong predictor of poor outcomes regardless of the previous history of diabetes and other confounders.

Metastasis patterns and racial disparities in gastrointestinal cancers: A SEER database population study 2010–2018.

3597 Background: Metastatic disease at the time of diagnosis of gastrointestinal (GI) malignancies is a strong predictor of poor outcomes. Differences in metastatic patterns among Caucasians (C) and African-Americans (AA) needs further elucidation. In this study, we analyzed the patterns of metastasis in C and AA in colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and liver cancer (LC). Methods: We identified patients with CRC, PC, GC, and LC from the Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2018. We obtained metastasis data to lungs, liver, bone, and brain at the time of diagnosis. We calculated the relative risk (RR), confidence interval (CI), and standard error with the use of SPSS software, 28.0 (IBM). Results: The most common metastasis site was the liver being highest at 39% in AA with PC. Brain metastasis was the least common. Significant racial disparities were noted. In CRC, AA had a 35-37% increased risk of metastasis to the liver, lung, or bone. AA had a higher risk of liver metastasis in PC and GC, whereas C had a higher risk of lung metastasis. Table 1 summarizes the data findings. Conclusions: This study illustrates the disparities of metastasis from GI cancers among AA and C. While a delay in screening, earlier onset of CRC in AA and socioeconomic factors may explain the disparities witnessed in CRC. However, these factors will fail to explain the difference in metastasis pattern in PC and GC in that AA had a higher risk of liver metastasis, and C had a higher risk of lung metastasis. Moreover, In GC, the brain metastasis rate in C was double that of AA. Further studies of possible biological and other risk factors are needed. [Table: see text]

Unusual Gram-negative bacteria cause more severe bacterial meningitis than the three classical agents in children.

AimTo compare the characteristics, mortality and sequelae at hospital discharge of childhood bacterial meningitis (BM) caused by the three “classical” agents Neisseria meningitidis, Haemophilus influenzae or Streptococcus pneumoniae versus BM due to other aetiology in Finland, Latin America and Angola.MethodsThis observational study is a secondary analysis of data from five prospective treatment trials on non‐neonatal BM in Finland, Latin America and Angola in 1984–2017.ResultsOf the 1568 cases, 1459 (93%) were caused by the classics, 80 (5%) by other Gram‐negative and 29 (2%) by other Gram‐positive bacteria. Nonclassical Gram‐negative disease was encountered especially in Angola (p < 0.0001). Overall, children in the nonclassical group presented later for treatment and were more often underweight and anaemic (p < 0.001). In multivariate analysis, even if the area was strongest predictor of poor outcome, nonclassical Gram‐negative BM increased the odds for death twofold and the odds for death or severe sequelae 2.5‐fold.ConclusionBM of a nonclassical aetiology is a particularly severe disease affecting especially Angolan children poorly armoured to fight infections. Since vaccinations are diminishing the role of classical agents, that of nonclassical agents is growing.

Factors Associated with Delirium in COVID-19 Patients and Their Outcome: A Single-Center Cohort Study.

Background: A significant proportion of patients with coronavirus disease 2019 (COVID-19) suffer from delirium during hospitalization. This single-center observational study investigates the occurrence of delirium, the associated risk factors and its impact on in-hospital mortality in an Italian cohort of COVID 19 inpatients. Methods: Data were collected in the COVID units of a general medical hospital in the South of Italy. Socio-demographic, clinical and pharmacological features were collected. Diagnosis of delirium was based on a two-step approach according to 4AT criteria and DSM5 criteria. Outcomes were: dates of hospital discharge, Intensive Care Unit (ICU) admission, or death, whichever came first. Univariable and multivariable proportional hazards Cox regression models were estimated, and risks were reported as hazard ratios (HR) along with their 95% confidence intervals (95% CI). Results: A total of 47/214 patients (22%) were diagnosed with delirium (21 hypoactive, 15 hyperactive, and 11 mixed). In the multivariable model, four independent variables were independently associated with the presence of delirium: dementia, followed by age at admission, C-reactive protein (CRP), and Glasgow Coma Scale. In turn, delirium was the strongest independent predictor of death/admission to ICU (composite outcome), followed by Charlson Index (not including dementia), CRP, and neutrophil-to-lymphocyte ratio. The probability of reaching the composite outcome was higher for patients with the hypoactive subtype than for those with the hyperactive subtype. Conclusions: Delirium was the strongest predictor of poor outcome in COVID-19 patients, especially in the hypoactive subtype. Several clinical features and inflammatory markers were associated with the increased risk of its occurrence. The early recognition of these factors may help clinicians to select patients who would benefit from both non-pharmacological and pharmacological interventions in order to prevent delirium, and in turn, reduce the risk of admission to ICU or death.