CaP Patients Research Articles

Age, Pulse, Urea, and Albumin Score: A Tool for Predicting the Short-Term and Long-Term Outcomes of Community-Acquired Pneumonia Patients With Diabetes

ObjectiveThe predictive performances of CURB-65 and pneumonia severity index (PSI) were poor in patients with diabetes. This study aimed to develop a tool for predicting the short-term and long-term outcomes of CAP in patients with diabetes.MethodsA retrospective study was conducted on 531 CAP patients with type 2 diabetes. The short-term outcome was in-hospital mortality. The long-term outcome was 24-month all-cause death. The APUA score was calculated according to the levels of Age (0-2 points), Pulse (0-2 points), Urea (0-2 points), and Albumin (0-4 points). The area under curves (AUCs) were used to evaluate the abilities of the APUA score for predicting short-term outcomes. Cox regression models were used for modeling relationships between the APUA score and 24-month mortality.ResultsThe AUC of the APUA score for predicting in-hospital mortality was 0.807 in patients with type 2 diabetes (P<0.001). The AUC of the APUA score was higher than the AUCs of CURB-65 and PSI class (P<0.05). The long-term mortality increased with the risk stratification of the APUA score (low-risk group (0-1 points) 11.5%, intermediate risk group (2-4 points) 16.9%, high risk group (≥5 points) 28.8%, P<0.05). Compared with patients in the low-risk group, patients in the high-risk group had significantly increased risk of long-term death, HR (95%CI) was 2.093 (1.041~4.208, P=0.038).ConclusionThe APUA score is a simple and accurate tool for predicting short-term and long-term outcomes of CAP patients with diabetes.

Transcriptomic Features of Cribriform and Intraductal Carcinoma of the Prostate

BackgroundCribriform (CF) and/or intraductal carcinoma (IDC) are associated with more aggressive prostate cancer (CaP) and worse outcomes. ObjectiveThe transcriptomic features that typify CF/IDC are not well described and the capacity for clinically utilized genomic classifiers to improve risk modeling for CF/IDC remains undefined. Design, setting, and participantsWe performed a retrospective review of CaP patients who had Decipher testing at a single high-volume institution. Index lesions from radical prostatectomy specimens were identified by genitourinary pathologists who simultaneously reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were grouped based on pathologic features, specifically the absence of CF/IDC (CF–/IDC–), CF positive only (CF+/IDC–), and CF/IDC positive (CF+/IDC+). Outcome measurements and statistical analysisClinical, pathologic, and genomic categorical variables were assessed using the Pearson chi-square test, while quantitative variables were assessed with the Kruskal-Wallis test. Multivariable logistic regression was used to identify the predictors of high-risk Decipher scores (>0.60). A gene set enrichment analysis was performed to identify genes and gene networks associated with CF/IDC status. Results and limitationsA total of 463 patients were included. Patients who were CF+/IDC+ had the highest Decipher risk scores (CF+/IDC+: 0.79 vs CF+/IDC–: 0.71 vs CF–/IDC–: 0.56, p < 0.001). On multivariate logistic regression, predictors of high-risk Decipher scores included the presence of CF, both alone (CF+/IDC–; odds ratio [OR]: 5.45, p < 0.001) or in combination with positive IDC status (CF+/IDC+; OR: 6.87, p < 0.001). On the gene set enrichment analysis, MYC pathway upregulation was significantly enriched in tumor samples from CF/IDC-positive patients (normalized enrichment score [NES]: 1.65, p = 0.046). Other enriched pathways included E2F targets (NES: 1.69, p = 0.031) and oxidative phosphorylation (NES: 1.68, =0 .033). ConclusionsThis is the largest series identifying an association between a clinically validated genomic classifier and the presence of CF and IDC at radical prostatectomy. Tumors with CF and intraductal features were associated with aggressive transcriptomic signatures. Patient summaryGenomic-based tests are becoming readily available for the management of prostate cancer. We observed that Decipher, a commonly used genomic test in prostate cancer, correlates with unfavorable features in tissue specimens.

Prevalence of Community-Acquired Pneumonia in Diabetic Patients in a Tertiary Care Hospital of Bangladesh

Background: For nearly two centuries, pneumonia has been recognized as a frequent and sometimes fatal illness. Community-acquired pneumonia and diabetes mellitus are frequently associated, and this relationship bears the burden of both diseases. Objective: The present study was conducted to access the Prevalence of community acquired pneumonia in diabetic patients in a tertiary care hospital in Bangladesh.Material &amp; Methods:This study was conducted among 110 controlled diabetic and 70 uncontrolled diabetic patients who were admitted to the Department of Medicine of Sher-E-Bangla Medical College Hospital in the period between January 2021 and June 2021. The data were analyzed using the SPSS version 25.0.Results:In this study of 110 controlled diabetic patients, 45% were men and 55 % were women. There were 57 % males and 43 % females among 70 uncontrolled diabetic patients. Controlled diabetic patients were 52% older than 60 years old, while uncontrolled diabetic patients were roughly 50 %older than 60 years old. . CAP associated with uncontrolled DM cases showed significantly more fever, RBS, ESR, pleural effusion and hospitalization days. There was no significant difference between controlled diabetic and uncontrolled diabetic CAP patients regarding cough, fever, chest pain, and pulse. The prevalence of CAP among 70 uncontrolled patients was 48% and among controlled diabetic patients was 45%.Conclusions:Specific care for diabetes patients with community-acquired pneumonia, as well as close monitoring for its control, will result in a reduction in infection exposure and, if any infection occurs, will a milder infection.

The effectiveness of the sarcopenia index in predicting septic\xa0shock and death in elderly patients with community-acquired\xa0pneumonia

BackgroundCommunity-acquired pneumonia (CAP) causes high morbidity and mortality in all age groups worldwide. Lower muscle radiodensity was associated with worse clinical outcomes (including shock) and higher in-hospital mortality. Prompt detection of sarcopenia in older adults with CAP is important. The measurement of muscle mass often involves specialized and expensive techniques. A relatively simple and inexpensive method such as the sarcopenia index (SI) to measure muscle mass would be helpful. Therefore, we performed a retrospective cohort study to assess the association between SI and septic shock risk and mortality in older patients with CAP.Study designIn this retrospective cohort study, information on hospitalized CAP patients, including general information and septic shock, were obtained from the medical record database of the Southwest Medical University Zigong Affiliated Hospital, China. Data on patient survival and mortality (all-cause) were acquired from government authorities and telephonic follow-up. Serum creatinine (Cr) and cystatin-C (CysC) levels on admission were included in the database. The SI was determined as the serum Cr/CysC ratio × 100 and the participants were assigned to low and high SI groups. The association between SI and septic shock was evaluated by logistic regression, and that between SI and mortality by Cox regression analysis.ResultsIn total, 769 older adults (≥ 60 years) with CAP were included, of which 480(62.4%) were male and 289(37.6%)were female. We found that the total prevalence of septic shock in older adults with CAP was 16.0%. In the female group, septic shock was more prevalent in the low SI group than in the high SI group (low SI vs. high SI, 22.22% vs. 11.52%, p = 0.024). Following adjustment for confounders, there was a significant association between high SI and a lower risk of septic shock in female patients (OR = 0.38, 95%CI: 0.16–0.94; p < 0.05). The total death toll of older adults with CAP was 332(43.2%). Irrespective of sex, there was a higher risk of mortality in the low SI group (total group: low SI vs. high SI, 63.02% vs. 36.57%, p < 0.001; male group: low SI vs. high SI, 63.03% vs. 39.34%, p < 0.001; female group: low SI vs. high SI, 73.61% vs. 28.57%, p < 0.001) and, after adjustment for confounding factors and irrespective of sex, high SI was a protective factor for mortality in older adults with CAP (total group: HR = 0.64, 95%CI: 0.48–0.84; p < 0.05; male: HR = 0.69, 95%CI: 0.49–0.97; p < 0.05; female: HR = 0.39, 95%CI: 0.24–0.62; p < 0.05).ConclusionWhile the SI effectively predicts mortality in older adults with CAP, it was only found to be associated with septic shock in older females.

Comparative study of CURB-65 and expanded CURB-65 score in community acquired pneumonia in a tertiary care hospital of Assam

Background: Community acquired pneumonia is one of the leading causes of morbidity and mortality in developing countries like India. The presentation of CAP may range from mild pneumonia characterized only by fever and productive cough to severe pneumonia leading to respiratory distress and sepsis syndrome requiring management in ICU. Any delay in ICU admission has been shown to be associated with increased mortality. This study was conducted to compare Expanded CURB-65 with CURB-65 scoring system in a tertiary care centre in Assam for early stratification of patients with CAP based of severity and expected prognosis.Methods: This hospital based prospective study was conducted between September 2020 to August 2021, and a total of 100 patients were taken and followed up form admission to up to 30 days. CURB65 and expanded CURB 65 score was calculated for each patient and the accuracy of each score was statistically compared.Results: In our study out of 100 patients mean age of 60±17.97 with Mortality rate of 16%. Total 29% patients were need ICU care. The Sensitivity, Specificity, PPV and NPV for predicting mortality and for ICU admission of Expanded CURB-65 score is found to be superior to CURB-65 Score.Conclusions: In comparison to the CURB-65 score system, the expanded CURB-65 score prioritises both clinical and laboratory criteria and is a more reliable marker for evaluating CAP severity and may improve the effectiveness of forecasting death in CAP patients.

Use of a frailty index based upon routine laboratory data to predict complication and mortality in older community-acquired pneumonia patients

ObjectiveCommunity-acquired pneumonia (CAP) is a common and potentially deadly infection that often arises in older adults. However, the relevance of frailty assessments in older CAP patients remains to be established. The present study was designed to assess the value of a pretreatment frailty index based upon routine laboratory parameters as a predictor of complication and mortality among older CAP patients. MeasurementsDesign: Retrospective cohort study. Setting and Participants: One of the teaching hospitals in western China. Hospitalized CAP patients ≥ 60 years of age. Relevant data were gathered from medical records, local government mortality databases, and telephone interviews. Analyzed outcomes included complication (including respiratory failure and septic shock) and all-cause mortality. A frailty index was constructed based upon 44 pre-treatment laboratory parameters (FI-LAB), and then three cut-off values were selected to define individuals that were robust (0.0–0.2), pre-frail (0.2–0.35), and frail (≥0.35). ResultsIn total, this study incorporated 627 patients (60.77% male; median age: 80 years). Rates of respiratory failure, septic shock and death were higher for frail and prefrail individuals relative to robust individuals (30.13% vs 21.13% vs 6.59%, p < 0.001; 40.38% vs 15.02% vs 3.88%, p < 0.001; 73.08% vs 54.93% vs 24.42%, p < 0.001). Following adjustment for potential confounders, both the pre-frail and frail groups exhibited elevated risk of respiratory failure (OR = 3.326, 95%CI: 1.799–6.15; OR = 5.353, 95%CI: 2.835–10.107), higher risk of septic shock (OR = 3.701, 95%CI: 1.736–7.889; OR = 12.713, 95%CI: 6.112–26.445), and a higher risk of death (HR = 2.173, 95%CI: 1.576–2.996; HR = 2.877, 95%CI: 2.026–4.083) than the robust group. Conclusions and implicationsFrailty, as defined using a scale based upon routine laboratory parameters, can predict a higher risk of complication and mortality in older CAP patients.

Prospective quality of life in men choosing open vs. robotic radical prostatectomy: long-term results from a racially diverse multi-institutional database.

To compare 5-year health-related quality of life (HRQoL) outcomes between prostate cancer (CaP) patients who underwent robotic-assisted laparoscopic radical prostatectomy (RALP) versus open radical retropubic prostatectomy (RRP) and assess for racial disparities between Caucasian American (CA) and African American (AA) men undergoing surgery. A prospective cohort study of HRQoL data was conducted on patients diagnosed with CaP from 2007 to 2017 and enrolled in the Center for Prostate Disease Research (CPDR) Multicenter National Database. Using the EPIC and SF-36 instruments, changes in urinary, sexual, bowel, and hormonal domains, as well as physical and mental component summary scores were compared across surgery type (RALP versus RRP) at pre-treatment ("baseline"), and annually for 5years. We further compared HRQoL outcomes in CA and AA men undergoing surgery. Longitudinal HRQoL patterns were modeled using generalized estimating equations (GEE), adjusting for baseline HRQoL and other characteristics. 448 CaP patients (22% AA) met study inclusion criteria, 66% underwent RALP and 34% underwent RRP. At baseline, HRQoL domains were comparable across treatment group (RALP vs. RRP). In the adjusted low-risk cohort, there were only three time points that met a statistically significant HRQoL difference in EPIC scores between RALP and RRP. Urinary function score during year 4 of follow-up showed a 7.5 (95% CI 3.1-11.9, P = 0.01) points difference in favor of RRP. Bowel bother scores favored RRP in year 1 with a difference of 3.1 (95% CI 0.7-5.4, P = 0.04) points, and in year 5 with a difference of 3.8 (95% CI 1.1-6.4, P = 0.03) points. In the intermediate/high-risk cohort, there were no statistically significant differences in any of the domain scores between RALP and RRP during follow-up. The robotic and open approach to radical prostatectomy led to comparable HRQoL outcomes at a follow-up length of 60months. No HRQoL racial disparities were found between AA and CA men during long-term follow-up.

Untargeted Metabolomics Study of Three Matrices: Seminal Fluid, Urine, and Serum to Search the Potential Indicators of Prostate Cancer.

The simultaneous determination of metabolites from biological fluids may provide more accurate information about the current body condition. So far, the metabolomics approach has been successfully applied to study the mechanism of several disorders and to search for novel biomarkers. Urine and plasma are widely accepted matrices for the evaluation of several pathologies, while prostate cancer (CaP) development is still unknown. For this reason, an alternative matrix, the seminal fluid, was proposed to expand the knowledge about the CaP pathomechanism. The main aim of this study was to develop and optimize the sample preparation protocol to ensure the highest coverage of the metabolome of ejaculate samples. Parameters like the type and composition of the solvent mixture, time of extraction, and applied volume of the solvent were tested. The optimized method was applied for the untargeted metabolomics profiling of seminal fluid samples obtained from CaP patients. Moreover, urine and serum samples were also prepared for untargeted metabolomics analysis. Analyses were carried out with the use of two complementary analytical techniques: GC-EI-QqQ/MS and LC-ESI-TOF/MS. Finally, the metabolic signature of seminal fluid (n = 7), urine (n = 7), and plasma (n = 7) samples was compared. Furthermore, the hypothesis of the increased level of metabolites in ejaculate samples related to the CaP development was evaluated. The results indicated that the developed and optimized sample preparation protocol for seminal fluid may be successfully applied for metabolomics study. Untargeted analysis of ejaculate enabled to determine the following classes of compounds: fatty acids, sphingolipids, phospholipids, sugars, and their derivatives, as well as amino acids. Finally, a comparison of the three tested matrices was carried out. To our best knowledge, it is the first time when the metabolic profile of the three matrices, namely, urine, plasma, and seminal fluid, was compared. Based on the results, it can be pointed out that ejaculate comprises the metabolic signature of both matrices (polar compounds characteristic for urine, and non-polar ones present in plasma samples). Compared to plasma, semen samples revealed to have a similar profile; however, determined levels of metabolites were lower in case of ejaculate. In case of urine samples, compared to semen metabolic profiles, the levels of detected metabolites were decreased in the latter ones.

A genomic classifier for prostate cancer correlates with adverse pathologic features: Transcriptomic features of cribriform and intraductal carcinoma of the prostate.

268 Background: Invasive cribriform and intraductal carcinoma (CF/IDC) portends an unfavorable prognosis for patients diagnosed with prostate cancer (CaP). Limited studies with small sample sizes have explored whether genomic classifiers are associated with IDC and/or CF status. We investigated the correlation between Decipher genomic risk score and IDC/CF status and assessed PCa transcriptomic features. Methods: We performed a retrospective review of CaP patients who had Decipher testing at a single high volume center between 2009-2020. The highest grade index lesion from radical prostatectomy specimens was identified by GU pathologists and used for Decipher testing. Genitourinary pathologists reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were divided into three groups based on pathologic features, absent CF/IDC (CF-/IDC-), CF positive only (CF+/IDC-), and CF/IDC positive (CF+/IDC+). Categorical clinical, genomic, and pathologic variables were assessed using the Pearson Chi-Square test, quantitative with the Kruskal-Wallis test. Multivariable logistic regression was used to identify predictors of high-risk Decipher GC scores. The Kaplan-Meier method with log-rank was used to compare biochemical recurrence free survival. Differential gene expression and gene network analysis was used to identify genes and pathways associated with IDC/CF features. Results: 463 patients were included with a median follow-up of 25 months. Patients who were CF+/IDC+ had higher GC scores (CF+/IDC+: 0.77 vs. CF+/IDC-: 0.71 vs. CF-/IDC-: 0.61, p&lt;0.001). Patients who were CF+/IDC+ had a higher percentage of Gleason grade group &gt;3 (CF+/IDC+: 79% vs. CF+/IDC-: 52% vs. CF-/IDC-: 52%, p&lt;0.001). On multivariate logistic regression, predictors of high-risk GC score were presence of CF+/IDC+ features on final pathology (OR: 3.94, p&lt;0.001) and pathologic Gleason grade group &gt;3 (OR: 1.58, p=0.04). Transcriptomic analysis revealed that the hallmark androgen response pathway was significantly upregulated in CF+/IDC+ patients (Log fold change: 15.7, p&lt;0001). Conclusions: This is the largest series investigating the association of a clinically validated genomic classifier and pathologic features such as cribriform and intraductal carcinoma. These findings have implications for the use of genomic classifiers in settings where expert GU pathology is not readily available and in potentially unmasking adverse histology at the time of biopsy.[Table: see text]

Liquid biopsy of extracellular vesicle biomarkers for prostate cancer personalized treatment decision

Liquid biopsy of tumor-derived extracellular vesicles (EVs) has great potential as a biomarker source for prostate cancer (CaP) early diagnosis and predicting the stages of cancer. The contents of EVs play an important role in intercellular communication and have specific expression in blood and urine samples from CaP patients. Powered by high-throughput, next-generation sequencing and proteomic technologies, novel EV biomarkers are easily detected in a non-invasive manner in different stages of CaP patients. These identified potential biomarkers can be further validated with a large sample size, machine learning model, and other different methods to improve the sensitivity and specificity of CaP diagnosis. The EV-based liquid biopsy is a novel and less-invasive alternative to surgical biopsies which would enable clinicians to potentially discover a whole picture of tumor through a simple blood or urine sample. In summary, this approach holds promise for developing personalized medicine to guide treatment decisions precisely for CaP patients.

Radium-223 in patients with prostate specific antigen (PSA) progression and without clinical metastases following maximal local therapy: A pilot study.

Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy. We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed. In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence. Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking.

Antibiotic Treatment of Pulmonary Infections: An Umbrella Review and Evidence Map.

Background: Considering the global burden of pulmonary infections, there is an urgent need for optimal empirical antimicrobial therapy strategies for pulmonary infections, which should rely on reliable evidence. Therefore, we aim to investigate the optimal treatment options for pulmonary infections in adults and assess the strength of that evidence. Methods: We searched PubMed, Embase, the Cochrane Library, and China Biology Medicine disc to identify systematic reviews and meta-analyses of randomized controlled trials (RCTs) focusing on antimicrobial treatments for pulmonary infections. The outcomes of the included meta-analyses should include all-cause mortality or clinical treatment success. For each meta-analysis, we estimated relative risk (RR) with 95% CI. We also created an evidence map to show the efficacy of each antimicrobial treatment strategy and the certainty of the evidence. Results: Twenty-six meta-analyses and two new RCTs were included that contained 31 types of antimicrobial therapy strategies. We found that carbapenems were related to lower mortality than other β-lactams or fluoroquinolones alone or in combination with aminoglycosides for HAP patients (RR 0.76, 95% CI: 0.58–0.99). There was no statistical difference in all-cause mortality between the other antimicrobial therapy strategies. As for clinical cure, treatment with fluoroquinolones was associated with better success versus macrolides or β-lactams alone for CAP patients in both the intention-to-treat (ITT) population (RR 1.22, 95% CI: 1.02–1.47) and clinically evaluable (CE) population (RR 1.37, 95% CI: 1.11–1.68). Treatment with carbapenems showed a better clinical cure over non-carbapenems for VAP patients (RR 1.21, 95% CI: 1.05–1.4). Adjunctive inhaled antibiotics compared with intravenous antibiotics alone showed a benefit for VAP (RR 1.2, 95% CI: 1.05–1.35). In addition, adjunctive nebulized aminoglycoside for nosocomial pneumonia was associated with a higher cure rate versus intravenous antibiotics alone in the ITT population (RR 1.28, 95% CI: 1.04–1.57), while no statistical difference in clinical cure was observed between other intervention groups. Conclusions: We cannot evaluate which antibiotic is the best choice for the treatment of pulmonary infection. Carbapenems or adjunctive inhaled antibiotics showed a reasonable choice for HAP or VAP. However, we do not find a statistical difference between most antimicrobial therapy strategies for CAP patients.

Incidence, Etiology, and Environmental Risk Factors of Community-Acquired Pneumonia Requiring Hospitalization in China: A 3-Year, Prospective, Age-Stratified, Multicenter Case-Control Study.

BackgroundCommunity-acquired pneumonia (CAP) is a leading infectious cause of hospitalization and death worldwide. Knowledge about the incidence and etiology of CAP in China is fragmented.MethodsA multicenter study performed at 4 hospitals in 4 regions in China and clinical samples from CAP patients were collected and used for pathogen identification from July 2016 to June 2019.ResultsA total of 1674 patients were enrolled and the average annual incidence of hospitalized CAP was 18.7 (95% confidence interval, 18.5–19.0) cases per 10000 people. The most common viral and bacterial agents found in patients were respiratory syncytial virus (19.2%) and Streptococcus pneumoniae (9.3%). The coinfections percentage was 13.8%. Pathogen distribution displayed variations within age groups as well as seasonal and regional differences. The severe acute respiratory syndrome coronavirus 2 was not detected. Respiratory virus detection was significantly positively correlated with air pollutants (including particulate matter ≤2.5 µm, particulate matter ≤10 µm, nitrogen dioxide, and sulfur dioxide) and significantly negatively correlated with ambient temperature and ozone content; bacteria detection was opposite.ConclusionsThe hospitalized CAP incidence in China was higher than previously known. CAP etiology showed that differences in age, seasons, regions, and respiratory viruses were detected at a higher rate than bacterial infection overall. Air pollutants and temperature have an influence on the detection of pathogens.

The Role of Red Blood Cell Distribution Width in the Severity and Prognosis of Community-Acquired Pneumonia.

Objectives The objective of this study is to unravel the correlation between RDW and the severity and prognosis of CAP, as well as exploring RDW with the inflammatory markers white blood cells (WBC), C-reactive protein (CRP), and procalcitonin (PCT). Methods According to the data characteristics, appropriate statistical methods were selected to analyze the relationship between RDW and the severity and prognosis of CAP patients and to determine whether RDW is associated with the inflammatory markers WBC, CRP, and PCT. Results The results show that with the increase of PSI and CURB-65 values, the proportion of patients with RDW ≥ 12.987% is significantly higher than that of RDW < 12.987% (P < 0.01). When RDW is combined with PSI or CURB-65 to predict the 90-day mortality of CAP patients, the area under the receiver operating characteristic (ROC) curve increased prominently, and if RDW, PSI, and CURB-65 are combined, the area under the ROC curve is maximized. Conclusions Our findings suggest that the higher RDW value is associated with short-term adverse outcomes in CAP patients. We also find that when RDW, PSI, and CURB-65 are combined, the best performance is achieved to predict CAP 90-day mortality risk.

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes.

Simple SummaryNRDP1 is an E3 ubiquitin ligase that has been shown by our group and others to target ErbB3 for proteasomal degradation in prostate and breast cancer cells and thereby decrease the likelihood cancer progression. Our group has found that NRDP1 can be located in the nucleus as well as the cytoplasm of prostate cancer (CaP) cells, which is unexpected as NRDP1 lacks a nuclear localization signal. Here we elucidate the mechanism by which nuclear translocation of NRDP1 can occur and demonstrate that nuclear NRDP1 retains its ubiquitin ligase activity. Our patient data and cell line studies indicate that increased levels of nuclear NRDP1 contributes CaP progression, thereby underscoring the clinical relevance of our findings and supporting continued investigation and elucidation of the specific role(s) played by NRDP1 in the nucleus of CaP cells.To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

PD65-12 GERMLINE MUTATION LANDSCAPE OF DNA REPAIR GENES IN AFRICAN AMERICAN PROSTATE CANCER PATIENTS HIGHLIGHT POTENTIALLY TARGETABLE RAD GENES

PD65-12 GERMLINE MUTATION LANDSCAPE OF DNA REPAIR GENES IN AFRICAN AMERICAN PROSTATE CANCER PATIENTS HIGHLIGHT POTENTIALLY TARGETABLE <i>RAD</i> GENES

Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer.

Simple SummaryFor patients whose prostate cancer spreads beyond the confines of the prostate, treatment options continue to increase. However, we are missing the information that is needed to choose for each patient the best treatment at each step of his cancer progression so we can ensure that maximal remissions and prolonged survival are achieved. In this review, we examine whether a better understanding of how the activity of the target for the default first treatment, the androgen receptor, is regulated in prostate cancer tissues can improve prostate cancer treatment plans. We consider the evidence for variability of androgen receptor activity among patients and examine the molecular basis for this variable action. We summarize clinical evidence supporting that information on a prostate cancer’s genomic composition may inform on its level of androgen receptor action, which may facilitate choice for the most effective first-line therapy and ultimately improve prostate cancer treatment plans overall.Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.

Efficacy and safety of corticosteroids in acute respiratory distress syndrome: An overview of meta-analyses.

Evidence-based recommendations on the efficacy and safety of corticosteroids in acute respiratory distress syndrome (ARDS) remain a therapeutic challenge. Findings from several systematic reviews and meta-analyses are inconsistent. We aimed to assess the published meta-analyses through a systematic review approach and provide further insight into the current uncertainty and also to perform an updated meta-analysis from all the available primary studies. We followed the Preferred Reporting Items for Systematic Review (PRISMA) guidelines to establish the patients, intervention, control and outcome (PICO) for reviewing published meta-analyses. Data sources such as PubMed/MEDLINE, SCOPUS, Cochrane and Google Scholar from inception to February 2021 were accessed. Prevention of ARDS, mortality, ventilator-free days, ICU stay and safety in terms of occurrence of adverse effects were the patient-related outcomes. The review also assessed meta-analysis design-related outcomes which includes the quality of meta-analysis, factors contributing to the risk of bias, extent and sources of heterogeneity, publication bias and robustness of findings. AMSTAR-2 checklist assessed the quality of published meta-analyses. A total of 18 meta-analyses were reviewed comprising a total of 38 primary studies and 3760 patients. Fourteen studies were in ARDS, three in community-acquired pneumonia and one in critical care. The overall quality of meta-analyses was observed to be critically low to high. A non-significant risk of publication bias and non-significant level of heterogeneity was observed in the reviewed meta-analysis. Corticosteroid was significantly effective in preventing ARDS among CAP patients. The effect of corticosteroids on mortality was observed to be still inconsistent, whereas significant improvement was observed with ICU and ventilator outcomes compared with the control group. Our meta-analysis observed a significant reduction of mortality in RCTs (RR: 0.78; 95% CI: 0.61 to 0.99) and the duration of mechanical ventilation (MD: -4.75; 95% CI: -7.63 to -1.88); and a significant increase in ventilator-free days (MD: 6.03; 95% CI: 3.59 to 8.47) and ICU-free days (MD: 8.04; 95% CI: 2.70 to 13.38) in ARDS patients treated with corticosteroids compared with the control group. The quality of included studies ranged from critically low to high demonstrating inconsistency in risk of bias. While older studies found no significant effect, recent meta-analyses of RCTs found a significant mortality reduction in the corticosteroid group with considerable levels of heterogeneity. The updated meta-analysis by our team found a significant reduction in mortality in the pooled estimation of RCTs but not in cohort studies. Corticosteroid therapy was effective in terms of ICU and ventilator outcomes with minimal safety concerns. Future meta-analyses should be well executed with specific research questions and well performed with minimal risk of bias to produce good quality evidence.

The role of angiopoietin-2 and surfactant protein-D levels in SARS-CoV-2-related lung injury: A prospective, observational, cohort study.

IntroductionCoronavirus disease‐2019 (COVID‐19) is a respiratory disease whose clinical manifestation ranges from asymptomatic to severe respiratory failure. The purpose of this study was to investigate the place of serum surfactant‐D (SP‐D) and angiopoetin‐2 (Ang‐2) levels in predicting severity of disease in patients diagnosed with COVID‐19.MethodsSixty‐four patients diagnosed with COVID‐19 between September 2020 and February 2021, 50 patients diagnosed with community‐acquired pneumonia and a 50‐member healthy control group were included in the study. Plasma samples and clinical data were collected within 72 h after admission, during hospital stay. Serum SP‐D and Ang‐2 concentrations were measured using the enzyme‐linked immunosorbent assay.ResultsSP‐D and Ang‐2 levels were significantly higher in the mild–moderate pneumonia and severe/critical patient groups compared to the asymptomatic and noncomplicated COVID‐19 patients (p < 0.001 for all groups). Serum SP‐D and Ang‐2 levels of severe‐critical COVID‐19 patients were significantly higher than CAP patients (p < 0.001). Powerful correlation was present between clinical severity of COVID‐19 and SP‐D and Ang‐2 levels (r = 0.885 p < 0.001 and r = 0.913 p < 0.001, respectively). Cut‐off values of 37.7 ng/ml (AUC = 0.763, p < 0.001, 95% confidence interval [CI] = 0.667–0.860) for SP‐D and 4208.3 pg/ml (AUC = 0.659, p = 0.004, 95% CI = 0.554–0.763) for Ang‐2 were identified as predictors of COVID‐19 disease at receiver operating characteristic curve analysis.ConclusionSP‐D and Ang‐2 are predictive factors in differentiating COVID‐19 patients and determining severity of disease. These data may be important for the initiation of treatment in the early stage of the disease in patients with COVID‐19.

Soluble form of suppression of tumorigenicity-2 predicts clinical stability of inpatients with community-acquired pneumonia

The soluble form of the suppression of tumorigenicity-2 (sST2) is a biomarker for risk classification and prognosis of heart failure, and its production and secretion in the alveolar epithelium are significantly correlated with the inflammation-inducing in pulmonary diseases. However, the predictive value of sST2 in pulmonary disease had not been widely studied. This study investigated the potential value in prognosis and risk classification of sST2 in patients with community-acquired pneumonia. Clinical data of ninety-three CAP inpatients were retrieved and their sST2 and other clinical indices were studied. Cox regression models were constructed to probe the sST2's predictive value for patients' restoring clinical stability and its additive effect on pneumonia severity index and CURB-65 scores. Patients who did not reach clinical stability within the defined time (30 days from hospitalization) have had significantly higher levels of sST2 at admission (P < 0.05). In univariate and multivariate Cox regression analysis, a high sST2 level (≥72.8 ng/mL) was an independent reverse predictor of clinical stability (P < 0.05). The Cox regression model combined with sST2 and CURB-65 (AUC: 0.96) provided a more accurate risk classification than CURB-65 (AUC:0.89) alone (NRI: 1.18, IDI: 0.16, P < 0.05). The Cox regression model combined with sST2 and pneumonia severity index (AUC: 0.96) also provided a more accurate risk classification than pneumonia severity index (AUC:0.93) alone (NRI: 0.06; IDI: 0.06, P < 0.05). sST2 at admission can be used as an independent early prognostic indicator for CAP patients. Moreover, it can improve the predictive power of CURB-65 and pneumonia severity index score.