Etiology of Anemia in Patients With Advanced Heart Failure

ObjectivesWe prospectively investigated the causes of anemia in patients with advanced congestive heart failure (CHF).BackgroundAnemia is common in patients with advanced CHF, and its etiology is generally considered to be multifactorial. However, despite its importance, precise information is lacking regarding the prevalence of putative etiologic factors.MethodsPatients who were hospitalized for decompensated advanced CHF and who were stabilized after their initial treatment underwent evaluation of “clinically significant” anemia, defined as a hemoglobin content <12 g/dl for men and <11.5 g/dl for women. Patients with a serum creatinine concentration >3 mg/dl or patients with concurrent diseases that are known to cause anemia were not included. The initial evaluation included measurements of vitamin B12, folic acid, thyroid-stimulating hormone, erythropoietin, lactate dehydrogenase, Coombs test, multiple fecal occult tests, and bone marrow aspiration. Patients without diagnosis by these methods underwent red cell mass measurement with 51Cr assay.ResultsThe mean age of the 37 patients was 57.9 ± 10.9 years and mean left ventricular ejection fraction 22.5 ± 5.9%. Iron deficiency anemia was confirmed by bone marrow aspiration in 27 patients (73%), 2 patients (5.4%) had dilutional anemia, and 1 patient (2.7%) had drug-induced anemia. No specific cause was identified in 7 patients (18.9%) who were considered to have “anemia of chronic disease.” Serum ferritin for the iron-deficient patients was not a reliable marker of iron deficiency in this population.ConclusionsIn this group of patients, iron deficiency was the most common cause of anemia. The iron status of patients with end-stage chronic CHF should be thoroughly evaluated and corrected before considering other therapeutic interventions

The Web Epoch of Reionization Lyman-α\alpha Survey (WERLS) I. MOSFIRE Spectroscopy of z∼7−8\mathbf{z \sim 7-8} Lyman-α\alpha Emitters

We present the first results from the Web Epoch of Reionization Lyman-$\alpha$ Survey (WERLS), a spectroscopic survey of Lyman-$\alpha$ emission using Keck I/MOSFIRE and LRIS. WERLS targets bright ($J<26$) galaxy candidates with photometric redshifts of $5.5\lesssim z \lesssim 8$ selected from pre-JWST imaging embedded in the Epoch of Reionization (EoR) within three JWST deep fields: CEERS, PRIMER, and COSMOS-Web. Here, we report 11 $z\sim7-8$ Lyman-$\alpha$ emitters (LAEs; 3 secure and 8 tentative candidates) detected in the first five nights of WERLS MOSFIRE data. We estimate our observed LAE yield is $\sim13$%, broadly consistent with expectations assuming some loss from redshift uncertainty, contamination from sky OH lines, and that the Universe is approximately half-ionized at this epoch, whereby observable Lyman-$\alpha$ emission is unlikely for galaxies embedded in a neutral intergalactic medium. Our targets are selected to be UV-bright, and span a range of absolute UV magnitudes with $-23.1 < M_{\text{UV}} < -19.8$. With two LAEs detected at $z=7.68$, we also consider the possibility of an ionized bubble at this redshift. Future synergistic Keck+JWST efforts will provide a powerful tool for pinpointing beacons of reionization and mapping the large scale distribution of mass relative to the ionization state of the Universe.Comment: 27 pages, 8 figures; ApJ submitte

The COSMOS-Web ring: in-depth characterization of an Einstein ring lensing system at z~2

Aims. We provide an in-depth analysis of the COSMOS-Web ring, an Einstein ring at z=2 that we serendipitously discovered in the COSMOS-Web survey and possibly the most distant lens discovered to date. Methods. We extract the visible and NIR photometry from more than 25 bands and we derive the photometric redshifts and physical properties of both the lens and the source with three different SED fitting codes. Using JWST/NIRCam images, we also produce two lens models to (i) recover the total mass of the lens, (ii) derive the magnification of the system, (iii) reconstruct the morphology of the lensed source, and (iv) measure the slope of the total mass density profile of the lens. Results. The lens is a very massive and quiescent (sSFR < 10^(-13) yr-1) elliptical galaxy at z = 2.02 \pm 0.02 with a total mass Mtot(<thetaE) = (3.66 \pm 0.36) x 10^11 Msun and a stellar mass M* = (1.37 \pm 0.14) x 10^11 Msun. Compared to SHMRs from the literature, we find that the total mass is consistent with the presence of a DM halo of mass Mh = 1.09^(+1.46)_(-0.57) x 10^13 Msun. In addition, the background source is a M* = (1.26 \pm 0.17) x 10^10 Msun star-forming galaxy (SFR=(78 \pm 15) Msun/yr) at z = 5.48 \pm 0.06. Its reconstructed morphology shows two components with different colors. Dust attenuation values from SED fitting and nearby detections in the FIR also suggest it could be partially dust-obscured. Conclusions. We find the lens at z=2. Its total, stellar, and DM halo masses are consistent within the Einstein ring, so we do not need any unexpected changes in our description of the lens (e.g. change its IMF or include a non-negligible gas contribution). The most likely solution for the lensed source is at z = 5.5. Its reconstructed morphology is complex and highly wavelength dependent, possibly because it is a merger or a main sequence galaxy with a heterogeneous dust distribution.Comment: 16 pages, submitted to A&

Necdin, a p53-Target Gene, Is an Inhibitor of p53-Mediated Growth Arrest

In vitro, cellular immortalization and transformation define a model for multistep carcinogenesis and current ongoing challenges include the identification of specific molecular events associated with steps along this oncogenic pathway. Here, using NIH3T3 cells, we identified transcriptionally related events associated with the expression of Polyomavirus Large-T antigen (PyLT), a potent viral oncogene. We propose that a subset of these alterations in gene expression may be related to the early events that contribute to carcinogenesis. The proposed tumor suppressor Necdin, known to be regulated by p53, was within a group of genes that was consistently upregulated in the presence of PyLT. While Necdin is induced following p53 activation with different genotoxic stresses, Necdin induction by PyLT did not involve p53 activation or the Rb-binding site of PyLT. Necdin depletion by shRNA conferred a proliferative advantage to NIH3T3 and PyLT-expressing NIH3T3 (NIHLT) cells. In contrast, our results demonstrate that although overexpression of Necdin induced a growth arrest in NIH3T3 and NIHLT cells, a growing population rapidly emerged from these arrested cells. This population no longer showed significant proliferation defects despite high Necdin expression. Moreover, we established that Necdin is a negative regulator of p53-mediated growth arrest induced by nutlin-3, suggesting that Necdin upregulation could contribute to the bypass of a p53-response in p53 wild type tumors. To support this, we characterized Necdin expression in low malignant potential ovarian cancer (LMP) where p53 mutations rarely occur. Elevated levels of Necdin expression were observed in LMP when compared to aggressive serous ovarian cancers. We propose that in some contexts, the constitutive expression of Necdin could contribute to cancer promotion by delaying appropriate p53 responses and potentially promote genomic instability

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido

The Hellenic emergency laparotomy study (HELAS): a prospective multicentre study on the outcomes of emergency laparotomy in Greece

Background Emergency laparotomy (EL) is accompanied by high post-operative morbidity and mortality which varies significantly between countries and populations. The aim of this study is to report outcomes of emergency laparotomy in Greece and to compare them with the results of the National Emergency Laparotomy Audit (NELA). Methods This is a multicentre prospective cohort study undertaken between 01.2019 and 05.2020 including consecutive patients subjected to EL in 11 Greek hospitals. EL was defined according to NELA criteria. Demographics, clinical variables, and post-operative outcomes were prospectively registered in an online database. Multivariable logistic regression analysis was used to identify independent predictors of post-operative mortality. Results There were 633 patients, 53.9% males, ASA class III/IV 43.6%, older than 65 years 58.6%. The most common operations were small bowel resection (20.5%), peptic ulcer repair (12.0%), adhesiolysis (11.8%) and Hartmann’s procedure (11.5%). 30-day post-operative mortality reached 16.3% and serious complications occurred in 10.9%. Factors associated with post-operative mortality were increasing age and ASA class, dependent functional status, ascites, severe sepsis, septic shock, and diabetes. HELAS cohort showed similarities with NELA patients in terms of demographics and preoperative risk. Post-operative utilisation of ICU was significantly lower in the Greek cohort (25.8% vs 56.8%) whereas 30-day post-operative mortality was significantly higher (16.3% vs 8.7%). Conclusion In this study, Greek patients experienced markedly worse mortality after emergency laparotomy compared with their British counterparts. This can be at least partly explained by underutilisation of critical care by surgical patients who are at high risk for death

Development and internal validation of a clinical prediction model for serious complications after emergency laparotomy

Purpose Emergency laparotomy (EL) is a common operation with high risk for postoperative complications, thereby requiring accurate risk stratification to manage vulnerable patients optimally. We developed and internally validated a predictive model of serious complications after EL. Methods Data for eleven carefully selected candidate predictors of 30-day postoperative complications (Clavien-Dindo grade >  = 3) were extracted from the HELAS cohort of EL patients in 11 centres in Greece and Cyprus. Logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) was applied for model development. Discrimination and calibration measures were estimated and clinical utility was explored with decision curve analysis (DCA). Reproducibility and heterogeneity were examined with Bootstrap-based internal validation and Internal–External Cross-Validation. The American College of Surgeons National Surgical Quality Improvement Program’s (ACS-NSQIP) model was applied to the same cohort to establish a benchmark for the new model. Results From data on 633 eligible patients (175 complication events), the SErious complications After Laparotomy (SEAL) model was developed with 6 predictors (preoperative albumin, blood urea nitrogen, American Society of Anaesthesiology score, sepsis or septic shock, dependent functional status, and ascites). SEAL had good discriminative ability (optimism-corrected c-statistic: 0.80, 95% confidence interval [CI] 0.79–0.81), calibration (optimism-corrected calibration slope: 1.01, 95% CI 0.99–1.03) and overall fit (scaled Brier score: 25.1%, 95% CI 24.1–26.1%). SEAL compared favourably with ACS-NSQIP in all metrics, including DCA across multiple risk thresholds. Conclusion SEAL is a simple and promising model for individualized risk predictions of serious complications after EL. Future external validations should appraise SEAL’s transportability across diverse settings

The additional value of patient-reported health status in predicting 1-year mortality after invasive coronary procedures: A report from the Euro Heart Survey on Coronary Revascularisation

Objective: Self-perceived health status may be helpful in identifying patients at high risk for adverse outcomes. The Euro Heart Survey on Coronary Revascularization (EHS-CR) provided an opportunity to explore whether impaired health status was a predictor of 1-year mortality in patients with coronary artery disease (CAD) undergoing angiographic procedures. Methods: Data from the EHS-CR that included 5619 patients from 31 member countries of the European Society of Cardiology were used. Inclusion criteria for the current study were completion of a self-report measure of health status, the EuroQol Questionnaire (EQ-5D) at discharge and information on 1-year follow-up, resulting in a study population of 3786 patients. Results: The 1-year mortality was 3.2% (n = 120). Survivors reported fewer problems on the five dimensions of the EQ-5D as compared with non-survivors. A broad range of potential confounders were adjusted for, which reached a p<0.10 in the unadjusted analyses. In the adjusted analyses, problems with self-care (OR 3.45; 95% CI 2.14 to 5.59) and a low rating (≤ 60) on health status (OR 2.41; 95% CI 1.47 to 3.94) were the most powerful independent predictors of mortality, among the 22 clinical variables included in the analysis. Furthermore, patients who reported no problems on all five dimensions had significantly lower 1-year mortality rates (OR 0.47; 95% CI 0.28 to 0.81). Conclusions: This analysis shows that impaired health status is associated with a 2-3-fold increased risk of all-cause mortality in patients with CAD, independent of other conventional risk factors. These results highlight the importance of including patients' subjective experience of their own health status in the evaluation strategy to optimise risk stratification and management in clinical practice

Controversies in the management of advanced prostate cancer

For advanced prostate cancer, the main hormone treatment against which other treatments are assessed is surgical castration. It is simple, safe and effective, however it is not acceptable to all patients. Medical castration by means of luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate provides an alternative to surgical castration. Diethylstilboestrol, previously the only non-surgical alternative to orchidectomy, is no longer routinely used. Castration reduces serum testosterone by around 90%, but does not affect androgen biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or surgical castration blocks the effect of remaining testosterone on prostate cells and is termed combined androgen blockade (CAB). CAB has now been compared with castration alone (medical and surgical) in numerous clinical trials. Some trials show advantage of CAB over castration, whereas others report no significant difference. The author favours the view that CAB has an advantage over castration. No study has reported that CAB is less effective than castration. Of the anti-androgens which are available for use in CAB, bicalutamide may be associated with a lower incidence of side-effects compared with the other non-steroidal anti-androgens and, in common with nilutamide, has the advantage of once-daily dosing. Only one study has compared anti-androgens within CAB: bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week follow-up, the groups were equivalent in terms of survival and time to progression. However, bicalutamide caused significantly less diarrhoea than flutamide. Withdrawal and intermittent therapy with anti-androgens extend the range of treatment options. © 1999 Cancer Research Campaig