Rare bleeding disorders: Real-world data from a Spanish tertiary hospital.

INTRODUCTION: Due to their low prevalence, rare bleeding disorders (RBDs) remain poorly characterized. AIM: To gain insight of RBDs through our clinical practice. METHODS: Retrospective study of the medical records of RBD patients followed up at the Central University Hospital of Asturias between January 2019 and December 2022. RESULTS: A total of 149 patients were included. Factor (F) VII (44 %) and FXI (40 %) deficiencies were the most common diagnosed coagulopathies. Most of the patients were asymptomatic (60.4 %) and the most frequent type of bleeding were mucocutaneous and after surgery. All replacement treatments were administered on demand and no patient was on a prophylaxis regimen. Currently available products were safe; allergic reactions after administration of plasma were the most frequent complication. Genetic analysis, carried out on 55 patients (37 %), showed that the most frequent mutations in RBDs are of missense type (71.9 %). We identified 11 different novel genetic alterations in affected genes. The c.802C > T (p.Arg268Cys) variant, previously described, was identified in 71 % (15 of 21) of the patients with FXI deficiency genotyped and none were related (probable founder effect). CONCLUSION: Our study on an unusual large single center cohort of RBD patients portrays location-dependent distinct genetic drives and clinical practice particularities.

A comprehensive, predictive mortality score for patients with bloodstream infections (PROBAC): a prospective, multicentre cohort study.

OBJECTIVES: Bloodstream infections (BSI) are an important cause of mortality, although they show heterogeneity depending on patients and aetiological factors. Comprehensive and specific mortality scores for BSI are scarce. The objective of this study was to develop a mortality predictive score in BSI based on a multicentre prospective cohort. METHODS: A prospective cohort including consecutive adults with bacteraemia recruited between October 2016 and March 2017 in 26 Spanish hospitals was randomly divided into a derivation cohort (DC) and a validation cohort (VC). The outcome was all-cause 30-day mortality. Predictors were assessed the day of blood culture growth. A logistic regression model and score were developed in the DC for mortality predictors; the model was applied to the VC. RESULTS: Overall, 4102 patients formed the DC and 2009 the VC. Mortality was 11.8% in the DC and 12.34% in the CV; the patients and aetiological features were similar for both cohorts. The mortality predictors selected in the final multivariate model in the DC were age, cancer, liver cirrhosis, fatal McCabe underlying condition, polymicrobial bacteraemia, high-risk aetiologies, high-risk source of infection, recent use of broad-spectrum antibiotics, stupor or coma, mean blood pressure <70 mmHg and PaO2/FiO2 ≤ 300 or equivalent. Mortality in the DC was <2% for ≤2 points, 6%-14% for 3-7 points, 26%-45% for 8-12 points and ≥60% for ≥13 points. The predictive score had areas under the receiving operating curves of 0.81 (95% CI 0.79-0.83) in the DC and 0.80 (0.78-0.83) in the VC. CONCLUSIONS: A 30 day mortality predictive score in BSI with good discrimination ability was developed and internally validated.

Clinical characteristics, predisposing factors and outcomes for Enterococcus faecalis versus Enterococcus faecium bloodstream infections: a prospective multicentre cohort study.

PURPOSES: Enterococcal BSI is associated with significant morbidity and mortality, with fatality rates of approximately 20-30%. There are microbiological and clinical differences between E. faecalis and E. faecium infections. The aim of this study was to investigate differences in predisposing factors for E. faecalis and E. faecium BSI and to explore prognostic factors. METHODS: This study was a post-hoc analysis of PROBAC, a Spanish prospective, multicenter, cohort in 2016-2017. Patients with E. faecalis or E. faecium BSI were eligible. Independent predictors for BSI development in polymicrobial and monomicrobial BSI and in-hospital mortality in the monomicrobial group were identified by logistic regression. RESULTS: A total of 431 patients were included. Independent factors associated with E. faecium BSI were previous use of penicillins (aOR 1.99 (95% CI 1.20-3.32)) or carbapenems (2.35 (1.12-4.93)), hospital-acquired BSI (2.58 (1.61-4.12)), and biliary tract source (3.36 (1.84-6.13)), while congestive heart failure (0.51 (0.27-0.97)), cerebrovascular disease (0.45 (0.21-0.98)), and urinary tract source (0.49 (0.26-0.92)) were associated with E. faecalis BSI. Independent prognostic factors for in-hospital mortality in E. faecalis BSI were Charlson Comorbidity Index (1.27 (1.08-1.51)), SOFA score (1.47 (1.24-1.73)), age (1.06 (1.02-1.10)), and urinary/biliary source (0.29 (0.09-0.90)). For E. faecium BSI, only SOFA score (1.34 (1.14-1.58) was associated with in-hospital mortality. CONCLUSIONS: The factors associated with E. faecium and E. faecalis BSI are different. These variables may be helpful in the suspicion of one or other species for empiric therapeutic decisions and provide valuable information on prognosis.

Differences in clinical outcomes of bloodstream infections caused by Klebsiella aerogenes, Klebsiella pneumoniae and Enterobacter cloacae: a multicentre cohort study.

BACKGROUND: Klebsiella aerogenes has been reclassified from Enterobacter to Klebsiella genus due to its phenotypic and genotypic similarities with Klebsiella pneumoniae. It is unclear if clinical outcomes are also more similar. This study aims to assess clinical outcomes of bloodstreams infections (BSI) caused by K. aerogenes, K. pneumoniae and Enterobacter cloacae, through secondary data analysis, nested in PRO-BAC cohort study. METHODS: Hospitalized patients between October 2016 and March 2017 with monomicrobial BSI due to K. aerogenes, K. pneumoniae or E. cloacae were included. Primary outcome was a composite clinical outcome including all-cause mortality or recurrence until 30 days follow-up. Secondary outcomes were fever ≥ 72 h, persistent bacteraemia, and secondary device infection. Multilevel mixed-effect Poisson regression was used to estimate the association between microorganisms and outcome. RESULTS: Overall, 29 K. aerogenes, 77 E. cloacae and 337 K. pneumoniae BSI episodes were included. Mortality or recurrence was less frequent in K. aerogenes (6.9%) than in E. cloacae (20.8%) or K. pneumoniae (19.0%), but statistical difference was not observed (rate ratio (RR) 0.35, 95% CI 0.08 to 1.55; RR 0.42, 95% CI 0.10 to 1.71, respectively). Fever ≥ 72 h and device infection were more common in K. aerogenes group. In the multivariate analysis, adjusted for confounders (age, sex, BSI source, hospital ward, Charlson score and active antibiotic therapy), the estimates and direction of effect were similar to crude results. CONCLUSIONS: Results suggest that BSI caused by K. aerogenes may have a better prognosis than E. cloacae or K. pneumoniae BSI.

Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

Validation of a 3D Local-Scale Adaptive Solar Radiation Model by Using Pyranometer Measurements and a High-Resolution Digital Elevation Model.

The result of the multidisciplinary collaboration of researchers from different areas of knowledge to validate a solar radiation model is presented. The MAPsol is a 3D local-scale adaptive solar radiation model that allows us to estimate direct, diffuse, and reflected irradiance for clear sky conditions. The model includes the adaptation of the mesh to complex orography and albedo, and considers the shadows cast by the terrain and buildings. The surface mesh generation is based on surface refinement, smoothing and parameterization techniques and allows the generation of high-quality adapted meshes with a reasonable number of elements. Another key aspect of the paper is the generation of a high-resolution digital elevation model (DEM). This high-resolution DEM is constructed from LiDAR data, and its resolution is two times more accurate than the publicly available DEMs. The validation process uses direct and global solar irradiance data obtained from pyranometers at the University of Salamanca located in an urban area affected by systematic shading from nearby buildings. This work provides an efficient protocol for studying solar resources, with particular emphasis on areas of complex orography and dense buildings where shadows can potentially make solar energy production facilities less efficient.

Structural Analysis and Diversity of Calmodulin-Binding Domains in Membrane and Intracellular Ca2+-ATPases.

The plasma membrane and autoinhibited Ca2+-ATPases contribute to the Ca2+ homeostasis in a wide variety of organisms. The enzymatic activity of these pumps is stimulated by calmodulin, which interacts with the target protein through the calmodulin-binding domain (CaMBD). Most information about this region is related to all calmodulin modulated proteins, which indicates general chemical properties and there is no established relation between Ca2+ pump sequences and taxonomic classification. Thus, the aim of this study was to perform an in silico analysis of the CaMBD from several Ca2+-ATPases, in order to determine their diversity and to detect specific patterns and amino acid selection in different species. Patterns related to potential and confirmed CaMBD were detected using sequences retrieved from the literature. The occurrence of these patterns was determined across 120 sequences from 17 taxonomical classes, which were analyzed by a phylogenetic tree to establish phylogenetic groups. Predicted physicochemical characteristics including hydropathy and net charge were calculated for each group of sequences. 22 Ca2+-ATPases sequences from animals, unicellular eukaryotes, and plants were retrieved from bioinformatic databases. These sequences allow us to establish the Patterns 1(GQILWVRGLTRLQTQ), 3(KNPSLEALQRW), and 4(SRWRRLQAEHVKK), which are present at the beginning of putative CaMBD of metazoan, parasites, and land plants. A pattern 2 (IRVVNAFR) was consistently found at the end of most analyzed sequences. The amino acid preference in the CaMBDs changed depending on the phylogenetic groups, with predominance of several aliphatic and charged residues, to confer amphiphilic properties. The results here displayed show a conserved mechanism to contribute to the Ca2+ homeostasis across evolution and may help to detect putative CaMBDs.

Fitness, body composition, and metabolic risk scores in children and adolescents: the UP&DOWN study.

We aimed to analyse the longitudinal association between physical fitness (PF) and body composition (BC) with a metabolic risk score (Met4) in children and adolescents and to elucidate whether the association between PF and Met4 differs when using relativized or absolute fitness variables. A total of 188 children (86 females) and 195 adolescents (97 females) were included. Cardiorespiratory fitness (CRF) was determined by the 20-m shuttle run test, and muscular fitness (MF) was determined by hand grip and standing long jump tests. Height and weight were measured, and the body mass index (Kg/m2) was calculated. Triceps and subscapular skinfolds were assessed to compute body fat percentage. Met4 was computed from systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose levels. Relative CRF was longitudinally and negatively associated with Met4 in female children (ß = -0.031, p = 0.025), while absolute CRF was positively associated with Met4 in male children and adolescents (ß = 0.000, p < 0.05). Relative upper and lower-body MF were longitudinally and negatively associated with Met4 in female adolescents (ß = -1.347, ß = -0.005, p < 0.05), while absolute lower-body MF was positively associated with Met4 in male children (ß = 0.000, p = 0.019). BC was longitudinally and positively associated with Met4 in male children (ß-ranging from 0.011 to 0.055, all p < 0.05) and male adolescents (ß-ranging from 0.011 to 0.046, all p < 0.05).  Conclusion: BC is more strongly associated with Met4 than PF in children and adolescents. An optimal body weight status should be considered the main objective of health-promoting programs at childhood and adolescence. Furthermore, the way of expressing the fitness variables determines the direction of the association with Met4. What is Known: • Physical fitness is an important health indicator in children and adolescents, with great amount of previous evidence supporting the preventive role of maintaining optimal levels of both cardiorespiratory and muscular fitness for future cardiometabolic issues. What is New: • The way of reporting physical fitness variables can affect the associations between physical fitness features and cardiometabolic outcomes. Since body composition variables have a great impact on both physical fitness and cardiometabolic health, relativizing physical fitness performance by body composition could lead to erroneous conclusions.

Impact of Acute High Glucose on Mitochondrial Function in a Model of Endothelial Cells: Role of PDGF-C.

An increase in plasma high glucose promotes endothelial dysfunction mainly through increasing mitochondrial ROS production. High glucose ROS-induced has been implicated in the fragmentation of the mitochondrial network, mainly by an unbalance expression of mitochondrial fusion and fission proteins. Mitochondrial dynamics alterations affect cellular bioenergetics. Here, we assessed the effect of PDGF-C on mitochondrial dynamics and glycolytic and mitochondrial metabolism in a model of endothelial dysfunction induced by high glucose. High glucose induced a fragmented mitochondrial phenotype associated with the reduced expression of OPA1 protein, high DRP1pSer616 levels and reduced basal respiration, maximal respiration, spare respiratory capacity, non-mitochondrial oxygen consumption and ATP production, regarding normal glucose. In these conditions, PDGF-C significantly increased the expression of OPA1 fusion protein, diminished DRP1pSer616 levels and restored the mitochondrial network. On mitochondrial function, PDGF-C increased the non-mitochondrial oxygen consumption diminished by high glucose conditions. These results suggest that PDGF-C modulates the damage induced by HG on the mitochondrial network and morphology of human aortic endothelial cells; additionally, it compensates for the alteration in the energetic phenotype induced by HG.

Taxes, Inequality, and Equal Opportunities.

Extreme inequality represents a grave challenge for impoverished individuals and poses a threat to economic growth and stability. Despite the fulfillment of affirmative action measures aimed at promoting equal opportunities, they often prove inadequate in effectively reducing inequality. Mathematical models and simulations have demonstrated that even when equal opportunities are present, wealth tends to concentrate in the hands of a privileged few, leaving the majority of the population in dire poverty. This phenomenon, known as condensation, has been shown to be an inevitable outcome in economic models that rely on fair exchange. In light of the escalating levels of inequality in the 21st century and the significant state intervention necessitated by the recent COVID-19 pandemic, an increasing number of scholars are abandoning neo-liberal ideologies. Instead, they propose a more robust role for the state in the economy, utilizing mechanisms such as taxation, regulation, and universal allocations. This paper begins with the assumption that state intervention is essential to effectively reduce inequality and to revitalize the economy. Subsequently, it conducts a comparative analysis of various taxation and redistribution mechanisms, with a particular emphasis on their impact on inequality indices, including the Gini coefficient. Specifically, it compares the effects of fortune and consumption-based taxation, as well as universal redistribution mechanisms or targeted redistribution mechanisms aimed at assisting the most economically disadvantaged individuals. The results suggest that fortune taxation are more effective than consumption-based taxation to reduce inequality.

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management.

BACKGROUND: High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR). METHODS: A total of 109 ready-available formalin-fixed paraffin-embedded HGSC tissues obtained at the time of HGSC diagnosis were selected for proteomic analysis. Clinical data, treatment approach and outcomes were collected for all patients. An initial discovery cohort (n = 21) were divided into chemoresistant and chemosensitive groups and evaluated using discovery mass-spectrometry (MS)-based proteomics. Proteins showing differential abundance between groups were verified in a verification cohort (n = 88) using targeted MS-based proteomics. A logistic regression model was used to select those proteins able to correctly classify patients into chemoresistant and chemosensitive. The classification performance of the protein and clinical data combinations were assessed through the generation of receiver operating characteristic (ROC) curves. RESULTS: Using the HGSC-1LTR strategy we have identified a molecular signature (TKT, LAMC1 and FUCO) that combined with ready available clinical data (patients' age, menopausal status, serum CA125 levels, and treatment approach) is able to predict patient response to first-line treatment with an AUC: 0.82 (95% CI 0.72-0.92). CONCLUSIONS: We have established a new strategy that combines molecular and clinical parameters to predict the response to first-line treatment in HGSC patients (HGSC-1LTR). This strategy can allow the identification of chemoresistance at the time of diagnosis providing the optimization of therapeutic decision making and the evaluation of alternative treatment strategies. Thus, advancing towards the improvement of patient outcome and the individualization of HGSC patients' care.

OVA-LEAK: Prognostic score for colo-rectal anastomotic leakage in patients undergoing ovarian cancer surgery.

OBJECTIVE: The objective of the present study was to define and validate an anastomotic leak prognostic score based on previously described and reported anastomotic leak risk factors (OVA-LEAK: https://n9.cl/ova-leakscore) and to establish if the use of OVA-LEAK score is better than clinical criteria (surgeon's choice) selecting anastomosis to be protected with a diverting ileostomy. MATERIAL & METHODS: This is a retrospective, multicentre cohort study that included patients who underwent cytoreductive surgery for primary advanced or relapsed ovarian cancer with colorectal resection and anastomosis between January 2011 and June 2021. Data from patients already included in the previous predictive model were not considered in the present analysis. To validate the performance of our logistic regression model, we used the OVA-LEAK formula (Annex I: https://n9.cl/ova-leakscore) for estimating leakage probabilities in a new independent cohort. Then, receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was used to measure the performance of the model. Additionally, the Brier score was also estimated. 95% confidence intervals (CI) for each of the estimated performance measures were also calculated. RESULTS: 848 out of 1159 recruited patients were finally included in the multivariable logistic regression model validation. The AUC of the new cohort was 0.63 for predicting anastomotic leak. Considering a cut-off point of 22.1% to be 'positive' (to get a leak) this would provide a sensitivity of 0.45, specificity of 0.80, positive predictive value of 0.09 and negative predictive value of 0.97 for anastomotic leak. If we consider this cut-off point to select patients at risk of leak for bowel diversion, up to 22.5% of the sampled patients would undergo a diverting ileostomy and 47% (18/40) of the anastomotic leaks would be 'protected' with the stoma. Nevertheless, if we consider only the 'clinical criteria' for performing or not a diverting ileostomy, only 12.5% (5/40) of the leaks would be 'protected' with a stoma, with a rate of diverting ileostomy of up to 24.3%. CONCLUSIONS: Compared with subjective clinical criteria, the use of a predictive model for anastomotic leak improves the selection of patients who would benefit from a diverting ileostomy without increasing the rate of stoma use.

Operative Time Is Independently Associated With Morbidity in Pediatric Complicated Appendicitis.

INTRODUCTION: Complicated appendicitis is a common cause of morbidity in children. Studies have analyzed the risk factors in the surgical treatment of this pathology, including obesity and disease severity, but not operative time (OT). We hypothesize that OT is independently associated with increased morbidity for children with complicated appendicitis. METHODS: Data were extracted from the 2018 and 2019 National Surgical Quality Improvement Program-Pediatrics data sets. Patients aged 2-18 y who underwent laparoscopic appendectomy for complicated appendicitis were identified. Patient demographics, disease severity, and operative details were evaluated. Surgical site infections (SSIs), hospital length of stay (LOS), ≤30-d readmissions and reoperations, interventional radiologic drain (IR-drain) placement, pneumonia, and death were analyzed. Logistic and linear regression analyses were performed. RESULTS: A total of 8168 patients were analyzed, with a mean age of 9.96 ± 3.9 y and a mean weight of 41.2 ± 21.2 kg. The mean OT was 55.8 ± 24.9 min, with a mean LOS of 5.15 ± 3.37 d. For every 1-min increase in OT, there was an independently associated increase in the likelihood of any SSI (odds ratio [OR] = 1.01; 95% confidence interval [CI] 1.008-1.013), superficial SSI (OR = 1.01; 95% CI 1.004-1.020), organ-space SSI (OR = 1.01; 95% CI 1.008-1.013), IR-drain placement (OR = 1.01; 95% CI 1.008-1.013), and readmission (OR = 1.004; 95% CI 1.000-1.007). CONCLUSIONS: Prolonged OT is independently associated with greater likelihood of any SSI, superficial SSI, organ-space SSI, IR-drain placement, readmission and reoperation within 30 d, and longer hospital LOS. There is a need to determine modifiable factors that prolong OT to aid in the optimization of routine operations to reduce patient morbidity.

Study of taxes, regulations and inequality using machine learning algorithms.

Genetic machine learning (ML) algorithms to train agents in the Yard-Sale model proved very useful for finding optimal strategies that maximize their wealth. However, the main result indicates that the more significant the fraction of rational agents, the greater the inequality at the collective level. From social and economic viewpoints, this is an undesirable result since high inequality diminishes liquidity and trade. Besides, with very few exceptions, most agents end up with zero wealth, despite the inclusion of rational behaviour. To deal with this situation, here we include a taxation-redistribution mechanism in the ML algorithm. Previous results show that simple regulations can considerably reduce inequality if agents do not change their behaviour. However, when considering rational agents, different types of redistribution favour risk-averse agents, to some extent. Even so, we find that rational agents looking for optimal wealth can always arrive to an optimal risk, compatible with a particular choice of parameters, but increasing inequality. This article is part of the theme issue 'Kinetic exchange models of societies and economies'.

In vivo imaging of emerging endocrine cells reveals a requirement for PI3K-regulated motility in pancreatic islet morphogenesis.

The three-dimensional architecture of the pancreatic islet is integral to beta cell function, but the process of islet formation remains poorly understood due to the difficulties of imaging internal organs with cellular resolution. Within transparent zebrafish larvae, the developing pancreas is relatively superficial and thus amenable to live imaging approaches. We performed in vivo time-lapse and longitudinal imaging studies to follow islet development, visualizing both naturally occurring islet cells and cells arising with an accelerated timecourse following an induction approach. These studies revealed previously unappreciated fine dynamic protrusions projecting between neighboring and distant endocrine cells. Using pharmacological compound and toxin interference approaches, and single-cell analysis of morphology and cell dynamics, we determined that endocrine cell motility is regulated by phosphoinositide 3-kinase (PI3K) and G-protein-coupled receptor (GPCR) signaling. Linking cell dynamics to islet formation, perturbation of protrusion formation disrupted endocrine cell coalescence, and correlated with decreased islet cell differentiation. These studies identified novel cell behaviors contributing to islet morphogenesis, and suggest a model in which dynamic exploratory filopodia establish cell-cell contacts that subsequently promote cell clustering.

Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? A multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases.

BACKGROUND: Carbapenem-resistant Gram-negative bacilli (CR-GNB) are among the most threatening microorganisms worldwide and carbapenem use facilitates their spread. Antimicrobial stewardship programmes (ASPs) can help to optimize the use of antibiotics. This study evaluates the impact of a multifaceted educational ASP on carbapenem use and on the epidemiology of CR-GNB. METHODS: We conducted a quasi-experimental, time-series study in seven hospitals, from January 2014 to September 2018. The key intervention was composed of educational interviews promoting the appropriate use of carbapenems. The primary endpoints were carbapenem consumption and incidence density (ID) of CR-GNB. All non-duplicated CR-GNB clinical isolates were tested using phenotypic assays and PCR for the presence of carbapenemases. Joinpoint regression and interrupted time-series analyses were used to determine trends. RESULTS: A decrease in carbapenem consumption throughout the study period [average quarterly percentage change (AQPC) -1.5%, P < 0.001] and a -8.170 (-16.064 to -0.277) level change following the intervention were observed. The ID of CR-Acinetobacter baumannii decreased (AQPC -3.5%, P = 0.02) and the overall ID of CR-GNB remained stable (AQPC -0.4%, P = 0.52). CR-GNB, CR-Pseudomonas aeruginosa and CR-A. baumannii IDs per hospital correlated with the local consumption of carbapenems. The most prevalent carbapenem resistance mechanisms were OXA-23 for CR-A. baumannii (76.1%), OXA-48 for CR-Klebsiella pneumoniae (66%) and no carbapenemases for CR-P. aeruginosa (91.7%). The epidemiology of carbapenemases was heterogeneous throughout the study, especially for carbapenemase-producing Enterobacteriaceae. CONCLUSIONS: In conclusion, a multifaceted, educational interview-based ASP targeting carbapenem prescribing reduced carbapenem use and the ID of CR-A. baumannii.

Importance of Enhanced Recovery After Surgery (ERAS) Protocol Compliance for Length of Stay in Ovarian Cancer Surgery.

OBJECTIVES: Enhanced Recovery After Surgery (ERAS) programs include multiple perioperative care elements, which when implemented together are designed to improve recovery after surgery with subsequent reduction in hospital length of stay (LOS). The aim of this study is to examine the impact of ERAS protocol compliance on LOS in patients undergoing advanced ovarian cancer surgery within the context of a randomized clinical trial. METHODS: Patients were enrolled in a prospective, consecutive, interventional randomized clinical trial between June 2014 and March 2018. Women with either suspected or confirmed advanced ovarian cancer with International Federation of Gynecology and Obstetrics (FIGO) stages IIB-IVA and recurrent ovarian cancer, who underwent cytoreduction surgery, were randomly assigned to either a conventional management (CM) protocol or an ERAS protocol. Demographic items, preoperative clinical data, and surgical characteristics of patients were recorded, as were LOS and ERAS protocol compliance. Negative binomial regression was used to model the relation between length of stay and ERAS protocol compliance. RESULTS: We included 49 patients in the CM group and 50 patients in the ERAS group. The overall rate of ERAS compliance was 92%. We observed that increasing ERAS protocol compliance was associated with shorter median LOS, and in patients who underwent higher complex surgeries, the length of stay reduction was greater. CONCLUSION: This study identifies a correlation between increasing ERAS protocol compliance and decreasing LOS in ovarian cancer surgery. This finding underlines the necessity to implement as many ERAS protocol elements as possible to achieve optimal clinical outcome improvements.

M-TRAP: Safety and performance of metastatic tumor cell trap device in advanced ovarian cancer patients.

OBJECTIVE: Despite radical surgery and chemotherapy, most patients with ovarian cancer die due to disease progression. M-Trap is an implantable medical device designed to capture peritoneal disseminated tumor cells with the aim to focalize the disease. This trial analyzed the safety and performance of the device. METHODS: This first-in-human prospective, multi-center, non-blinded, single-arm study enrolled 23 women with high-grade serous advanced ovarian cancer. After primary or interval debulking surgery, 3 M-Trap devices were placed in the peritoneum of the abdominal cavity. 18-months post-implantation or at disease progression, devices were initially removed by laparoscopy. The primary safety endpoint was freedom from device and procedure-related major adverse events (MAEs) through 6-months post-implantation compared to an historical control. The primary performance endpoint was histopathologic evidence of tumor cells capture. RESULTS: Only one major adverse event was attributable to the device. 18 women were free of device and procedure related MAEs (78.3%). However, the primary safety endpoint was not achieved (p = 0.131), primarily attributable to the greater surgical complexity of the M-Trap patient population. 62% of recurrent patients demonstrated tumor cell capture in at least one device with a minimal tumor cell infiltration. No other long-term device-related adverse events were reported. The secondary performance endpoint demonstrated a lack of disease focalization. CONCLUSIONS: The M-Trap technology failed to meet its primary safety objective, although when adjusted for surgical complexity, the study approved it. Likewise, the devices did not demonstrate the anticipated benefits in terms of tumor cell capture and disease focalization in recurrent ovarian cancer.

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19.

BACKGROUND: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. AREAS OF UNCERTAINTY: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. DATA SOURCES: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. THERAPEUTIC ADVANCES: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. CONCLUSIONS: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies' recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working," the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.