BACKGROUND: The benefit of mitral valve repair over replacement in patients with ischemic mitral regurgitation is still controversial. We report our early postoperative outcomes of repair versus replacement. METHODS: Data were collected for patients undergoing first-time mitral valve surgery for ischemic mitral regurgitation between 1990 and 2009 (n = 393). Patients who underwent combined procedures for papillary muscle rupture, post-infarction ventricular septal defect, endocarditis, or any previous cardiac surgery were excluded. Preoperative demographics, operative variables, and hospital outcomes were analyzed, and multivariable regression analysis was employed to identify independent predictors of hospital mortality. RESULTS: Valve repair was performed in 42% (n=164) of patients and replacement in 58% (n=229). Patients who underwent replacement were older and had a higher prevalence of unstable angina, New York Heart Association class IV symptoms, preoperative cardiogenic shock, preoperative myocardial infarction, peripheral vascular disease, renal failure, and urgent or emergency surgery (all p < 0.05). Unadjusted hospital mortality was higher in patients undergoing valve replacement (13% versus 5%, p = 0.01). Valve repair was associated with a lower prevalence of postoperative low cardiac output syndrome. Multivariable analysis revealed that age, urgency of operation, and preoperative left ventricular function were independent predictors of hospital mortality. Importantly, mitral valve repair versus replacement was not an independent predictor of hospital mortality. CONCLUSION: Our data did not suggest an early survival benefit to mitral valve repair over replacement for ischemic mitral regurgitation. However, age, left ventricular dysfunction, and the need for urgent surgery were independently associated with hospital mortality.
Providing complex therapies such as ECMO during outbreaks of infectious diseases has singular challenges. The impact of the SARS-CoV-2 pandemic has implied a mentality change by force of circumstances, and cardiac surgery has not been stranger to this trend. The need to treat critically ill patients with an unknown evolution has compelled cardiovascular surgeons to decide whether or not to implant an ECMO system, despite the limited scientific evidence available in the context of COVID-19. To add some confusion, doubts were raised about its potential deleterious outcome in COVID-19 patients, due to its effect on lymphocyte counts and interleukin-6 concentrations. The care of the critically ill patient in a moment of national emergency in Spain took precedence over those possible formal doubts. The Spanish perspective on Ventricular Assist Devices during and after the COVID-19 pandemic, focused on ECMO as a particular case of mechanical circulatory support, is presented. We address both the challenges posed by the pandemic and the organizational model established in Spain; changes in ECMO therapy and some lessons learned for the next outbreaks are also described. It is not about reinventing the wheel in each country; it is enough to learn from experience and take advantage of the knowledge generated by those who have already gone through similar situations in our environment.
COVID-19 hit hard worldwide. There has been an impact on global activity of cardiac surgery. Spain has been one of the hardest hit countries with one of the highest per population incidences and death. Cardiac surgical activity has suffered a negative impact all over the country. The following is an overview of the epidemiology and impact on resources, the caseload and surgical societal implemented recommendations, the description of the ECMO activity and nosocomial transmission among healthcare workers.
Asymptomatic cardiac neoplasms are often diagnosed incidentally. Right atrial mass close to septum needs careful evaluation and multimodality imaging to manage appropriately. This case highlights the utilization of multimodality imaging and heart team approach in the management of the right atrial mass.
Sphincter reconstruction and stoma in situ is an exploratory surgery for abdominoperineal resection of rectal cancer; its functional outcome is a major concern. This is a rare case of long-term survival with unilateral gluteus maximus fasciculus reconstruction, in a patient with the ability to control defecation and distinguish gas.
Background: Children and adolescents with cancer are at risk of a poor health-related quality of life. Exercise interventions to enhance movement may be a valid strategy for managing some symptoms, including fatigue. Methods: Forty-four consecutive patients (20 females; aged 5-21 years old, median 15.5 years), without any contraindications significantly limiting their movements were invited to join an in-hospital 6-week supervised exercise program, and asked afterwards to complete the PedsQL-4.0 quality of life Generic Core Scales and the PedsQL Multidimensional Fatigue Scale. The program consisted of personalized workout sessions of aerobic, resistance and flexibility exercises. The results obtained on the scales were compared between patients who engaged in the exercise program (GYM group, n=21) and those who did not (No-GYM, n=23), with the aim of examining the different dimensions of health-related quality of life (physical, emotional, cognitive, social) and fatigue (general, sleep/rest, cognitive) comparing the two groups. Results: For 43 of 44 patients, being diagnosed with cancer initially prompted a drop-out from previous physical exercise or sports routines despite no contraindications to their continuation. After 6 weeks, the scores for patients in the GYM group showed a statistically significant better perceived emotional functioning, and a possible indication of improved social functioning compared with the No-GYM group. Conclusion: These findings suggest that to exercise improves the satisfaction of children and adolescents with cancer with their physical, mental and social functioning. It is worth further investigating the value of systematically including exercise workouts in their routine cancer practices.
CPX-351 is a promising new therapeutic option for patients with treatment related (tAML) or secondary acute myeloid leukemia (sAML). It exceeded classic 7+3 therapy in overall survival (OS) and complete remission rates (CR) while providing a similar risk profile. Until now, this sub-group of AML patients had a worse overall
Abstract Background: the survival of Wilms tumor is very low when evaluated in 2008. The impact of establishing pediatric oncology service on survival is studied, and the obstacles of treating Wilms tumor patients were identified. Procedure: All Wilms tumor patients from 2005 to 2014 were analyzed retrospectively. Patients received treatment based on the NWTS IV protocol. Patients were analyzed for overall survival, and event-free survival, and these outcomes were correlated with age, sex, stage at presentation, and histology. Results: We analyzed 143 files of Wilms tumor. The male to female ratio is 1.75. The mean age of patients at diagnosis is 3.5. The follow-up period is five years. Most patients (83%) had advanced disease stage 3, and 4.There is a very high abandonment rate (37%). The event-free survival among patients who completed treatment is 75.6%, and the overall survival is 43.4% Conclusions: There is a remarkable improvement in Wilms tumor survival from 11% to 43 % and 75.6%. Much needs to be done to reduce abandonment rates and establish a surgical pediatric oncology service.
Objective: Antihistamines are among the most prescribed medicines in otorhinolaryngology. This drug is excellent for rhinorrhea, sneezing and itching, however, it has a debatable effect in rhinosinusitis. At this point, it is useful to examine the relationship between antihistamine and the incidence of sinusitis based on large-cohort data analysis. Design: Retrospective study Setting: A Nationwide cohort study which used population-based insurance data (consisting of data from approximately 1 million patients). Participants: The antihistamine (AH) group consisted of patients who were diagnosed with allergic rhinitis (AR) between January 1, 2003 and December 31, 2003, taking at least one dose of antihistamine. Non-antihistamine (non-AH) group of patients who did not take antihistamines was obtained by 1:4 propensity score matching. Main outcome measures: Primary endpoint was the occurrence of sinusitis. Results: The adjusted hazard ratio for the sinusitis in the AH group was 1.53 [95% CI: 1.36-1.72] compared with the non-AH group. Sinusitis was more frequent in women (HR: 1.34), and less frequent the older the age (HR: 0.74, 0.58, 0.46, respectively) after exposure to antihistamine. In the subgroup analysis regarding the AH usage duration, there was no significant difference between the four subgroups. Conclusion: Antihistamines are probably the most prescribed medicines in the rhinologic area. But as all things have advantages and disadvantages, this large-scale longitudinal study shows that antihistamines are closely associated with sinusitis regardless of prescription duration and thus should be cautiously prescribed.
In this study, the binding of multimodal chromatographic ligands to the IgG1 FC domain were studied using nuclear magnetic resonance and molecular dynamics simulations. Nuclear magnetic resonance experiments carried out with chromatographic ligands and a perdeuterated 15N-labeled FC domain indicated that while single mode ion exchange ligands interacted very weakly throughout the FC surface, multimodal ligands interacted with specific clusters of residues with relatively high affinity, forming distinct binding regions on the Fc. The multimodal ligand binding sites on the FC were concentrated in the hinge region and near the interface of the CH2 and CH3 domains. Further, the multimodal binding sites were primarily composed of positively charged, polar and aliphatic residues in these regions, with histidine residues exhibiting some of the strongest binding affinities with the multimodal ligand. Interestingly, comparison of protein surface property data with ligand interaction sites indicated that the patch analysis on FC corroborated molecular level binding information obtained from the nuclear magnetic resonance experiments. Finally, molecular dynamics simulation results were shown to be qualitatively consistent with the nuclear magnetic resonance results and to provide further insights into the binding mechanisms. An important contribution to multimodal ligand-FC binding in these preferred regions was shown to be electrostatic interactions and pi-pi stacking of surface exposed histidines with the ligands. This combined biophysical and simulation approach has provided a deeper molecular level understanding of multimodal ligand-FC interactions and sets the stage for future analyses of even more complex biotherapeutics.
The development of highly productive, genetically stable manufacturing cell lines is on the critical path to IND filing for protein based biologic drugs. Here we describe Leap-In Transpoasase® platform, a novel transposon-based mammalian (e.g. CHO) cell line development system that produces high titer stable pools with productivity and product quality attributes that are highly comparable to clones that are subsequently derived therefrom. The productivity distributions of clones are strongly biased towards high producers and both genetic and expression stability is consistently high. By avoiding the poor integration rates, concatemer formation, detrimental transgene recombination, low average expression level, unpredictable product quality and inconsistent genetic stability characteristic of non-homologous recombination methods, Leap-In provides several opportunities to de-risk programs early and reduce timelines and resources.
The aim of this study was to investigate the effect of rosuvastatin treatment on memory impairment, and anxiogenic-like effects in mice chronically infected with Toxoplasma gondii. For this, Balb/c mice were infected orally with chronic ME-49 strain of Toxoplasma gondii. Oral treatment with rosuvastatin (40mg/kg/day) started on the 51th day post-infection and was performed daily for 21 days. After completion of treatment, anxiety-like effects and locomotion were investigated in the open field (OF) test, whereas novel object recognition (NOR) test was used for evaluation of short- and long-term memory. At the end of the experiments, the brain was collected for Toxoplasma gondii DNA quantification and histopathological analysis. Infection with ME-49 strain decreased the time spent in the center of OF, indicating an anxiogenic effect, without affecting total and peripheral locomotion. Rosuvastatin treatment inhibited the change in the center time. Besides, pharmacological treatment increased total and central locomotion in both non-infected and infected animals. Infection also impaired both short- and long-term memory in the NOR test, and these effects were reverted by rosuvastatin treatment. In addition to effects in behavioral changes, rosuvastatin also reduced parasite load in the brain and attenuated signs of brain inflammation such as perivascular cuffs, inflammatory cell infiltration and tissue damage. These findings indicate for the first time the efficacy of rosuvastatin in treatment of memory impairment and anxiogenic effect evoked by infection with Toxoplasma gondii. These effects might be mediated by reduced cyst load, which in turn decrease inflammation and damage in the brain.
Flux experiments and fluorescence microscopy were combined and optimized to visualize the membrane surface during biofouling of two mixed cellulose ester membranes. Using flux measurements, the fouling by bovine serum albumin (BSA) was measured in the presence of 1 to 12% labeled BSA. By fitting the relative flux decays to an exponential decay for statistical analysis, the dye in this range of labeled protein was found to not affect the fouling nature of the protein. A 2.5% or 5% labeled protein sample was determined to be the best percent labeled protein for fluorescence imaging the membrane because the beginning of cake formation was observed within 25 min of experimental time. Finally, by fitting the flux data to four different biofouling mechanism equations, we conclude that both membranes, though at different rates, have BSA depositing inside the membrane pores restricting the flow eventually leading to cake formation. The combination of the two techniques allows for further insight into the biofouling mechanism of BSA, and this method can be applied to other biological molecules.
To the Editor, Drug provocation test (DPT) is considered the gold standard test to diagnose drug hypersensitivity reactions (DHR), in absence of contraindications. However, it may be very time consuming. The procedure usually consists in the administration of a medication with cautious incremental doses under close medical observation.1-4Vital sign measurements (e.g., blood pressure (BP), pulse) and surveillance of the patient’ symptoms and signs are usually performed several times during the entire procedure to capture and prevent as soon as possible any severe reaction. However, learned societies only set a frame for DPT performance and do not make specific recommendations about the type and rhythm of these measurements.1, 3, 4 In our center, data-driven DPT (i.e., based on patterns of reactions detected through Kaplan Meier curves) is performed in 4-7 step dosing for beta-lactams (BL),5 2-6 steps for nonsteroidal anti-inflammatory drugs (NSAID),6 3-4 steps for paracetamol,7 and 5-7 steps for fluoroquinolones (article in press), with time increments of 30 or 60 minutes (up to 3h for certain NSAID). The BL pattern is generally applied to DPTs for other drugs. Empirically, we considered the measurement of BP and pulse as mandatory and required before starting the DPT, before every incremental dose and at any time during the DPT if symptoms of a DHR occurred. We presumed this would ensure the best safety for patients undergoing DPT, particularly for those with immediate severe reactions, namely anaphylaxis with or without shock. However, the benefit of such an attitude in patients with non-immediate reactions or immediate non-severe reactions could be questioned and to the best of our knowledge, no study has been published on this issue. In addition, measurement of BP during ST is not common practice.During the past two decades of our center experience, based on clinical observation and previous analyses,8, 9 we observed that isolated symptoms and signs evocative of shock during drug allergy work-up are very rare. Patients usually presented those signs in conjunction with symptoms and signs from other systems, including mucocutaneous (CU), respiratory (RS), and gastrointestinal (GI). Therefore, we hypothesized that BP measurement could be reduced in number in some circumstances, according to risk stratification (that we presumed related to the patient’s individual situation and involved drug class). This retrospective analysis was then carried out in order to identify cases with symptoms and signs evocative of shock during drug allergy investigation in our center. The patients (or their parents, in case of children) gave their written informed consent at the time of the allergy work-up for their anonymous data to be used for research purposes.We conducted a retrospective analysis using data retrieved from the Drug Allergy and Hypersensitivity Database (DAHD) between January 1996 and June 2019 in the Allergy Unit of the University Hospital of Montpellier, France. Patients with suspicions of DHR who underwent drug allergy work-up and presented with symptoms and signs evocative of shock during the tests were included in the analysis. The search terms included: “malaise”, “hypotension”, “collapse”, “loss of consciousness”, and “unspecified cardiovascular problem”. Drug allergy work-up including skin test (ST) and DPT was performed according to the European Network of Drug Allergy (ENDA) recommendations.During the study period, 10 198 patients were tested with 53 059 single tests (a single test is defined as ST or DPT for an allergen). A total of 32 patients (0.3%) (9 males, mean age at tests of 37.0 ± 14.9 years) with 36 reactions (0.06%) who presented with the above mentioned cardiovascular (CV) signs/symptoms were identified (31 during DPT, 5 during ST). Antibiotics were the most frequent drug classes involved (47.2%), followed by NSAIDs (13.9%), and paracetamol (13.9%) (Supplementary Table 1 ). Among these reactions, 4 were found to be isolated CV signs/symptoms (3/11000 DPT (0.03%), and 1/42059 ST (0.002%), while CV with other systemic signs/symptoms were present in 32 reactions (88.9%). (Table 1 and Supplementary Text 1) Using retrospective analysis from the DAHD during the past 25 years, we have demonstrated that patients with CV symptoms and signs evocative of a severe immediate DHR (shock) during the drug allergy investigation are rare, namely 0.3% of all tested patients and 0.06% of all single tests. Amongst them, only 4 patients (0.04%) with 4 reactions (0.007%) were found to have isolated CV signs/symptoms. Whether these signs were markers of true DHR could be debatable for patients no. 1 (considering her multiple similar episodes, ruled out by further investigations) and no. 3 , while patient no. 4 developed anaphylactic shock during positive ST to BL drugs (meaning that the systemic symptoms were associated to positivity at the injection site). Therefore, only one case (patient no. 2) could be classified as having isolated CV signs/symptoms as an allergic reaction.Based on this analysis and previous analyses of patterns of reactivity and severity during DPT for different drug classes (e.g., BL, NSAIDs, paracetamol, quinolones), we propose criteria to reduce the frequency of BP measurements during DPT, according to risk stratification based on patient clinical history and drug class. Clinical history could be classified into three categories: immediate severe (high risk), immediate non-severe (low risk), and non-immediate non-severe (low risk) reactions (i.e., severe non-immediate reactions being classical contraindications to DPT).3 Regarding drug class, we based our risk stratification on previous studies tackling patterns of DPT reactions to BL, NSAIDs, paracetamol and quinolones showing that the frequency of anaphylaxis elicited by DPT was 15%, 10%, 25% and 20% respectively.5-7 For NSAIDs, the immediate non-severe reaction (e.g., urticaria, angioedema, rhino-conjunctivitis) is a typical clinical presentation and for such an index reaction, 90% of the positive DPT are benign cutaneous reactions (6). Thus, NSAIDs could be classified as low risk drug class. Therefore, the criteria of BP measurement could be categorized as in Table 2. Regarding our 4 patients with isolated CV symptoms, all of them would’ve been classified in the high-risk groups (patient no. 1 and no. 3 because of index history of immediate severe reaction, patient no. 2 and no. 4 because of the drug class).It could be argued that by reducing the number of CV vital signs measurements, the professional performing the DPT could be distracted from the very core of the allergy work-up, which is ensuring patient safety during the procedures. However, our study shows that isolated CV signs/symptoms are extremely rare during the drug allergy work-up performed according to safety recommendations (i.e., step-wise exposure to allergen). In contrast, the decrease in this technical workload could be beneficial to patients because physicians/nurses would then have more time to concentrate on patient questioning and reassurance during the tests. In addition, the reduction of this measurement could reduce the uncomfortable, or painful feeling of the BP measurement, particularly for young children.To the best of our knowledge, this is the first study specifically addressing the outcome of the BP measurement during drug allergy work-up in an evidence-based manner. Reporting and analyzing the rarity of cases with isolated CV signs/symptoms enabled us to propose 4 frames for BP measurement. In a prospective trial for 1 month, BP frequency could be reduced by 14.3% (range 10.3-26.5), alleviating the technical task and favoring the medical one instead. The prospective evaluation is ongoing in our center.In conclusion, patients with symptoms and signs evocative of shock are extremely rare during drug allergy work-up, therefore BP measurement could be reduced in number according to patient clinical history of DHR and drug class risk stratification.
A novel bioinformatic approach for drug repurposing against emerging viral epidemics like Covid-19 is described. It exploits the COMPARE algorithm, a public program from the NCI to sort drugs according to their patterns of growth inhibitory profiles from a diverse panel of human cancer cell lines. The data repository of the NCI includes the growth inhibitory patterns of more than 55000 molecules. When drugs with purported anti-SARS-CoV-2 activities were used as seeds (e.g., hydroxychloroquine and ritonavir) in COMPARE, the analysis uncovered several drugs with fingerprints similar to the seeded drugs. Interestingly, the uncovered drugs were all reportedly known to exert antiviral activities, confirming that COMPARE analysis is valuable for predicting antiviral drug repurposing. Unlike pure in-silico approaches, this approach is biologically more relevant and able to pharmacologically correlate compounds regardless of their structures. This is an untapped resource, reliable and readily exploitable for drug repurposing against surprising viral outbreaks.
Background and Purpose: The immune system is implicated in the pathogenesis of pathological cardiac hypertrophy (PCH). However, there is currently no therapeutic intervention to prevent PCH. Here, we aimed at preventing pathological cardiac hypertrophy (PCH) during chronic catecholamine stress via modulating adaptive inflammatory by targeting adenylyl cyclases (ACs) and G protein-coupled receptor kinase 5 (GRK5) in cardiomyocytes and immune cells. Experimental Approach: PCH was induced in mice by chronic isoproterenol injections. In vitro, peritoneal macrophages were challenged with lipopolysaccharide under stress. Further experiments employed the therapeutic interventions Amlexanox and Forskolin to inhibit GRK5 and activate ACs-cAMP, respectively. Cardiac functions were assessed with echocardiography. Inflammatory markers were assessed with ELISA and RT-qPCR (in vivo and in vitro). GRK5 localizations in macrophages were assessed by immunofluorescence, and alterations in protein expression were analyzed with immunoblotting. Histological assessments were done with Masson, H&E and IHC staining. Key Results: PCH mice had deteriorating cardiac functions and morphological remodeling, accompanied by massive immune cell infiltrations. Similarities were observed proinflammatory markers upregulation, as were IL-10 found downregulated both in vivo and in vitro. However, the combination of Amlexanox and Forskolin modulated adaptive inflammatory responses and also maintained proper cardiac morphology and function. The single therapies of neither Amlexanox nor Forskolin were able to attain the aforementioned with much efficacy as their combination therapy. Conclusion: The combination therapy of ALX and FSK has the therapeutic potential of preventing the occurrence of pathological cardiac hypertrophy during CCS by modulating adaptive inflammatory responses while maintaining normal cardiac function.
Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage were associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin converting enzyme 2 (ACE2). As a result of SARS-Cov-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1R) axis associated with oxidative stress. This leads to insulin resistance, lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block the AT1R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects helpful in mitigating COVID-19 severity.
Plasticity in salt tolerance can be crucial for successful biological invasions of novel habitats by marine gastropods. The intertidal snail Batillaria attramentaria, which is native to East Asia but invaded the western shores of North America from Japan eighty years ago, provides an opportunity to examine how environmental salinity may shape behavioral and morphological traits. In this study, we compared the movement distance of four B. attramentaria populations from native (Korea and Japan) and introduced (USA) habitats under various salinity levels (13, 23, 33, and 43 PSU) during 30 days of exposure in the lab. We sequenced a partial mitochondrial CO1 gene to infer phylogenetic relationships among populations and confirmed two divergent mitochondrial lineages constituting our sample sets. Using a statistic model-selection approach, we investigated the effects of geographic distribution and genetic composition on locomotor performance in response to salt stress. Snails exposed to acute low salinity (13 PSU) reduced their locomotion and were unable to perform at their normal level (the moving pace of snails exposed to 33 PSU). We did not detect any meaningful differences in locomotor response to salt stress between the two genetic lineages or between the native snails (Japan versus Korea populations), but we found significant locomotor differences between the native and introduced groups (Japan or Korea versus the USA). We suggest that the greater magnitude of tidal salinity fluctuation at the USA location may have influenced locomotor responses to salt stress in introduced snails.