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Summary: Background: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). Methods: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). Findings: Sixteen genes showed an association with PDAC risk (FDR

Summary: Targeted genome editing holds great promise in biology. However, efficient genome modification, including gene knock-in (KI), remains an unattained goal in multiple cell types and loci due to poor transfection efficiencies and low target genes expression, impeding the positive selection of recombined cells. Here, we describe a genome editing approach to achieve efficient gene targeting using hard to transfect erythroid cell lines. We demonstrate robust fluorescent protein KI efficiency in low expressed transcription factor (TF) genes (e.g., Myb or Zeb1). We further show the ability to target two independent loci in individual cells, exemplified by MYB-GFP and NuMA-Cherry double KI, allowing multicolor labeling of regulatory factors at physiological endogenous levels. Our KI tagging approach allowed us to perform genome-wide TF analysis at increased signal-to-noise ratios, and highlighted previously unidentified MYB target genes and pathways. Overall, we establish a versatile CRISPR-Cas9-based platform, offering attractive opportunities for the dissection of the erythroid differentiation process.

Summary: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett’s oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

The French National Forest Inventory provides detailed forest information up to large national and regional scales. Forest inventory for small areas of interest within a large population is equally important for decision making, such as for local forest planning and management purposes. However, sampling these small areas with sufficient ground plots is often not cost efficient. In response, small area estimation has gained increasing popularity in forest inventory. It consists of a set of techniques that enables predictions of forest attributes of subpopulation with the help of auxiliary information that compensates for the small field samples.Common sources of auxiliary information usually come from remote sensing technology, such as airborne laser scanning and satellite imagery. The newly launched NASA’s Global Ecosystem Dynamics Investigation (GEDI), a full waveform Lidar instrument, provides an unprecedented opportunity of collecting large-scale and dense forest sample plots given its sampling frequency and spatial coverage. However, the geolocation uncertainty associated with GEDI footprints create important challenges for their use for small area estimations.In this study, we designed a process that provides NFI measurements at plot level with GEDI auxiliary information from nearby footprints. We demonstrated that GEDI RH98 is equivalent to NFI dominant height at plot level. We stressed the importance of pairing NFI plots with nearby GEDI footprints, based on not only the distance in between but also their similarities, i.e., forest heights and forest types. Subsequently, these NFI-GEDI pairs were used for small area estimations following a two-phase sampling scheme. We showcased that, with an adequate sample size, small area estimation with GEDI auxiliary data can improve the accuracy of forest volume estimates.

The ever-increasing availability of remote sensing data allows production of forest attributes maps, which are usually made using model-based approaches. These map products are sensitive to various bias sources, including model extrapolation. To identify, over a case study forest, the proportion of extrapolated predictions, we used a convex hull method applied to the auxiliary data space of an airborne laser scanning (ALS) flight. The impact of different sampling efforts was also evaluated. This was done by iteratively thinning a set of 487 systematic plots using nested sub-grids allowing to divide the sample by two at each level. The analysis were conducted for all alternative samples and evaluated against 56 independent validation plots. Residuals of the extrapolated validation plots were computed and examined as a function of their distance to the model calibration domain. Extrapolation was also characterized for the pixels of the area of interest (AOI) to upscale at population level. Results showed that the proportion of extrapolated pixels greatly reduced with an increasing sampling effort. It reached a plateau (ca. 20% extrapolation) with a sampling intensity of ca. 250-calibration plots. This contrasts with results on model’s root mean squared error (RMSE), which reached a plateau at a much lower sampling intensity. This result emphasizes the fact that with a low sampling effort, extrapolation risk remains high, even at a relatively low RMSE. For all attributes examined (i.e., stand density, basal area, and quadratic mean diameter) estimations were generally found to be biased for validation plots that were extrapolated. The method allows an easy identification of map pixels that are out of the calibration domain, making it an interesting tool to evaluate model transferability over an area of interest (AOI). It could also serve to compare “competing” models at a variable selection phase. From a model calibration perspective, it could serve a posteriori, to evaluate areas (in the auxiliary space) that merit further sampling efforts to improve model reliability.

Summary: Background: Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions. Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to both European Center for Diseases Control (ECDC) criteria for COVID-19 (ECDC+ or ECDC-) and serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on persistent symptoms and its indirect effect via the initial clinical presentation. Findings: The analysis was performed in 25,910 participants. There was a higher risk of persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47–10.42], 1.69 [1.07–2.6] and 1.48 [1.05–2.07], respectively). Abdominal pain, sensory symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24–0.96], 0.40 [0.16–0.85], and 0.69 [0.49–0.95], respectively). The mediation analysis revealed that the association of the serological test results with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50–107%). Conclusion: A greater risk of persistent dysgeusia/anosmia, dyspnea and asthenia was observed in SARS-CoV-2 infected people. The initial clinical presentation substantially drives the association of positive serological test results with persistent symptoms. Funding: French National Research Agency

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior.

Macroporous polymeric monoliths were prepared using, as main raw material, mixtures of hydrolysable and condensed tannins and Kraft black liquor from pulp industry. The process consists of mechanical frothing of aqueous solutions constituted with the different polyphenols, a hardener, and in the presence of a surfactant that maintains the foam stable before curing. The aim of this work was to study the contribution in the formulations of Kraft black liquor on physical properties for the foams. This objective was justified by the significantly lower cost of black liquor as compared with that of tannins. The target application is the thermal and sound insulation in the building industry. The materials obtained were characterized by scanning electronic microscopy, mercury porosimetry and mechanical, thermal and acoustical measurements.Solid, self-standing foams with an average porosity of 90% and an average cell diameter between 170 and 329 μm were obtained. The measured values of compression modulus ranged from 1.8 up to 21.6 MPa and the thermal conductivity was around 40 mW·K−1 m−1. The materials showed also good sound absorption characteristics at medium frequencies with coefficients of 0.5 (500 Hz) and 0.8 (1000 Hz) and at high frequencies with coefficients of 0.7 (2000 Hz) and 0.8 (4000 Hz). Keywords: Kraft black liquor, Tannins, Biobased porous materials, Physical characterizations

Background Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame—that is, compatible with the clinical pathway—is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli).Methods Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié’s Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified.Results Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days.Conclusion Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.

Genetic variations contribute to phenotypic individual vulnerabilities to sleep debt, particularly for five single nucleotide polymorphisms (SNPs). Loop-mediated isothermal amplification and melting curve analysis (LAMP-MC) is a recently developed method to characterize SNPs. The aim of present study was to evaluate the LAMP-MC method on blood and buccal cells for detection of five SNPs of interest in healthy humans.We first analyzed signals obtained from LAMP-MC method on 42 samples. Then we compared the results with those of referent TaqMan method.The LAMP-MC method produced specific melting curves for the five SNPs. A high concordance of genotyping results was observed between the two methods for rs5751876_ADORA2A, rs1800629_TNF-α, rs73598374_ADA and rs228697_PER3 in blood and saliva (Cohen’s kappa coefficient >0.80). A good agreement ( = 0.61) was observed for rs4680_COMT in blood only.LAMP-MC is a simple and reliable method to study genetic influences on health, sleep debt-related performance impairments and countermeasures.

Summary: In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity. : Lourenço et al. demonstrate that burst firing of layer 5 pyramidal neurons (PNs) induces long-term potentiation of inhibition (LTPi). LTPi strongly affects PN input/output spikes, prevents transfer of information across cortical layers, and affects phase locking of PN firing to cognition-relevant rhythmic activity. Keywords: neocortex, GABAergic plasticity, PV cells, gamma oscillations, E/I ratio, feedforward inhibition, layer 5

The interest in studying addictive use of online sexual activities (OSA) has grown sharply over the last decade. Despite the burgeoning number of studies conceptualizing the excessive use of OSA as an addictive disorder, few have tested its relations to impulsivity, which is known to constitute a hallmark of addictive behaviors. To address this missing gap in the literature, we tested the relationships between addictive OSA use, impulsivity traits, and affect among a convenience sample of men (N = 182; age, M = 29.17, SD = 9.34), building upon a theoretically driven model that distinguishes the various facets of impulsivity. Results showed that negative urgency (an impulsivity trait reflecting the tendency to act rashly in negative emotional states) and negative affect interact in predicting addictive OSA use. These results highlight the pivotal role played by negative urgency and negative affect in addictive OSA use, supporting the relevance of psychological interventions that focus on improving emotional regulation (e.g., to reduce negative affect and learn healthier coping strategies) to mitigate excessive use of OSA.

While addictions to substances such as alcohol, tobacco, and other drugs have been extensively investigated, interest has been growing in potential non-substance-related addictive behaviors (e.g., excessive gambling, buying or playing video games). In the current study, we sought to determine the prevalence and characteristics of a wide range of addictive behaviors in a general population sample and to identify reliable subgroups of individuals displaying addictive behaviors. Seven hundred seventy participants completed an online survey. The survey screened for the presence and characteristics of the main recognized substance and behavioral addictions (alcohol, tobacco, cannabis, other drugs, gambling, compulsive shopping, intensive exercise, Internet and mobile phone overuse, intensive work involvement, and overeating) in a three-month period. Key aspects of addiction were measured for each reported behavior, including negative outcomes, emotional triggers (positive and negative emotional contexts), search for stimulation or pleasure, loss of control, and cognitive salience. Latent class analysis allowed us to identify three theoretically and clinically relevant subgroups of individuals. The first class groups problematic users, i.e., addiction-prone individuals. The second class groups at-risk users who frequently engage in potentially addictive behaviors to regulate emotional states (especially overinvolvement in common behaviors such as eating, working, or buying). The third class groups individuals who are not prone to addictive behaviors. The existence of different groups in the population sheds new light on the distinction between problematic and non-problematic addiction-like behaviors.

Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies.

The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE ɛ4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT+TT)=1.3, 95% CI 1.0–1.6, p=0.09) and the G allele frequency (OR=1.3, 95%CI 1.0–1.6, p=0.05) in ɛ4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.

Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.

Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimer's disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence. Based on these data, we postulated that genetic variation in the related and brain-specific ABCA2 gene leads to increase risk of AD. A large case–control study was conducted where the sample was randomly divided into a hypothesis-testing sample (230 cases/286 controls) and a validation sample (210 cases/233 controls). Among the 45 SNPs we tested, one synonymous SNP (rs908832) was found significantly associated with AD in both samples. Additional analyses performed on the whole sample showed a very strong association between this marker and early-onset AD (OR = 3.82, 95% C.I. = [2.00 – 7.30], P = 5 × 10−5). Further research is needed to understand the functional role of this polymorphism. However, together with the reported associations of AD with APOE, CYP46A1 and ABCA1, the present result adds a very significant support for the role of cholesterol and phospholipid homeostasis in AD and a rationale for testing novel cholesterol homeostasis-related therapeutic strategies in AD.

We report 4 cases of off-pump ascending aorta wrapping combined with ascending aorta stenting in retrograde Stanford A acute aortic dissection (SAAD). Since 2008, 18 patients have undergone wrapping of the ascending aorta at our institution. Four patients had a persistent circulating false lumen in the ascending aorta after wrapping, with a threat to the aortic root. We chose an endovascular approach with ascending aorta stenting. Follow-up computed tomography showed a reapplication of the intimal flap in the reinforced aorta. Ascending aorta stenting after aortic wrapping for retrograde SAAD is a safe and efficient technique to prevent proximal progression of the dissection., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Destructive aortic valve endocarditis is a serious condition that can result in aortoventricular disjunction. The appropriate surgical approach for severe excavating lesions remains a matter of debate. Homografts, prosthetic valves associated with a pericardial patch for annulus repair, and prosthetic valve conduits can be used. We report the technical issue of subcoronary inclusion of the full root Freestyle xenograft for complicated aortic endocarditis extending to the left ventricular outflow tract., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Conventional surgical treatment of Stanford type A acute aortic dissection (AAD) is associated with considerable in-hospital mortality. As regards very elderly or high-risk patients with type A AAD, some may meet the criteria for less invasive surgery likely to prevent the complications associated with aortic replacement., Methods: We have retrospectively analyzed a cohort of patients admitted to our center for Stanford type A AAD and having undergone surgery between 2008 and 2012. The outcomes of the patients having had an aortic replacement under cardiopulmonary bypass (group A) have been compared with the outcomes of the patients who underwent off-pump wrapping of the ascending aorta (group B)., Results: Among the 54 patients admitted for Stanford type A AAD, 15 with a mean age of 77 years [46 to 94] underwent wrapping of the aorta. Regarding the new standard European system for cardiac operative risk evaluation (EuroSCORE II), the median result in our group B patients was 10.47 [5.02 to 30.07]. In-hospital mortality was 12.80% in group A and 6.6% in group B (p=0.66). For patients who underwent external wrapping of the ascending aorta, follow-up mortality rate was 13.3% with a median follow-up of 15 months [range 0 to 47]., Conclusions: The gold standard in cases of Stanford type A AAD consists of emergency surgical replacement of the dissected ascending aorta. In some cases in which the aortic root is not affected a less invasive surgical approach consisting of wrapping the dissected ascending aorta can be suggested as an alternative., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report the case of a man presenting with a Pierre Marie-Bamberger syndrome. This paraneoplastic syndrome revealed an undifferentiated intracardiac sarcoma. This case emphasizes the need for multimodality imaging to characterize intracardiac tumor., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

We describe our surgical technique to manage a small aortic annulus during aortic valve replacement. Starting with the posterior annular enlargement incision described by Manouguian, a stentless porcine aortic root, with excision of the left and right porcine coronary segments and conservation of the mural wall (Freestyle MS design, Medtronic, Minneapolis, MN ), was used. The Freestyle bioprosthesis enlarges the aortic annulus using a direct suture of the valve on the enlarged annulus, and the aorta is closed by a direct suture of the mural wall of the bioprosthesis. Therefore, the aortic annulus enlargement is made only using the aortic bioprosthesis, without other material., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Heart patients who have undergone a coronary bypass may present with renewed myocardial ischemia, often connected with bypass dysfunction. The saphenous bypass is the most frequently implicated, and palliative revascularization may be envisaged, either by further bypass surgery, or by angioplasty. The latter approach has been developed since the beginning of the 1980s, and since that time there has been considerable technical and pharmacological progress in performing this type of graft. However the indications for angioplasty and its comparison with reoperation remain controversial. In the present study, it therefore seemed pertinent to include the respective opinions of two experts in the field of angioplasty and coronary bypass surgery.

Background: The purpose of this study was to determine whether, with appropriate techniques, diabetic patients could benefit from the advantages of double internal thoracic artery (ITA) coronary bypass without an increased hospital risk., Methods: Between January 1990 and December 1996, 207 consecutive diabetic patients underwent coronary artery bypass graft operations. In 74 patients both arteries (bilateral ITA group) were used, whereas 133 patients received one ITA and vein grafts or vein grafts alone (nonbilateral group). Patients in the bilateral ITA group were younger (p<0.0001), predominantly male (p<0.0001), and were operated on more electively. The internal thoracic arteries were harvested by skeletonization without electrocautery, and strict glycemic control was pursued., Results: No death was observed in the bilateral ITA group, whereas 7 patients died in the nonbilateral ITA group (p<0.05). Deep sternal wound infection was observed in 2 patients in the nonbilateral ITA group (1.5%) and in none of the bilateral ITA group (p = NS). There was no significant difference in the morbidity rate between the two groups except for greater blood losses in the bilateral ITA group., Conclusion: Double ITA coronary revascularization in young diabetic patients was performed without increased morbidity and mortality. The low rate of sternal wound infections may be related to ITA harvesting by a skeletonization technique, but larger studies are required to confirm these data.

Coronary vein grafts are frequently become occluded or develop atherosclerotic lesions in the long-term. In contrast, the internal mammary artery has a very satisfactory long-term patency rate. The use of an internal mammary artery on the LAD consequently increases the benefit of coronary surgery. The benefit of using 2 internal mammary arteries or other arterial grafts for coronary artery bypass surgery is more controversial. The advantages and disadvantages of the various coronary artery grafts are reported together with the clinical experience of several teams in this area. Coronary artery surgery should be reserved to patients with a good general condition, who are likely to benefit from this type of revascularization. The right internal mammary artery is unsuitable for revascularization of the right coronary network and the two internal mammary arteries must be used to revascularize the left coronary network, in order to obtain a good result. However, surgeons must be aware of the limitations of coronary artery surgery and these techniques should be used cautiously.

Background: Although hemodynamic stability and renal function are important and are monitored closely in patients with implanted left ventricular assist devices (LVAD), the gastrointestinal tract may be underestimated in the early postoperative period with regard to adequate perfusion. We investigated renal, intestinal, and whole body metabolic changes in response to variations in LVAD flow and inspired oxygen concentration (FiO2)., Methods: Left ventricular assist devices were implanted in 10 adult pigs (weight, 55 +/- 1.76 kg). Renal vein (RV), superior mesenteric vein (SMV), and pulmonary artery (PA) blood oxygen saturation and lactate concentration were measured and used as tissue perfusion markers. These measurements were made at baseline and after changes in LVAD flow or FiO2., Results: Oxygen saturation in the PA, SMV, and RV decreased significantly after a reduction in LVAD flow (P < 0.05), with a greater reduction in the SMV than in the PA and RV (p < 0.05 at LVAD flow 3.5L/min; p < 0.01 at LVAD flow 2.0 and 1.0 L/min). The lactate concentration in the PA and SMV increased significantly (p < 0.01) with decreased flow, with a greater increase in the SMV than in the PA (p< 0.05), whereas it remained unchanged in the RV. Oxygen saturation in the PA, SMV, and RV decreased significantly after a reduction in FiO2 (p < 0.05). Lactate concentration in the PA, SMV, and RV increased significantly at FiO2 of 0.10 (p < 0.05). Lactate concentration in the PA and SMV was significantly higher than that in the RV at Fi)2 of 0.10 (p < 0.01)., Conclusions: The results show that the gastrointestinal tract is at high risk during low perfusion or low FiO2, whereas the kidneys' metabolic function appears to be less disturbed. In clinical practice, this emphasizes the need to ensure adequate blood flow and respiratory function, especially after extubation, in patients with implanted LVAD. This might avoid intestinal ischemia and subsequent endotoxemia. Gastrointestinal tonometry may help in the assessment of intestinal perfusion.

Background: Optimal timing of implantation of a mechanical circulatory support system in the treatment of acute cardiogenic shock is still unsettled. The issue has been addressed in a retrospective analysis of a group of 98 patients in cardiogenic shock refractory to medical therapy who were candidates for cardiac transplantation, admitted from 1987 to 1994., Methods: The treatment included reinforced inotropic support by addition of phosphodiesterase inhibitors to sympathomimetic agents. The patients who did not improve were immediately brought to the operating room for mechanical circulatory support system implantation., Results: The overall survival in the group of 28 patients selected for mechanical bridge is 50%. No predictive factors of death or multiorgan failure while on the device could be identified, suggesting a lack of contraindications to mechanical circulatory support system implantation., Conclusions: The high death rate in patients maintained on medical therapy because of initial improvement as they are awaiting transplantation suggests the benefit of a rapid semielective implantation of an intracorporeal device.

Background: Histologic changes in cardiac allografts resulting from fibrosis or acute rejection can modify ventricular diastolic function and ventricular inflow characteristics. These abnormalities may be detected by color M-mode Doppler echocardiography which has been shown to be sensitive in assessing ventricular diastolic function., Methods: Twelve cardiac allograft recipients were prospectively studied with serial color M-mode and single-gated Doppler echocardiography, as well as with endomyocardial biopsy, with a follow-up of approximately 10 weeks. The myocardial interstitial collagen content as evaluated by videodensitometry was compared with right and left ventricular late filling termination times measured in the absence of a severe episode of rejection., Results: A positive and significant correlation was found between the collagen content and the corresponding right ventricular late filling termination time (r = 0.89, p < 0.0001), but no correlation was found with the left ventricular late filling termination time. Moreover, variations in collagen content and variations in right ventricular late filling termination time were also highly correlated (r = 0.91, p < 0.0001). In allograft recipients who had episodes of rejection of grade 3A or greater, both right and left ventricular late filling termination times were significantly increased during rejection., Conclusions: Measurements of right ventricular late filling termination time by color M-mode Doppler echocardiography performed in the absence of acute rejection can be use to monitor the evolution of interstitial collagen content in cardiac allografts. The early detection of abnormally prolonged late filling termination time could be followed by endomyocardial biopsy to confirm the histologic changes.

In 6 pigs, a 14F Hemopump was placed through the pulmonary artery into the right ventricle. The pulmonary artery was banded proximal to the outflow port of the Hemopump, and tightening the band increased right ventricular peak systolic pressure by 50%. There were significant falls in right ventricular stroke volume (from 43 +/- 7.3 mL [+/- the standard deviation] to 27 +/- 8.0 mL; p < 0.001) and cardiac output (from 4.94 +/- 0.76 L/min to 3.70 +/- 0.95 L/min; p < 0.01) and increases in right ventricular peak systolic pressure (from 28 +/- 9.7 mm Hg to 42 +/- 17.1 mm Hg; p < 0.01) and end-diastolic pressure (from 2 +/- 0.8 mm Hg to 12 +/- 6.4 mm Hg; p < 0.02). Mean aortic pressure fell (from 65 +/- 29.9 mm Hg to 61 +/- 9.6 mm Hg; p < 0.01), but systemic vascular resistance was unchanged, thus indicating a fall in left ventricular output reflected by a decrease in mixed venous oxygen saturation (from 60% +/- 8.9% to 47% +/- 7.6%; p < 0.01). After 15 minutes with the Hemopump at maximum speed, these variables returned to control levels (stroke volume, 38 +/- 4.5 mL; cardiac output, 4.50 +/- 0.63 L/min; right ventricular peak systolic pressure, 29 +/- 8.3 mm Hg; right ventricular end-diastolic pressure, 4 +/- 2.0 mm Hg; mean aortic pressure, 72 +/- 10.4 mm Hg; mixed venous oxygen saturation, 56% +/- 4.6% [all, p = not significant versus controls]).(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to assess whether acute rejection affects myocardial energy content of the human orthotopically transplanted heart. Adenosine triphosphate content was measured in one tissue sample obtained during 46 routine right ventricular endomyocardial biopsies 6 to 455 days (98 +/- 110) after transplantation in 19 cyclosporine-treated transplant recipients. Tissue samples were immediately frozen in liquid nitrogen within 10 seconds after excision. Adenosine triphosphate analysis was performed with high performance liquid chromatography. Three groups of biopsy specimens were classified according to the standardized cardiac biopsy grading system. Group 1: Eight biopsy specimens without rejection; group 2: 24 biopsy specimens with mild rejection; group 3: 14 biopsy specimens with moderate or severe rejection. Graft systolic function evaluated by echocardiographic fractional shortening was in the normal range the day of biopsy. All patients had normal coronary angiograms within 1 month of the study. In the presence of mild rejection (grade 1A or 1B), adenosine triphosphate content was not significantly different from that of nonrejecting hearts (26.15 +/- 7.1 and 28.57 +/- 8.23 nmol/mg protein, respectively). By contrast, a significant decrease in adenosine triphosphate content was observed when moderate or severe rejection with focal or diffuse aggressive infiltrates were present (10.46 +/- 4.11 nmol/mg protein; p < 0.01 versus two other groups). In seven cases, sequential analysis showed a significant increase in adenosine triphosphate content after rejection therapy concomittant with histologic improvement: 10.19 +/- 2.9 before and 30.13 +/- 7.0 nmol/mg protein after treatment (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Implantation of the wearable Novacor electrically powered left ventricular assist system was performed on March 16, 1993, in a 44-year-old man hospitalized for an acute episode of myocardial decompensation after a 6-year history of dilated cardiomyopathy. He was rehabilitated fully and became ambulatory, awaiting a suitable cardiac graft for 59 days. He is now back to work, enjoying a normal life. This case illustrates the progress made by miniaturization of the external components of the system. General acceptance of the system and psychological adaptation to the new way of life were remarkable.

Isolated aortic (n = 107), mitral (n = 63), and tricuspid (n = 1) valve replacement and 28 double-valve replacements were performed with a second generation of pericardial valves, the Mitroflow valve, in 199 patients from March 1983 to December 1986. Follow-up (total, 1,058 patient-years) was extended to 106 months and 91.5% complete. Mean age was 58 +/- 13 years. The operative mortality included 22 deaths, non-cardiac-related in 7. The actuarial probability of survival for all patients was 66% +/- 4% at 8.5 years. There were no significant differences between patients with aortic valve replacement, mitral valve replacement, or double-valve replacement. The rate of thromboembolic events, antithromboembolic therapy-related hemorrhage, periprosthetic leak, and endocarditis is extremely minimal. Structural valve dysfunction occurred at a rate of 3.2% +/- 0.5%/patient-year. Actuarial freedom from the event was 94.6% +/- 1.7% at 5 years and 63.7% +/- 6.5% at 8.5 years for all valves. There were no difference in structural valve dysfunction rate between patients having aortic, mitral, or double-valve replacement. Thirty-five patients were reoperated on (3.4 +/- 0.6%/patient-year for all). The rate of all valve-related morbidity and mortality was 5.6% +/- 0.7%/patient-year for all patients, actuarial freedom from the event being 44% +/- 7% at 8.5 years. These data suggest that the excellent hemodynamic characteristics of the valve are balanced by a risk of valve failure that is slightly increased when compared with porcine valves.

The aim of the present study was to determine the long-term status of the native aortic valve after surgical treatment of acute aortic dissection involving the ascending aorta. From 1972 to 1991, 93 patients underwent operation for type I or II aortic dissection. There were 76 men and 17 women. Mean age was 54 +/- 13 years. Eighty patients (86%) had a conservative procedure regarding the aortic root and aortic cusps: 74 had prosthetic replacement of the ascending aorta and 6, complete replacement of the aortic arch. Thirteen patients (14%) had simultaneous replacement of the aortic valve and the ascending aorta. The overall hospital mortality rate was 29% (27/93). The overall actuarial survival rate was 60.2% +/- 5.2%, 49.7% +/- 6.1%, and 35.9% +/- 8.1% at 5, 10, and 15 years, respectively. The survival rates for patients who had an ascending aortic procedure only were 63% +/- 5.5%, 54% +/- 6.5%, and 39% +/- 8.5% at 5, 10, and 15 years, respectively, and for patients who required aortic valve replacement, 45% +/- 14% and 22% +/- 17.5% at 5 and 10 years, respectively. Fifty long-term survivors (94% follow-up) with preservation of the aortic valve and aortic root were studied. Among them, 9 (18%) died within a mean interval of 97 +/- 46 months after operation. Causes of death were ischemic cardiac failure (2), aortic rupture or extension of dissection (4), renal disease (1), stroke (1), and sudden death (1). Forty-one patients had long-term clinical and echocardiographic evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Addition of intravenous enoximone to sympathomimetic agents permits a rapid and drastic improvement in the clinical and hemodynamical condition of patients in cardiogenic shock referred for a mechanical bridge to transplantation. The present experience, based on the management of 52 patients, permits us to point out the current limitations of this pharmacological bridge: the rate of sudden death, the incompleteness of the physical rehabilitation of the patients, and the vanishing effect of intravenous enoximone.

The Hemopump, a catheter-mounted left ventricular assist device, has been demonstrated to be effective in supporting patients with potentially reversible cardiac failure. The mechanism of recovery of the hearts with this device is not fully understood. The effects of the Hemopump on hemodynamics and coronary blood flow with and without myocardial ischemia and failure have been studied in 8 anesthetized open-chest dogs. Coronary blood flow in the left circumflex artery was assessed with an intracoronary Doppler catheter. Myocardial ischemia was induced by ligation of the left anterior descending and diagonal branches. The effects of maximum support were compared with those of minimum support. The effects of the Hemopump varied according to cardiac function. When cardiac dysfunction was mild, the Hemopump support slightly reduced myocardial O2 demand (assessed by pressure-work index) by volume unloading. When cardiac dysfunction was severe, total bypass was achieved and myocardial O2 demand decreased by 45%, owing to both volume and pressure unloading. Coronary blood flow was incompletely auto-regulated, and the ratio of blood flow to O2 demand increased.

From 1973 to 1989, 66 patients received early surgical repair for acute postinfarction ventricular septal rupture. Mean age was 64 +/- 7 years (range, 45 to 80 years). Ventricular septal rupture occurred soon after acute myocardial infarction (3.4 +/- 4 days), and the first medical treatment occurred 6.7 +/- 7 days after onset of acute myocardial infarction. Three patients had a previous myocardial infarction. The site of the rupture was anterior in 38 patients (57%) and posterior in 28 (43%). Forty-four patients (67%) were in shock at the time of admission. Intraaortic balloon pumping was used preoperatively in 28. Operation was performed at the time of maximal efficacy of medical treatment. The same technique was used in all cases. Associated procedures included coronary bypass grafting in 5 patients and valvar operation in 5. The patients have been carefully followed up for up to 16 years. Hospital mortality was 45% (30 patients) and was cardiac related or due to acute renal failure in 25 patients (83%). No correlation could be revealed between early death and age, sex, preoperative intraaortic balloon pumping, or year of operation. Location of the ventricular septal rupture (early mortality of 57% for posterior versus 37% for anterior ventricular septal rupture) and shock at the time of admission (52% versus 32%) showed a trend toward significance (0.08 less than or equal to p less than 0.10). Response to initial active therapy has a strong predictive value (mortality of 70% in unresponsive patients versus 14% in responders; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

This case report describes a patient with massive pulmonary embolism and acute circulatory failure in whom transesophageal echocardiography permitted the diagnosis of thrombi in the main pulmonary truncus and in the right branch and guided intraoperatively the surgical embolectomy performed under simple venous inflow occlusion because of a contraindication to heparin administration. Transesophageal echocardiography seems to be a very helpful technique to diagnose promptly massive pulmonary embolism and a very useful tool at the time of operation to guide the embolectomy.

From 1981 to 1989, 60 patients more than 80 years of age were referred for operation for severe calcific aortic stenosis. All patients were symptomatic: 13 in New York Heart Association (NYHA) functional class II, 28 in class III, and 19 in class IV. The preoperative mean cardiothoracic ratio was 0.58 +/- 0.09; the mean valve area, 0.52 +/- 0.14 cm2; and the mean aortic valve gradient, 62 +/- 18 mm Hg. Left ventricular function was impaired in 30 patients (ejection fraction less than 0.40). Coronary arteriography was performed in 10 patients. Aortic replacement used bioprosthesis in all 60 patients associated with aortocoronary bypass (in 5) and mitral valve replacement (in 1). One-month mortality rate was 28% (17 patients) due to cardiac failure (in 9), pulmonary complications (in 6), and neurological complications (in 2). Early mortality was not correlated with preoperative angina, cardiothoracic ratio, associated operation, and cross-clamping time. It was not obviously correlated with preoperative functional class but correlated positively with urgent operations and with left ventricular function (40% mortality in patients with ejection fraction less than 0.40 versus 16% mortality in others). Hospital morbidity was 68%. Mean hospitalization was 15 +/- 7 days. There were four late deaths. Thirty-nine patients are long-term survivors (3 months to 7 years): 27 in class I, 10 in class II, and 2 in class III due to primary valve failure. The actuarial survival probability is 65% at 1 year and 61% at 5 years. In summary, the good long-term quality of life justifies the high postoperative risk in octogenarians. Early operation before cardiac function impairment improves the results.

Immediate cardiac transplantation, or urgent implantation of devices for mechanical support of the failing heart, has been shown to be effective as life-saving procedures in patients with cardiogenic shock unresponsive to maximal sympathomimetic treatment. The intravenous administration of enoximone in these patients, in addition to previous inotropic support, should permit a 'buying of time' strategy, leading to a reduction in the need for complex, invasive and costly techniques, such as artificial hearts. In addition, it should permit improved selection of candidates for cardiac transplantation. A prospective study was started in 1985 to obtain data on the haemodynamic and clinical efficacy of intravenous enoximone in these critically ill patients, and to determine the time gained for evaluation of the need for urgent transplantation. Cardiac index rose from 1.82 +/- 0.26 litres/minute/m2 to 2.67 +/- 0.56 litres/minute/m2 after 30 minutes, while pulmonary capillary wedge pressure decreased from 29.9 +/- 7 mm Hg to 18.0 +/- 7 mm Hg (n = 30). This early beneficial effect waned progressively after 6 hours. Prior to the next intravenous infusion at 8 hours, cardiac index was 2.07 +/- 0.53 litres/minute/m2 and pulmonary capillary wedge pressure was 25 +/- 8.5 mm Hg. Only four patients could not wait for a biological graft and had to be implanted with a complete artificial heart (3 patients), or a ventricular assist device (1 patient). In all, 30 patients improved and their increased survival allowed a re-evaluation for cardiac transplantation itself; 13 were rapidly (1.7 days; range 0.5-5) confirmed as good candidates. As a whole, this strategy compares favourably with the results of a strategy based on mechanical bridging alone.

We report seven cases of dissection of the abdominal aorta. Three patients had acute back pain, whereas four patients had more chronic courses. In six cases, as a result of the palpation of a pulsatile abdominal mass, clinical diagnosis was an atheromatous aneurysm. Angiography and CT scanning demonstrated a dissected abdominal aorta and a normal thoracic aorta. Six patients with an infrarenal dissection were treated by replacement of the aorta with a Dacron prothesis, and one patient with an suprarenal dissection was treated conservatively. With a mean follow-up of 3 years, all patients were alive and free of symptoms. These results favor graft replacement in case of infrarenal aortic dissection and more selective surgical indications in suprarenal aortic dissection.

The 'Hemopump', an axial flow pump, when inserted in the left ventricle brings about mechanical unloading of the ventricle, thus reducing the risk of cardiac arrest during coronary angioplasty. In this study eight very ill patients with unstable myocardial ischaemia and various contraindications for coronary artery surgery were selected for coronary angioplasty with insertion of the hemopump. Anatomical difficulties prevented insertion in three patients, but coronary angioplasty was carried out successfully with the pump in place in the other five. When the pump was working the cardiac index rose by an average of 23% (8-50%) and the pulmonary capillary wedge pressure fell by 17% (0-22%). Though electrocardiographic monitoring showed temporary rhythm instability during angioplasty in four of the five patients, there was no clinical deterioration. Four of the five patients are symptom-free on medical treatment and the other is well after surgical revascularisation.

A 56-year-old woman was admitted to the Emergency Department for profuse diarrhoea, associated with hypokaliemia and dehydration. A subclavian venous catheter was inserted after she had a cardiac arrest. Six days later, the subclavian and innominate veins were thrombosed. Prophylactic low molecular weight heparin was then replaced by sodium heparinate. The patient's platelet count decreased to 65 G.1-1. It was nevertheless decided to remove her villous tumour. After the operation, the patient became shocked, with worsening thrombocytopaenia (15 G.1-1). She was unresponsive to fluid replacement. Transoesophageal echocardiography (TEE) was carried out, as pulmonary arterial catheterization was considered too dangerous. A "white" thromboembolus was discovered in the right pulmonary artery. Embolectomy was successfully performed without extracorporeal circulation. Flow was completely restored in the main pulmonary artery, but only partially in the right branch. Oral anticoagulation was started postoperatively. It is concluded that TEE might be a very helpful technique to promptly diagnose acute pulmonary embolism; moreover, it could be an alternative to pulmonary angiography, especially in patients in a poor state.

A prospective study was undertaken in a multidisciplinary intensive care unit to determine the proportion of complications due to anticoagulant therapy, to evaluate their severity and to estimate what proportion was potentially avoidable. Among 1911 hospitalized patients over a 3 year period, 30 patients had a complication of anticoagulant therapy (1,57 p. 100). The causality was definite in 14 cases, probable in 14 and possible in 2 cases. Nineteen p. 100 were hemorrhagic complications. These iatrogenic illnesses were fatal in 5 cases, life-threatening in 6, moderate in 15 and minor in 4 cases. Potentially avoidable complications accounted for 60 p. 100 of the cases and were due to biological overdosage or interaction between drugs. Our results indicate that some complications of anticoagulant therapy could be reduced or eliminated by medical education and increased information.