Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry's disease.

Introduction: Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Methods: Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. Results: It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). Discussion: In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.

Wearable pulmonary monitoring system with integrated functional lung imaging and chest sound recording: a clinical investigation in healthy subjects.

Objective.Current wearable respiratory monitoring devices provide a basic assessment of the breathing pattern of the examined subjects. More complex monitoring is needed for healthcare applications in patients with lung diseases. A multi-sensor vest allowing continuous lung imaging by electrical impedance tomography (EIT) and auscultation at six chest locations was developed for such advanced application. The aims of our study were to determine the vest's capacity to record the intended bio-signals, its safety and the comfort of wearing in a first clinical investigation in healthy adult subjects.Approach.Twenty subjects (age range: 23-65 years) were studied while wearing the vests during a 14-step study protocol comprising phases of quiet and deep breathing, slow and forced full expiration manoeuvres, coughing, breath-holding in seated and three horizontal postures. EIT, chest sound and accelerometer signals were streamed to a tablet using a dedicated application and uploaded to a back-end server. The subjects filled in a questionnaire on the vest properties using a Likert scale.Main results.All subjects completed the full protocol. Good to excellent EIT waveforms and functional EIT images were obtained in 89% of the subjects. Breathing pattern and posture dependent changes in ventilation distribution were properly detected by EIT. Chest sounds were recorded in all subjects. Detection of audible heart sounds was feasible in 44%-67% of the subjects, depending on the sensor location. Accelerometry correctly identified the posture in all subjects. The vests were safe and their properties positively rated, thermal and tactile properties achieved the highest scores.Significance.The functionality and safety of the studied wearable multi-sensor vest and the high level of its acceptance by the study participants were confirmed. Availability of personalized vests might further advance its performance by improving the sensor-skin contact.

Treatment of advanced trigger finger by ulnar superficialis slip resection: Long-term outcome and predictive factors for poor prognosis.

The aim of this study was to evaluate the outcome of ulnar superficialis slip resection and to determine predictive factors for poor prognosis in patients with advanced trigger finger. Over a 5-year-period, 55 patients (58 fingers) were included. After surgery, two groups were identified: group 1, with complete extension or <10° extension deficit in the proximal interphalangeal (PIP) joint (n = 27 fingers/27 patients); and group 2, with ≥10° residual PIP extension deficit (n = 31 fingers/28 patients). Factors associated with PIP extension deficit were assessed on logistic regression. There was a median extension gain of 20° (range, 10-30°) after surgery. The difference between pre- and post-operative extension deficits was significant (p < 0.001). There was no significant inter-group difference in DASH score (p > 0.9). Two predictive factors were found: >12 months' preoperative symptom duration (OR = 1.02; p = 0.045), and lack of self-rehabilitation (OR = 20; p < 0.001). Ulnar superficialis slip resection was effective in advanced trigger finger. Hand surgeons should operate early on these patients, and encourage self-rehabilitation. LEVEL OF EVIDENCE: 4.

Bariatric surgery in liver cirrhosis.

Introduction: Obesity is frequently associated with its hepatic manifestation, the nonalcoholic fatty liver disease (NAFLD). The most effective treatment for morbid obesity is bariatric surgery (BS) also improving NAFLD and liver function. In patients where NAFLD has already progressed to liver cirrhosis, BS can be considered a high-risk procedure. Hence, consideration of the procedure and the most appropriate timing is crucial. Material and Methods: Obese patients suffering from NAFLD who underwent BS from two German University Medical Centers were retrospectively analyzed. Results: Twenty-seven patients underwent BS. Most common procedures were laparoscopic Roux-en-Y-gastric (RYGB) and laparoscopic sleeve gastrectomy (SG). All patients suffered from liver cirrhosis Child A. A preoperative transjugular portosystemic shunt (TIPS) was established in three patients and failed in another patient. Postoperative complications consisted of wound healing disorders (n = 2), anastomotic bleeding (n = 1), and leak from the staple line (n = 1). This patient suffered from intraoperatively detected macroscopic liver cirrhosis. Excess weight loss was 73% and 85% after 1 and 2 years, respectively. Two patients suffered from postoperative aggravation of their liver function, resulting in a higher Child-Pugh score, while three could be removed from the waiting list for a liver transplantation. Conclusion: BS leads to weight loss, both after SG and RYGB, and potential improvement of liver function in liver cirrhosis. These patients need to be considered with care when evaluated for BS. Preoperative TIPS implantation may reduce the perioperative risk in selected patients.

[Amendments to the Transplantation Act and impact on the donor situation in Germany]. / Änderungen im Transplantationsgesetz und Auswirkungen auf das Spenderaufkommen in Deutschland.

In Germany, the scarcity of donor organs has persisted over decades and reached an historical low point in the year 2017. A thorough analysis of the causes revealed structural deficits in the identification and registration of possible donors as one of the central reasons for the low donation rate. This prompted the political authorities to act and resulted in two new laws, which led to a modification of the German Transplantation Act. On 1 April 2019, the Act on Improvement of the Cooperation and the Structural Framework for Organ Donation came into force. This Act strengthens the role of the transplant coordinators in the harvesting hospitals and establishes adequate reimbursement of the organ donation-related costs in the harvesting hospitals. Furthermore, it fosters the cooperation of the transplant coordinators with the German organ procurement organization. On 16 January 2020, the existing opt-in legislation was modified. While the general principle of the opt-in legislation stayed unchanged, different measures were introduced that aim to repeatedly inform all citizens about organ donation and thereby motivate them to make a decision on organ donation. In order to enable a reliable and transparent documentation an organ donor registry will be established. The practical implementation of the various measures of both Acts is supported by a multi-institutional collaborative initiative plan for organ donation. The legal regulations and their practical implementation are depicted in detail.

Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.

Epidemiological Data on Anaphylaxis in French Emergency Departments.

BACKGROUND: Although anaphylaxis has been considered a priority public health issue in the world allergy community, epidemiological data on morbidity and mortality remain suboptimal. We performed the first multicenter epidemiological study in French emergency departments (EDs). The study covered 7 EDs over a period of 1 year. The objectives were to identify areas that are amenable to change and to support ongoing national and international efforts for better diagnosis, management, and prevention of anaphylaxis. METHODS: Ours was a descriptive study based on data routinely reported to French institutional administrative databases from 7 French public health institutions in the Lorraine region between January and December 2015. Data were collected based on the anaphylaxisrelated codes of the International Classification of Diseases (ICD)-10, and cases were clinically validated as anaphylaxis. RESULTS: Of the 202 079 admissions to the EDs, 4817 had anaphylaxis-related codes; of these, 323 were clinically validated as anaphylaxis. Although 45.8% were severe, adrenaline was prescribed in only 32.4% of cases. Of the 323 cases, 57.9% were subsequently referred for an allergy work-up or evaluation (after or during hospitalization), and 17.3% were prescribed autoinjectable epinephrine. CONCLUSION: Our results highlight an urgent need for improved public health initiatives with respect to recognition and treatment of anaphylaxis. We flag key problems that should be managed in the coming years through implementation of national and international actions.

Epidemiological data on anaphylaxis in French emergency departments

BACKGROUND: Although anaphylaxis has been considered a priority public health issue in the world allergy community, epidemiological data on morbidity and mortality remain suboptimal. We performed the first multicenter epidemiological study in French emergency departments (EDs). The study covered 7 EDs over a period of 1 year. The objectives were to identify areas that are amenable to change and to support ongoing national and international efforts for better diagnosis, management, and prevention of anaphylaxis. METHODS: Ours was a descriptive study based on data routinely reported to French institutional administrative databases from 7 French public health institutions in the Lorraine region between January and December 2015. Data were collected based on the anaphylaxis-related codes of the International Classification of Diseases (ICD)-10, and cases were clinically validated as anaphylaxis. RESULTS: Of the 202 079 admissions to the EDs, 4817 had anaphylaxis-related codes; of these, 323 were clinically validated as anaphylaxis. Although 45.8% were severe, adrenaline was prescribed in only 32.4% of cases. Of the 323 cases, 57.9% were subsequently referred for an allergy work-up or evaluation (after or during hospitalization), and 17.3% were prescribed autoinjectable epinephrine. CONCLUSION: Our results highlight an urgent need for improved public health initiatives with respect to recognition and treatment of anaphylaxis. We flag key problems that should be managed in the coming years through implementation of national and international actions

ANTECEDENTES: La anafilaxia es un problema prioritario de salud pública en la comunidad mundial alergológica. Sin embargo, los datos epidemiológicos disponibles de morbilidad y mortalidad son mejorables. Presentamos el primer estudio epidemiológico multicéntrico, realizado en siete departamentos de urgencias franceses durante un año, que tuvo como objetivo identificar las cuestiones relevantes para lograr cambios en futuras estrategias, nacionales e internacionales, que deriven en un mejor diagnóstico, tratamiento y prevención de la anafilaxia. MÉTODOS: Se trata de un estudio descriptivo que utilizó la información proveniente de las bases de datos de siete instituciones francesas de salud pública, de la región de Lorena, desde enero hasta diciembre de 2015. Se buscaron nomenclatura y códigos relacionados con la anafilaxia, de la Clasificación Internacional de Enfermedades (CIE-10), y los pacientes fueron validados clínicamente como casos de anafilaxia. RESULTADOS: De los 202.079 ingresos en urgencias, 4.817 tenían códigos relacionados con la anafilaxia CIE-10, 323 de los cuales se validaron clínicamente con el diagnóstico de anafilaxia. Aunque el 45,8% presentó criterios de gravedad, la adrenalina se prescribió solo en el 32,4% de estos casos. En total, 323 casos, el 57,9%, se remitieron posteriormente para un estudio o evaluación alergológica (después o durante la hospitalización) y el 17,3% recibió una receta de adrenalina autoinyectable . CONCLUSIÓN: Según los resultados de este estudio, existe una necesidad urgente e imperiosa de mejorar los planes de salud pública respecto al reconocimiento y tratamiento de la anafilaxia. Los problemas clave detectados en este trabajo, señalan el camino de la toma de decisiones e implementación de acciones de mejora, nacionales e internacionales, para una mejor atención de los pacientes con anafilaxia

Sex-specific and lasting effects of a single course of antenatal betamethasone treatment on human placental 11ß-HSD2.

INTRODUCTION: We have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11ß-hydroxysteroiddehydrogenase type 2 (11ß-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. METHODS: Pregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11ß-hydroxysteroiddehydrogenase type 1 (11ß-HSD1) protein levels and 11ß-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. RESULTS: In term born females, BET administration was associated with reduced head circumference and decreased 11ß-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11ß-HSD2 protein levels. CONCLUSION: A single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11ß-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11ß-HSD2 levels in males.

Targeting nucleolin for better survival in diffuse large B-cell lymphoma.

Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA-binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90-month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP-based therapy.

Treatment of unstable proximal interphalangeal joint fractures with hemi-hamate osteochondral autografts.

The primary aim of this study was to assess the clinical and radiological results after hemi-hamate resurfacing arthroplasty in patients with acute or chronic unstable fractures of the base of the middle phalanx and to describe technical features that can facilitate the surgical procedure. Hemi-hamate arthroplasties were done in 19 patients (mean age 39 years) with an isolated fracture at the base of the middle phalanx that involved more than 40% of the articular surface. We assessed ten chronic cases (treated >6 weeks after fracture) and nine acute ones (<6 weeks) at a mean of 24 months. Pain scores, QuickDASH scores, grip strengths, range of motion and radiological findings were recorded at follow-up. At follow-up, the mean active flexion at the proximal interphalangeal joint was to 83° with a mean fixed flexion of 17° (active range of motion 66°). The mean active distal interphalangeal motion was 41°. The mean visual analogue scale score was 1.1. The mean QuickDASH score was 11. The mean pinch strength was 82% of the opposite side. Radiographs revealed one partial graft lysis. LEVEL OF EVIDENCE: IV.

[Immunological Markers in Organ Transplantation]. / Marker der Immunantwort bei Organtransplantation.

The immunological monitoring in organ transplantation is based mainly on the determination of laboratory parameters as surrogate markers of organ dysfunction. Structural damage, caused by alloreactivity, can only be detected by invasive biopsy of the graft, which is why inevitably rejection episodes are diagnosed at a rather progressive stage. New non-invasive specific markers that enable transplant clinicians to identify rejection episodes at an earlier stage, on the molecular level, are needed. The accurate identification of rejection episodes and the establishment of operational tolerance permit early treatment or, respectively, a controlled cessation of immunosuppression. In addition, new prognostic biological markers are expected to allow a pre-transplant risk stratification thus having an impact on organ allocation and immunosuppressive regimen. New high-throughput screening methods allow simultaneous examination of hundreds of characteristics and the generation of specific biological signatures, which might give concrete information about acute rejection, chronic dysfunction as well as operational tolerance. Even though multiple studies and a variety of publications report about important advances on this subject, almost no new biological marker has been implemented in clinical practice as yet. Nevertheless, new technologies, in particular analysis of the genome, transcriptome, proteome and metabolome will make personalised transplantation medicine possible and will further improve the long-term results and graft survival rates. This article gives a survey of the limitations and possibilities of new immunological markers in organ transplantation.

[Overnight polysomnography versus respiratory polygraphy in the diagnosis of pediatric obstructive sleep apnea]. / Diagnostic du syndrome d'apnée obstructive du sommeil chez l'enfant (2­18 ans) : place de la polysomnographie et de la polygraphie ventilatoire.

The French Society of Research and Sleep Medicine (SFRMS) organized a meeting on obstructive sleep apnea syndrome (OSAS) in children. A multidisciplinary group of specialists (pulmonologists, ENT surgeons, pediatricians, neurophysiologists, sleep specialists) drew up a consensus document on the value of electrophysiological recordings in the diagnosis of OSAS in children. Technical considerations and recommended sensors, respiratory event definitions, and scoring criteria are presented according to the 2012 and 2014 recommendations of the American Academy of Sleep Medicine (AASM). Polysomnographic criteria for sleep-disordered breathing in children and the French National Authority for Health guidelines for indications of polysomnographic studies were reported. Relevance and limits of in-lab PSG, home PSG, and respiratory polygraphy were presented and guidelines were proposed to improve the diagnosis and follow-up of these children.

Bilateral carpal tunnel surgery in one operation: Retrospective study.

Carpal tunnel syndrome is the most common entrapment syndrome. The incidence of a bilateral condition varies between 22% and 87%. The aim of our study was to assess the level of satisfaction and the clinical outcomes in a group of patients operated on through a bilateral neurolysis on the median nerve in the carpal tunnel, in one operating session. This is a retrospective study involving patients with an electromyographic and clinical diagnosis of bilateral carpal tunnel syndrome. Patients were treated on an outpatient basis and the bilateral neurolysis was performed by endoscopy. The postoperative data was collected during consultation by a senior surgeon or during telephone interviews. Patients were asked to respond to a satisfaction questionnaire and the functional outcome was assessed through the Quick-Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) questionnaire. Twenty-nine patients with bilateral carpal tunnel syndrome were operated on in single operating sessions between January 2009 and January 2014. The average follow-up was 46 months. The average age at the time of the intervention was 45 years. Two patients were lost to follow-up, and 27 were able to be assessed. In relation to the clinical and functional outcomes, the average Quick-DASH score was 6.78 (ranges: 0-43.2). Twenty-five patients (92.5%) were satisfied with this simultaneous treatment and 26 patients (96%) would choose the same technique again. One-stage surgery in cases of bilateral carpal tunnel syndrome appears to constitute a benefit for the patient, the surgeon and the anaesthetist, but it is reserved for patients who request it and who are motivated by this type of intervention.

[Decline in renal function in old age : Part of physiological aging versus age-related disease]. / Rückgang der Nierenfunktion im Alter : Teil des physiologischen Alterns vs. Alterskrankheit.

The incidence and prevalence of chronic renal disease (CKD) in elderly patients are continuously increasing worldwide. Loss of renal function is not only considered to be part of the aging process itself but also reflects the multimorbidity of many geriatric patients. Calculating the glomerular filtration rate using specific algorithms validated for the elderly population and measuring the amount of proteinuria allow an estimation of renal function in elderly patients with high accuracy. Chronic renal failure has many clinical consequences and not only results in a delayed excretion of toxins cleared by the kidneys but also affects hematogenesis, water and electrolyte balance as well as mineral bone metabolism. Furthermore, CKD directly leads to and aggravates geriatric syndromes and in particular the onset of frailty. Therapeutic strategies to halt progression of CKD not only comprise treatment of the underlying disease but also efficient blood pressure and diabetic control and the avoidance of nephrotoxic medications.

The importance of selecting the right internal control gene to study the effects of antenatal glucocorticoid administration in human placenta.

RT-qPCR requires a suitable set of internal control genes (ICGs) for an accurate normalization. The usefulness of 7 previously published ICGs in the human placenta was analyzed according to the effects of betamethasone treatment, sex and fetal age. Raw RT-qPCR data of the ICGs were evaluated using published algorithms. The algorithms revealed that a reliable normalization was achieved using the geometrical mean of PPIA, RPL19, HMBS and SDHA. The use of a different subset ICGs out of the 7 investigated, although not statistically affected by the conditions, biased the results, as demonstrated through changes in expression of glucocorticoid receptor (NR3C1) mRNA as a target gene.

[Expert recommendations: Hepatitis C and transplantation]. / Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation.

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.

Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL.

Proapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.

Non-invasive monitoring of pulmonary artery pressure at the bedside.

Current solutions for the monitoring of pulmonary artery pressure (PAP) in patients suffering from pulmonary hypertension are limited to invasive means. Non-invasive alternatives, such as Doppler echocardiography, are incompatible with continuous monitoring due to their dependency on qualified personnel to perform the measurements. In the present study, a novel non-invasive and unsupervised approach based on the use of electrical impedance tomography (EIT) is presented. The approach was evaluated in three healthy subjects undergoing hypoxia-induced variations in PAP. A timing parameter - physiologically linked to the PAP via the so-called pulse wave velocity principle - was automatically extracted from the EIT data. Reference systolic PAP estimates were obtained by echocardiography. Strong correlation scores (r e [0.844, 0.990]) were found between the EIT-derived parameter and the reference PAP, thereby suggesting the validity of the proposed approach. If confirmed in larger datasets, these findings could open the way for a new branch of fully non-invasive hemodynamic monitors for patients with pulmonary hypertension.