Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators

Early surgical complications after congenital diaphragmatic hernia repair by thoracotomy vs. laparotomy: A bicentric comparison

Purpose: The surgical strategy for congenital diaphragmatic hernia (CDH) repair remains debated and mainly depends on the training and preference of the surgeon. Our aim was to evaluate the occurrence and nature of surgical reinterventions within the first year of life, following repair through thoracotomy as compared to laparotomy. / Methods: This is a retrospective bi-centric cohort study comparing postero-lateral thoracotomy (n = 55) versus subcostal laparotomy (n = 62) for CDH repair (IRB: MP001882). We included neonates with isolated, left-sided, Bochdalek-type CDH who were operated on between 2000 and 2017, and had a minimum follow-up of 1 year. Excluded were patients treated prenatally and/or had extra-corporeal membrane oxygenation. Outcomes were occurrence and nature of surgical reinterventions and mortality by 1 year of life. / Results: Both groups had comparable neonatal severity risk profiles. The overall surgical reintervention rate by 1 year of age was higher in the thoracotomy group (29.1% vs. 6.5%; p = 0.001), mainly because of a higher prevalence of acute bowel complications (18.1% vs. 3.2%; p = 0.012) requiring surgery, such as perforation, obstruction and volvulus. At 1 year of follow-up, groups were similar in terms of recurrence (5.5% vs. 1.6%; p = 0.341), surgical interventions related to severe gastroesophageal reflux disease (3.6% vs. 1.6%; p = 0.600) and mortality (5.5% vs. 6.6%; p = 1.000). / Conclusion: Postnatal CDH repair through thoracotomy was associated with a higher rate of surgical reinterventions within the first year of life, especially for severe acute gastro-intestinal complications. There seemed to be no difference in recurrence and mortality rate. / Type of Study: Retrospective Comparative Cohort Study. / Level of Evidence: Level III

Clinical significance in the number of involved lymph nodes in patients that underwent surgery for pathological stage III-N2 non-small cell lung cancer

<p>Abstract</p> <p>Purpose</p> <p>This study investigated whether the number of involved lymph nodes is associated with the prognosis in patients that underwent surgery for pathological stage (p-stage) III/N2 NSCLC.</p> <p>Subjects</p> <p>This study evaluated 121 patients with p-stage III/N2 NSCLC.</p> <p>Results</p> <p>The histological types included 65 adenocarcinomas, 39 squamous cell carcinomas and 17 others. The average number of dissected lymph nodes was 23.8 (range: 6-55). The average number of involved lymph nodes was 5.9 (range: 1-23). The 5-year survival rate of the patients was 51.0% for single lymph node positive, 58.9% for 2 lymph nodes positive, 34.2% for 3 lymph nodes positive, and 30.0% for 4 lymph nodes positive, and 20.4% for more than 5 lymph nodes positive. The patients with either single or 2 lymph nodes positive had a significantly more favorable prognosis than the patients with more than 5 lymph nodes positive. A multivariate analysis revealed that the number of involved lymph nodes was a significant independent prognostic factor.</p> <p>Conclusion</p> <p>Surgery appears to be preferable as a one arm of multimodality therapy in p-stage III/N2 patients with single or 2 involved lymph nodes. The optimal incorporation of surgery into the multimodality approach therefore requires further clinical investigation.</p

Optimal gestational age at delivery for congenital diaphragmatic hernia.

OBJECTIVE: To evaluate the neonatal morbidity and mortality of babies with isolated congenital diaphragmatic hernia (CDH) according to gestational age at delivery. METHODS: We conducted a retrospective study in the University Hospitals of Antoine Béclère-Bicêtre and Leuven between January 1, 2010 and December 31, 2018. Isolated left-sided CDH cases were included. The Kaplan-Meier method was used to calculate cumulative survival at 28 days according to gestational age at delivery. The association between gestational age at delivery, as a continuous variable, and survival at 28 days was modeled using a fractional polynomial. Adjustment for position of the liver, management center, and mode of delivery was performed. The association was studied according to the severity of the CDH, defined by the o/e LHR, categorized in three classes: below 25%, between 25 and 45%, above 45%. RESULTS: We included 213 fetuses with isolated left-sided CDH, with a median gestational age at delivery of 38+2 WG [IQR: 37+0 -39+6 ]. Survival rates at 28 days and 6 months were 66.7% (142/213) and 64.3% (137/213), respectively. Kaplan-Meier curves showed higher survival up to 28 days for babies born between 37+0 and 39+0 WG than for those born after 39+0 WG (log-rank test, p<.001). In the subgroup of moderate forms, the survival rates at 28 days and 6 months were significantly higher for newborns delivered between 37+0 and 39+0 WG, compared to newborns delivered after 39+0 WG: 81.5% vs 61.5% (p=0.03). In this subgroup, 28-day survival significantly increased with advancing gestational age at birth until 38-39 WG (p=0.005) and significantly decreased from 39 WG. CONCLUSIONS: Delivery between 37+0 and 39+0 WG is associated with a higher survival rate at 28 days of life for moderate forms independently of intrathoracic liver, management center, and mode of delivery. This article is protected by copyright. All rights reserved.status: Published onlin

The implications of deteriorating state‐owned enterprise performance on the South African economy

International audienc

Donation after Euthanasia (DCD-V) Results in Excellent Long-Term Outcome after Lung Transplantation, Equal to Donation after Brain Death (DBD) and Circulatory Death (DCD-III).

PURPOSE: In countries with a legal framework for physician-assisted death, organ donation after euthanasia (DCD-V) can increase the donor pool. DCD-V grafts are characterized by absence of lung injury related to brain-death, intubation and a long agonal phase. We review our experience with LTx after DCD-V and compare outcome with DBD and DCD-III experience in the same era. METHODS: Between 01/2007-09/2019, 797 LTx were performed, of which 158 from DCD donors, including 20 DCD-V {8M/12F; mean age (range): 50 (28-66y)} due to neuromuscular (8) / mental (9) disorder or untreatable pain (3). After the request for euthanasia was granted in accordance with legislation, an explicit wish for organ donation was expressed by the patient and approved by the Institutional Review Board. Euthanasia was carried out in-hospital (local: 4; remote: 16) adjacent to the operating room in absence of the retrieval team. RESULTS: Twenty patients {7M/13F; age: 53y (27-64)} underwent bilateral LTx for emphysema (n=10), pulmonary fibrosis (n=5), cystic fibrosis (n=3, liver transplant in 1) and bronchiolitis obliterans (n=2). Waiting time was 326d (34-662). Agonal phase was short: 3min (0-14). Warm ischemia time between circulatory arrest and flush was 12min (7-21). Intensive care unit and hospital stay were 6d (2-10) and 28d (16-44). Three patients died due to cardiac problem (3mo), haematological disorder (3mo) or aspergillosis (10y). Follow-up was 4y (2mo-10.5y), CLAD occurred in 4. Five-year patient survival for DCD-V was 89%, equaling the DBD {80% (p=0.68)} and DCD-III cohort {81% (p=0.78)}. CLAD-free survival was 66.7%, equal to DBD {68.2% (p=0.68)} and DCD-III {69.9% (p=0.91)}. CONCLUSION: Our series represents the largest LTx experience from DCD-V and demonstrates for the first time that long-term outcome is comparable with DBD and DCD-III. DCD-V can further expand the donor pool in nations with a legal framework for physician-assisted death.status: publishe