The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH. METHODS: REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH. DISCUSSION: In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39).

Unravelling the Adaptation Mechanisms to High Pressure in Proteins.

Life is thought to have appeared in the depth of the sea under high hydrostatic pressure. Nowadays, it is known that the deep biosphere hosts a myriad of life forms thriving under high-pressure conditions. However, the evolutionary mechanisms leading to their adaptation are still not known. Here, we show the molecular bases of these mechanisms through a joint structural and dynamical study of two orthologous proteins. We observed that pressure adaptation involves the decoupling of protein-water dynamics and the elimination of cavities in the protein core. This is achieved by rearranging the charged residues on the protein surface and using bulkier hydrophobic residues in the core. These findings will be the starting point in the search for a complete genomic model explaining high-pressure adaptation.

Combining High-Pressure NMR and Geometrical Sampling to Obtain a Full Topological Description of Protein Folding Landscapes: Application to the Folding of Two MAX Effectors from Magnaporthe oryzae.

Despite advances in experimental and computational methods, the mechanisms by which an unstructured polypeptide chain regains its unique three-dimensional structure remains one of the main puzzling questions in biology. Single-molecule techniques, ultra-fast perturbation and detection approaches and improvement in all-atom and coarse-grained simulation methods have greatly deepened our understanding of protein folding and the effects of environmental factors on folding landscape. However, a major challenge remains the detailed characterization of the protein folding landscape. Here, we used high hydrostatic pressure 2D NMR spectroscopy to obtain high-resolution experimental structural information in a site-specific manner across the polypeptide sequence and along the folding reaction coordinate. We used this residue-specific information to constrain Cyana3 calculations, in order to obtain a topological description of the entire folding landscape. This approach was used to describe the conformers populating the folding landscape of two small globular proteins, AVR-Pia and AVR-Pib, that belong to the structurally conserved but sequence-unrelated MAX effectors superfamily. Comparing the two folding landscapes, we found that, in spite of their divergent sequences, the folding pathway of these two proteins involves a similar, inescapable, folding intermediate, even if, statistically, the routes used are different.

Pressure and Chemical Unfolding of an α-Helical Bundle Protein: The GH2 Domain of the Protein Adaptor GIPC1.

When combined with NMR spectroscopy, high hydrostatic pressure is an alternative perturbation method used to destabilize globular proteins that has proven to be particularly well suited for exploring the unfolding energy landscape of small single-domain proteins. To date, investigations of the unfolding landscape of all-ß or mixed-α/ß protein scaffolds are well documented, whereas such data are lacking for all-α protein domains. Here we report the NMR study of the unfolding pathways of GIPC1-GH2, a small α-helical bundle domain made of four antiparallel α-helices. High-pressure perturbation was combined with NMR spectroscopy to unravel the unfolding landscape at three different temperatures. The results were compared to those obtained from classical chemical denaturation. Whatever the perturbation used, the loss of secondary and tertiary contacts within the protein scaffold is almost simultaneous. The unfolding transition appeared very cooperative when using high pressure at high temperature, as was the case for chemical denaturation, whereas it was found more progressive at low temperature, suggesting the existence of a complex folding pathway.

Bacterial infections in children after liver transplantation: A single-center surveillance study of 345 consecutive transplantations.

BACKGROUND: Infectious complications after pediatric liver transplantation frequently occur and are potentially serious. Data concerning strictly defined bacterial infections and their associated risk factors are lacking. METHODS: For the pediatric liver transplant postoperative period, we analyzed data from the nosocomial infection surveillance (2006-2015). RESULTS: A total of 235 bacterial infections in 162 transplantations (47%) occurred, including 32 bacterial pneumonia cases, 104 surgical site infections, 27 urinary tract infections, and 40 bloodstream infections. Sepsis was diagnosed in 127 cases (54%), severe sepsis in 22 (9%) cases, and septic shock in 41 (17%) cases. Thirty patients (9%) died, and septic shock was the leading cause of death. The carrier status of multi-drug resistant bacteria and a tacrolimus level >20 ng/mL were independent risk factors for surgical site infections and the occurrence of severe sepsis or septic shock. The length of mechanical ventilation was an independent risk factor for pneumonia and surgical site infection. CONCLUSION: Bacterial infections in the early postoperative period after pediatric liver transplantation are associated with high morbidity and mortality. Physicians involved in the medical care of these patients should be aware of the specific risk factors, and further development of prevention programs is highly recommended.

Combining High-Pressure Perturbation with NMR Spectroscopy for a Structural and Dynamical Characterization of Protein Folding Pathways.

High-hydrostatic pressure is an alternative perturbation method that can be used to destabilize globular proteins. Generally perfectly reversible, pressure exerts local effects on regions or domains of a protein containing internal voids, contrary to heat or chemical denaturant that destabilize protein structures uniformly. When combined with NMR spectroscopy, high pressure (HP) allows one to monitor at a residue-level resolution the structural transitions occurring upon unfolding and to determine the kinetic properties of the process. The use of HP-NMR has long been hampered by technical difficulties. Owing to the recent development of commercially available high-pressure sample cells, HP-NMR experiments can now be routinely performed. This review summarizes recent advances of HP-NMR techniques for the characterization at a quasi-atomic resolution of the protein folding energy landscape.

East African diploid and triploid bananas: a genetic complex transported from South-East Asia.

Background and Aims: Besides bananas belonging to the AAA triploid Mutika subgroup, which predominates in the Great Lakes countries, other AAA triploids as well as edible AA diploids, locally of considerable cultural weight, are cultivated in East Africa and in the nearby Indian Ocean islands as far as Madagascar. All these varieties call for the genetic identification and characterization of their interrelations on account of their regional socio-economic significance and their potential for banana breeding strategies. Methods: An extensive sampling of all traditional bananas in East Africa and near Indian Ocean islands was genotyped with simple sequence repeat (SSR) markers, with particular emphasis on the diploid forms and on the bananas of the Indian Ocean islands, which remain poorly characterized. Key Results: All the edible AA varieties studied here are genetically homogeneous, constituting a unique subgroup, here called 'Mchare', despite high phenotypic variation and adaptions to highly diverse ecological zones. At triploid level, and besides the well-known AAA Mutika subgroup, at least two other genetically related AAA subgroups specific to this region are identified. Neither of these East African AAA genotypes can be derived directly from the local AA Mchare diploids. However, it is demonstrated that the East African diploids and triploids together belong to the same genetic complex. The geographical distribution of their wild acuminata relatives allowed identification of the original area of this complex in a restricted part of island South-East Asia. The inferred origin leads to consideration of the history of banana introduction in Africa. Linked to biological features, documentation on the embedding of bananas in founding legends and myths and convincing linguistic elements were informative regarding the period and the peoples who introduced these Asian plants into Africa. The results point to the role of Austronesian-speaking peoples who colonized the Indian Ocean islands, particularly Madagascar, and reached the East African coasts. Conclusions: Understanding of the relations between the components of this complex and identifying their Asian wild relatives and related cultivars will be a valuable asset in breeding programmes and will boost the genetic improvement of East African bananas, but also of other globally important subgroups, in particular the AAA Cavendish.

Quality of care and variability in lung cancer management across Belgian hospitals: a population-based study using routinely available data.

OBJECTIVE: To evaluate the quality of care for all patients diagnosed with lung cancer in Belgium based on a set of evidence-based quality indicators and to study the variability of care between hospitals. DESIGN, SETTING, PARTICIPANTS: A retrospective study based on linked data from the cancer registry, insurance claims and vital status for all patients diagnosed with lung cancer between 2010 and 2011. Evidence-based quality indicators were identified from a systematic literature search. A specific algorithm to attribute patients to a centre was developed, and funnel plots were used to assess variability of care between centres. INTERVENTION: None. MAIN OUTCOME MEASURE: The proportion of patients who received appropriate care as defined by the indicator. Secondary outcome included the variability of care between centres. RESULTS: Twenty indicators were measured for a total of 12 839 patients. Good results were achieved for 60-day post-surgical mortality (3.9%), histopathological confirmation of diagnosis (93%) and for the use of PET-CT before treatment with curative intent (94%). Areas to be improved include the reporting of staging information to the Belgian Cancer Registry (80%), the use of brain imaging for clinical stage III patients eligible for curative treatment (79%), and the time between diagnosis and start of first active treatment (median 20 days). High variability between centres was observed for several indicators. Twenty-three indicators were found relevant but could not be measured. CONCLUSION: This study highlights the feasibility to develop a multidisciplinary set of quality indicators using population-based data. The main advantage of this approach is that not additional registration is required, but the non-measurability of many relevant indicators is a hamper. It allows however to easily point to areas of large variability in care.

Ultrasound-Guided Subclavian Vein Cannulation in Low Birth Weight Neonates.

OBJECTIVES: Central venous access in critically ill, small infants remains technically challenging even in experienced hands. Several vascular accesses exist, but the subclavian vein is often preferred for central venous catheter insertion in infants where abdominal malformation and/or closure of the vein preclude the use of umbilical venous catheters, as catheterization of the subclavian vein is easier in very short necks than the internal jugular vein for age-related anatomical reasons. The subclavian vein approach is yet relatively undescribed in low birth weight infants (i.e., < 2,500 g), and this study aims to explore the feasibility of this technique in very small infants. DESIGN: Retrospective data collection of prospectively registered data on central venous catheter insertion in infants. SETTING: Neonatal ICU and PICU at a university hospital. PATIENTS: One hundred and five newborn children hospitalized in at the ICU. INTERVENTIONS: An ultrasound-guided supraclavicular approach was applied on all infants who had an subclavian vein catheterization during a 30-month period from January 2013 to July 2015. MEASUREMENTS AND MAIN RESULTS: One hundred seven supraclavicular subclavian vein catheters were placed in 105 children weighing less than 5,000 g. Among those, 40 patients weighed less than 2,500 g and 10 patients weighed less than 1,500 g. Successful central venous catheter insertion, defined as the correct placement of a functional double-lumen catheter (3F or 4F), was obtained in 97.3%. All three registered failed attempts were due to hematomas from venous bleeding and occurred in infants weighing greater than 2,500 g. No case of accidental arterial puncture or pleural puncture was registered. CONCLUSIONS: This large series of subclavian vein catheterizations in small infants demonstrates the feasibility of subclavian vein catheterizations even in very small neonates weighing less than 1,500 g.

Effectiveness and Safety of Tapentadol Prolonged Release (PR) Versus a Combination of Tapentadol PR and Pregabalin for the Management of Severe, Chronic Low Back Pain With a Neuropathic Component: A Randomized, Double-blind, Phase 3b Study.

OBJECTIVE: To evaluate the effectiveness and tolerability of tapentadol PR monotherapy versus tapentadol PR/pregabalin combination therapy for severe, chronic low back pain with a neuropathic component. METHODS: Eligible patients had painDETECT "unclear" or "positive" ratings and average pain intensity ≥ 6 (11-point NRS-3 [average 3-day pain intensity]) at baseline. Patients were titrated to tapentadol PR 300 mg/day over 3 weeks. Patients with ≥ 1-point decrease in pain intensity and average pain intensity ≥ 4 were randomized to tapentadol PR (500 mg/day) or tapentadol PR (300 mg/day)/pregabalin (300 mg/day) during an 8-week comparative period. RESULTS: In the per-protocol population (n = 288), the effectiveness of tapentadol PR was clinically and statistically comparable to tapentadol PR/pregabalin based on the change in pain intensity from randomization to final evaluation (LOCF; LSMD [95% CI], -0.066 [-0.57, 0.43]; P < 0.0001 for noninferiority). Neuropathic pain and quality-of-life measures improved significantly in both groups. Tolerability was good in both groups, in line with prior trials in the high dose range of 500 mg/day for tapentadol PR monotherapy, and favorable compared with historical combination trials of strong opioids and anticonvulsants for combination therapy. The incidence of the composite of dizziness and/or somnolence was significantly lower with tapentadol PR (16.9%) than tapentadol PR/pregabalin (27.0%; P = 0.0302). CONCLUSIONS: Tapentadol PR 500 mg is associated with comparable improvements in pain intensity and quality-of-life measures to tapentadol PR 300 mg/pregabalin 300 mg, with improved central nervous system tolerability, suggesting that tapentadol PR monotherapy may offer a favorable treatment option for severe low back pain with a neuropathic component.

Effectiveness and Tolerability of a Moderate Dose of Tapentadol Prolonged Release for Managing Severe, Chronic Low Back Pain with a Neuropathic Component: An Open-label Continuation Arm of a Randomized Phase 3b Study.

OBJECTIVE: To evaluate the effectiveness and tolerability of tapentadol prolonged release (PR) for severe, chronic low back pain with a neuropathic component in a subpopulation that achieved adequate pain relief with tapentadol PR 300 mg/day in a randomized, double-blind, phase 3b study. METHODS: Patients with painDETECT "unclear" or "positive" ratings and pain intensity ≥ 6 (11-point NRS-3 [average 3-day pain intensity]) were titrated to tapentadol PR 300 mg/day over 3 weeks. A subpopulation with pain intensity < 4 continued receiving tapentadol PR 300 mg/day during an 8-week, open-label continuation arm. For the primary study population, patients with ≥ 1-point decrease from baseline and pain intensity ≥ 4 were randomized to tapentadol PR 500 mg/day or tapentadol PR 300 mg/day plus pregabalin 300 mg/day during a concurrent 8-week, double-blind comparative period. RESULTS: From baseline to end of titration and to final evaluation, significant improvements were observed in pain intensity (mean [SD] changes from baseline to: end of titration; - 5.3 [1.78]; final evaluation; - 5.2 [2.39]; both P < 0.0001), neuropathic pain symptoms, and quality-of-life measures in the open-label continuation arm, with greater improvements in this selected subpopulation than in either group in the primary study population. A favorable tolerability profile was observed, with incidences of all individual treatment-emergent adverse events ≤ 5.1% during the continuation period. CONCLUSIONS: A subpopulation of patients with low back pain with a neuropathic component responded very well to tapentadol PR 300 mg/day, with significant improvements in pain intensity, neuropathic pain-related symptoms, and quality of life. Further research is needed to identify factors associated with a very positive treatment response.

Musa species in mainland Southeast Asia: From wild to domesticate.

Many species are defined in the Musa section within its natural diversification area in Southeast Asia. However, their actual number remains debated as botanical characterisation, distribution and intraspecific variability are still poorly known, compromising their preservation and their exploitation as crop wild relatives of cultivated forms. To address the underexplored Musa diversity in mainland Southeast Asia, at the northern edge of the natural range, 208 specimens were collected in Vietnam, Laos and China, mainly belonging to Musa balbisiana, M. itinerans, M. acuminata and M. yunnanensis. Data on location, morphology, environment and local knowledge were recorded, and leaf samples collected for high-throughput genotyping. This study combines geographical, morphological, and genomic diversity to clarify the taxonomic classification. The collected species exhibit highly distinctive morphologies and genomes, just as they differ in ranges and life traits. Intraspecific genomic diversity was also observed, although not necessarily morphologically perceptible. Mainland Southeast Asia is confirmed as a primary diversification centre for the Musa section. The diversity observed is only partially represented in major international ex situ collections, calling for their urgent enrichment and the promotion of in situ management procedures, for the protection of these threatened species and to better harness their potential in breeding programmes. Although considered wild, the species studied are all affected to varying extents by human use. Musa yunnanensis and M. acuminata subsp. burmannica are the most strictly wild forms, with spontaneous interspecific hybrids first described in this study. Although gathered as fodder, they were only occasionally dispersed outside their endemic zones. Musa itinerans is not cultivated per se, but natural populations are widely exploited, leading to a geographically structured diversity. The diversity of M. balbisiana is widely distributed and geographically structured by human activities. This species should be regarded as domesticated. These various stages, from simple opportunistic gathering to true domestication, shed light on the evolutionary history of today's cultivated varieties.

REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

Risk Assessment of Infectious Endogenous Banana Streak Viruses in Guadeloupe.

Infectious alleles of endogenous banana streak viruses (eBSVs) are present in the genome of all banana interspecific cultivars, including plantains and cooking types. Activation of these infectious eBSV alleles by biotic and abiotic stresses leads to spontaneous infections by cognate viruses and raises concerns about their ability to promote outbreaks of banana streak viruses under field cultivation conditions. We undertook a comprehensive risk assessment study of infectious eBSV alleles of species BSOLV, BSGFV and BSIMV in banana interspecific cultivars in Guadeloupe, a tropical island of the Caribbean where bananas are grown for export and local markets. We carried out a prevalence survey of BSOLV, BSGFV and BSIMV species in a range of cultivars grown in Guadeloupe. Our results suggest that BSOLV and BSGFV infections arise from the activation of infectious eBSVs rather than vector-borne transmission and point to a correlation between altitude and infection rates in interspecific hybrids with AAB genotypes. We studied the dynamics of activation of infectious eBSOLV and eBSGFV alleles by tissue culture and field cultivation in a range of cultivars. We showed that tissue culture and field cultivation trigger distinct activation pathways, resulting in distinct activation patterns. We also showed that activation decreased over time during cell culture and field cultivation and that BSV infections arising from the activation of infectious eBSV alleles cause symptomless infections in the most cultivated plantain in Guadeloupe, French Clair. Overall, our study shows that the risk of BSV outbreaks resulting from the activation of infectious eBSVs in plantain originating from vegetative multiplication is negligible in Guadeloupe.

Comparative Assessment of NMR Probes for the Experimental Description of Protein Folding Pathways with High-Pressure NMR.

Multidimensional NMR intrinsically provides multiple probes that can be used for deciphering the folding pathways of proteins: NH amide and CαHα groups are strategically located on the backbone of the protein, while CH3 groups, on the side-chain of methylated residues, are involved in important stabilizing interactions in the hydrophobic core. Combined with high hydrostatic pressure, these observables provide a powerful tool to explore the conformational landscapes of proteins. In the present study, we made a comparative assessment of the NH, CαHα, and CH3 groups for analyzing the unfolding pathway of ∆+PHS Staphylococcal Nuclease. These probes yield a similar description of the folding pathway, with virtually identical thermodynamic parameters for the unfolding reaction, despite some notable differences. Thus, if partial unfolding begins at identical pressure for these observables (especially in the case of backbone probes) and concerns similar regions of the molecule, the residues involved in contact losses are not necessarily the same. In addition, an unexpected slight shift toward higher pressure was observed in the sequence of the scenario of unfolding with CαHα when compared to amide groups.

Correlation between the Crohn's disease activity and Harvey-Bradshaw indices in assessing Crohn's disease severity.

BACKGROUND & AIMS: Clinical trials of Crohn's disease generally use the Crohn's Disease Activity Index to assess disease activity; these calculations are complex, time-consuming, and impracticable. We investigated whether a simpler tool, the Harvey-Bradshaw Index, was equally effective in assessing disease severity. METHODS: Crohn's Disease Activity and Harvey-Bradshaw Index scores were collected from 2 large multicenter Crohn's disease studies. The PEGylated antibody fragment evaluation in Crohn's disease: safety and efficacy (PRECiSE) 1 and 2 trials assessed efficacy and tolerability of certolizumab pegol (PEGylated, humanized, Fab' fragment of an antitumor necrosis factor alpha antibody). PRECiSE 1 and 2 data were analyzed to determine if results from the Crohn's Disease Activity Index correlated with those from the Harvey-Bradshaw Index criteria for defining response and remission. RESULTS: Analysis of almost 1000 data pairs showed a positive correlation between scores. The correlation between the indices for pooled data from PRECiSE 1 and PRECiSE 2 was 0.800 (Spearman correlation coefficient). The correlations between indices for the PRECiSE 1 or PRECiSE 2 were 20.698 and 0.716, respectively (Kronecker product variance). A 3-point change in the Harvey-Bradshaw Index score corresponded to a 100-point change in the Crohn's Disease Activity Index (clinical response); scores < or =4 points corresponded to a Crohn's Disease Activity Index score < or =150 points (clinical remission). CONCLUSIONS: Results from the Crohn's Disease Activity Index correlate with those from the Harvey-Bradshaw Index; use of the Harvey-Bradshaw Index might permit simpler Crohn's disease activity assessment in long-term clinical trials, and facilitate standardized disease activity measurements and cross-center comparisons.

Interplay between ionizing radiation effects and aging in C. elegans.

Living species are chronically exposed to environmental ionizing radiations from sources that can be overexpressed by nuclear accidents. In invertebrates, reproduction is the most radiosensitive studied endpoint, likely to be connected with aging. Surprisingly, aging is a sparsely investigated endpoint after chronic ionizing radiation, whereas understanding it is of fundamental interest in biology and medicine. Indeed, aging and aging-related diseases (e.g., cancer and degenerative diseases) cause about 90% of deaths in developed countries. Therefore, glp-1 sterile Caenorhabditis elegans nematode was used to assess the impact of chronic gamma irradiation on the lifespan. Analyses were performed, at the individual level, on aging and, in order to delve deeper into the mechanisms, at the molecular level, on oxidative damage (carbonylation), biomolecules (lipids, proteins and nucleic acids) and their colocalization. We observed that ionizing radiation accelerates aging (whatever the duration (3-19 days)/dose (0.5-24 Gy)/dose rate (7 and 52 mGy h-1) tested) leading to a longevity value equivalent to that of wt nematode (∼25-30 days). Moreover, the level of protein oxidative damage (carbonylation) turned out to be good cellular biomarker of aging, since it increases with age. Conversely, chronic radiation treatments reduced carbonylation levels and induced neutral lipid catabolism whatever the dose rate and the final delivered dose. Finally, under some conditions a lipid-protein colocalization without any carbonyl was observed; this could be linked to yolk accumulation in glp-1 nematodes. To conclude, we noticed through this study a link between chronic gamma exposure, lifespan shortening and lipid level decrease associated with a decrease in the overall carbonylation.

Evaluating the need to reform the organisation of care for major trauma patients in Belgium: an analysis of administrative databases.

PURPOSE: In light of the international evolutions to establish inclusive trauma systems and to concentrate the care for the most severely injured in major trauma centres, we evaluated the degree of dispersion of trauma care in Belgium. METHODS: We used descriptive statistics to illustrate the dispersion of major trauma care in Belgium based on two independent administrative databases: the registry of Mobile Intensive Care Units (2009-2015) and the Belgian Hospital Discharge Dataset (2009-2014). RESULTS: Patients with a severe trauma (n = 3856 in 2015) were transported towards 145 different hospital sites (on a total of 198 hospital sites) resulting in a median of 17 cases per hospital site (min = 1; P25 = 4; P75 = 30; max = 165). A minority of major trauma patients is after admission transferred to another hospital (8%) with a median of 10 days after admission to the hospital (IQR 3.5-24). CONCLUSIONS: The dispersion of care for major trauma patients in Belgium is so high that a reorganisation of care for severe injured patients in major trauma centres concentrating professional expertise and specialised equipment is recommended to guarantee a high quality of care in a qualitative and sustainable way.

Differential modification of the C. elegans proteome in response to acute and chronic gamma radiation: Link with reproduction decline.

Emission of ionizing radiation (IR) in the environment is a natural phenomenon which can be enhanced by human activities. Ecosystems are then chronically exposed to IR. But environmental risk assessment of chronic exposure suffers from a lack of knowledge. Extrapolation of data from acute to chronic exposure is not always relevant, and can lead to uncertainties as effects could be different between the two irradiation modes, especially regarding reproduction endpoint, which is an ecologically relevant parameter. In the present study, we decided to refine the understanding of the molecular mechanisms involved in response to acute and chronic γ-irradiation by a global proteome label free LC-MS/MS analysis. C. elegans were exposed to 3 common cumulated radiation doses for acute or chronic exposure condition and global modification of the proteome was studied. This analysis of protein expression has demonstrated the modulation of proteins involved in regulatory biological processes such as lipid transport, DNA replication, germ cell development, apoptosis, ion transport, cuticle development, and aging at lower doses than those for which individual effects on reproduction have been previously observed. Thus, these proteins could constitute early and sensitive markers of radio-induced reprotoxicity; more specifically HAT-1, RPS-19 in acute and VIT-3 for chronic conditions that are expressed in a dose-dependent manner. Finally, to focus on reproduction process, this analysis showed either repression or overexpression of 12 common proteins in organisms exposed to acute or chronic irradiation, respectively. These proteins include the vitellogenin cluster notably involved in lipid transport and oocyte maturation and proteins involved in cuticle development and molting i.e. COL-14, GLF-1, NOAH-1, NOAH-2, ACN-1. These results show that protein expression modulation is a sensitive and predictive marker of radio-induced reproductive effects, but also highlight limitation of data extrapolation from acute to chronic exposure for environmental risk assessment.

Association between surgical volume and post-operative mortality and survival after surgical resection in lung cancer in Belgium: A population-based study.

OBJECTIVES: The existence of a relationship between hospital surgical volume and outcome after lung cancer surgery remains an ongoing debate. We aimed to evaluate the association between volume and 60-day mortality, 1- and 3-year observed survival (OS) in non-small cell lung cancer (NSCLC) patients in Belgium. METHODS: Patients diagnosed with NSCLC in 2010-2011 were identified in the database of the Belgian Cancer Registry, excluding patients with multiple tumours. Regression models were applied to assess the relationship between hospital surgical volume, 60-day mortality and 1- and 3-year OS, adjusting for different patient and tumour characteristics. Surgical volume was taken into account as a continuous variable in the models. RESULTS: In 2010-2011 a total of 9,817 patients with NSCLC were diagnosed in Belgium and 2,084 of them underwent surgery. After adjusting for patient and tumour characteristics, a relationship between hospital surgical volume and patients' outcome was found. Postoperative mortality and survival improved with increasing annual surgical volume up to 10 interventions. However, no further gain in outcome has been observed above 10. While the 60-day postoperative mortality is 3.5% for hospitals with an annual volume larger than 10, the predicted mortality rate for a hospital with an annual volume of only 5 interventions is 6.5%. Similar results were observed for 1- and 3-year OS. CONCLUSION: In Belgium, a higher hospital surgical volume is associated with improved outcome in NSCLC patients after surgical resection. Minimally 10 surgical interventions per year seem to be required to achieve an optimal performance.