Regulation of hedgehog Ligand Expression by the N-End Rule Ubiquitin-Protein Ligase Hyperplastic Discs and the Drosophila GSK3β Homologue, Shaggy

Hedgehog (Hh) morphogen signalling plays an essential role in tissue development and homeostasis. While much is known about the Hh signal transduction pathway, far less is known about the molecules that regulate the expression of the hedgehog (hh) ligand itself. Here we reveal that Shaggy (Sgg), the Drosophila melanogaster orthologue of GSK3β, and the N-end Rule Ubiquitin-protein ligase Hyperplastic Discs (Hyd) act together to co-ordinate Hedgehog signalling through regulating hh ligand expression and Cubitus interruptus (Ci) expression. Increased hh and Ci expression within hyd mutant clones was effectively suppressed by sgg RNAi, placing sgg downstream of hyd. Functionally, sgg RNAi also rescued the adult hyd mutant head phenotype. Consistent with the genetic interactions, we found Hyd to physically interact with Sgg and Ci. Taken together we propose that Hyd and Sgg function to co-ordinate hh ligand and Ci expression, which in turn influences important developmental signalling pathways during imaginal disc development. These findings are important as tight temporal/spatial regulation of hh ligand expression underlies its important roles in animal development and tissue homeostasis. When deregulated, hh ligand family misexpression underlies numerous human diseases (e.g., colorectal, lung, pancreatic and haematological cancers) and developmental defects (e.g., cyclopia and polydactyly). In summary, our Drosophila-based findings highlight an apical role for Hyd and Sgg in initiating Hedgehog signalling, which could also be evolutionarily conserved in mammals

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Brain monitoring in adult and pediatric ECMO patients : The importance of early and late assessments

Monitoring brain integrity and neurocognitive function is a new and important target for the management of a patient treated with extracorporeal membrane oxygenation (ECMO), in particular because of the increasing awareness of cerebral abnormalities that may potentially occur in this setting. Continuous regular monitoring, as well as repeated assessment for cerebral complications has become an essential element of the ECMO patient management. Besides well-known complications, like bleeding, ischemic stroke, seizures, and brain hypoperfusion, other less defined yet relevant injury and clinical manifestations are increasingly reported and impacting on ECMO patient prognosis at short term. Furthermore, it is becoming more evident that neurologic complication may not occur only in the early phase. Indeed, other potential adverse events related to the long-Term neurocognitive function have been also recently documented either in children or adult ECMO patients. Despite increasing awareness of these aspects, generally accepted protocols and clinical management strategies in this respect are still lacking. Current means to monitor brain perfusion or detecting ongoing cerebral tissue injury are rather limited, and most techniques provide indirect or post-insult recognition of irreversible tissue injury. Continuous monitoring of brain perfusion, serial assessment of brain-derived serum biomarkers, timely neuro-imaging, profesand post-discharge counselling for neurocognitive dysfunction, particularly in pediatric patients, are novel pathways focusing on neurologic assessment with important implications in daily practice to assess brain function and integrity not only during the ECMO-related hospitalization, but also at long-Term to re-evaluate the neuropsychological integrity, although well designed studies will be necessary to elucidate the cost-effectiveness of these management strategies

Brain monitoring in adult and pediatric ECMO patients: The importance of early and late assessments

Monitoring brain integrity and neurocognitive function is a new and important target for the management of a patient treated with extracorporeal membrane oxygenation (ECMO), in particular because of the increasing awareness of cerebral abnormalities that may potentially occur in this setting. Continuous regular monitoring, as well as repeated assessment for cerebral complications has become an essential element of the ECMO patient management. Besides well-known complications, like bleeding, ischemic stroke, seizures, and brain hypoperfusion, other less defined yet relevant injury and clinical manifestations are increasingly reported and impacting on ECMO patient prognosis at short term. Furthermore, it is becoming more evident that neurologic complication may not occur only in the early phase. Indeed, other potential adverse events related to the long-Term neurocognitive function have been also recently documented either in children or adult ECMO patients. Despite increasing awareness of these aspects, generally accepted protocols and clinical management strategies in this respect are still lacking. Current means to monitor brain perfusion or detecting ongoing cerebral tissue injury are rather limited, and most techniques provide indirect or post-insult recognition of irreversible tissue injury. Continuous monitoring of brain perfusion, serial assessment of brain-derived serum biomarkers, timely neuro-imaging, profesand post-discharge counselling for neurocognitive dysfunction, particularly in pediatric patients, are novel pathways focusing on neurologic assessment with important implications in daily practice to assess brain function and integrity not only during the ECMO-related hospitalization, but also at long-Term to re-evaluate the neuropsychological integrity, although well designed studies will be necessary to elucidate the cost-effectiveness of these management strategies.SCOPUS: re.jinfo:eu-repo/semantics/publishe