Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Beyond image defined risk factors (IDRFs): a delphi survey highlighting definition of the surgical complexity index (SCI) in neuroblastoma.

PURPOSE: Preoperative evaluation of Image Defined Risk Factors (IDRFs) in neuroblastoma (NB) is crucial for determining suitability for upfront resection or tumor biopsy. IDRFs do not all carry the same weighting in predicting tumor complexity and surgical risk. In this study we aimed to assess and categorize a surgical complexity (Surgical Complexity Index, SCI) in NB resection. METHODS: A panel of 15 surgeons was involved in an electronic Delphi consensus survey to identify and score a set of shared items predictive and/or indicative of surgical complexity, including the number of preoperative IDRFs. A shared agreement included the achievement of at least 75% consensus focused on a single or two close risk categories. RESULTS: After 3 Delphi rounds, agreement was established on 25/27 items (92.6%). A severity score was established for each item ranging from 0 to 3 with an overall SCI range varying from a minimum score of zero to a maximum score of 29 points for any given patient. CONCLUSIONS: A consensus on a SCI to stratify the risks related to neuroblastoma tumor resection was established by the panel experts. This index will now be deployed to critically assign a better severity score to IDRFs involved in NB surgery.

Minimally invasive surgery for neuroblastic tumours: A SIOPEN multicentre study: Proposal for guidelines.

INTRODUCTION: Surgery plays a key role in the management of Neuroblastic tumours (NB), where the standard approach is open surgery, while minimally invasive surgery (MIS) may be considered an option in selected cases. The indication(s) and morbidity of MIS remain undetermined due to small number of reported studies. The aim of this study was to critically address the contemporary indications, morbidity and overall survival (OS) and propose guidelines exploring the utility of MIS for NB. MATERIALS & METHODS: A SIOPEN study where data of patients with NB who underwent MIS between 2005 and 2018, including demographics, tumour features, imaging, complications, follow up and survival, were extracted and then analysed. RESULTS: A total of 222 patients from 16 centres were identified. The majority were adrenal gland origin (54%) compared to abdominal non-adrenal and pelvic (16%) and thoracic (30%). Complete and near complete macroscopic resection (>95%) was achieved in 95%, with 10% of cases having conversion to open surgery. Complications were reported in 10% within 30 days of surgery. The presence of IDRF (30%) and/or tumour volume >75 ml were risk factors for conversion and complications in multivariate analysis. Overall mortality was 8.5%. CONCLUSIONS: MIS for NB showed that it is a secure approach allowing more than 95% resection. The presence of IDRFs was not an absolute contraindication for MIS. Conversion to open surgery and overall complication rates were low, however they become significant if tumour volume >75 mL. Based on these data, we propose new MIS guidelines for neuroblastic tumours.

Thoracoscopic oesophageal atresia/tracheo-oesophageal fistula (OA/TOF) repair is associated with a higher stricture rate: a single institution's experience.

PURPOSE: Thoracoscopic OA/TOF repair was first described in 1999. Currently, less than 10% of surgeons routinely employ minimally access surgery. Our primary aim was to review our immediate-, early- and long-term outcomes with this technique compared with the open approach. METHODS: A retrospective review of all patients undergoing primary OA/TOF (Type C) repair at our institution from 2009 was conducted. Outcome measures included length of surgery, conversion rate from thoracoscopy, early complications such as anastomotic leak and post-operative complications such as anastomotic strictures needing dilatations. Fisher's exact and Kruskal-Wallis tests were used for statistical analysis. RESULTS: 95 patients in total underwent OA/TOF repair during the study period of which 61 (64%) were completed via an open approach. 34 were attempted thoracoscopically of which 11 (33%) were converted. There was only one clinically significant anastomotic leak in our series that took place in the thoracoscopic group. We identified a significantly higher stricture rate in our thoracoscopic cohort (72%) versus open surgery (43%, P < 0.05). However, the median number of dilations (3) performed was not significantly different between the groups. There was one recurrent fistula in the thoracoscopic converted to open group. Our median follow-up was 60 months across the groups. CONCLUSION: In our experience, the clinically significant leak rate for both open and thoracoscopic repair as well as recurrent fistula is much lower than has been reported in the literature. We do not routinely perform contrast studies and are, thus, reporting clinically significant leaks only. The use of post-operative neck flexion, ventilation and paralysis is likely to be protective towards a leak. Thoracoscopic OA/TOF repair is associated with a higher stricture rate compared with open surgery; however, these strictures respond to a similar number of dilatations and are no more refractory. Larger, multicentre studies may be useful to investigate these finding further.

Single-Cell Genomics and the Oral Microbiome.

The human oral cavity is one of the first environments where microbes have been discovered and studied since the dawn of microbiology. Nevertheless, approximately 200 types of bacteria from the oral microbiota have remained uncultured in the laboratory. Some are associated with a healthy oral microbial community, while others are linked to oral diseases, from dental caries to gum disease. Single-cell genomics has enabled inferences on the physiology, virulence, and evolution of such uncultured microorganisms and has further enabled isolation and cultivation of several novel oral bacteria, including the discovery of novel interspecies interactions. This review summarizes some of the more recent advances in this field, which is rapidly moving toward physiologic characterization of single cells and ultimately cultivation of the yet uncultured. A combination of traditional microbiological approaches with genomic-based physiologic predictions and isolation strategies may lead to the oral microbiome being the first complex microbial community to have all its members cultivable in the laboratory. Studying the biology of the individual microbes when in association with other members of the community, in controlled laboratory conditions and in vivo, should lead to a better understanding of oral dysbiosis and its prevention and reversion.

The multi-disciplinary management of complex congenital and acquired tracheo-oesophageal fistulae.

AIM OF THE STUDY: Complex tracheo-oesophageal fistulae (TOF) are rare congenital or acquired conditions in children. We discuss here a multidisciplinary (MDT) approach adopted over the past 5 years. METHODS: We retrospectively collected data on all patients with recurrent or acquired TOF managed at a single institution. All cases were investigated with neck and thorax CT scan. Other investigations included flexible bronchoscopy and bronchogram (B&B), microlaryngobronchoscopy (MLB) and oesophagoscopy. All cases were subsequently discussed in an MDT meeting on an emergent basis if necessary. MAIN RESULTS: 14 patients were referred during this study period of which half had a congenital aetiology and the other half were acquired. The latter included button battery ingestions (5/7) and iatrogenic injuries during oesophageal atresia (OA) repair. Surgical repair was performed on cardiac bypass in 3/7 cases of recurrent congenital fistulae and all cases of acquired fistulae. Post-operatively, 9/14 (64%) patients suffered complications including anastomotic leak (1), bilateral vocal cord paresis (1), further recurrence (1), and mortality (1). Ten patients continue to receive surgical input encompassing tracheal/oesophageal stents and dilatations. CONCLUSIONS: MDT approach to complex cases is becoming increasingly common across all specialties and is important in making decisions in these difficult cases. The benefits include shared experience of rare cases and full access to multidisciplinary expertise.

Meta-analysis of the use of surgical sealants for suture-hole bleeding in arterial anastomoses.

BACKGROUND: Suture-hole bleeding in arterial anastomoses prolongs operating time and increases blood loss, particularly with the use of prosthetic grafts. Surgical sealants (such as fibrin) may be used as haemostatic adjuncts in vascular surgery. This is a systematic review and meta-analysis of published studies that investigated the utility of surgical sealants in arterial-to-prosthetic graft anastomoses. METHODS: A systematic review was undertaken of papers published until January 2015 on Embase, MEDLINE, PubMed, PubMed Central and Cochrane databases that analysed the use of surgical sealants as haemostatic adjuncts after arterial anastomoses. RCTs were included, with study endpoints of time to haemostasis or haemostasis at 5 min. Secondary outcomes included treatment failure, mean difference in estimated blood loss and duration of surgery. Sensitivity and subgroup analyses were performed, as well as funnel plot analysis for publication bias. RESULTS: A total of 2513 citations were reviewed; 19 RCTs comprising 1560 patients were ultimately included in the analysis. The majority of studies compared fibrin sealant with control haemostatic measures. Pooled analysis suggested that surgical sealants reduced the time to haemostasis (mean difference 243·26 (95 per cent c.i. 183·99 to 302·53) s; P < 0·001), improved haemostasis at 5 min (odds ratio 4·50, 95 per cent c.i. 2·59 to 7·81; P < 0·001), and were associated with less treatment failure, blood loss and shorter duration of surgery. CONCLUSION: Surgical sealants appear to reduce suture-hole bleeding significantly in vascular prosthetic graft anastomoses compared with standard haemostatic measures.

Octopamine stabilizes conduction reliability of an unmyelinated axon during hypoxic stress.

Mechanisms that could mitigate the effects of hypoxia on neuronal signaling are incompletely understood. We show that axonal performance of a locust visual interneuron varied depending on oxygen availability. To induce hypoxia, tracheae supplying the thoracic nervous system were surgically lesioned and action potentials in the axon of the descending contralateral movement detector (DCMD) neuron passing through this region were monitored extracellularly. The conduction velocity and fidelity of action potentials decreased throughout a 45-min experiment in hypoxic preparations, whereas conduction reliability remained constant when the tracheae were left intact. The reduction in conduction velocity was exacerbated for action potentials firing at high instantaneous frequencies. Bath application of octopamine mitigated the loss of conduction velocity and fidelity. Action potential conduction was more vulnerable in portions of the axon passing through the mesothoracic ganglion than in the connectives between ganglia, indicating that hypoxic modulation of the extracellular environment of the neuropil has an important role to play. In intact locusts, octopamine and its antagonist, epinastine, had effects on the entry to, and recovery from, anoxic coma consistent with octopamine increasing overall neural performance during hypoxia. These effects could have functional relevance for the animal during periods of environmental or activity-induced hypoxia.

Umbilical hernia following gastroschisis closure: a common event?

PURPOSE: To assess incidence and natural history of umbilical hernia following sutured and sutureless gastroschisis closure. METHODS: With audit approval, we undertook a retrospective clinical record review of all gastroschisis closures in our institution (2007-2013). Patient demographics, gastroschisis closure method and umbilical hernia occurrence were recorded. Data, presented as median (range), underwent appropriate statistical analysis. RESULTS: Fifty-three patients were identified, gestation 36 weeks (31-38), birth weight 2.39 kg (1-3.52) and 23 (43 %) were male. Fourteen patients (26 %) underwent sutureless closure: 12 primary, 2 staged; and 39 (74 %) sutured closure: 19 primary, 20 staged. Sutured closure was interrupted sutures in 24 patients, 11 pursestring and 4 not specified. Fifty patients were followed-up over 53 months (10-101) and 22 (44 %) developed umbilical hernias. There was a significantly greater hernia incidence following sutureless closure (p = 0.0002). In sutured closure, pursestring technique had the highest hernia rate (64 %). Seven patients underwent operative hernia closure; three secondary to another procedure. Seven patients had their hernias resolve. One patient was lost to follow-up and seven remain under observation with no reported complications. CONCLUSIONS: There is a significant umbilical hernia incidence following sutureless and pursestring sutured gastroschisis closure. This has not led to complications and the majority have not undergone repair.

Mycotic Aneurysm of the Extracranial Internal Carotid Artery, Resect and Ligate or Reconstruct?

Mycotic aneurysmal disease of the extracranial carotid arteries (ECA) is a rare entity associated with a high morbidity, including rupture, hemorrhage, airway obstruction, and stroke. Surgical management is challenging due to difficult dissection through infected or inflamed tissue. This report highlights a case of ECA-aneurysm infection presenting with stroke and an occluded internal carotid artery, likely due to microbial arteritis on a background of osteomyelitis. Operative intervention was performed to definitively treat the infection and prevent the potential associated complications. In this case, the incident vessel was 100% occluded at presentation, allowing vessel ligation and resection without carotid complex reconstruction.

Using the diamond intermediate anastomosis in composite sequential bypass grafting for critical limb ischemia.

Composite sequential bypass grafting is an effective alternative in the treatment of peripheral vascular disease when autologous vein is limited. We describe a modified technique for composite sequential bypass grafting anastomosis using a combination of synthetic graft with native vein connected via a common intermediate anastomotic junction, which also benefits from having additional outflow at the native, noncontiguous arteriotomy in a diamond configuration. This technique was piloted on six patients to treat critical limb ischemia when no other revascularization options were deemed suitable. Limb salvage with resolution of symptoms was achieved in all six patients at the 6-month follow-up. The diamond anastomosis is a promising method to maximize limb salvage using a unique composite sequential bypass configuration when native vein is limited.

Peripheral artery disease: a marked lack of awareness in Ireland.

OBJECTIVES: Patients with symptomatic peripheral artery disease (PAD) have a 30% risk of death within 5 years. However, public awareness of vascular disease has been shown to be low. The aim of this study was to assess awareness regarding risk factors, significance and potential sequelae of PAD in an Irish population. DESIGN: A cross-sectional, anonymous survey of patients and members of the public. MATERIALS: An anonymous questionnaire was developed to collect details on basic demographics, presence of and treatment for risk factors for cardiovascular disease, awareness of PAD and its risk factors and sequelae. The local ethics committee granted ethical approval. METHODS: Two investigators in face-to-face interviews administered the survey with patients and members of the general public, older than 40 years of age, attending a range of outpatient clinics, day care services and in patients. RESULTS: A total of 336 questionnaires were administered. A post-secondary school course had been completed by 32% of respondents. Only 19% of patients reported familiarity with PAD, a figure considerably lower than those reporting familiarity with stroke (94%), coronary artery disease (78%) or diabetes (98%) (Chi Squared p<0.001). The only independent predictor of awareness of PAD was having a post-secondary school course with an odds ratio or 4.2. CONCLUSIONS: This study demonstrates a disturbing lack of awareness of PAD and highlight the need for a meaningful targeted public health awareness campaign on PAD in order to close the gap of knowledge in Irish patients, prior to any prevention campaign.

Bioinformatic investigation of the cost management strategies of five oral microbes.

Some amino acids are more energetically costly to synthesize de novo, therefore many microbes have evolved to regulate the metabolic expenditure of the cell and reduce the energy burden of extracellular unrecyclable proteins. Several oral bacterial species take up amino acids and peptides obtained from proteolysis of host proteins and hence do not rely only on de novo synthesis. The aim of this study was to investigate if five oral bacterial species implement cost management strategies to reduce the energy burden of extracellular unrecyclable proteins. Since the relative de novo amino acid synthesis costs are proportional to the masses of the amino acids, the energy costs of producing proteins were assessed by calculating the mean amino acid mass for each protein. For Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia and Streptococcus sanguinis, the outer membrane/extracellular proteins are made up of a much larger percentage of lower average mass amino acids whereas cytoplasmic proteins are made up of a larger proportion of higher average mass amino acid residues. These results are consistent with the five oral bacterial species employing energy-saving mechanisms in the production of extracellular unrecyclable proteins. Interestingly, the P. gingivalis and S. sanguinis genomes exhibited significantly lower predicted mean amino acid masses compared with those of the genomes of the other three species, suggesting that this may provide them with an energy advantage with respect to protein biosynthetic cost.

Esophageal atresia and malrotation: what association?

INTRODUCTION: Esophageal atresia/tracheo-esophageal fistula (EA/TEF) has an incidence of approximately 1:3,500. The incidence of malrotation is thought to be 1:200-500. We attempted to define the incidence of a combination and discuss the implications. METHODS: This was a retrospective review of all patients admitted to a single institution with a diagnosis of EA or EA/TEF or TEF between April 1981 and January 2013. Patients were included if the position of the duodeno-jejunal flexure (DJF) was determined by upper GI contrast study (UGIS), surgery or post-mortem. RESULTS: Case notes were reviewed for 235 patients. In the EA type A group, 3/28 (11 %; 95 % CI 3.7-27.2 %) had malrotation, significantly higher than the reported incidence of malrotation in the general population (p = 0.0008). All three patients in this group were symptomatic with one patient found to have a volvulus at emergency surgery. In the type C group, 6/196 (3 %, 95 % CI 1.4-6.5 %) had malrotation, significantly higher than the incidence reported for the general population (p = 0.0033) but not significantly different to that of the type A group (p = 0.0878). There were no patients with malrotation identified in any other EA/TEF type. In total, 9/235 (3.8 %; 95 % CI 2.0-7.2 %) patients with EA had malrotation, significantly higher than the 5/1,050 (0.48 %) reported for the general population (p = 0.0002). CONCLUSION: There is a high incidence of malrotation in patients with pure EA. In the type A group an attempt to identify the DJF position at gastrostomy siting and/or performance of UGIS in the neonatal period should be undertaken. There should also be a low threshold for UGIS in all EA/TEF patients.

Predicting acute appendicitis? A comparison of the Alvarado score, the Appendicitis Inflammatory Response Score and clinical assessment.

BACKGROUND: Patients presenting with suspected appendicitis pose a diagnostic challenge. The appendicitis inflammatory response (AIR) score has outperformed the Alvarado score in two retrospective studies. The aim of this study was to evaluate the AIR Score and compare its performance in predicting risk of appendicitis to both the Alvarado score and the clinical impression of a senior surgeon. METHODS: All parameters included in the AIR and Alvarado scores as well as the initial clinical impression of a senior surgeon were prospectively recorded on patients referred to the surgical on call team with acute right iliac fossa pain over a 6-month period. Predictions were correlated with the final diagnosis of appendicitis. RESULTS: Appendicitis was the final diagnosis in 67 of 182 patients (37 %). The three methods of assessment stratified similar proportions (~40 %) of patients to a low probability of appendicitis (p = 0.233) with a false negative rate of <8 % that did not differ between the AIR score, Alvarado score or clinical assessment. The AIR score assigned a smaller proportion of patients to the high probability zone than the Alvarado score (14 vs. 45 %) but it did so with a substantially higher specificity (97 %) and positive predictive value (88 %) than the Alvarado score (76 and 65 %, respectively). CONCLUSIONS: The AIR score is accurate at excluding appendicitis in those deemed low risk and more accurate at predicting appendicitis than the Alvarado score in those deemed high risk. Its use as the basis for selective CT imaging in those deemed medium risk should be considered.

Predicting carotid artery disease and plaque instability from cell-derived microparticles.

OBJECTIVES: Cell-derived microparticles (MPs) are small plasma membrane-derived vesicles shed from circulating blood cells and may act as novel biomarkers of vascular disease. We investigated the potential of circulating MPs to predict (a) carotid plaque instability and (b) the presence of advanced carotid disease. METHODS: This pilot study recruited carotid disease patients (aged 69.3 ± 1.2 years [mean ± SD], 69% male, 90% symptomatic) undergoing endarterectomy (n = 42) and age- and sex-matched controls (n = 73). Plaques were classified as stable (n = 25) or unstable (n = 16) post surgery using immunohistochemistry. Blood samples were analysed for MP subsets and molecular biomarkers. Odds ratios (OR) are expressed per standard deviation biomarker increase. RESULTS: Endothelial MP (EMP) subsets, but not any vascular, inflammatory, or proteolytic molecular biomarker, were higher (p < .05) in the unstable than the stable plaque patients. The area under the receiver operator characteristic curve for CD31(+)41(-) EMP in discriminating an unstable plaque was 0.73 (0.56-0.90, p < .05). CD31(+)41(-) EMP predicted plaque instability (OR = 2.19, 1.08-4.46, p < .05) and remained significant in a multivariable model that included transient ischaemic attack symptom status. Annexin V(+) MP, platelet MP (PMP) subsets, and C-reactive protein were higher (p < .05) in cases than controls. Annexin V(+) MP (OR = 3.15, 1.49-6.68), soluble vascular cell adhesion molecule-1 (OR = 1.64, 1.03-2.59), and previous smoking history (OR = 3.82, 1.38-10.60) independently (p < .05) predicted the presence of carotid disease in a multivariable model. CONCLUSIONS: EMP may have utility in predicting plaque instability in carotid patients and annexin V(+) MPs may predict the presence of advanced carotid disease in aging populations, independent of established biomarkers.