Intraoperative near infrared functional imaging of rectal cancer using artificial intelligence methods - now and near future state of the art.

Colorectal cancer remains a major cause of cancer death and morbidity worldwide. Surgery is a major treatment modality for primary and, increasingly, secondary curative therapy. However, with more patients being diagnosed with early stage and premalignant disease manifesting as large polyps, greater accuracy in diagnostic and therapeutic precision is needed right from the time of first endoscopic encounter. Rapid advancements in the field of artificial intelligence (AI), coupled with widespread availability of near infrared imaging (currently based around indocyanine green (ICG)) can enable colonoscopic tissue classification and prognostic stratification for significant polyps, in a similar manner to contemporary dynamic radiological perfusion imaging but with the advantage of being able to do so directly within interventional procedural time frames. It can provide an explainable method for immediate digital biopsies that could guide or even replace traditional forceps biopsies and provide guidance re margins (both areas where current practice is only approximately 80% accurate prior to definitive excision). Here, we discuss the concept and practice of AI enhanced ICG perfusion analysis for rectal cancer surgery while highlighting recent and essential near-future advancements. These include breakthrough developments in computer vision and time series analysis that allow for real-time quantification and classification of fluorescent perfusion signals of rectal cancer tissue intraoperatively that accurately distinguish between normal, benign, and malignant tissues in situ endoscopically, which are now undergoing international prospective validation (the Horizon Europe CLASSICA study). Next stage advancements may include detailed digital characterisation of small rectal malignancy based on intraoperative assessment of specific intratumoral fluorescent signal pattern. This could include T staging and intratumoral molecular process profiling (e.g. regarding angiogenesis, differentiation, inflammatory component, and tumour to stroma ratio) with the potential to accurately predict the microscopic local response to nonsurgical treatment enabling personalised therapy via decision support tools. Such advancements are also applicable to the next generation fluorophores and imaging agents currently emerging from clinical trials. In addition, by providing an understandable, applicable method for detailed tissue characterisation visually, such technology paves the way for acceptance of other AI methodology during surgery including, potentially, deep learning methods based on whole screen/video detailing.

CLASSICA: Validating artificial intelligence in classifying cancer in real time during surgery.

AIM: Treatment pathways for significant rectal polyps differ depending on the underlying pathology, but pre-excision profiling is imperfect. It has been demonstrated that differences in fluorescence perfusion signals following injection of indocyanine green (ICG) can be analysed mathematically and, with the assistance of artificial intelligence (AI), used to classify tumours endoscopically as benign or malignant. This study aims to validate this method of characterization across multiple clinical sites regarding its generalizability, usability and accuracy while developing clinical-grade software to enable it to become a useful method. METHODS: The CLASSICA study is a prospective, unblinded multicentre European observational study aimed to validate the use of AI analysis of ICG fluorescence for intra-operative tissue characterization. Six hundred patients undergoing transanal endoscopic evaluation of significant rectal polyps and tumours will be enrolled in at least five clinical sites across the European Union over a 4-year period. Video recordings will be analysed regarding dynamic fluorescence patterns centrally as software is developed to enable analysis with automatic classification to happen locally. AI-based classification and subsequently guided intervention will be compared with the current standard of care including biopsies, final specimen pathology and patient outcomes. DISCUSSION: CLASSICA will validate the use of AI in the analysis of ICG fluorescence for the purposes of classifying significant rectal polyps and tumours endoscopically. Follow-on studies will compare AI-guided targeted biopsy or, indeed, AI characterization alone with traditional biopsy and AI-guided local excision versus traditional excision with regard to marginal clearance and recurrence.

Minimally invasive approaches to the management of anastomotic leakage following restorative rectal cancer resection.

AIM: Management of anastomotic leakage (AL) following rectal resection has evolved with increasing use of less invasive techniques. The aim of this study was to review the management of AL following restorative rectal cancer resection in a tertiary referral centre. METHOD: A retrospective review of a prospectively maintained database was performed. The primary outcome was successful management of AL. The secondary outcome was the impact of AL on oncological outcome. RESULTS: Five hundred and two restorative rectal cancer resections were performed during the study period. The incidence of AL was 9.9% (n = 50). AL occurred more commonly following neoadjuvant chemoradiotherapy (n = 31/252, 12.3%) than in those who did not receive neoadjuvant chemoradiotherapy (n = 19/250, 7.6%; P = 0.107); however, this was not statistically significant. Successful minimally invasive drainage was achieved in 28 patients (56%, radiological n = 24, surgical n = 4). Trans-rectal drainage was the most common drainage method (n = 14). The median duration of drainage was longer in the neoadjuvant group (27 vs 18 days). Surgical intervention was required in 11 patients, with anastomotic takedown and end-colostomy formation was most commonly required. Successful management of AL with drainage (maintenance of the anastomosis without the need for further intervention) was achieved in 26 of the 28 patients. There were no significant differences in overall or disease-free survival when patients with AL were compared with patients without AL (69.4% vs 72.6%, P = 0.99 and 78.7% vs 71.3%, P = 0.45, respectively). CONCLUSION: In selected patients, AL following restorative rectal resection can be effectively controlled using minimally invasive radiological or surgical drainage without the need for further intervention.

Effect of standardizing the lactose content of cheesemilk on the properties of low-moisture, part-skim Mozzarella cheese.

The texture, functionality, and quality of Mozzarella cheese are affected by critical parameters such as pH and the rate of acidification. Acidification is typically controlled by the selection of starter culture and temperature used during cheesemaking, as well as techniques such as curd washing or whey dilution, to reduce the residual curd lactose content and decrease the potential for developed acidity. In this study, we explored an alternative approach: adjusting the initial lactose concentration in the milk before cheesemaking. We adjusted the concentration of substrate available to form lactic acid. We added water to decrease the lactose content of the milk, but this also decreased the protein content, so we used ultrafiltration to help maintain a constant protein concentration. We used 3 milks with different lactose-to-casein ratios: one at a high level, 1.8 (HLC, the normal level in milk); one at a medium level, 1.3 (MLC); and one at a low level, 1.0 (LLC). All milks had similar total casein (2.5%) and fat (2.5%) content. We investigated the composition, texture, and functional and sensory properties of low-moisture, part-skim Mozzarella manufactured from these milks when the cheeses were ripened at 4°C for 84d. All cheeses had similar pH values at draining and salting, resulting in cheeses with similar total calcium contents. Cheeses made with LLC milk had higher pH values than the other cheeses throughout ripening. Cheeses had similar moisture contents. The LLC and MLC cheeses had lower levels of lactose, galactose, lactic acid, and insoluble calcium compared with HLC cheese. The lactose-to-casein ratio had no effect on the levels of proteolysis. The LLC and MLC cheeses were harder than the HLC cheese during ripening. Maximum loss tangent (LT), an index of cheese meltability, was lower for the LLC cheese until 28d of ripening, but after 28d, all treatments exhibited similar maximum LT values. The temperature where LT=1 (crossover temperature), an index of softening point during heating, was higher for MLC and LLC cheese at 56 and 84d of ripening. The LLC cheese also had lower blister color and less stretch than MLC and HLC cheese. Adjusting the lactose content of milk while maintaining a constant casein level was a useful technique for controlling cheese pH, which affected the texture, functionality, and sensory properties of low-moisture, part-skim Mozzarella cheese.

Effect of camel chymosin on the texture, functionality, and sensory properties of low-moisture, part-skim Mozzarella cheese.

The objective of this study was to compare the effect of coagulant (bovine calf chymosin, BCC, or camel chymosin, CC), on the functional and sensory properties and performance shelf-life of low-moisture, part-skim (LMPS) Mozzarella. Both chymosins were used at 2 levels [0.05 and 0.037 international milk clotting units (IMCU)/mL], and clotting temperature was varied to achieve similar gelation times for each treatment (as this also affects cheese properties). Functionality was assessed at various cheese ages using dynamic low-amplitude oscillatory rheology and performance of baked cheese on pizza. Cheese composition was not significantly different between treatments. The level of total calcium or insoluble (INSOL) calcium did not differ significantly among the cheeses initially or during ripening. Proteolysis in cheese made with BCC was higher than in cheeses made with CC. At 84 d of ripening, maximum loss tangent values were not significantly different in the cheeses, suggesting that these cheeses had similar melt characteristics. After 14 d of cheese ripening, the crossover temperature (loss tangent = 1 or melting temperature) was higher when CC was used as coagulant. This was due to lower proteolysis in the CC cheeses compared with those made with BCC because the pH and INSOL calcium levels were similar in all cheeses. Cheeses made with CC maintained higher hardness values over 84 d of ripening compared with BCC and maintained higher sensory firmness values and adhesiveness of mass scores during ripening. When melted on pizzas, cheese made with CC had lower blister quantity and the cheeses were firmer and chewier. Because the 2 types of cheeses had similar moisture contents, pH values, and INSOL Ca levels, differences in proteolysis were responsible for the firmer and chewier texture of CC cheeses. When cheese performance on baked pizza was analyzed, properties such as blister quantity, strand thickness, hardness, and chewiness were maintained for a longer ripening time than cheeses made with BCC, indicating that use of CC could help to extend the performance shelf-life of LMPS Mozzarella.

Technical and functional design considerations for a real-world interpretable AI solution for NIR perfusion analysis (including cancer).

Near infrared (NIR) analysis of tissue perfusion via indocyanine green fluorescence assessment is performed clinically during surgery for a range of indications. Its usefulness can potentially be further enhanced through the application of interpretable artificial intelligence (AI) methods to improve dynamic interpretation accuracy in these and also open new applications. While its main use currently is for perfusion assessment as a tissue health check prior to performing an anastomosis, there is increasing interest in using fluorophores for cancer detection during surgical interventions with most research being based on the paradigm of static imaging for fluorophore uptake hours after preoperative dosing. Although some image boosting and relative estimation of fluorescence signals is already inbuilt into commercial NIR systems, fuller implementation of AI methods can enable actionable predictions especially when applied during the dynamic, early inflow-outflow phase that occurs seconds to minutes after ICG (or indeed other fluorophore) administration. Already research has shown that such methods can accurately differentiate cancer from benign tissue in the operating theatre in real time in principle based on their differential signalling and could be useful for tissue perfusion classification more generally. This can be achieved through the generation of fluorescence intensity curves from an intra-operative NIR video stream. These curves are processed to adjust for image disturbances and curve features known to be influential in tissue characterisation are extracted. Existing machine learning based classifiers can then use these features to classify the tissue in question according to prior training sets. The use of this interpretable methodology enables accurate classification algorithms to be built with modest training sets in comparison to those required for deep learning modelling in addition to achieving compliance with medical device regulations. Integration of the multiple algorithms required to achieve this classification into a desktop application or medical device could make the use of this method accessible and useful to (as well as useable by) surgeons without prior training in computer technology. This document details some technical and functional design considerations underlying such a novel recommender system to advance the foundational concept and methodology as software as medical device for in situ cancer characterisation with relevance more broadly also to other tissue perfusion applications.

Sexual selection on male development time in the parasitoid wasp Nasonia vitripennis.

Mating systems are shaped by a species' ecology, which sets the stage for sexual selection. Males of the gregarious parasitoid wasp Nasonia vitripennis compete to mate virgin females at the natal site, before females disperse. Males could increase their fitness by being larger and monopolizing female emergence sites or by emerging earlier pre-empting access to females. We consider sexual selection on male body size and development time in Nasonia, and a potential trade-off between the two traits. We explored sex-specific patterns of larval and pupal development, finding that smaller wasps developed slower than their host-mates. Using competition experiments between brothers, we found that earlier eclosing males mated more females independently of absolute and relative body size. Our data explain the lack of relationship between fitness and body size in male Nasonia and reinforce the importance of protandry in mating systems where access to mates is time-limited.

Developmental shifts in the behavioral phenotypes of inbred mice: the role of postnatal and juvenile social experiences.

The interaction between genotype and environment is an important feature of the process of development. We investigate this interaction by examining the influence of postnatal cross-fostering and post-weaning cross-housing on the behavioral development of 129S and B6 mice. Following cross-fostering, we found significant alterations in the frequency of maternal care as a function of maternal strain and pup type as well as interactions between these variables. In adulthood, we find there are sex-specific and strain-specific alterations in anxiety-like behavior as a function of rearing environment, with males exhibiting more pronounced rearing-induced effects. Mixed-strain housing of weanlings was found to lead to alterations in home-cage social and feeding behavior as well as changes in adult anxiety-like responses of 129S mice. Anxiety-like behavior in B6 mice was altered as a function of the interaction between housing condition and weaning weight. These data illustrate the complex pathways through which early and later social experiences may lead to variations in behavior.

Perioperative factors associated with postoperative morbidity after emergency laparotomy: a retrospective analysis in a university teaching hospital.

Emergency Laparotomy (EL) is associated with significant morbidity and mortality. Variation in practice and patient outcomes for patients undergoing emergency laparotomy has been identified through the UK National Emergency Laparotomy Audit (NELA), with 30-day mortality ranging from 11 to 15%. A correlation between preoperative haemodynamic parameters and increased postoperative mortality has been demonstrated by both NELA and other observational studies. The association between intraoperative haemodynamic parameters and overall postoperative morbidity has not been evaluated in EL patients. The aims of our study were to investigate the association between perioperative haemodynamic and logistic parameters and postoperative morbidity in a tertiary referral university hospital; and to compare our outcomes to that of the NELA data. A retrospective analysis correlating a range of perioperative parameters with Comprehensive Complication Index (CCI) among 86 patients who underwent EL during 2018 was conducted. Mean age was 64 years (SD 16). Median CCI was 27 [9-45], and 30-day mortality was 11.7%. Several intraoperative parameters correlated with CCI on univariate analysis. On multivariate analysis, ASA status (P = 0.005) and unplanned escalation to postoperative intensive care (P = 0.03) were independently associated with CCI. Our study shows a correlation between ASA status and unplanned escalation to ITU with increased postoperative morbidity in patients undergoing emergency laparotomy. We did not demonstrate an independent correlation between intraoperative parameters and postoperative morbidity. These findings warrant confirmation in a larger scale observational study. Outcomes in our institution are comparable to those seen in the NELA.

General practitioners knowledge, practice and training requirements in relation to doping in sport.

This study examined General Practitioner's (GP) knowledge, practice and training requirements in relation to doping in sport in Ireland. All 2083 GPs on the Irish College of General Practitioners (ICGP) register received a postal questionnaire, yielding a 37% response rate (N=771, 63% male, average age 46.2 +/- 9SD, range 28-74 years). Results revealed that 14% (112) deemed their knowledge of doping agents to be good or very good, 12% (94) had completed specific training modules in doping or sport, and 24% (183) were connected with a specific sport as a team doctor/advisor. Over one in four (28%: 217) had been consulted for advice on doping in Sport, 33% (256) possessed the current list of prohibited substances, and 25% (190) knew of the Irish Sports Council's drug-testing procedures. The current initiatives to discourage doping in sport were felt to be ineffective, and although 92% (716) indicated that GPs had a role to play in the prevention of doping in sport, only 9% (66) felt adequately trained for such a role. There was overwhelming support for further training among GPs, although the most appropriate method of providing training is complex and requires strategic planning.

Spontaneous atrial thrombosis in aged Syrian hamsters. II. Hemostasis.

Coagulation and fibrinolysis were studied in a colony of aged Syrian hamsters with spontaneous atrial thrombosis, and the results are consistent with concomitant consumption coagulopathy. In comparison to age- and sex-matched hamsters from the same colony, those with atrial thrombi had significantly prolonged prothrombin and partial thromboplastin times, reduced levels of factors II, VII, VIII and X activities and plasminogen; and concentrations of fibrinogen-fibrin split products in excess of 80 microgram/ml. Hematocrits of the thrombosed animals were significantly decreased, total plasma proteins were increased, leukocyte counts were within normal limits, and platelet counts were about half those of the controls. Thrombosed hamsters had significantly reduced plasma albumin content, increased alpha1-, beta-, and gamma-globulins, and reduced A/G ratios. Aged sick hamsters demonstrable thrombi also had reduced coagulation and fibrinolytic activities and platelet counts, but their fibrinogen levels were markedly elevated, and fibrinogen-fibrin split products were either absent or present in trace amounts. This suggests an earlier and/or less acute form of the thrombotic process.

Blood coagulation of the West Indian manatee (Trichechus manatus).

Blood was obtained from 10 clinically normal West Indian manatees. Many coagulation screening tests were performed on the blood as well as specific clotting factor assays. All clotting factors were present and their activities compared to those of the dog. The clotting factor activities of the intrinsic system of the manatee are much higher than those of the dog. Factor X activity is about the same as that of the dog. The clotting factor activities of the extrinsic system seems to be less than that of the the dog.

The value of age- and sex-matched controls for coagulation studies.

Several coagulation parameters and plasminogen levels were studied in 80 normal people divided into eight paired and sex-matched age groups: prepubertal children, postpubertal children, young adults, and adults over 50. The data indicate that factor-VII and -IX activities increase with age, with a cluster of lower activity for children and higher activity for adults. Factor-VIII levels appear to decrease with age, although this effect could be due to greater anxiety in the pre- and postpubertal children at the time of venipuncture. The adults showed no significant change in factor-VIII activity with age, but partial data indicate that factor-VIII levels are higher in adults with blood group A than those with blood group O. The age-related changes in factor-VII, -IX, and possibly -VIII activities did not vary between sexes. By contrast, plasminogen increased strikingly with age in males and decreased with age in females. With fibrinogen, a similar effect was found for adults, though not for the entire population. These findings indicate the importance of using appropriate age- and sex-matched controls for coagulation and plasminogen assays, especially in patients with mild inherited or acquired coagulation disorders.

Hereditary factor VII and IX deficiencies in a large kindred.

A large kindred with combined deficiencies of factors VII and IX is presented. The deficiencies appeared to be independent and the data were not consistent with a diagnosis of haemophilia BM. The identification of mildly affected family members, including carriers of haemophilia B and heterozygotes for factor-VII deficiency, was facilitated by comparison with the 95% confidence interval of an age- and sex-matched control population. The bleeding patterns were those of mild to moderate haemophilia B and did not appear to have been modified by the presence of factor-VII deficiency.