Lessons learnt from the construction and implementation of a prospective ventral hernia database.

PURPOSE: The New England VA Hernia Registry was created in 2011 to prospectively collect relevant details of ventral hernia repairs, with the intention to assess and improve long term outcomes. The goal of this study is to assess registry compliance. METHODS: All ventral hernia operations performed in five VA hospitals between 2011-2022 were obtained. We assessed compliance at the hospital and surgeon level. RESULTS: 3,516 cases were performed. Overall compliance with registry entry was 37.5%, ranging from 10.8% to 67.2% across hospitals. At the hospital level, there was a negative correlation between average yearly hernia volume per surgeon and registry compliance (r2 = 0.53). Surgeon compliance varied within hospitals and over time. CONCLUSION: Registry compliance was low and highly variable. Lack of interest, incentives, oversight, and surgeon turnover are possible factors for noncompliance. Building a registry with these factors in mind, providing timely feedback, and conducting frequent audits may improve compliance.

Consensus conference statement on fluorescence-guided surgery (FGS) ESSO course on fluorescence-guided surgery.

BACKGROUND: Fluorescence-guided surgery (FGS) has emerged as an innovative technique with promising applications in various surgical specialties. However, clinical implementation is hampered by limited availability of evidence-based reference work supporting the translation towards standard-of-care use in surgical practice. Therefore, we developed a consensus statement on current applications of FGS. METHODS: During an international FGS course, participants anonymously voted on 36 statements. Consensus was defined as agreement ≥70% with participation grade of ≥80%. All participants of the questionnaire were stratified for user and handling experience within five domains of applicability (lymphatics & lymph node imaging; tissue perfusion; biliary anatomy and urinary tracts; tumor imaging in colorectal, HPB, and endocrine surgery, and quantification and (tumor-) targeted imaging). Results were pooled to determine consensus for each statement within the respective sections based on the degree of agreement. RESULTS: In total 43/52 (81%) course participants were eligible as voting members for consensus, comprising the expert panel (n = 12) and trained users (n = 31). Consensus was achieved in 17 out of 36 (45%) statements with highest level of agreement for application of FGS in tissue perfusion and biliary/urinary tract visualization (71% and 67%, respectively) and lowest within the tumor imaging section (0%). CONCLUSIONS: FGS is currently established for tissue perfusion and vital structure imaging. Lymphatics & lymph node imaging in breast cancer and melanoma are evolving, and tumor tissue imaging holds promise in early-phase trials. Quantification and (tumor-)targeted imaging are advancing toward clinical validation. Additional research is needed for tumor imaging due to a lack of consensus.

Controlled Continuous Evolution of Enzymatic Activity Screened at Ultrahigh Throughput Using Drop-Based Microfluidics.

Enzymes are highly specific catalysts delivering improved drugs and greener industrial processes. Naturally occurring enzymes must typically be optimized which is often accomplished through directed evolution; however, this is still a labor- and capital-intensive process, due in part to multiple molecular biology steps including DNA extraction, in vitro library generation, transformation, and limited screening throughput. We present an effective and broadly applicable continuous evolution platform that enables controlled exploration of fitness landscape to evolve enzymes at ultrahigh throughput based on direct measurement of enzymatic activity. This drop-based microfluidics platform cycles cells between growth and mutagenesis followed by screening with minimal human intervention, relying on the nCas9 chimera with mutagenesis polymerase to produce in vivo gene diversification using sgRNAs tiled along the gene. We evolve alditol oxidase to change its substrate specificity towards glycerol, turning a waste product into a valuable feedstock. We identify a variant with a 10.5-fold catalytic efficiency.

Inter-Rater Agreement of the Classification of Intraoperative Adverse Events (ClassIntra) in Abdominal Surgery.

OBJECTIVE AND SUMMARY OF BACKGROUND DATA: Adverse events in surgical patients can occur preoperatively, intraoperatively, and postoperatively. Universally accepted classification systems are not yet available for intraoperative adverse events (iAEs). ClassIntra has recently been developed and validated as a tool for grading iAEs that occur between skin incision and skin closure irrespective of the origin, that is, surgery, anesthesia, or organizational. The aim of this study is to assess the inter-rater agreement of ClassIntra and assess its predictive value for postoperative complications in elective abdominal surgery. METHODS: This study is a secondary use of data from the LAParotomy or LAParoscopy and ADhesiolysis (LAPAD) study, with detailed data on incidence and management of intra-operative and post-operative complications. Data were collected in a cohort of elective abdominal surgeries. Two teams graded all recorded events in the LAPAD study according to ClassIntra. Cohen Kappa coefficient was calculated to determine inter-rater agreement. Uni- and multivariable linear regression was used to assess the predictive value of the ClassIntra grades for postoperative complications. RESULTS: IAEs were rated in 333 of 755 (44%) surgeries by team 1, and in 324 of 755 (43%) surgeries by team 2. Cohen kappa coefficient for ClassIntra grades was 0.87 [95% confidence interval (CI) 0.84-0.90]. Discrepancies in grading were most frequent for intraoperative bleeding and adhesions' associated injuries. At least 1 postoperative complication was observed in 278 (37%) patients. The risk of a postoperative complications increased with every increase in severity grade of ClassIntra. Intraoperative hypotension [mean difference (MD) 23.41, 95% CI 12.93-33.90] and other organ injuries (MD 18.90, 95% CI -4.22 - 42.02) were the strongest predictors for postoperative complications. CONCLUSIONS: ClassIntra has an almost perfect inter-rater agreement for the classification of iAEs. An increasing grade of ClassIntra was associated with a higher incidence of postoperative complications. Discrepancies in grading related to common complications in abdominal procedures mostly consisted of intraoperative bleeding and adhesion-related injuries. Grading of interoperative events in abdominal surgery might further improve by consensus regarding the definitions of a number of frequent events.

Prevalence, diagnosis, and surgical management of complex ileocolic-duodenal fistulas in Crohn's disease.

BACKGROUND: The aim of the present study was to review the prevalence and surgical management of patients with Crohn's disease (CD) complicated by ileocolic-duodenal fistulas (ICDF). METHODS: We performed a retrospective chart review of CD patients who underwent surgical takedown and repair of ICDF during January 2011-December 2021 at two inflammatory bowel disease referral centers. RESULTS: We identified 17 patients with ICDF (1.3%) out of 1283 CD patients who underwent abdominal surgery. Median age was 42 (20-71) years, 13 patients were male (76%) and median body mass index was 22.7 (18.4-30.3) kg/m2. Four patients (24%) were diagnosed preoperatively and only 2 (12%) were operated on for ICDF-related symptoms. The most common procedure was ileocolic resection (13 patients, 76%) including 4 repeat ileocolic resections (24%). The duodenal defect was primarily repaired in all patients with no re-fistulization or duodenal stenosis, regardless of the repair technique. A laparoscopic approach was attempted in the majority of patients (14 patients, 82%); however, only 5 (30%) were laparoscopically completed. The overall postoperative complication rate was 65% including major complications in 3 patients (18%) and 2 patients (12%) who required surgical re-intervention for abdominal wall dehiscence and postoperative bleeding. Preoperative nutritional optimization was performed in 9 patients (53%) due to malnutrition. These patients had significantly less intra-operative blood loss (485 vs 183 ml, p = 0.05), and a significantly reduced length of stay (18 vs 8 days, p = 0.05). CONCLUSION: ICDF is a rare manifestation of CD which may go unrecognized despite the implementation of a comprehensive preoperative evaluation. Although laparoscopic management of ICDF may be technically feasible, it is associated with a high conversion rate. Preoperative nutritional optimization may be beneficial in improving surgical outcomes in this select group of patients.

Systematic review and simulation study of ignoring clustered data in surgical trials.

BACKGROUND: Multiple surgical procedures in a single patient are relatively common and lead to dependent (clustered) data. This dependency needs to be accounted for in study design and data analysis. A systematic review was performed to assess how clustered data were handled in inguinal hernia trials. The impact of ignoring clustered data was estimated using simulations. METHODS: PubMed, Embase and the Cochrane Library were reviewed systematically for RCTs published between 2004 and 2013, including patients undergoing unilateral or bilateral inguinal hernia repair. Study characteristics determining the appropriateness of handling clustered data were extracted. Using simulations, various statistical methods accounting for clustered data were compared with an analysis ignoring clustering by assuming 100 hernias, with a varying percentage of patients having bilateral hernias. RESULTS: Of the 50 eligible trials including patients with bilateral hernias, 20 (40 per cent) did not provide information on how they dealt with clustered data and 18 (36 per cent) avoided clustering by assessing the outcome by patient and not by hernia. None of the remaining 12 trials (24 per cent) considered clustering in the design or analysis. In the simulations, ignoring clustering led to an increased type I error rate of up to 12 per cent and to a loss in power of up to 15 per cent, depending on whether the patient or the hernia was the randomization unit. CONCLUSION: Clustering was rarely considered in inguinal hernia trials. The simulations underline the importance of considering clustering as part of the statistical analysis to avoid false-positive and false-negative results, and hence inappropriate study conclusions.

Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution.

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma.

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.

Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.

BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.

Towards a situation-and-user-aware multi-modal motorized toilet system to assist older adults with disabilities: A user requirements study.

In the recent decades state of the art technologies appeared in many areas to assist older adults with disabilities. However, one very essential activity of daily life, the toileting remained without any relevant development. The iToilet project of the European Union focuses on the development of an intelligent and motorized toilet system to enable independent toilet use for older adults with disabilities. To begin the development, the user requirements of end-users were assessed by means of focus group interviews and questionnaires. The survey was conducted in Austria and Hungary with the participation of 74 persons in total (41 subjects with movement disorders, 21 caregivers and 12 healthcare managers). From the interviews, the ranking of functions and features based on the number of their mentions was derived. The raw ranking was modulated by the average ratings from the questionnaires that resulted in the final list of priorities. Our results suggest that a safe and intelligent motorized toilet system should have foldable handrails on both sides (especially for wheelchair users), motorized height and tilt adjusting mechanism for the toilet bowl, fixed toilet paper holder on both sides and emergency recognition with call function. Simple operation, storage and retrieval of user specific settings including bowl height, and user identification were also deemed as very important features, while the possibility to control functions with gestures was valued rather low.

Surgical treatment of uncomplicated diverticulitis in Switzerland: comparison of population-based data over two time periods.

AIM: The standard of care for acute uncomplicated diverticulitis used to be an elective colon resection after the second or third episode. This practice was replaced by a more conservative and individualized approach. This study investigates current surgical practice in the treatment of acute uncomplicated diverticulitis in Switzerland. METHOD: Retrospective cross-sectional analysis of all hospital admissions due to uncomplicated diverticulitis in Switzerland using prospectively collected data from the Swiss Federal Statistical Office in two periods: 2004/2005 and 2010/2011. Treatment options were compared between the two periods with adjustment for baseline characteristics of patients and treating institutions. RESULTS: A total of 24 497 patients (11 835 in 2004/2005; 12 662 in 2010/2011) were admitted to Swiss hospitals for uncomplicated diverticulitis. Between periods, the incidence increased from 81 to 85 admissions per 105 inhabitants per year. Elective admissions decreased from 46% (n = 5490) to 34% (n = 4294). The unadjusted resection rate decreased from 40% (n = 4730) to 34% (n = 4308). In the adjusted analysis, inpatients were more likely to have a resection in 2010/2011 than in 2004/2005 [odds ratio of 1.38 (95% confidence interval 1.25-1.54)]. In addition, private insurance, elective mode of admission and younger age increased the odds for resection while there was no evidence of an association between resection and either gender or comorbidities. CONCLUSION: The probability of colon resection for patients hospitalized with acute uncomplicated diverticulitis increased between periods while the overall number of colon resections declined. A change of practice expected given the paradigm shift towards conservative treatment could not be confirmed in this analysis.

Claudin-2-mediated cation and water transport share a common pore.

AIM: Claudin-2 is a tight junction protein typically located in 'leaky' epithelia exhibiting large paracellular permeabilities like small intestine and proximal kidney tubule. Former studies revealed that claudin-2 forms paracellular channels for small cations like sodium and potassium and also paracellular channels for water. This study analyses whether the diffusive transport of sodium and water occurs through a common pore of the claudin-2 channel. METHODS: Wild-type claudin-2 and different claudin-2 mutants were expressed in MDCK I kidney tubule cells using an inducible system. Ion and water permeability and the effect of blocking reagents on both were investigated on different clones of the mutants. RESULTS: Neutralization of a negatively charged cation interaction site in the pore with the mutation, D65N, decreased both sodium permeability and water permeability. Claudin-2 mutants (I66C and S68C) with substitution of the pore-lining amino acids with cysteine were used to test the effect of steric blocking of the claudin-2 pore by thiol-reactive reagents. Addition of thiol-reactive reagents to these mutants simultaneously decreased conductance and water permeability. Remarkably, all experimental perturbations caused parallel changes in ion conductance and water permeability, disproving different or independent passage pathways. CONCLUSION: Our results indicate that claudin-2-mediated cation and water transport are frictionally coupled and share a common pore. This pore is lined and determined in permeability by amino acid residues of the first extracellular loop of claudin-2.

Reversal after Hartmann's procedure in patients with complicated sigmoid diverticulitis.

AIM: Hartmann's procedure (HP) is commonly used for the emergency treatment of complicated sigmoid diverticulitis (CSD). It is intended to restore intestinal continuity; however, in practice, reversal is not carried out in all patients. It is important to know the frequency of reversal and the impact of patient-related factors on the decision for reversal. METHOD: A retrospective study was conducted on all patients who underwent HP for CSD at a tertiary referral hospital between 1 May 2005 and 31 December 2010. We assessed the frequency of reversal over time and the prognostic factors affecting the decision for reversal. RESULTS: Of 67 patients [median age 76 (interquartile range: 68-81) years] who had HP for CSD, 28 (42%) underwent reversal. The cumulative incidence of reversal after 48 weeks was 48% (95% CI: 36-62%). Reversal was less likely in elderly patients [hazard ratio (HR) per decade increase = 0.43; 95% CI: 0.26-0.71], with cardiac insufficiency or coronary heart disease (HR = 0.60; 95% CI: 0.26-1.40) and with preoperative immunosuppression or chemotherapy (HR = 0.31; 95% CI: 0.07-1.33). There was no apparent effect of these factors on mortality. CONCLUSION: Approximately half of the patients having HP for CSD undergo reversal within 48 weeks of the initial operation. The finding that age, cardiac or coronary heart disease and preoperative immunosuppression or chemotherapy have an impact on the decision for reversal is relevant to healthcare professionals and patients.

Mitigating effect of EUK-207 on radiation-induced cognitive impairments.

The brain could be exposed to irradiation as part of a nuclear accident, radiological terrorism (dirty bomb scenario) or a medical radiological procedure. In the context of accidents or terrorism, there is considerable interest in compounds that can mitigate radiation-induced injury when treatment is initiated a day or more after the radiation exposure. As it will be challenging to determine the radiation exposure an individual has received within a relatively short time frame, it is also critical that the mitigating agent does not negatively affect individuals, including emergency workers, who might be treated, but who were not exposed. Alterations in hippocampus-dependent cognition often characterize radiation-induced cognitive injury. The catalytic ROS scavenger EUK-207 is a member of the class of metal-containing salen manganese (Mn) complexes that suppress oxidative stress, including in the mitochondria, and have been shown to mitigate radiation dermatitis, promote wound healing in irradiated skin, and mitigate vascular injuries in irradiated lungs. As the effects of EUK-207 against radiation injury in the brain are not known, we assessed the effects of EUK-207 on sham-irradiated animals and the ability of EUK-207 to mitigate radiation-induced cognitive injury. The day following irradiation or sham-irradiation, the mice started to receive EUK-207 and were cognitively tested 3 months following exposure. Mice irradiated at a dose of 15Gy showed cognitive impairments in the water maze probe trial. EUK-207 mitigated these impairments while not affecting cognitive performance of sham-irradiated mice in the water maze probe trial. Thus, EUK-207 has attractive properties and should be considered an ideal candidate to mitigate radiation-induced cognitive injury.

Heller oesophagomyotomy as treatment for achalasia after gastric bypass for morbid obesity.

When achalasia is unrecognised during the preoperative phase in patients who have undergone bariatric procedures, a late Heller oesophagomyotomy may be used as the treatment modality to prevent the development of megaoesophagus. We present the case of a 66-year-old man with achalasia 3 years after a Roux-en-Y gastric bypass procedure.

Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation.

The epithelial tight junction determines the paracellular water and ion movement in the intestine and also prevents uptake of larger molecules, including antigens, in an uncontrolled manner. Claudin-2, one of the 27 mammalian claudins regulating that barrier function, forms a paracellular channel for small cations and water. It is typically expressed in leaky epithelia like proximal nephron and small intestine and provides a major pathway for the paracellular transport of sodium, potassium, and fluid. In intestinal inflammation (Crohn's disease, ulcerative colitis), immune-mediated diseases (celiac disease), and infections (HIV enteropathy), claudin-2 is upregulated in small and large intestine and contributes to diarrhea via a leak flux mechanism. In parallel to that upregulation, other epithelial and tight junctional features are altered and the luminal uptake of antigenic macromolecules is enhanced, for which claudin-2 may be partially responsible through induction of tight junction strand discontinuities.

Changing trends in bariatric surgery.

BACKGROUND AND AIMS: Bariatric surgery is considered the only long-lasting treatment for morbid obesity. Techniques and procedures have changed dramatically. We report on some of the major changes in the field. MATERIALS AND METHODS: We reviewed some of the major changes in trends in bariatric surgery based on some landmark paper published in the literature. RESULTS: We identified three major phases in the evolution of bariatric surgery. The pioneer phase was mostly characterized by discovery of weight loss procedures serendipitously from procedures done for other purposes. The second phase can be identified with the advent of laparoscopic techniques. This is considered the phase of greatest expansion of bariatric surgery. The metabolic phase derives from the improved understanding of the mechanisms of actions of the bariatric operations at the hormonal and molecular level. CONCLUSIONS: Bariatric surgery has changed significantly over the years. The safety of the laparoscopic approach, along with the better understanding of the metabolic changes obtained postoperatively, has led to a more individualized approach and also an attempt to expand the indications for these procedures.