Appraisal of Intraoperative Adverse Events to Improve Postoperative Care.

BACKGROUND: Intraoperative adverse events (iAEs) are associated with adverse postoperative outcomes and cause a significant healthcare burden. However, a critical appraisal of iAEs is lacking. Considering the details of iAEs could benefit postoperative care. We comprehensively analyzed iAEs in a large series including all types of operations and their relation to postoperative complications. METHODS: All patients enrolled in the multicenter ClassIntra® validation study (NCT03009929) were included in this analysis. The surgical and anesthesia team prospectively recorded all iAEs. Two researchers, blinded to each other's ratings, appraised all recorded iAEs according to their origin into four categories: surgery, anesthesia, organization, or other, including subcategories such as organ injury, arrhythmia, or instrument failure. They further descriptively analyzed subcategories of all iAEs. Postoperative complications were assessed using the Comprehensive Complication Index (CCI®), a weighted sum of all postoperative complications according to the Clavien-Dindo classification. The association of iAE origins in addition to the severity grade of ClassIntra® on CCI® was assessed with a multivariable mixed-effects generalized linear regression analysis. RESULTS: Of 2520 included patients, 778 iAEs were recorded in 610 patients. The origin was surgical in 420 (54%), anesthesia in 283 (36%), organizational in 34 (4%), and other in 41 (5%) events. Bleeding (n = 217, 28%), hypotension (n = 118, 15%), and organ injury (n = 98, 13%) were the three most frequent subcategories in surgery and anesthesia, respectively. In the multivariable mixed-effect analysis, no significant association between the origin and CCI® was observed. CONCLUSION: Analyzing the type and origin of an iAE offers individualized and contextualized information. This detailed descriptive information can be used for targeted surveillance of intra- and postoperative care, even though the overall predictive value for postoperative events was not improved by adding the origin in addition to the severity grade.

Clinical Utility of Patient-Reported Outcome Measures Used for Tendon and Nerve Transfers for Tetraplegia in New Zealand.

Purpose: This study determines the clinical utility of patient-reported outcome measures used to measure outcomes of upper extremity (UE) reconstructive procedures in individuals with tetraplegia. The patient-reported outcome measures are the Canadian Occupational Performance Measure, the Capabilities of Upper Extremity Questionnaire (CUE-Q), and the Personal Wellbeing Index. Methods: Retrospective data of 43 individuals with spinal cord injury (SCI) levels C4-C7 tetraplegia, and American Spinal Injury Association Impairment Scale grades A-D who had upper limb reconstructive surgery were reviewed. Participants were grouped according to their SCI level and resultant surgical procedures into higher SCI severity and lower SCI severity groups. Results: The mean age of participants was 26.3 years (SD 13.4; range 13-64 years). The higher-severity SCI group required elbow and hand reconstruction surgery, whereas the lower-severity group only required hand reconstruction surgery. Important differences in Canadian Occupational Performance Measure priorities were identified between the higher and lower SCI severity groups. Question redundancy was evident with the CUE-Q. The self-report Personal Wellbeing Index captures the possible impacts of improved UE function on an individual's perceived sense of personal wellbeing. Conclusions: In this patient-reported outcome measure analysis, we found that the level of impairment influences patient priorities. Functional measures ought to consider UE impairment and personal wellbeing as a construct in this population, given the demands of surgery. Type of Study/Level of Evidence: Prognostic II.

WSES guidelines on blunt and penetrating bowel injury: diagnosis, investigations, and treatment.

The aim of this paper was to review the recent literature to create recommendations for the day-to-day diagnosis and surgical management of small bowel and colon injuries. Where knowledge gaps were identified, expert consensus was pursued during the 8th International Congress of the World Society of Emergency Surgery Annual (September 2021, Edinburgh). This process also aimed to guide future research.

The draining surgical wound post total hip and knee arthroplasty: what are my options? A narrative review.

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are successful orthopaedic procedures with an ever-increasing demand annually worldwide, and persistent wound drainage (PWD) is a well-known complication following these procedures. Despite many definitions for PWD having been proposed, a validated description remains elusive.PWD is a risk factor for periprosthetic joint infection (PJI). PJI is a devastating complication of THA and TKA, and a leading cause of revision surgery with dramatic morbidity and mortality and a significant burden on health socioeconomics.Prevention of PJI has become an essential focus in THA and TKA. Understanding the pathophysiology, risk factors and subsequent management of PWD may aid in decreasing the rate of PJI.Risk factors of PWD can be divided into modifiable and non-modifiable patient risk factors, pharmacological and surgical risk factors. No gold standard treatment protocol to address PWD exists; however, non-operative options progressing to surgical interventions have been described.The aim of this study was to review the current literature regarding PWD and consolidate the risk factors and management strategies available. Cite this article: EFORT Open Rev 2021;6:872-880. DOI: 10.1302/2058-5241.6.200054.

Deceitful red-flag: angina secondary to iron deficiency anaemia as a presenting complaint for underlying malignancy.

A 73-year-old man with an 8-week history of angina underwent an exercise tolerance test at the rapid access clinic, which indicated inducible ischaemia and he was subsequently referred for angiogram. His angiogram demonstrated no coronary pathology. It was later discovered that bloods taken on the day of the procedure showed a haemoglobin of 54 g/L (130-180 g/L). His haemoglobin used to book the angiogram 3 months before was 143 g/L. Following angiogram, a mass was identified in the right iliac fossa and CT scan confirmed a caecal tumour. The patient ultimately underwent a curative right hemicolectomy as an outpatient. The case is a reminder of the importance of basic preangiogram investigations, in particularly a full blood count, to rule-out angina secondary to anaemia through a low haemoglobin. Most importantly, it also questions when the appropriate time is for these investigations to be carried out, prior to coronary angiography.

Iatrogenic Nontraumatic CPAP-Induced Pneumocephalus in a Patient With Meningitis.

ABSTRACT: Pneumocephalus, or air within the cranium, can be caused by trauma, intracranial infections, or tumors, and can also occur as a complication of neurosurgery and lumbar puncture. Continuous positive airway pressure (CPAP) therapy can precipitate or worsen pneumocephalus in cases of known head trauma. However, nontraumatic pneumocephalus being caused by CPAP is a highly unexpected clinical event. We describe a case of a patient who presented with meningitis due to an atypical organism that usually resides in the oral cavity, and who developed nontraumatic pneumocephalus in the hospital due to CPAP therapy. The underlying cause, a cerebrospinal fluid leak, was likely the mediator for both pathologies. In the setting of the increasing prevalence of obstructive sleep apnea, physicians can benefit from being aware of this atypical presentation of meningitis and atypical complication of CPAP therapy.

Single cell RNA-seq reveals profound transcriptional similarity between Barrett's oesophagus and oesophageal submucosal glands.

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma. In this common condition, squamous epithelium in the oesophagus is replaced by columnar epithelium in response to acid reflux. Barrett's oesophagus is highly heterogeneous and its relationships to normal tissues are unclear. Here we investigate the cellular complexity of Barrett's oesophagus and the upper gastrointestinal tract using RNA-sequencing of single cells from multiple biopsies from six patients with Barrett's oesophagus and two patients without oesophageal pathology. We find that cell populations in Barrett's oesophagus, marked by LEFTY1 and OLFM4, exhibit a profound transcriptional overlap with oesophageal submucosal gland cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barrett's oesophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.

A Shared Decision Approach to Chronic Abdominal Pain Based on Cine-MRI: A Prospective Cohort Study.

OBJECTIVES: Chronic abdominal pain develops in 11-20% of patients undergoing abdominal surgery, partly owing to post-operative adhesions. In this study we evaluate results of a novel diagnostic and therapeutic approach for pain associated with adhesions. METHODS: Prospective cohort study including patients with a history of abdominal surgery referred to the outpatient clinic of a tertiary referral center for the evaluation of chronic abdominal pain. Subgroups were made based on outcome of adhesion mapping with cine-MRI and shared decision making. In operatively managed cases, anti-adhesion barriers were applied after adhesiolysis. Long-term results for pain were evaluated by a questionnaire. RESULTS: A total of 106 patients were recruited. Seventy-nine patients had adhesions on cine-MRI, 45 of whom underwent an operation. Response rate to follow-up questionnaire was 86.8%. In the operative group (Group 1), the number of negative laparoscopies was 3 (6%). After a median of 19 (range 6-47) months follow-up, 80.0% of patients in group 1 reported improvement of pain, compared with 42.9% in patients with adhesions on cine-MRI who declined surgery (group 2), and 26.3% in patients with no adhesions on cine-MRI (group 3), P = 0.002. Consultation of medical specialists was significantly lower in group 1 compared with groups 2 and 3 (35.7 vs. 65.2 vs. 58.8%; P = 0.023). CONCLUSION: We demonstrate long-term pain relief in two-thirds of patients with chronic pain likely caused by adhesions, using cine-MRI and a shared decision-making process. Long-term improvement of pain was achieved in 80% of patients who underwent surgery with concurrent application of an anti-adhesion barrier.

Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts.

Numerous studies have suggested that Cancer Initiating Cells (CIC) can be identified/enriched in cell populations obtained from solid tumors based on the expression of cell surface marker proteins. We used early passage primary cervix cancer xenografts to sort cells based on the expression of the intrinsic hypoxia marker Carbonic Anhydrase 9 (CA9) and tested their cancer initiation potential by limiting dilution assay. We demonstrated that CICs are significantly enriched in the CA9+ fraction in 5/6 models studied. Analyses of the expression of the stem cell markers Oct4, Notch1, Sca-1 & Bmi1 showed a trend toward an increase in the CA9+ populations, albeit not significant. We present evidence that enhanced autophagy does not play a role in the enhanced growth of the CA9+ cells. Our study suggests a direct in vivo functional link between hypoxic cells and CICs in primary cervix cancer xenografts.

Direct Tumor Embolization of Sinonasal Unclassified Spindle Cell Sarcoma with Onyx.

OBJECTIVES: To evaluate the use of a new tumor embolization agent, Onyx (Covidien, Dublin, Ireland), for the use of intraoperative embolization of a sinonasal unclassified spindle cell sarcoma. METHODS: A 45-year-old female patient presented to the rhinology clinic with a nasal mass. A biopsy revealed a highly vascular mass consistent with a sinonasal unclassified spindle cell sarcoma. Secondary to its extensive vascularity, the patient underwent preoperative transarterial embolization (TAE) before definitive resection. Due to complex vascular anatomy including feeding vessels emanating from intracranial circulation, incomplete embolization was achieved. Subsequently, intraoperative embolization with Onyx at the time of resection was performed. RESULTS: Intraoperative Onyx use resulted in almost complete devascularization of the tumor with decreased risk of intracranial embolization. CONCLUSIONS: Intraoperative embolization with Onyx after an incomplete TAE can be a safe and effective method of achieving near-total embolization of sinonasal tumors.

Biochemical and Structural Characterisation of DNA Ligases from Bacteria and Archaea.

DNA ligases are enzymes that seal breaks in the backbones of DNA, leading to them being essential for the survival of all organisms. DNA ligases have been studied from many different types of cells and organisms and shown to have diverse sizes and sequences, with well conserved specific sequences that are required for enzymatic activity. A significant number of DNA ligases have been isolated or prepared in recombinant forms and, here, we review their biochemical and structural characterisation. All DNA ligases contain an essential lysine that transfers an adenylate group from a co-factor to the 5'-phosphate of the DNA end that will ultimately be joined to the 3'-hydroxyl of the neighbouring DNA strand. The essential DNA ligases in bacteria use nicotinamide adenine dinucleotide ( ß -NAD+) as their co-factor whereas those that are essential in other cells use adenosine-5'-triphosphate (ATP) as their co-factor. This observation suggests that the essential bacterial enzyme could be targeted by novel antibiotics and the complex molecular structure of ß -NAD+ affords multiple opportunities for chemical modification. Several recent studies have synthesised novel derivatives and their biological activity against a range of DNA ligases has been evaluated as inhibitors for drug discovery and/or non-natural substrates for biochemical applications. Here, we review the recent advances that herald new opportunities to alter the biochemical activities of these important enzymes. The recent development of modified derivatives of nucleotides highlights that the continued combination of structural, biochemical and biophysical techniques will be useful in targeting these essential cellular enzymes.

Ku80 Counters Oxidative Stress-Induced DNA Damage and Cataract Formation in the Human Lens.

PURPOSE: Oxidative stress in the human lens leads to a wide range of damage including DNA strand breaks, which are likely to contribute to cataract formation. The protein Ku80 is a fundamental component of the nonhomologous end-joining pathway that repairs DNA double strand breaks. This study investigates the putative impact of Ku80 in cataract prevention in the human lens. METHODS: The present study used the human lens epithelial cell line FHL124 and whole human lens organ culture. Targeted siRNA was used to deplete Ku80, with Western blot and immunocytochemistry employed to assess Ku80 expression levels. Oxidative stress was induced with hydrogen peroxide and DNA strand breaks measured by alkaline comet assay and γH2AX foci counts. Visual quality of whole human lenses was measured with image analysis software. RESULTS: Expression of Ku80 was predominately found in the cell nucleus of both FHL124 cells and native human lens epithelium. Treatment of FHL124 cells and whole lens cultures with siRNA targeted against Ku80 resulted in a significant knockdown at the protein level. Application of oxidative stress (30 µM H2O2) created more DNA strand breaks when added to Ku80 knockdown cells than in scrambled siRNA control cells as determined by the alkaline comet assay and the number of γH2AX foci. In whole lens cultures, exposure to 1 mM H2O2 resulted in more lens opacity in Ku80 knockdown lenses than match-paired controls. CONCLUSIONS: Depletion of Ku80 in the lens through acute change or a consequence of aging is likely to increase levels of DNA strand breaks, which could negatively influence physiological function and promote lens opacity. It is therefore feasible that Ku80 plays a role in retarding cataract formation.

The determination of tRNALeu recognition nucleotides for Escherichia coli L/F transferase.

Escherichia coli leucyl/phenylalanyl-tRNA protein transferase catalyzes the tRNA-dependent post-translational addition of amino acids onto the N-terminus of a protein polypeptide substrate. Based on biochemical and structural studies, the current tRNA recognition model by L/F transferase involves the identity of the 3' aminoacyl adenosine and the sequence-independent docking of the D-stem of an aminoacyl-tRNA to the positively charged cluster on L/F transferase. However, this model does not explain the isoacceptor preference observed 40 yr ago. Using in vitro-transcribed tRNA and quantitative MALDI-ToF MS enzyme activity assays, we have confirmed that, indeed, there is a strong preference for the most abundant leucyl-tRNA, tRNA(Leu) (anticodon 5'-CAG-3') isoacceptor for L/F transferase activity. We further investigate the molecular mechanism for this preference using hybrid tRNA constructs. We identified two independent sequence elements in the acceptor stem of tRNA(Leu) (CAG)-a G3:C70 base pair and a set of 4 nt (C72, A4:U69, C68)-that are important for the optimal binding and catalysis by L/F transferase. This maps a more specific, sequence-dependent tRNA recognition model of L/F transferase than previously proposed.

Optimising assessment intervals improves visual outcomes in ranibizumab-treated age-related neovascular degeneration: using the stability phase as a benchmark.

BACKGROUND: To observe visual acuity change in the stability phase when follow-up intervals are decreased in ranibizumab-treated neovascular age-related macular degeneration (nvAMD). METHODS: Selection of patients was based on a review of a cohort of 189 eyes of 154 patients with nvAMD treated with intravitreal ranibizumab in routine clinical practice. Patients were transferred from a base hospital with a 8-week follow-up interval to a community eye clinic, enabling a new follow-up interval of 4 weeks. Staff, assessment, and treatment protocols were equivalent in the two centres. Patients were included when they were in the stability phase of treatment defined 1 month after having completed their three initiation treatments with ranibizumab. Each patient was required to have attended at least a further 12 visits; this means a follow-up time for a year or longer, consisting of six visits at the base hospital followed by six visits at the new eye clinic. The best-corrected visual acuity (BCVA), follow-up intervals and injection numbers were collected. RESULTS: Seventy-two eyes of 62 patients were included. The mean follow-up interval for the six visits in the base hospital was 56.81 days, and in the new eye centre 31.81 days. The BCVA loss in the base hospital was -1.13 letters, compared to a gain of +4.61 letters in the community eye clinic over the six visits. The number of ranibizumab injections was 3.67 in the base hospital, compared with 3.91 in the other centre over the respective periods. CONCLUSION: Visual acuity improves and severe visual loss decreases when follow-up intervals reduce from approximately 8 weeks to 4 weeks. Furthermore, using the stability phase to evaluate the outcome and effectiveness of our treatments for age-related macular degeneration appeared to be an efficient tool.

Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia.

Numerous studies have demonstrated the presence of cancer stem cells (CSCs) within solid tumors. Although the precursor of these cells is not clearly established, recent studies suggest that the phenotype of CSCs may be quite plastic and associated with the epithelial-to-mesenchymal transition (EMT). In patients, the presence of EMT and CSCs has been implicated in increased resistance to radiotherapy. Hypoxia, a negative prognostic factor for treatment success, is a potent driver of a multitude of molecular signalling pathways that allow cells to survive and thrive in the hostile tumor microenvironment and can induce EMT. Hypoxia also provides tumor cells with cues for maintenance of a stem-like state and may help to drive the linkage between EMT and CSCs. Understanding the biology of CSCs, the EMT phenotype and their implications in therapeutic relapse may provide crucial new approaches in the development of improved therapeutic strategies.

Atropine sulphate: rescue therapy for pyloric stenosis.

Infantile hypertrophic pyloric stenosis (IHPS) is a common condition which presents with non-bilious vomiting and failure to thrive secondary to gastric outlet obstruction. In the UK, management is by fluid resuscitation followed by pyloromyotomy. Incomplete myotomy complicates 0.3% of cases necessitating further surgery and exposing the patient to further risk. Medical management of IHPS with antimuscarinics to promote pyloric relaxation is a well-described treatment modality that is used as first-line therapy in some countries. The use of this technique is limited by the need for extended hospital admission with parenteral nutrition administration. We describe a case of IHPS complicated by incomplete pyloromyotomy and subsequently managed successfully by atropine sulphate therapy.

Investigations into the role of inflammation in normal tissue response to irradiation.

PURPOSE: Radiation-induced inflammation and production of reactive oxygen species (ROS) play a critical role in normal tissue response. In this study we have examined some aspects of these effects in lung and skin. METHODS: The superoxide dismutase (SOD) catalase mimetic, EUK-207, and genistein, an isoflavone with anti-inflammatory properties, were given post-irradiation and micronuclei (MN) formation was determined in cells derived from irradiated lung and skin. Changes in breathing rate were measured using a plethysmograph following irradiation of C57Bl6 mice knocked out for tumor necrosis factor (TNF)-alpha or its receptors, TNFR1/2, or treated with endotoxin (lipopolysaccharide - LPS). RESULTS: Both EUK-207 and genistein given after irradiation caused a large reduction in MN levels observed in lung cells during 14 weeks post-irradiation but ceasing treatment resulted in a rebound in MN levels at 28 weeks post-irradiation. In contrast, treatment with EUK-207 was largely ineffective in reducing MN observed in skin cells post-irradiation. Knock-out of TNF-alpha resulted in a reduced increase in breathing rate (peak at 12 weeks post-irradiation) relative to wild-type and TNFR1/2 knock-out. Treatment with LPS 1 h post-irradiation also reduced the increase in breathing rate. CONCLUSIONS: The increase in MN in lung cells after treatment with EUK-207 or genistein was stopped suggests that continuing ROS production contributes to DNA damage in lung cells over prolonged periods. That this effect was not seen in skin suggests this mechanism is less prominent in this tissue. The reduced level of radiation pneumonitis (as monitored by breathing rate changes) in animals knocked out for TNF-alpha suggests that this cytokine plays a significant role in inducing inflammation in lung following irradiation. The similar effect observed following LPS given post-irradiation suggests the possibility that such treatment modifies the long-term cyclic inflammatory response following irradiation in lungs.

Saccharomyces cerevisiae engineered to produce D-xylonate.

Saccharomyces cerevisiae was engineered to produce D-xylonate by introducing the Trichoderma reesei xyd1 gene, encoding a D-xylose dehydrogenase. D-xylonate was not toxic to S. cerevisiae, and the cells were able to export D-xylonate produced in the cytoplasm to the supernatant. Up to 3.8 g of D-xylonate per litre, at rates of 25-36 mg of D-xylonate per litre per hour, was produced. Up to 4.8 g of xylitol per litre was also produced. The yield of D-xylonate from D-xylose was approximately 0.4 g of D-xylonate per gramme of D-xylose consumed. Deletion of the aldose reductase encoding gene GRE3 in S. cerevisiae strains expressing xyd1 reduced xylitol production by 67%, increasing the yield of D-xylonate from D-xylose. However, D-xylose uptake was reduced compared to strains containing GRE3, and the total amount of D-xylonate produced was reduced. To determine whether the co-factor NADP+ was limiting for D-xylonate production the Escherichia coli transhydrogenase encoded by udhA, the Bacillus subtilis glyceraldehyde 3-phosphate dehydrogenase encoded by gapB or the S. cerevisiae glutamate dehydrogenase encoded by GDH2 was co-expressed with xyd1 in the parent and GRE3 deficient strains. Although each of these enzymes enhanced NADPH consumption on D-glucose, they did not enhance D-xylonate production, suggesting that NADP+ was not the main limitation in the current D-xylonate producing strains.