Electrochemical control of organic reactions involving phase transfer

Phase transfer catalysis reactions are reactions where the reactants are soluble in different solvents. The phase transfer catalyst facilitates the transfer of a reactant from one phase to another, hence enabling the reaction. This can be explained electrochemically: By partitioning between the phases, the catalyst establishes a potential difference across the interface, which drives the transfer of reagent into the other phase (usually an inorganic anion is being transferred into the organic phase), or controls the reaction at the interface. A similar potential difference can also be applied with electrochemical instrumentation and the reactions can be investigated in electrochemical systems. Electrochemistry at ITIES (Interface between Two Immiscible Electrolyte Solutions) provides a fast, convenient and simple way of investigating the electrochemistry of a synthetic phase transfer reaction. The organic syntheses were also carried out to confirm the electrochemical results. Using an SN2 reaction involving a catalytic step, it has been shown how to use electrochemical measurements of ion transfer across the aqueous-organic interface to understand the reactions following this ion transfer. The reaction investigated was the reaction between 2-bromo-3-methyl butyric acid and iodide and hydroxide. The experiments show that mechanistic details of consecutive steps in organic reactions, inseparable when carrying out the organic experiments, can be observed when the reaction is carried out electrochemically. Another reaction that has been investigated is a two-phase oxidation reaction, where cis-cyclooctene in an organic solvent is oxidised by aqueous permanganate. These experiments prove that ITIES can be used for investigations of two-phase reactions, which are too slow to be investigated on a normal cyclovoltammetric timescale. Again, the first reaction step can be investigated separately. In synthetic methods the further reaction of the intermediate makes the determination of the rate constant of the initial step difficult, whereas this rate constant is obtainable through simulations of the electrochemical experiments. Also, the experiments show that through electrochemical experiments at a liquid-liquid interface, it is possible to determine in which phase the initial step of a two-phase reaction takes place. An SN1 reaction has been investigated using synthetic methods. SN1 reactions with a chiral substrate normally proceed by racemisation. The reaction chosen was the hydrolysis of [alpha]-phenylethyl chloride. By using a two-phase system the reaction mechanism was altered to preserve optical rotation through inversion of configuration

Design and synthesis of ferrocene probe molecules for detection by electrochemical methods

A series of ferrocenyl conjugates to fatty acids have been designed and synthesized to establish the key properties required for use in biomolecular binding studies. Amperometric detection of the ferrocene conjugates was sought in the region of 0.3 V (vs Ag/AgCl) for use in protein/blood solutions. Different linkers and solubilizing moieties were incorporated to produce a conjugate with optimal electrochemical properties. In electrochemical studies, the linker directly attached to the ferrocene was found to affect significantly the E 1/2 value and the stability of the ferrocenium cation. Ester-linked ferrocene conjugates had E 1/2 ranging from +400 to +410 mV, while amide-linked compounds ranged from +350 to +370 mV and the amines +260 to +270 mV. Folding of long-chain substituents around the ferrocene, also significantly affected by the choice of linker, was inferred as a secondary effect that increased E 1/2. The stability of the ferrocenium cation decreased systematically as E 1/2 increased. Disubstituted ferrocene ester and amide conjugates, with oxidation potentials of +640 and +570 mV, respectively, showed only a barely discernible reduction wave in cyclic voltammetry at 50 mV/s. Electrochemical measurements identified two lead compounds with the common structural characteristics of an amide and carbamate linker (compounds 17 and 21) with a C 11 fatty acid chain attached. It is envisaged that such molecules can be used to mimic and study the biomolecular binding interaction between fatty acids and molecules such as human serum albumin

Techniques for mesoappendix transection and appendix resection: insights from the ESTES SnapAppy study

Introduction: Surgically managed appendicitis exhibits great heterogeneity in techniques for mesoappendix transection and appendix amputation from its base. It is unclear whether a particular surgical technique provides outcome benefit or reduces complications. Material and methods: We undertook a pre-specified subgroup analysis of all patients who underwent laparoscopic appendectomy at index admission during SnapAppy (ClinicalTrials.gov Registration: NCT04365491). We collected routine, anonymized observational data regarding surgical technique, patient demographics and indices of disease severity, without change to clinical care pathway or usual surgeon preference. Outcome measures of interest were the incidence of complications, unplanned reoperation, readmission, admission to the ICU, death, hospital length of stay, and procedure duration. We used Poisson regression models with robust standard errors to calculate incident rate ratios (IRRs) and 95% confidence intervals (CIs). Results: Three-thousand seven hundred sixty-eight consecutive adult patients, included from 71 centers in 14 countries, were followed up from date of admission for 90 days. The mesoappendix was divided hemostatically using electrocautery in 1564(69.4%) and an energy device in 688(30.5%). The appendix was amputated by division of its base between looped ligatures in 1379(37.0%), with a stapler in 1421(38.1%) and between clips in 929(24.9%). The technique for securely dividing the appendix at its base in acutely inflamed (AAST Grade 1) appendicitis was equally divided between division between looped ligatures, clips and stapled transection. However, the technique used differed in complicated appendicitis (AAST Grade 2 +) compared with uncomplicated (Grade 1), with a shift toward transection of the appendix base by stapler (58% vs. 38%; p < 0.001). While no statistical difference in outcomes could be detected between different techniques for division of appendix base, decreased risk of any [adjusted IRR (95% CI): 0.58 (0.41-0.82), p = 0.002] and severe [adjusted IRR (95% CI): 0.33 (0.11-0.96), p = 0.045] complications could be detected when using energy devices. Conclusions: Safe mesoappendix transection and appendix resection are accomplished using heterogeneous techniques. Technique selection for both mesoappendix transection and appendix resection correlates with AAST grade. Higher grade led to more ultrasonic tissue transection and stapled appendix resection. Higher AAST appendicitis grade also correlated with infection-related complication occurrence. Despite the overall well-tolerated heterogeneity of approaches to acute appendicitis, increasing disease acuity or complexity appears to encourage homogeneity of intraoperative surgical technique toward advanced adjuncts

Clinical practice selectively follows acute appendicitis guidelines

Introduction: Acute appendicitis is a common surgical emergency, and the standard approach to diagnosis and management has been codified in several practice guidelines. Adherence to these guidelines provides insight into independent surgical practice patterns and institutional resource constraints as impediments to best practice. We explored data from the recent ESTES SnapAppy observational cohort study to determine guideline compliance in contemporary practice to identify opportunities to close evidence-to-practice gaps. Methods: We undertook a preplanned analysis of the ESTES SnapAppy observational cohort study, identifying, at a patient level, congruence with, or deviation from WSES Jerusalem guidelines for the diagnosis and management of acute appendicitis and the Surviving Sepsis Campaign in our cohort. Compliance was then correlated with the incidence of postoperative complications. Results: Four thousand six hundred and thirteen (4613) consecutive adult and adolescent patients with acute appendicitis were followed from date of admission (November 1, 2020, and May 28, 2021) for 90 days. Patient-level compliance with guideline elements allowed patients to be grouped into those with full compliance (all 5 elements: 13%), partial compliance (1-4 elements: 87%) or noncompliance (0 elements: 0.2%). We identified an excess postoperative complication rate in patients who received noncompliant and partially compliant care, compared with those who received fully guideline-compliant care (36% and 16%, versus 7.3%, p < 0.001). Conclusions: The observed diagnostic and treatment practices of the participating institutions displayed variability in compliance with key recommendations from existing guidelines. In general, practice was congruent with recommendations for preoperative antibiotic surgical site infection prophylaxis administration, time to surgery, and operative approach. However, there remains opportunities for improvement in the choice of diagnostic imaging modality, postoperative antibiotic stewardship to timely discontinue prophylactic antibiotics, and the implementation of ambulatory treatment pathways for uncomplicated appendicitis in the healthy young adult

Graded operative autonomy in emergency appendectomy mirrors case-complexity: surgical training insights from the SnapAppy prospective observational study

Introduction: Surgical skill, a summation of acquired wisdom, deliberate practice and experience, has been linked to improved patient outcomes. Graded mentored exposure to pathologies and operative techniques is a cornerstone of surgical training. Appendectomy is one of the first procedures surgical trainees perform independently. We hypothesize that, given the embedded training ethos in surgery, coupled with the steep learning curve required to achieve trainer-recognition of independent competency, 'real-world' clinical outcomes following appendectomy for the treatment of acute appendicitis are operator agnostic. The principle of graded autonomy matches trainees with clinical conditions that they can manage independently, and increased complexity drives attending input or assumption of the technical aspects of care, and therefore, one cannot detect an impact of operator experience on outcomes. Materials and methods: This study is a subgroup analysis of the SnapAppy international time-bound prospective observational cohort study (ClinicalTrials.gov Trial #NCT04365491), including all consecutive patients aged ≥ 15 who underwent appendectomy for appendicitis during a three-month period in 2020-2021. Patient- and surgeon-specific variables, as well as 90-day postoperative outcomes, were collected. Patients were grouped based on operating surgeon experience (trainee only, trainee with direct attending supervision, attending only). Poisson and quantile regression models were used to (adjusted for patient-associated confounders) assess the relationship between surgical experience and postoperative complications or hospital length of stay (hLOS), respectively, adjusted for patient-associated confounders. The primary outcome of interest was any complications within 90 days. Results: A total of 4,347 patients from 71 centers in 14 countries were included. Patients operated on by trainees were younger (Median (IQR) 33 [24-46] vs 38 [26-55] years, p < 0.001), had lower ASA classifications (ASA ≥ 3: 6.6% vs 11.6%, p < 0.001) and fewer comorbidities compared to those operated on by attendings. Additionally, trainees operated alone on fewer patients with appendiceal perforation (AAST severity grade ≥ 3: 8.7% vs 15.6%, p < 0.001). Regression analyses revealed no association between operator experience and complications (IRR 1.03 95%CI 0.83-1.28 for trainee vs attending; IRR 1.13 95%CI 0.89-1.42 for supervised trainee vs attending) or hLOS. Conclusion: The linkage of case complexity with operator experience within the context of graduated autonomy is a central tenet of surgical training. Either subconsciously, or by design, patients operated on by trainees were younger, fitter and with earlier stage disease. At least in part, these explain why clinical outcomes following appendectomy do not differ depending on the experience of the operating surgeon

Surgical management of acute appendicitis during the European COVID-19 second wave: safe and effective

Introduction: The COVID-19 (SARS-CoV-2) pandemic drove acute care surgeons to pivot from long established practice patterns. Early safety concerns regarding increased postoperative complication risk in those with active COVID infection promoted antibiotic-driven non-operative therapy for select conditions ahead of an evidence-base. Our study assesses whether active or recent SARS-CoV-2 positivity increases hospital length of stay (LOS) or postoperative complications following appendectomy. Methods: Data were derived from the prospective multi-institutional observational SnapAppy cohort study. This preplanned data analysis assessed consecutive patients aged ≥ 15 years who underwent appendectomy for appendicitis (November 2020-May 2021). Patients were categorized based on SARS-CoV-2 seropositivity: no infection, active infection, and prior infection. Appendectomy method, LOS, and complications were abstracted. The association between SARS-CoV-2 seropositivity and complications was determined using Poisson regression, while the association with LOS was calculated using a quantile regression model. Results: Appendectomy for acute appendicitis was performed in 4047 patients during the second and third European COVID waves. The majority were SARS-CoV-2 uninfected (3861, 95.4%), while 70 (1.7%) were acutely SARS-CoV-2 positive, and 116 (2.8%) reported prior SARS-CoV-2 infection. After confounder adjustment, there was no statistically significant association between SARS-CoV-2 seropositivity and LOS, any complication, or severe complications. Conclusion: During sequential SARS-CoV-2 infection waves, neither active nor prior SARS-CoV-2 infection was associated with prolonged hospital LOS or postoperative complication. Despite early concerns regarding postoperative safety and outcome during active SARS-CoV-2 infection, no such association was noted for those with appendicitis who underwent operative management

Evaluation of the Panbio™ COVID-19 IgG rapid test device performance

Background: The Panbio™ COVID-19 IgG Rapid Test Device (“Panbio™”) detects IgG antibodies against the SARS-CoV-2 spike protein from viral infection or vaccination. Objectives: To determine the diagnostic sensitivity and specificity of the Panbio™ professional use test, using fingerstick whole blood and venous plasma. Study design: Fingerstick whole blood and venous plasma from each participant were tested with Panbio™ and compared against the SARS-CoV-2 IgG II assay on the Abbott Architect™ platform (Europe) or the equivalent AdviseDx SARS-CoV-2 IgG II Abbott Alinity i™ platform (US). 447 evaluable participants were enrolled across 6 US and 9 European clinical centers. Results: For unvaccinated participants with PCR-confirmed infection ≥21 days post-symptom onset, the Panbio™ sensitivity with fingerstick whole blood was 92.6 % (95 % CI: 85.9, 96.7), and the specificity was 97.0 % (95 % CI: 93.1, 99.0). For venous plasma, the sensitivity was 90.0 % (95 % CI: 79.5, 96.2) for participants with PCR-confirmed infection and symptom onset 22–180 days ago; the specificity was 96.3 % (92.2, 98.6). For vaccinated participants, the sensitivity was 98.4 % (95 % CI: 91.2, 100.0) for fingerstick whole blood and 96.7 % (95 % CI: 88.7, 99.6) for venous plasma. Conclusion: The Panbio™ test had high sensitivity and specificity for detecting IgG against the SARS-CoV-2 spike protein