Flavonoids and post haemorrhoidectomy recovery: a systematic review and meta-analysis.

BACKGROUND: Haemorrhoidectomy is the gold standard for definitive treatment of high-grade symptomatic haemorrhoids but is often associated with substantial pain. This systematic review aims to explore the potential of flavonoids in alleviating the postoperative symptom burden following excisional haemorrhoidectomy. METHODS: A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD42023472711). Randomized controlled trials (RCTs) published PubMed, MEDLINE, Embase, and Scopus from inception to 1st December 2023 were retrieved. The primary outcome investigated was post-operative pain. Meta-analysis was performed using Review Manager version 5.4.1. RESULTS: Ten articles with 775 patients were included. The meta-analysis identified statistically significant decreases in post-operative pain in favour of the flavonoid groups (Standardized Mean Difference -0.66 [95% confidence intervals (CI) -0.82, -0.52]; P < 0.00001), and bleeding (Odds Ratio 0.13 [95% CI 0.09, 0.19]; P < 0.00001). CONCLUSION: Flavonoids show promise as a means of reducing pain associated with excisional haemorrhoidectomy. Further research is required to investigate topical routes of administration and standardize regimes.

Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study.

BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS: A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS: Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER: NCT02060188.

Association between frailty, long-term mortality and functional outcomes for older adults undergoing emergency laparotomy.

BACKGROUND: An increasing number of older patients are undergoing emergency laparotomy (EL). Frailty is thought to contribute to adverse outcomes in this group. The best method to assess frailty and impacts on long-term mortality and other important functional outcomes for older EL patients have not been fully explored. METHODS: A prospective multicenter study of older EL patients was conducted across four hospital sites in New Zealand from August 2017 to September 2022. The Clinical Frailty Scale (CFS) was used to measure frailty-defined as a CFS of ≥5. Primary outcomes were 30-day and one-year mortality. Secondary outcomes were postoperative morbidity, admission for rehabilitation, and increased care level on discharge. A multivariate logistic regression analysis was conducted, adjusting for age, sex, and ethnicity. RESULTS: A total of 629 participants were included. Frailty prevalence was 14.6%. Frail participants demonstrated higher 30-day and 1-year mortality-20.7% and 39.1%. Following adjustment, frailty was directly associated with a significantly increased risk of short- and long-term mortality (30-day aRR 2.6, 95% CI 1.5, 4.3, p = <0.001, 1-year aRR 2.0, 95% CI 1.5, 2.8, p < 0.001). Frailty was correlated with a 2-fold increased risk of admission for rehabilitation and propensity of being discharged to an increased level of care, complications, and readmission within 30 days. CONCLUSION: Frailty was associated with increased risk of postoperative mortality up to 1-year and other functional outcomes for older patients undergoing EL. Identification of frailty in older EL patients aids in patient-centered decision-making, which may lead to improvement in outcomes.

Robot-assisted general surgery in Aotearoa New Zealand.

Robot-assisted surgery refers to a surgeon controlling a robotic device that performs an operation. This viewpoint explores the current state of robot-assisted surgery in Aotearoa New Zealand using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, California, United States), the only currently available robotic surgical system for general surgery in the country. We describe the contemporary progress in Aotearoa New Zealand compared to Australia and globally, and present emerging high-level evidence from randomised controlled trials regarding the utility of the robot-assisted approach for general surgery procedures. From the available evidence, we suggest that the value of robot-assisted general surgery in the public healthcare system arises from its emerging clinical benefits for complex procedures and its potential to engender equitable access and outcomes, particularly for Maori and Pacific peoples, improve education and training and contribute towards quality assurance and workforce development. Therefore, its implementation aligns with the New Zealand Health Strategy's long-term goals and priority areas to achieve pae ora, healthy futures for all.

Catalytic C-H Trifluoromethylation of Arenes and Heteroarenes via Visible Light Photoexcitation of a Co(III)-CF3 Complex.

A cobalt photocatalyst for direct trifluoromethylation of (hetero)arene C(sp2)-H bonds is described and shown to operate via visible light activation of a Co-CF3 intermediate, which functions as a combined chromophore and organometallic reaction center. Chemical oxidations of previously reported (OCO)Co complexes containing a redox-active [OCO] pincer ligand afford a Co-CF3 complex two oxidation states above Co(II). Computational and spectroscopic studies are consistent with formulation of the product as [(OCO•)CoIII(CF3)(THF)(OTf)] (II) containing an open-shell [OCO•]1- radical ligand bound to a S = 0 Co(III) center. II is thermodynamically stable, but exposure to blue (440 nm) light induces Co-CF3 bond homolysis and release of •CF3, which is trapped by radical acceptors including TEMPO•, (hetero)arenes, or the radical [OCO•] ligand in II. The latter comprises a competitive degradation pathway, which is overcome under catalytic conditions by using excess substrate. Accordingly, generation of II from the reaction of [(OCO)CoIIL] (III) (L = THF, MeCN) with Umemoto's dibenzothiophenium trifluoromethylating reagent (1) followed by photolytic Co-CF3 bond activation completes a photoredox catalytic cycle for C-H (hetero)arene trifluoromethylation utilizing visible light. Electronic structure and photophysical studies, including time-dependent density functional theory (TDDFT) calculations, suggest that Co-CF3 bond homolysis at II occurs via an ligand-to-metal charge-transfer (LMCT) (OCO0)CoII(CF3) state, revealing ligand redox activity as a critical design feature and establishing design principles for the use of base metal chromophores for selectivity in photoredox bond activations occurring via free radical intermediates.

Consensus-defined sarcopenia predicts adverse outcomes after elective abdominal surgery: meta-analysis.

BACKGROUND: Sarcopenia refers to the progressive age- or pathology-associated loss of skeletal muscle. When measured radiologically as reduced muscle mass, sarcopenia has been shown to independently predict morbidity and mortality after elective abdominal surgery. However, the European Working Group on Sarcopenia in Older People (EWGSOP) recently updated their sarcopenia definition, emphasizing both low muscle 'strength' and 'mass'. The aim of this systematic review and meta-analysis was to determine the prognostic impact of this updated consensus definition of sarcopenia after elective abdominal surgery. METHODS: MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched for studies comparing prognostic outcomes between sarcopenic versus non-sarcopenic adults after elective abdominal surgery from inception to 15 June 2022. The primary outcomes were postoperative morbidity and mortality. Sensitivity analyses adjusting for confounding patient factors were also performed. Methodological quality assessment of studies was performed independently by two authors using the QUality in Prognosis Studies (QUIPS) tool. RESULTS: Twenty articles with 5421 patients (1059 sarcopenic and 4362 non-sarcopenic) were included. Sarcopenic patients were at significantly greater risk of incurring postoperative complications, despite adjusted multivariate analysis (adjusted OR 1.56, 95 per cent c.i. 1.39 to 1.76). Sarcopenic patients also had significantly higher rates of in-hospital (OR 7.62, 95 per cent c.i. 2.86 to 20.34), 30-day (OR 3.84, 95 per cent c.i. 1.27 to 11.64), and 90-day (OR 3.73, 95 per cent c.i. 1.19 to 11.70) mortality. Sarcopenia was an independent risk factor for poorer overall survival in multivariate Cox regression analysis (adjusted HR 1.28, 95 per cent c.i. 1.13 to 1.44). CONCLUSION: Consensus-defined sarcopenia provides important prognostic information after elective abdominal surgery and can be appropriately measured in the preoperative setting. Development of targeted exercise-based interventions that minimize sarcopenia may improve outcomes for patients who are undergoing elective abdominal surgery.

Weekend effect in emergency laparotomy: a propensity score-matched analysis.

BACKGROUND: The 'weekend effect' is the term given to the observed discrepancy regarding patient care and outcomes on weekends compared to weekdays. This study aimed to determine whether the weekend effect exists within Aotearoa New Zealand (AoNZ) for patients undergoing emergency laparotomy (EL), given recent advances in management of EL patients. METHODS: A cohort study was conducted across five hospitals, comparing the outcomes of weekend and weekday acute EL. A propensity-score matched analysis was used to remove potential confounding patient characteristics. RESULTS: Of the 487 patients included, 132 received EL over the weekend. There was no statistically significant difference between patients undergoing EL over the weekend compared to weekdays. Mortality rates were comparable between the weekday and weekend cohorts (P = 0.464). CONCLUSIONS: These results suggest that modern perioperative care practice in New Zealand obviates the 'weekend' effect.

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238.

PURPOSE: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. PATIENTS AND METHODS: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. RESULTS: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. CONCLUSIONS: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

BACKGROUND: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. METHODS: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. RESULTS: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). CONCLUSIONS: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02043665.

Increasing the Hydrophobic Component of Poloxamers and the Inclusion of Salt Extend the Release of Bupivacaine from Injectable In Situ Gels, While Common Polymer Additives Have Little Effect.

Various strategies have been applied to reduce the initial burst of drug release and sustain release from poloxamer-based thermoresponsive gels. This work focussed on investigating different formulation approaches to minimise the initial burst of release and sustain the release of the small hydrophilic drug bupivacaine hydrochloride from poloxamer-based thermoresponsive gels. Various in situ gel formulations were prepared by varying the polypropylene oxide (PPO)/polyethylene oxide (PEO) ratio and by adding additives previously described in the literature. It was observed that increasing the PPO/PEO ratio from 0.28 to 0.30 reduced the initial burst release from 17.3% ± 1.8 to 9.1% ± 1.2 during the first six hours and extended the release profile from 10 to 14 days. Notably, the inclusion of sodium chloride (NaCl 0.4% w/w) further reduced the initial burst release to 1.8% ± 1.1 over the first 6 h. Meanwhile, physical blending with additive polymers had a negligible effect on the burst release and overall release profile. The findings suggest that extended release of bupivacaine hydrochloride, with reduced initial burst release, can be achieved simply by increasing the PPO/PEO ratio and the inclusion of NaCl.

Have Factors Influencing Female Medical Students' Intention to Pursue a Career in Surgery Changed over the Last 10 Years? A Systematic Review.

In 2012, a systematic review reported on factors influencing female medical students, career intentions for surgery. This current review is a direct follow-up of that article with the aim of assessing whether factors affecting female medical student career choices have changed over the last decade. This review has identified access to research opportunities as a new factor that can be used to promote female medical student and trainee interest in surgery. Other factors have largely remained unchanged over the last 10 years, such as lack of access to leave, part-time work, and same-gender role models.

Investigating Predictors of Psychological Distress for Healthcare Workers in a Major Saudi COVID-19 Center.

This study investigated the relationship between fear of COVID-19, previous exposure to COVID-19, perceived vulnerability to disease, sleep quality, and psychological distress among healthcare workers (HCWs) in Taif city in Saudi Arabia, which has a population of 702,000 people. A cross-sectional study design was adopted. HCWs (n = 202) completed a survey containing the Fear of COVID-19 Scale (FCV-19S), Perceived Vulnerability to Disease (PVD), Pittsburgh Sleep Quality Index (PSQI), and Depression, Anxiety, and Stress Scale (DASS-21). FCV-19S and sleep quality were significant predictors for psychological distress. Female gender was a significant predictor for depression and stress. Single, divorced, and widowed marital status were predictive for anxiety. FCV-19S was weakly correlated with PVD but moderately with depression, anxiety, and stress. Of the two PVD subscales, perceived infectability was weakly correlated with psychological distress. PVD and previous experience with COVID-19 were not significant predictors. Sleep quality and FCV-19S were major predictors of psychological distress. Findings indicated that poor sleep quality was strongly associated with psychological distress, while fear of COVID-19 had a moderate association. Such results support the need to design and implement psychological programs to assist HCWs in dealing with the psychological impact of this ongoing pandemic.

Changing the routine: a move to patient initiated follow up to improve surgical outpatient clinic.

INTRODUCTION: Patient initiated follow up (PIFU) allows patients to initiate a hospital follow up appointment on an 'as required' basis in contrast to the traditional physician-initiated model. We present a clinical pathway for patients referred with rectal bleeding at a large tertiary public hospital in South Auckland, New Zealand and demonstrate the utility of PIFU and its impact on reducing follow up appointments. METHOD: The purpose of the pathway was to allow standardized care by the clinicians and allow for PIFU. Two separate protocols were developed - 'Painful PR bleeding' and 'Painless PR bleeding'. A new clinic (NC) was started following these protocols, and this was compared to historical controls (HC). The primary outcome was the rate of follow up appointments. RESULTS: There were 133 patients in the NC and 135 in the HC, with significantly less follow ups in the NC (6% versus 45%, p < 0.0001). A small percentage of patients in the NC group were directly discharged (10%) whilst 70% of patients were discharged with a PIFU card. Thirty phone calls were made using PIFU, with 10 patients returning to clinic and 20 requiring advice and reassurance only. At 5 year follow up, there was a single colorectal malignancy found in both groups. CONCLUSION: Initiating a protocol that includes patient initiated follow up vastly reduces the need for routine return to clinic for the majority of patients, without sacrificing patient care. A protocolised approach to clinic for other areas in general surgery should be considered.

Short- and long-term impact of sarcopenia on outcomes after emergency laparotomy: A systematic review and meta-analysis.

BACKGROUND: Sarcopenia refers to the progressive age and pathology-associated loss of skeletal muscle, which has been shown to independently predict mortality in patients undergoing major elective surgery. Emergency laparotomy is commonly performed for a range of procedures and is associated with high rates of mortality. However, the prognostic utility of sarcopenia after emergency laparotomy remains unknown. The aim of this study was to compare short and long-term survival between patients with and without sarcopenia undergoing emergency laparotomy. METHODS: MEDLINE, EMBASE, and Scopus databases were systematically searched for articles comparing survival outcomes between adults with and without radiologically defined sarcopenia after emergency gastrointestinal surgery regardless of indication and approach (open/laparoscopic). The primary outcome was postoperative mortality. Sensitivity analysis of adjusted multivariate analyses was performed. RESULTS: Twenty articles comprising 6,737 patients were included. Sarcopenia was most commonly assessed using axial abdominal computerized tomography at L3, although cut-off thresholds were heterogeneous and rarely sex-specific. Postoperative mortality was higher among patients with sarcopenia than without in the in-hospital setting, and at 30- and 90-day follow-up on univariate but not on multivariate meta-analysis. However, mortality was significantly higher among sarcopenic cohorts in the 1-year (odds ratio 2.8, 95% confidence interval: 1.5-5.6; P = .002) follow-up period, despite adjusting for confounding preoperative and patient factors. CONCLUSION: The meta-analysis has shown sarcopenia to provide useful long-term prognostic information following emergency laparotomy. This may aid with preoperative risk assessment, patient counseling, and in perioperative decision-making for patients undergoing emergency laparotomy.

A systematic review and network meta-analysis comparing treatments for anal fissure.

BACKGROUND: There are multiple treatments for anal fissures. These range from medical treatment to surgical procedures, such as sphincterotomy. The aim of this study was to compare the relative clinical outcomes and effectiveness of interventional treatments for anal fissure. METHODS: Randomized controlled trials were identified by means of a PRISMA-compliant systematic review using the Medline, EMBASE, and CENTRAL databases. Inclusion criteria were randomized controlled trials comparing treatments for anal fissure. A Bayesian network meta-analysis was performed using BUGSnet package in R. Outcomes of interest were healing (6-8-, 10-16-, and >16-week follow-up), symptom recurrence, pain (measured on a visual analog scale), and fecal or flatus incontinence. PROPSERO Registration: CRD42021229615. RESULTS: Sixty-nine randomized controlled trials were included in the analysis. Lateral sphincterotomy remains the treatment with the highest odds of healing compared to botulinum toxin and medical therapy at all follow-up time points. There was no significant difference in healing between botulinum toxin and medical therapy at any time point. Advancement flap showed similar effectiveness compared to lateral sphincterotomy. Medical treatment and botulinum toxin had the highest pain scores at follow-up. Sphincterotomy had the highest odds of fecal and flatus incontinence. CONCLUSION: Lateral sphincterotomy had the highest rates of healing and should be considered as the definitive treatment after failed initial therapy with botulinum toxin or medical treatment. Botulinum toxin was equally effective compared to medical treatment. Advancement flap shows similar effectiveness compared to lateral sphincterotomy, but more studies are needed to evaluate its efficacy.