Developing a pathway for remote assessment of surgical wounds with partners in low- and middle-income countries: An approach for efficient trials and resilient perioperative systems

Background: Surgical site infection (SSI) is the most common complication of abdominal surgery, and commonly occurs after hospital discharge. When patients in low- and middle-income countries (LMICs) undergo surgery, they are three times more likely to have a SSI than patients in high-income countries. Returning to hospital for routine face-to-face follow-up is the accepted gold standard for diagnosing a SSI but can be challenging in many environments, and resource intensive for healthcare teams. Aims: The overall aim of this thesis was to develop a high-quality pathway for remote surgical wound assessment using telemedicine that can be delivered flexibly across diverse healthcare settings. First, I aimed to evaluate the feasibility and accuracy of telemedicine in the detection of SSI in existing data. Second, I aimed to explore the cross-cultural equivalence of a Wound Healing Questionnaire (WHQ) across several LMICs and make recommendations for its adaptation for use in global surgery research and practice. Third, I aimed to test the feasibility and accuracy of the adapted WHQ in diagnosis of SSI. Methods: The primary outcome of interest in this thesis was SSI reported up to 30-days after surgery using the US Centres for Disease Control criteria. First, I compared the rates of SSI using telemedicine to those with in-person review in two data sources: (A) an international cohort study of adult patients discharged from hospital before 30-days after abdominal surgery; (B) a systematic review with meta-analysis of rates of SSI detection conducted in accordance with PRIMSA guidelines (PROSPERO:192596). Second, to recommend adaptations to the WHQ outcome measure for global implementation, I conducted a mixed-methods study across seven LMICs. Qualitative data were obtained from interviews and focus groups with local researchers with deductive coding aligned to cognitive theory. Quantitative data were collected in a prospective cohort study and Rasch analysis was used to explore measurement properties of the WHQ. I triangulated these data to make recommendations for cross-cultural and cross-language adaptation. Third, I conducted a validation cohort study within a randomised trial (FALCON, NCT03700749) where consecutive patients undergoing abdominal surgery for a range of indications underwent telephone assessment with the WHQ (index test) up to 72-hours before their face-to-face assessment (reference test). I worked with Community Engagement and Involvement (CEI) partners to optimise the measurement pathway. Results: The SSI rate reported using telemedicine in the cohort data was lower than with in-person follow-up (11.1% versus 13.4%, p4 demonstrated sensitivity of 0.701 (0.610-0.792), specificity of 0.911 (0.878-0.9430), positive predictive value of 0.723 (0.633-0.814) and negative predictive value of 0.901 (0.867-0.935). Discussion: Current methods for remote detection of SSI are inadequate, missing 1 in 3 patients with infection. This thesis describes the adaptation and validation of the WHQ, demonstrating that a telephone pathway for wound assessment is feasible and moderately accurate. The adapted WHQ is now ready for global implementation in research and routine postoperative surveillance, using the co-designed toolkit to optimise local measurement processes

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARSCoV- 2 infection: an international cohort study.

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p<0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p<0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p<0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.pre-print450 K

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. Methods First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. Findings In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings. Interpretation The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs

Expression of hepatocyte growth factor-like protein in human wound tissue and its biological functionality in human keratinocytes

Hepatocyte growth factor-like protein (HGFl) and its receptor, Recepteur d'Origine Nantais (RON), have been implicated in the development of wound chronicity. HGFl and RON expression was detected in acute wound tissue, chronic wound tissue and in normal skin using quantitative polymerase chain reaction (Q-PCR). HGFl and RON expression was also assessed in chronic healing and chronic non-healing wound tissues using Q-PCR and immunohistochemical staining. Expression was similarly detected in the HaCaT immortalized human keratinocyte cell line using reverse transcription polymerase chain reaction (RT-PCR). rhHGFl was used to assess the impact of this molecule on HaCaT cell functionality using in vitro growth assays and electric cell-substrate impendence sensing (ECIS) migration assays. HGFl and RON transcript expression were significantly increased in acute wound tissue compared to chronic wound tissue and were also elevated, though non-significantly, in comparison to normal skin. Minimal expression was seen in both healing and non-healing chronic wounds. Treatment of HaCaT cells with rhHGFl had no effect on growth rates but did enhance cell migration. This effect was abolished by the addition of a phospholipase C gamma (PLCγ) small molecule inhibitor. The increased expression of HGFl and RON in acute, healing wounds and the pro-migratory effect of HGFl in an in vitro human keratinocyte model, may indicate a role for HGFl in active wound healing

Personalizing neoadjuvant chemotherapy for locally advanced colon cancer:protocols for the international phase III FOxTROT2 and FOxTROT3 randomized controlled trials

AIM: FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared with proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will aim to investigate NAC in older adults and those with frailty. FOxTROT3 will aim to assess whether intensified triplet NAC provides additional benefits over OxFp.METHOD: FOxTROT2 and FOxTROT3 are international, open-label, phase III randomized controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomized 2:1 to the intervention or control arm: 6 weeks of dose-adapted neoadjuvant OxFp versus STS in FOxTROT2 and 6 weeks of neoadjuvant modified oxaliplatin, 5-fluorouracil and irinotecan versus OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints.DISCUSSION: FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimize the use of NAC in CC.</p

Prognostic models for surgical-site infection in gastrointestinal surgery: systematic review

BACKGROUND: Identification of patients at high risk of surgical-site infection may allow clinicians to target interventions and monitoring to minimize associated morbidity. The aim of this systematic review was to identify and evaluate prognostic tools for the prediction of surgical-site infection in gastrointestinal surgery.METHODS: This systematic review sought to identify original studies describing the development and validation of prognostic models for 30-day SSI after gastrointestinal surgery (PROSPERO: CRD42022311019). MEDLINE, Embase, Global Health, and IEEE Xplore were searched from 1 January 2000 to 24 February 2022. Studies were excluded if prognostic models included postoperative parameters or were procedure specific. A narrative synthesis was performed, with sample-size sufficiency, discriminative ability (area under the receiver operating characteristic curve), and prognostic accuracy compared.RESULTS: Of 2249 records reviewed, 23 eligible prognostic models were identified. A total of 13 (57 per cent) reported no internal validation and only 4 (17 per cent) had undergone external validation. Most identified operative contamination (57 per cent, 13 of 23) and duration (52 per cent, 12 of 23) as important predictors; however, there remained substantial heterogeneity in other predictors identified (range 2-28). All models demonstrated a high risk of bias due to the analytic approach, with overall low applicability to an undifferentiated gastrointestinal surgical population. Model discrimination was reported in most studies (83 per cent, 19 of 23); however, calibration (22 per cent, 5 of 23) and prognostic accuracy (17 per cent, 4 of 23) were infrequently assessed. Of externally validated models (of which there were four), none displayed 'good' discrimination (area under the receiver operating characteristic curve greater than or equal to 0.7).CONCLUSION: The risk of surgical-site infection after gastrointestinal surgery is insufficiently described by existing risk-prediction tools, which are not suitable for routine use. Novel risk-stratification tools are required to target perioperative interventions and mitigate modifiable risk factors.</p

Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries : an international, prospective, cohort study

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restrictions. Methods This international, prospective, cohort study enrolled 20 006 adult (>= 18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index 60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926. Findings Of eligible patients awaiting surgery, 2003 (10middot0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16-30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0middot6% non-operation rate (26 of 4521), moderate lockdowns with a 5middot5% rate (201 of 3646; adjusted hazard ratio [HR] 0middot81, 95% CI 0middot77-0middot84; p Funding National Institute for Health Research Global Health Research Unit, Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, Medtronic, Sarcoma UK, The Urology Foundation, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.Peer reviewe

COVID-19-related absence among surgeons: development of an international surgical workforce prediction model

Background: During the initial COVID-19 outbreak up to 28.4 million elective operations were cancelled worldwide, in part owing to concerns that it would be unsustainable to maintain elective surgery capacity because of COVID-19-related surgeon absence. Although many hospitals are now recovering, surgical teams need strategies to prepare for future outbreaks. This study aimed to develop a framework to predict elective surgery capacity during future COVID-19 outbreaks. Methods: An international cross-sectional study determined real-world COVID-19-related absence rates among surgeons. COVID-19-related absences included sickness, self-isolation, shielding, and caring for family. To estimate elective surgical capacity during future outbreaks, an expert elicitation study was undertaken with senior surgeons to determine the minimum surgical staff required to provide surgical services while maintaining a range of elective surgery volumes (0, 25, 50 or 75 per cent). Results: Based on data from 364 hospitals across 65 countries, the COVID-19-related absence rate during the initial 6 weeks of the outbreak ranged from 20.5 to 24.7 per cent (mean average fortnightly). In weeks 7-12, this decreased to 9.2-13.8 per cent. At all times during the COVID-19 outbreak there was predicted to be sufficient surgical staff available to maintain at least 75 per cent of regular elective surgical volume. Overall, there was predicted capacity for surgeon redeployment to support the wider hospital response to COVID-19. Conclusion: This framework will inform elective surgical service planning during future COVID-19 outbreaks. In most settings, surgeon absence is unlikely to be the factor limiting elective surgery capacit

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05-1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4-7 days or >= 8 days of 1.25 (1.04-1.48), p = 0.015 and 1.31 (1.11-1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care