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BACKGROUND: Ex vivo tissue morphometric (TM) measurements have been proposed as a quality marker for colorectal cancer (CRC) surgery. However, their survival associations require clarification. This study aimed to evaluate the feasibility of capturing TM measurements based on ex vivo fresh specimen images and explore the association between these TM measurements and survival outcomes. METHODS: A prospective cohort study at Concord Hospital, Sydney was conducted with Stage I to III CRC patients (2009-2019) who underwent an anterior resection (AR) or right hemicolectomy (RH). Using high-resolution digital photographs of fresh CRC specimens, ex vivo tissue morphometric (TM) measurements-resected mesentery area (TM A), distances from high vascular tie to tumour (TM B) and bowel wall (TM C), and bowel length (TM D)-were recorded using Image J. Overall survival (OS) and disease-free survival (DFS) estimates and their associations to clinicopathological variables were investigated with Kaplan-Meier and Cox regression analyses. Linear regression models tested association between TM measurements and lymph node (LN) yield. RESULTS: Of the 1,425 patients who underwent CRC surgery, TM measurements were performed on 312 patients, with an average age of 69.4 years (SD 12.3), of whom 52.9% were male. The majority had an AR (57.8%). Among AR patients, a 5-year OS rate of 77.4% and a DFS rate of 70.1% were observed, with TM measurements bearing no relationship to survival outcomes. Similarly, RH patients exhibited a 5-year OS rate of 67.2% and a DFS rate of 63.1%, with TM measurements again showing no association with survival. Only TM D (P = 0.02) measurements were associated with the number of LNs examined. CONCLUSION: This study successfully demonstrates the feasibility of measuring TM measurements on photographs of ex vivo fresh specimens following CRC surgery. The lack of association with survival outcomes questions the utility of TM measurements as a quality metric of CRC surgery.
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Colectomía , Neoplasias Colorrectales , Humanos , Masculino , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/mortalidad , Femenino , Anciano , Estudios Prospectivos , Tasa de Supervivencia , Pronóstico , Colectomía/métodos , Colectomía/mortalidad , Estudios de Seguimiento , Persona de Mediana Edad , Estudios de FactibilidadRESUMEN
Background: Postoperative pain following abdominal surgery is a significant obstacle to patient recovery, often necessitating high analgesic doses associated with adverse effects like cognitive impairment and cardiorespiratory depression. Reliable animal models are crucial for understanding the pathophysiology of post surgical pain and developing more effective pain-relieving strategies. Methods: We developed a mouse model to replicate peritoneal trauma induced by abdominal surgery. 30 C57BL/6 mice underwent laparotomy, with half undergoing standardised peritoneal abrasion and the rest serving as controls. Mouse recovery was assessed using two validated scoring systems of surgical recovery: Post surgery Severity Assessment (PSSA) and Mouse Grimace Score (MGS). Blood samples were taken for cytokine analysis. Adhesions were evaluated on day 6, and peritoneal tissue was examined for healing markers. Results: After laparotomy, all mice exhibited expected pain profiles. Mice with peritoneal abrasion had significantly higher PSSA (7.2 ± 1.2 vs 4.68 ± 0.82, p ≤ 0.001) and MGS scores (3.62 ± 0.74 vs 0.82 ± 0.40, p ≤ 0.05) with slower recovery. Serum inflammatory cytokine levels were significantly elevated in the abraded group, and adhesion formation was higher in this group. Immunohistochemical analysis showed significantly increased expression of α-SMA, CD31, CD68, and F4/80 in peritoneal tissue in the abraded group. Discussion: A mouse model involving laparotomy and standardised peritoneal abrasion replicates the expected pathophysiological changes following abdominal surgery. It will be a useful model for better understanding the mechanisms of post surgical pain and developing improved pain-relief strategies. It also has utility for the study of intra-abdominal adhesion formation. Key message: To understand the intricate relationship between peritoneal trauma-induced pain, cytokine response, and post-operative adhesion formation in mouse models for advancing therapeutic interventions and enhancing post-operative recovery outcomes.
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Objective: The Global IDEAL Sub-Framework Study aimed to combine the intended effects of the 2009/2019 IDEAL (Idea, Development, Exploration, Assessment, Long-term study) Framework recommendations on evaluating surgical innovation with the vision outlined by the 2015 Lancet Commission on Global Surgery to provide recommendations for evaluating surgical innovation in low-resource environments. Design: A mixture of methods including an online global survey and semistructured interviews (SSIs). Quantitative data were summarized with descriptive statistics and qualitative data were analyzed using the Framework Method. Participants: Surgeons and surgical researchers from any country. Main outcome measures: Findings were used to suggest the nature of adaptations to the IDEAL Framework to address the particular problems of evaluation in low-resource settings. Results: The online survey yielded 66 responses representing experience from 40 countries, and nine individual SSIs were conducted. Most respondents (n=49; 74.2%) had experience evaluating surgical technologies across a range of life cycle stages. Innovation was most frequently adopted based on colleague recommendation or clinical evaluation in other countries. Four themes emerged, centered around: frugal innovation in technological development; evaluating the same technology/innovation in different contexts; additional methodologies important in evaluation of surgical innovation in low/middle-income countries; and support for low-income country researchers along the evaluation pathway. Conclusions: The Global IDEAL Sub-Framework provides suggestions for modified IDEAL recommendations aimed at dealing with the special problems found in this setting. These will require validation in a stakeholder consensus forum, and qualitative assessment in pilot studies. From assisting researchers with identification of the correct evaluation stage, to providing context-specific recommendations relevant to the whole evaluation pathway, this process will aim to develop a comprehensive and applicable set of guidance that will benefit surgical innovation and patients globally.
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Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antracenos , Neoplasias Colorrectales , Febuxostat , Proteínas de Neoplasias , Perileno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Antracenos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Perileno/análogos & derivados , Perileno/farmacología , Febuxostat/farmacología , Febuxostat/uso terapéutico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Células HEK293 , Supervivencia Celular/efectos de los fármacos , Células HT29 , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are synthetic proteins capable of binding specific targets, with additional advantages over antibodies for targeting. We fabricated silica nanoparticles using a water-in-oil microemulsion technique, loaded them with the photosensitiser Foslip, and functionalised the surface with anti-CEA Affimers to facilitate fluorescence imaging and photodynamic therapy of colorectal cancer. CEA-specific fluorescence imaging and phototoxicity were quantified in colorectal cancer cell lines and a LS174T murine xenograft colorectal cancer model. Anti-CEA targeted nanoparticles exhibited CEA-specific fluorescence in the LoVo, LS174T and HCT116 cell lines when compared to control particles (p < 0.0001). No toxicity was observed in LS174T cancer mouse xenografts or other organs. Following photo-irradiation, the anti-CEA targeted particles caused significant cell death in LoVo (60%), LS174T (90%) and HCT116 (70%) compared to controls (p < 0.0001). Photodynamic therapy (PDT) at 24 h in vivo showed a 4-fold reduction in tumour volume compared to control mouse xenografts (p < 0.0001). This study demonstrates the efficacy of targeted fluorescence imaging and PDT using Foslip nanoparticles conjugated to anti-CEA Affimer nanoparticles in in vitro and in vivo colorectal cancer models.
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Neoplasias Colorrectales , Mesoporfirinas , Nanopartículas , Humanos , Animales , Ratones , Antígeno Carcinoembrionario , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Nanopartículas/uso terapéuticoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour-stromal cell interactions. So far, the pre-clinical studies have suggested that PDT can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. However, the complexity of this interplay, including the combined tumour promoting and suppressing effects, poses unknowns for the clinical application of photodynamic stromal depletion in PDAC.
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We developed a carcinoembryonic antigen (CEA) conjugated polymer nanoparticle (CPN510-CEA-Af) probe to target CEA-expressing CRC cells in vitro. Its efficacy was evaluated in 2D and 3D cultures of LS174T, LoVo, and HT29 CRC cell lines. CPN510-CEA-Af produced greater fluorescent signal intensity than unconjugated particles in both 2D cells and 3D spheriods, indicating its potential as a probe for image-guided colorectal cancer surgery.
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Neoplasias Colorrectales , Nanopartículas , Humanos , Antígeno Carcinoembrionario , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/metabolismo , Células HT29 , Colorantes Fluorescentes , PolímerosRESUMEN
Contactless photoplethysmography (cPPG) is a method of physiological monitoring. It differs from conventional monitoring methods (e.g., saturation probe) by ensuring no contact with the subject by use of a camera. The majority of research on cPPG is conducted in a laboratory setting or in healthy populations. This review aims to evaluate the current literature on monitoring using cPPG in adults within a clinical setting. Adhering to the Preferred Items for Systematic Reviews and Meta-analysis (PRISMA, 2020) guidelines, OVID, Webofscience, Cochrane library, and clinicaltrials.org were systematically searched by two researchers. Research articles using cPPG for monitoring purposes in adults within a clinical setting were selected. Twelve studies with a total of 654 individuals were included. Heart rate (HR) was the most investigated vital sign (n = 8) followed by respiratory rate ((n = 2), Sp02 (n = 2), and HR variability (n = 2). Four studies were included in a meta-analysis of HR compared to ECG data which demonstrated a mean bias of -0.13 (95% CI, -1.22-0.96). This study demonstrates cPPG can be a useful tool in the remote monitoring of patients and has demonstrated accuracy for HR. However, further research is needed into the clinical applications of this method.
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BACKGROUND: Postoperative complications are common, but there are limited data regarding their implications on patients' quality of life. This study aimed to address this gap in the literature by analysing the impact of postoperative complications on patients' health-related quality of life. METHODS: Data from the Perioperative Quality Improvement Programme were analysed, and included patient-level data for 19 685 adults who underwent elective major abdominal procedures in England since 2016. Postoperative complications were graded using the Clavien-Dindo classification. Quality of life was assessed by responses to the EuroQol five-dimension five-levels-of-response (EQ-5D-5L™) questionnaire before surgery, and at 6 and 12 months after operation. Ordinal logistic regression was used to estimate the association between Clavien-Dindo grades and quality of life. Tobit and ordinary least squares regression analyses were used to estimate the quality-adjusted life-year (QALY) loss resulting from postoperative complications between admission and 12 months after surgery. RESULTS: At 6 and 12 months after surgery, increasingly severe postoperative complications were significantly associated with poorer health-related quality of life. The effect of postoperative complications on quality of life was sustained until at least 12 months after operation. Between admission and 12 months after surgery, 0.012, 0.026, 0.033, and 0.086 QALYs were lost for those experiencing a grade I, II, III, or IV postoperative complication respectively. CONCLUSION: Postoperative complications have a significant and sustained effect on patients' quality of life after surgery; this effect worsens as the severity of the complications increases.
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This paper presents the engineering and validation of an enabling technology that facilitates new capabilities in in vitro cell models for high-throughput screening and tissue engineering applications. This is conducted through a computerized system that allows the design and deposition of high-fidelity microscale patterned coatings that selectively alter the chemical and topographical properties of cell culturing surfaces. Significantly, compared to alternative methods for microscale surface patterning, this is a digitally controlled and automated process thereby allowing scientists to rapidly create and explore an almost infinite range of cell culture patterns. This new capability is experimentally validated across six different cell lines demonstrating how the precise microscale deposition of these patterned coatings can influence spatiotemporal growth and movement of endothelial, fibroblast, neuronal and macrophage cells. To further demonstrate this platform, more complex patterns are then created and shown to guide the behavioral response of colorectal carcinoma cells.
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Técnicas de Cultivo de Célula , Ingeniería de Tejidos , Ingeniería de Tejidos/métodos , Técnicas de Cultivo de Célula/métodos , Células Cultivadas , Fibroblastos , Línea CelularRESUMEN
BACKGROUND: Surgical interventions are complex. Key elements of this complexity are the surgeon and their learning curve. They pose methodological challenges in the design, analysis and interpretation of surgical RCTs. We identify, summarise, and critically examine current guidance about how to incorporate learning curves in the design and analysis of RCTs in surgery. EXAMINING CURRENT GUIDANCE: Current guidance presumes that randomisation must be between levels of just one treatment component, and that the evaluation of comparative effectiveness will be made via the average treatment effect (ATE). It considers how learning effects affect the ATE, and suggests solutions which seek to define the target population such that the ATE is a meaningful quantity to guide practice. We argue that these are solutions to a flawed formulation of the problem, and are inadequate for policymaking in this setting. REFORMULATING THE PROBLEM: The premise that surgical RCTs are limited to single-component comparisons, evaluated via the ATE, has skewed the methodological discussion. Forcing a multi-component intervention, such as surgery, into the framework of the conventional RCT design ignores its factorial nature. We briefly discuss the multiphase optimisation strategy (MOST), which for a Stage 3 trial would endorse a factorial design. This would provide a wealth of information to inform nuanced policy but would likely be infeasible in this setting. We discuss in more depth the benefits of targeting the ATE conditional on operating surgeon experience (CATE). The value of estimating the CATE for exploring learning effects has been previously recognised, but with discussion limited to analysis methods only. The robustness and precision of such analyses can be ensured via the trial design, and we argue that trial designs targeting CATE represent a clear gap in current guidance. CONCLUSION: Trial designs that facilitate robust, precise estimation of the CATE would allow for more nuanced policymaking, leading to patient benefit. No such designs are currently forthcoming. Further research in trial design to facilitate the estimation of the CATE is needed.
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Proyectos de Investigación , Cirujanos , Humanos , Curva de AprendizajeRESUMEN
Objectives: This study examines the conduct of systematic reviews during the early stages of the COVID-19 pandemic, including compliance to protocol registration and duplication of reviews on similar topics. The methodological and reporting quality were also explored. Methods: A cross-sectional, bibliometric study was undertaken of all systematic review manuscripts on a COVID-19 intervention published between January 1st and June 30th, 2020. Protocol registration on a publicly accessible database was recorded. Duplication was determined by systematically recording the number of reviews published on each topic of analysis. Methodological quality and reporting quality were assessed using the AMSTAR-2 and PRISMA 2009 instruments, respectively. Results: Thirty-one eligible systematic reviews were identified during the inclusion period. The protocol of only four (12.9%) studies was registered on a publicly accessible database. Duplication was frequent, with 15 (48.4%) of the 31 included studies focusing on either hydroxychloroquine (and/or chloroquine) or corticosteroids. Only one study (3.2%) was of "high" methodological quality, four (12.9%) were "low" quality, and the remainder (n = 26, 83.9%) were of "critically low" quality. The median completeness of reporting was 20 out of 27 items (74.1%) with a range of 5-26 (interquartile range: 14-23). Conclusion: Systematic reviews during the early stages of the COVID-19 pandemic were uncommonly registered, frequently duplicated, and mostly of low methodological quality. In contrast, the reporting quality of manuscripts was generally good but varied substantially across published reports. There is a need for heightened stewardship of systematic review research, particularly during times of medical crisis where the generation of primary evidence may be rapid and unstable.
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BACKGROUND: Medical technologies have the potential to improve quality and efficiency of healthcare. The design of clinical trials should consider participants' perspectives to optimise enrolment, engagement and satisfaction. This study aims to assess patients' perceptions of their involvement in medical device trials, to inform the designs of future medical technology implementation and evaluation. METHODS: Four focus groups were undertaken with a total of 16 participants who had participated in a study testing hospital inpatient remote monitoring devices. Interviews were audio-recorded, transcribed verbatim and underwent thematic analysis. RESULTS: Four main themes emerged: patients' motivations for participating in medical device research; patients' perceptions of technology in medicine; patients' understanding of trial methodology; and patients' perceptions of the benefits of involvement in medical device trials. The appeal of new technology is a contributing factor to the decision to consent, although concerns remain regarding risks associated with technology in healthcare settings. Perceived benefits of participating in device trials include extra care, social benefits and comradery with other participants seen using the devices, although there is a perceived lack of confidence in using technology amongst older patients. CONCLUSION: Future device trials should prioritise information sharing with participants both before and after the trial. Verbal and written information alongside practical demonstrations can help to combat a lack of confidence with technology. Randomised trials and those with placebo- or sham-controlled arms should not be considered as barriers to participation. Study results should be disseminated to participants in lay format as soon as possible, subject to participant permission.
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Investigación Biomédica , Humanos , Grupos FocalesRESUMEN
Photodynamic therapy (PDT) offers several advantages for treating cancers, but its efficacy is highly dependent on light delivery to activate a photosensitizer. Advances in wireless technologies enable remote delivery of light to tumors, but suffer from key limitations, including low levels of tissue penetration and photosensitizer activation. Here, we introduce DeepLabCut (DLC)-informed low-power wireless telemetry with an integrated thermal/light simulation platform that overcomes the above constraints. The simulator produces an optimized combination of wavelengths and light sources, and DLC-assisted wireless telemetry uses the parameters from the simulator to enable adequate illumination of tumors through high-throughput (<20 mice) and multi-wavelength operation. Together, they establish a range of guidelines for effective PDT regimen design. In vivo Hypericin and Foscan mediated PDT, using cancer xenograft models, demonstrates substantial suppression of tumor growth, warranting further investigation in research and/or clinical settings.
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Neoplasias , Fotoquimioterapia , Animales , Inteligencia Artificial , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , TelemetríaRESUMEN
BACKGROUND: The c-Met protein is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. METHODS: HT-29 SiRNA transfection confirmed specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in BALB/c mice, EMI-137 was injected and biodistribution analysed through in vivo fluorescent imaging. Nine patients, received a single intravenous EMI-137 bolus (0.13 mg/kg), 1-3 h before laparoscopic-assisted colon cancer surgery (NCT03360461). Tumour and LN fluorescence was assessed intraoperatively and correlated with c-Met expression in eight samples by immunohistochemistry. FINDINGS: c-Met expression HT-29 cells was silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed up to 6 h post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all participants, 4/9 showed increased tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited high c-Met protein expression. INTERPRETATION: EMI-137, binds specifically to the human c-Met protein, is safe, and with further refinement, shows potential for application in fluorescence-guided surgery.
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Colectomía , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/cirugía , Imagen Óptica , Proteínas Proto-Oncogénicas c-met/metabolismo , Anciano , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Femenino , Fluorescencia , Humanos , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
PURPOSE: The primary aim was to explore the perceived barriers that lower limb amputees and service providers face when accessing or providing rehabilitation services. The secondary aim was to describe the lower limb amputations performed in public hospitals in the Western Area of Sierra Leone in 2018. MATERIALS AND METHODS: A mixed methodology was employed, involving the collection of amputation data from surgical logbooks and interviews with amputees (n = 10) and group discussion and interviews with service providers (n = 11). RESULTS: Of the 37 primary lower limb amputations (49% men, 51% women; median age 56 years; 62% transtibial and 35% transfemoral amputations) 86% were for diabetic and vascular causes. Barriers to accessing services included poor transportation access, high service fees, rural living, gender and a lack of government support. Insufficient funding and supplies, skilled staff shortages and a lack of local training programmes were frequently reported barriers to providing rehabilitation services. CONCLUSIONS: A low prioritisation means rehabilitation services are underfunded, resulting in numerous barriers to both accessing and providing amputee rehabilitation services. Subsidised services and an outreach programme may improve access for patients. Increased funding and local training programmes are needed to improve service delivery.Implications for RehabilitationComprehensive and accessible amputee rehabilitation services can enable people with amputations to regain their independence and aid their participation in their community and workplace.There are numerous barriers to both accessing and providing amputee rehabilitation services in the Western Area, Sierra Leone, chiefly financial. We recommend a revised effort by the Sierra Leonean government to implement the progressive policies on disability they have already adopted into law, which will aid the improvement of amputee rehabilitation services. New education and training programmes for all levels of prosthetic and orthotic professions are needed to secure the future of prosthetics and orthotics in Sierra Leone.
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Amputados , Miembros Artificiales , Amputación Quirúrgica/rehabilitación , Amputados/rehabilitación , Femenino , Humanos , Extremidad Inferior/cirugía , Masculino , Persona de Mediana Edad , Sierra LeonaRESUMEN
BACKGROUND: Chronic wounds pose a significant healthcare burden in low- and middle-income countries. Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, causes wounds with high morbidity and financial burden. Although highly endemic in West and Central Africa, the presence of BU in Sierra Leone is not well described. This study aimed to confirm or exclude BU in suspected cases of chronic wounds presenting to Masanga Hospital, Sierra Leone. METHODOLOGY: Demographics, baseline clinical data, and quality of life scores were collected from patients with wounds suspected to be BU. Wound tissue samples were acquired and transported to the Swiss Tropical and Public Health Institute, Switzerland, for analysis to detect Mycobacterium ulcerans using qPCR, microscopic smear examination, and histopathology, as per World Health Organization (WHO) recommendations. FINDINGS: Twenty-one participants with wounds suspected to be BU were enrolled over 4-weeks (Feb-March 2019). Participants were predominantly young working males (62% male, 38% female, mean 35yrs, 90% employed in an occupation or as a student) with large, single, ulcerating wounds (mean diameter 9.4cm, 86% single wound) exclusively of the lower limbs (60% foot, 40% lower leg) present for a mean 15 months. The majority reported frequent exposure to water outdoors (76%). Self-reports of over-the-counter antibiotic use prior to presentation was high (81%), as was history of trauma (38%) and surgical interventions prior to enrolment (48%). Regarding laboratory investigation, all samples were negative for BU by microscopy, histopathology, and qPCR. Histopathology analysis revealed heavy bacterial load in many of the samples. The study had excellent participant recruitment, however follow-up proved difficult. CONCLUSIONS: BU was not confirmed as a cause of chronic ulceration in our cohort of suspected cases, as judged by laboratory analysis according to WHO standards. This does not exclude the presence of BU in the region, and the definitive cause of these treatment-resistance chronic wounds is uncertain.
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Úlcera de Buruli/microbiología , Mycobacterium ulcerans/aislamiento & purificación , Enfermedades Desatendidas/microbiología , Heridas y Lesiones/microbiología , Adolescente , Adulto , Anciano , Antibacterianos/uso terapéutico , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/epidemiología , Enfermedad Crónica/epidemiología , Estudios de Cohortes , Femenino , Hospitales/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium ulcerans/efectos de los fármacos , Mycobacterium ulcerans/genética , Mycobacterium ulcerans/fisiología , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/epidemiología , Sierra Leona/epidemiología , Heridas y Lesiones/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Ileus is a common and distressing condition characterised by gut dysfunction after surgery. While a number of interventions have aimed to curtail its impact on patients and healthcare systems, ileus is still an unmet challenge. Electrical stimulation of the vagus nerve is a promising new treatment due to its role in modulating the neuro-immune axis through a novel anti-inflammatory reflex. The protocol for a feasibility study of non-invasive vagus nerve stimulation (nVNS), and a programme of mechanistic and qualitative studies, is described. METHODS AND ANALYSIS: This is a participant-blinded, parallel-group, randomised, sham-controlled feasibility trial (IDEAL Stage 2b) of self-administered nVNS. One hundred forty patients planned for elective, minimally invasive, colorectal surgery will be randomised to four schedules of nVNS before and after surgery. Feasibility outcomes include assessments of recruitment and attrition, adequacy of blinding and compliance to the intervention. Clinical outcomes include bowel function and length of hospital stay. A series of mechanistic substudies exploring the impact of nVNS on inflammation and bowel motility will inform the design of the final stimulation schedule. Semistructured interviews with participants will explore experiences and perceptions of the intervention, while interviews with patients who decline participation will explore barriers to recruitment. ETHICS AND DISSEMINATION: The protocol has been approved by the Tyne and Wear South National Health Service (NHS) Research Ethics Committee (19/NE/0217) on 2 July 2019. Feasibility, mechanistic and qualitative findings will be disseminated to national and international partners through peer-reviewed publications, academic conferences, social media channels and stakeholder engagement activities. The findings will build a case for or against progression to a definitive randomised assessment as well as informing key elements of study design. TRIAL REGISTRATION NUMBER: ISRCTN62033341.
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Cirugía Colorrectal , Ileus , Estimulación del Nervio Vago , Estudios de Factibilidad , Humanos , Ileus/etiología , Ileus/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Medicina Estatal , Resultado del TratamientoRESUMEN
The transmembrane protein, c-Met, is thought to be overexpressed and activated in colorectal cancer (CRC). This study explored its potential as a diagnostic tissue biomarker for CRC in a large human CRC tissue collection obtained from a randomized clinical trial. Tissue microarrays of matched normal colorectal epithelium and primary cancer were prepared from specimens obtained from 280 patients recruited to the MRC CLASICC trial (ISRCTN 74883561) and interrogated using immunohistochemistry for c-Met expression. The distribution and intensity of immunopositivity was graded using a validated, semi-quantifiable score, and differences in median scores analysed using the Wilcoxon signed-rank test. A receiver operating characteristic (ROC) curve was plotted to measure the diagnostic accuracy of c-Met as a biomarker in CRC. Epithelial cell membrane expression of c-Met differed significantly between CRC and normal colorectal tissue: median 12.00 (Interquartile range (IQR) 6-15) versus median 6.00 (IQR 2.70-12.00) respectively (P = <.0001). ROC-AUC analysis of c-Met expression yielded a CRC diagnostic probability of 0.66 (95% CI: 0.61 to 0.70; P < .0001). A score of ≥14.50 showed high specificity at 85.32% (95% CI 80.33%-89.45%) but sensitivity of only 30.92% (CI 25.37%-36.90%). Thus c-Met is consistently overexpressed in human CRC as compared to normal colorectal epithelium tissue. c-Met expression may have a role in diagnosis and prognostication if combined with other biomarkers.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Proteínas Proto-Oncogénicas c-met/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-met/análisisRESUMEN
Scleroderma is a chronic autoimmune disorder involving multiple organs and very commonly the gastrointestinal (GI) system; nevertheless, data on the involvement of the anal sphincter and consequent faecal incontinence (FI) are inadequate. FI in scleroderma was first reported in 1994 by Engel and colleagues, but its impact of added health care costs and declining quality of life (QoL) is poorly determined. Up to 40% of patients with GI involvement complain of FI, however, the quality of data available is poor owing to majority of the studies being retrospective and case reports or series of small study size. A direct involvement of internal anal sphincter muscularis propria has been demonstrated on anorectal ultrasound imaging suggesting a thin, atrophic or scarred internal sphincter. Treatment guidelines for incontinence in scleroderma are mainly symptomatic, with radical surgeries burdened by poor outcomes. Sacral neuromodulation is being used with good outcomes in a subgroup of patients, but larger, controlled studies are required to assess its efficacy on symptoms and prognosis.