Sensitivity of the Wound Edge Gene Signature “WD14” in Responding to Clinical Change: A Longitudinal Cohort Study

Introduction: Genetic prognostication of chronic wounds is one recognised method of early identification of clinical wound healing status in order to target rigorous and advanced treatment regimens to hard-to-heal wounds. The WounD14 (WD14) gene signature is a recently developed scoring tool, derived from genetic interrogation of wound edge biopsies. It has been shown to predict the propensity of chronic venous leg ulcers to heal. However, it is unknown how WD14 responds with time and to changes in clinical wound healing status. The aim of this pilot study was therefore to evaluate if changes in the clinical healing status of wounds were identified by WD14 gene signature changes. Methods: WD14 was developed through a process of gene screening, refining and subsequent validation in three separate patient cohorts. Validation was undertaken in 85 consecutive patients referred to a tertiary wound healing unit with chronic venous leg ulcers, who underwent a wound edge biopsy to interrogate for a ‘healing’ or ‘non-healing’ genotype. A smaller cohort of patients (18%) underwent a second biopsy, which comprises this pilot cohort reported herein. 12 weeks after the biopsy wounds were clinically assessed for healing status and compared to WD14 genotype. Results: Sequential biopsies and WD14 scores were obtained from 16 patients. WD14 gene signature predicted clinical wound healing status among this cohort at either visit (total analysis of 32 wound edge biopsies) with a positive predictive value (PPV) of 85.2% (95% CI 74.1% to 92.0%) and negative predictive value (NPV) of 80.0% (95% CI 34.2% to 96.9%). Six wounds altered their clinical status between the two visits; in this cohort WD14 has a PPV of 66.7% (95% CI 47.3% to 81.7%) and NPV of 100%. Conclusion: Although the WD14 gene signature did change with wound healing status, further and larger studies are required to clarify precisely the role of this gene signature and its ability to prognosticate accurately over time with wounds of differing clinical status

Sensitivity of the wound edge gene signature "WD14" in responding to clinical change: a longitudinal cohort study

Introduction: WounD14 (WD14) gene signature is a recently developed tool derived from genetic interrogation of wound edge biopsies of chronic venous leg ulcers to identify heard-to-heal wounds and enable clinicians to target aggressive therapies to promote wound healing. This study aimed to evaluate if changes in wound clinical healing status were detected by the WD14 gene signature over time as this is currently poorly understood. Material and methods: WD14 was developed through gene screening and subsequent validation in 3 patient cohorts involving 85 consecutive patients with chronic venous leg ulcers referred to a tertiary wound healing unit. Patients underwent a wound edge biopsy to interrogate for a “healing” or “non-healing” genotype. A smaller cohort (18%) underwent a second biopsy, which comprised this pilot cohort reported herein. Twelve weeks following biopsy, wounds were clinically assessed for healing status based on reduction in size and compared to WD14 genotype. Results: Sequential biopsies and WD14 scores were derived from 16 patients. WD14 signature predicted wound healing status among this cohort at either visit (32 wound edge biopsies) with a positive predictive value (PPV) of 85.2% (95% CI 74.1%-92.0%) and negative predictive value (NPV) of 80.0% (95% CI 34.2%-96.9%). A total of 6 wounds underwent altered clinical status between the 2 visits. In this cohort, WD14 has a PPV of 66.7% (95% CI 47.3%-81.7%) and NPV of 100%. Conclusion: Although the WD14 gene signature did change with wound healing status, larger studies are required to precisely clarify its role and ability to prognosticate wounds of differing clinical status over time

Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse

There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS. </jats:p

The perceived impact of the Covid-19 pandemic on medical student education and training – an international survey

Abstract: Background: The Covid-19 pandemic led to significant changes and disruptions to medical education worldwide. We evaluated medical student perceived views on training, their experiences and changes to teaching methods during the pandemic. Methods: An online survey of medical students was conducted in the Autumn of 2020. An international network of collaborators facilitated participant recruitment. Students were surveyed on their perceived overall impact of Covid-19 on their training and several exposure variables. Univariate analyses and adjusted multivariable analysis were performed to determine strengths in associations. Results: A total of 1604 eligible participants from 45 countries took part in this survey and 56.3% (n = 860) of these were female. The median age was 21 (Inter Quartile Range:21–23). Nearly half (49.6%, n = 796) of medical students were in their clinical years. The majority (n = 1356, 84.5%) were residents of a low or middle income country. A total of 1305 (81.4%) participants reported that the Covid-19 pandemic had an overall negative impact on their training. On adjusted analysis, being 21 or younger, females, those reporting a decline in conventional lectures and ward based teaching were more likely to report an overall negative impact on their training (p ≤ 0.001). However, an increase in clinical responsibilities was associated with lower odds of participants reporting a negative impact on training (p < 0.001). The participant’s resident nation economy and stage of training were associated with some of the participant training experiences surveyed (p < 0.05). Conclusion: An international cohort of medical students reported an overall significant negative impact of the Covid-19 pandemic on their undergraduate training. The efficacy of novel virtual methods of teaching to supplement traditional teaching methods warrants further research

Virtual surgical education for core surgical trainees in the Yorkshire deanery during the COVID-19 pandemic

Background and AimsAn online teaching programme for Core Surgical Trainees (CSTs) was designed and delivered during the COVID-19 pandemic. The aim of this study is to assess the feasibility and the reception of a fully online teaching programme.MethodsTwenty teaching sessions were delivered either via Zoom™ or were pre-recorded and uploaded onto a Google Classroom™ and YouTube™ website. Online feedback, delivered via Google Forms™, were completed by CSTs following each teaching session. YouTube Studio™ analytics were used to understand patterns in viewing content.Results89.9% of trainees were satisfied with the teaching series. Trainees preferred short, weekly sessions (79%), delivered by senior surgeons, in the form of both didactical and interactive teaching. YouTube analytics revealed that the highest peak in views was documented on the weekend before the deadline for evidence upload on the Intercollegiate Surgical Collegiate Programme (ISCP) portfolio.ConclusionAn entirely online teaching programme is feasible and well-received by CSTs. Trainees preferred live, interactive, procedure-based, consultant-led sessions lasting approximately thirty minutes to one hour and covering a myriad of surgical specialties. This feedback can be used to improve future online surgical teaching regionally and nationally in order to gain training opportunities lost during the pandemic

Systematic review and meta-analysis of the effect of perineural catheters in major lower limb amputations

Objective Controlling pain after major lower limb amputation (MLLA) is of critical importance to patients and clinicians. The aim of this systematic review and meta-analysis was to assess the effect of perineural catheters (PNCs) on post-operative pain, post-operative morphine requirement, in-hospital mortality, long term phantom limb pain, and chronic stump pain. Methods A systematic review using PubMed, EMBASE via OVID and the Cochrane library from database inception (1946) to 20 October 2020 was performed according to PRISMA guidelines. Studies involving patients undergoing MLLA which reported on post-operative morphine requirement, pain scores, in-hospital mortality, phantom limb pain (PLP), and chronic stump pain were included. Studies comparing PNC use with epidural or wound site local anaesthetic infusions were excluded. Outcome data were extracted from individual studies and meta-analysis was performed using a random effects (Mantel-Haenszel) model for dichotomous data using an odds ratio (OR) summary statistic with 95% confidence intervals (CI), and with an inverse variance random effects model for continuous data using a standardised mean difference (SMD) summary statistic with 95% CIs. Sensitivity analyses were performed for post-operative pain scores and post-operative morphine requirement. Study quality was assessed using the Downs and Black score, and outcomes were assessed using the GRADE tool. Results Ten studies reporting on 731 patients were included, with 350 patients receiving a PNC and 381 receiving standard care. PNC use is associated with a reduction in post-operative pain (SMD −0.30, 95% CI −0.58 – −0.01, p = .040, I2 = 54%, GRADE quality of evidence: low) and post-operative morphine requirements (SMD −0.63, 95% CI −1.03 – −0.23, p = .002, I2 = 75%, GRADE quality of evidence: moderate), although the effect of PNC on reduced post-operative morphine requirements is lost on sensitivity analysis of randomised trials only (p = .40). No demonstrable effect was found on in-hospital mortality, PLP, or chronic stump pain (GRADE quality of evidence: low). Conclusion PNC use in amputees is associated with a significant reduction in post-operative pain scores and post-operative morphine requirements, although this latter finding is lost on sensitivity analysis of randomised trials only

Systematic review and meta-analysis of the effect of perineural catheters in major lower limb amputations.

Objective Controlling pain after major lower limb amputation (MLLA) is of critical importance to patients and clinicians. The aim of this systematic review and meta-analysis was to assess the effect of perineural catheters (PNCs) on post-operative pain, post-operative morphine requirement, in-hospital mortality, long term phantom limb pain, and chronic stump pain. Methods A systematic review using PubMed, EMBASE via OVID and the Cochrane library from database inception (1946) to 20 October 2020 was performed according to PRISMA guidelines. Studies involving patients undergoing MLLA which reported on post-operative morphine requirement, pain scores, in-hospital mortality, phantom limb pain (PLP), and chronic stump pain were included. Studies comparing PNC use with epidural or wound site local anaesthetic infusions were excluded. Outcome data were extracted from individual studies and meta-analysis was performed using a random effects (Mantel-Haenszel) model for dichotomous data using an odds ratio (OR) summary statistic with 95% confidence intervals (CI), and with an inverse variance random effects model for continuous data using a standardised mean difference (SMD) summary statistic with 95% CIs. Sensitivity analyses were performed for post-operative pain scores and post-operative morphine requirement. Study quality was assessed using the Downs and Black score, and outcomes were assessed using the GRADE tool. Results Ten studies reporting on 731 patients were included, with 350 patients receiving a PNC and 381 receiving standard care. PNC use is associated with a reduction in post-operative pain (SMD −0.30, 95% CI −0.58 – −0.01, p = .040, I2 = 54%, GRADE quality of evidence: low) and post-operative morphine requirements (SMD −0.63, 95% CI −1.03 – −0.23, p = .002, I2 = 75%, GRADE quality of evidence: moderate), although the effect of PNC on reduced post-operative morphine requirements is lost on sensitivity analysis of randomised trials only (p = .40). No demonstrable effect was found on in-hospital mortality, PLP, or chronic stump pain (GRADE quality of evidence: low). Conclusion PNC use in amputees is associated with a significant reduction in post-operative pain scores and post-operative morphine requirements, although this latter finding is lost on sensitivity analysis of randomised trials only

Prophylactic antibiotic use following cardiac arrest: A systematic review and meta-analysis.

OBJECTIVE To evaluate the effect of prophylactic/ early antibiotics (intervention group) compared with clinically driven/ delayed antibiotics (control group) on patient and infectious outcomes in adult cardiac arrest patients admitted to hospital. DATA SOURCES We searched MEDLINE (1946-current), EMBASE (1947-current) and the Cochrane library (inception-current) on 8th May 2018. Additional citations were identified through forward and backward citation tracking. STUDY SELECTION Two reviewers independently screened titles, abstracts, and full-texts. We included observational and interventional primary research studies with a concurrent or retrospective control group that were relevant to our study objective. DATA EXTRACTION We extracted data using a piloted data extraction form. Risk of bias was assessed using the Cochrane tool for randomised controlled trials or the GRADE tool for risk of bias in observational studies. Overall evidence quality for each outcome was assessed using the GRADE system. DATA SYNTHESIS Databases searches and citation tracking identified 6825 citations, of which ten citations containing 11 studies (3 randomised controlled trials, 8 observational studies) were eligible for inclusion. Data were summarised in meta-analyses using random-effect models. The intervention was not associated with increased survival (odds ratio 1.16, 95% CI 0.97-1.40), survival with good neurological outcome (odds ratio 2.25, 95% CI 0.93-5.45), critical care length of stay (mean difference -0.6, 95% CI -3.6 to 2.4) or incidence of pneumonia (odds ratio 0.58, 95% CI 0.23-1.46). Findings were generally consistent between observational studies and randomised controlled trials. CONCLUSIONS Antibiotic prophylaxis following cardiac arrest is not associated with a change in key clinical outcomes. Further high-quality trials may be needed to address this important clinical question. Review registration: PROSPERO CRD42016039358

Lithography-based manufacturing of advanced ceramics for orthopaedic applications:a comparative tribological study

Ceramics long history in biomedical field is related to their high biocompatibility and mechanical properties. Precisely, for joint replacements, wear resistance is fundamental, so advanced ceramics as alumina and zirconia are preferred. Developments in ceramic additive manufacturing allow for dense ceramic parts with improved mechanical properties and shape accuracy.This paper focuses on the tribological analysis of stereolithography-manufactured components for orthopaedics. Alumina, yttria-stabilised zirconia, 10 and 20 wt% zirconia toughened alumina (ZTA) samples were analysed. The effect of surface finishing, microstructure and microhardness on wear was considered.Printing orientation does not significantly impact microhardness, wettability, and microporosity. However, some printing artefacts as the staircase effect were observed on spherical surfaces. Zirconia system presented high wear rates and friction coefficient, while alumina system showed more acceptable and stable values, with the formation of a self-mated tribofilm. ZTA composites presented the lowest wear volume and better mechanical and surface properties in general