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

Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry : A bridge to individualized medicine

Background We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. Patients and Methods Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. Results The sensitivity of single drugs is assessed for standard efficacy (E) and potency (EC) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. Conclusion We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection. © 2014 The Authors. Published by Elsevier Inc. All rights reserved

A Historiometric Examination of Machiavellianism and a New Taxonomy of Leadership

Although researchers have extensively examined the relationship between charismatic leadership and Machiavellianism (Deluga, 2001; Gardner & Avolio, 1995; House & Howell, 1992), there has been a lack of investigation of Machiavellianism in relation to alternative forms of outstanding leadership. Thus, the purpose of this investigation was to examine the relationship between Machiavellianism and a new taxonomy of outstanding leadership comprised of charismatic, ideological, and pragmatic leaders. Using an historiometric approach, raters assessed Machiavellianism via the communications of 120 outstanding leaders in organizations across the domains of business, political, military, and religious institutions. Academic biographies were used to assess twelve general performance measures as well as twelve general controls and five communication specific controls. The results indicated that differing levels of Machiavellianism is evidenced across the differing leader types as well as differing leader orientation. Additionally, Machiavellianism appears negatively related to performance, though less so when type and orientation are taken into account.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-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\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), 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

Response to cladribine in previously treated patients with chronic lymphocytic leukaemia identi®ed by ex vivo assessment of drug sensitivity by DiSC assay

Summary. The ability to identify non-responders to cytotoxic chemotherapy has signi®cant clinical and economic bene®ts. Differential staining cytotoxicity (DiSC) assays were performed in 34 previously treated patients with chronic lymphocytic leukaemia prior to treatment with cladribine. Of the 28 identi®ed as ex vivo sensitive, 26 achieved a complete (CR) or partial response (PR) (median length of response 1´5 years, median survival 3´37 years) and two had a >70% fall in lymphocytes: six identi®ed as ex vivo resistant failed to respond. The DiSC assay can accurately identify a subgroup of patients resistant to cladribine