Addressing Full-Thickness Skin Defects: A Review of Clinically Available Autologous Skin Replacements.

Autologous keratinocyte culture, and combinations of scaffolds, different cell types, solutions of macromolecules, or growth factors have contributed to the resurfacing of full-thickness skin defects. Ideally, a treatment for full-thickness skin defects should not merely reestablish continuity of the surface of the skin but should restore its structure to allow skin to function as a dynamic biological factory that can participate in protein synthesis, metabolism, and cell signaling, and form an essential part of the body's immune, nervous, and endocrine systems. This paper provides a review of clinically available autologous skin replacements, highlighting the importance of regenerating an organ that will function physiologically.

Cognitive Behavioral Treatment for Acute Posttrauma Distress: A Randomized, Controlled Proof-of-Concept Study Among Hospitalized Adults With Burns.

OBJECTIVE: (1) To evaluate the feasibility of conducting a randomized controlled trial (RCT) of the Safety, Meaning, Activation and Resilience Training (SMART) intervention vs nondirective supportive psychotherapy (NDSP) in an acutely hospitalized adult survivor of burn injury sample; and (2) to assess the preliminary effect of SMART on acute stress disorder (ASD), posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) symptom reduction as secondary prevention. DESIGN: Proof-of-concept, parallel group RCT design. SETTING: Regional burn center. PARTICIPANTS: Acutely injured, hospitalized adult survivors of burn injury (N=50) were randomly assigned to SMART (n=28) or nondirective supportive psychotherapy (n=22). Due to dropout and missing data, final sample size was 40, SMART (n=21) and nondirective supportive psychotherapy (n=19). INTERVENTIONS: SMART is a manualized, 4-session cognitive behavioral therapy-based psychological intervention targeting ASD, PTSD, and MDD symptoms. NDSP is a manualized, 4-session protocol. MAIN OUTCOME MEASURES: Davidson Trauma Scale ([DTS]; diagnostic proxy for ASD and PTSD; clinical cutoff=40, with higher score=higher severity) and the Patient Health Questionnaire-9 ([PHQ-9]; diagnostic proxy for MDD; clinical cutoff=10, with higher score=higher severity) at pretreatment, immediate posttreatment, and 1 month posttreatment. RESULTS: At baseline, median DTS scores and PHQ-9 scores were above clinical cutoffs and did not differ across groups. At 1 week and 1 month posttreatment, median DTS and PHQ-9 scores were beneath clinical cutoffs in the SMART group; scores remained above clinical cutoffs in the NDSP group at these time points. CONCLUSIONS: It is feasible to conduct an RCT of SMART in hospitalized adult survivors of burn injury. SMART has the potential to yield clinically significant outcomes. Additional studies are needed to replicate and extend these findings.

In vivo expansion and regeneration of full-thickness functional skin with an autologous homologous skin construct: Clinical proof of concept for chronic wound healing.

A new cell-tissue technology uses a patient's skin to create an in vivo expanding and self-organising full-thickness skin autograft derived from potent cutaneous appendages. This autologous homologous skin construct (AHSC) is manufactured from a small full-thickness skin harvest obtained from an uninjured area of the patient. All the harvested tissue is incorporated into the AHSC including the endogenous regenerative cellular populations responsible for skin maintenance and repair, which are activated during the manufacturing process. Without any exogenous supplementation or culturing, the AHSC is swiftly returned to the patient's wound bed, where it expands and closes the defect from the inside out with full-thickness fully functional skin. AHSC was applied to a greater than two-year old large (200 cm2 ) chronic wound refractory to multiple failed split-thickness skin grafts. Complete epithelial coverage was achieved in 8 weeks, and complete wound coverage with full-thickness functional skin occurred in 12 weeks. At 6-month follow-up, the wound remained covered with full-thickness skin, grossly equivalent to surrounding native skin qualitatively and quantitatively equivalent across multiple functions and characteristics, including sensation, hair follicle morphology, bio-impedance and composition, pigment regeneration, and gland production.

Animal origin of 13th-century uterine vellum revealed using noninvasive peptide fingerprinting.

Tissue-thin parchment made it possible to produce the first pocket Bibles: Thousands were made in the 13th century. The source of this parchment, often called "uterine vellum," has been a long-standing controversy in codicology. Use of the Latin term abortivum in many sources has led some scholars to suggest that the skin of fetal calves or sheep was used. Others have argued that it would not be possible to sustain herds if so many pocket Bibles were produced from fetal skins, arguing instead for unexpected alternatives, such as rabbit. Here, we report a simple and objective technique using standard conservation treatments to identify the animal origin of parchment. The noninvasive method is a variant on zooarchaeology by mass spectrometry (ZooMS) peptide mass fingerprinting but extracts protein from the parchment surface by using an electrostatic charge generated by gentle rubbing of a PVC eraser on the membrane surface. Using this method, we analyzed 72 pocket Bibles originating in France, England, and Italy and 293 additional parchment samples that bracket this period. We found no evidence for the use of unexpected animals; however, we did identify the use of more than one mammal species in a single manuscript, consistent with the local availability of hides. These results suggest that ultrafine vellum does not necessarily derive from the use of abortive or newborn animals with ultrathin hides, but could equally well reflect a production process that allowed the skins of maturing animals of several species to be rendered into vellum of equal quality and fineness.

Do questions help? The impact of audience response systems on medical student learning: a randomised controlled trial.

BACKGROUND: Audience response systems (ARSs) are electronic devices that allow educators to pose questions during lectures and receive immediate feedback on student knowledge. The current literature on the effectiveness of ARSs is contradictory, and their impact on student learning remains unclear. OBJECTIVES: This randomised controlled trial was designed to isolate the impact of ARSs on student learning and students' perception of ARSs during a lecture. METHODS: First-year medical student volunteers at Johns Hopkins were randomly assigned to either (i) watch a recorded lecture on an unfamiliar topic in which three ARS questions were embedded or (ii) watch the same lecture without the ARS questions. Immediately after the lecture on 5 June 2012, and again 2 weeks later, both groups were asked to complete a questionnaire to assess their knowledge of the lecture content and satisfaction with the learning experience. RESULTS: 92 students participated. The mean (95% CI) initial knowledge assessment score was 7.63 (7.17 to 8.09) for the ARS group (N=45) and 6.39 (5.81 to 6.97) for the control group (N=47), p=0.001. Similarly, the second knowledge assessment mean score was 6.95 (6.38 to 7.52) for the ARS group and 5.88 (5.29 to 6.47) for the control group, p=0.001. The ARS group also reported higher levels of engagement and enjoyment. CONCLUSIONS: Embedding three ARS questions within a 30 min lecture increased students' knowledge immediately after the lecture and 2 weeks later. We hypothesise that this increase was due to forced information retrieval by students during the learning process, a form of the testing effect.

Probing bacterial uptake of glycosylated ciprofloxacin conjugates.

Mono- and disaccharide-functionalised conjugates of the fluoroquinolone antibiotic ciprofloxacin have been synthesised and used as chemical probes of the bacterial uptake of glycosylated ciprofloxacin. Their antimicrobial activities against a panel of clinically relevant bacteria were determined: the ability of these conjugates to inhibit their target DNA gyrase and to be transported into the bacteria was assessed by using in vivo and in vitro assays. The data suggest a lack of active uptake through sugar transporters and that although the addition of monosaccharides is compatible with the inhibition of DNA gyrase, the addition of a disaccharide results in a significant decrease in antimicrobial activity.

Probing linker design in citric acid-ciprofloxacin conjugates.

A series of structurally related citric acid-ciprofloxacin conjugates was synthesised to investigate the influence of the linker between citric acid and ciprofloxacin on antibacterial activities. Minimum inhibitory concentrations (MICs) were determined against a panel of reference strains and clinical isolates of bacteria associated with infection in humans and correlated with the DNA gyrase inhibitory activity. The observed trend was rationalised by computational modelling.

Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics.

A series of fluoroquinolone conjugates was synthesised by linking the carboxylic acid functionality of the carboxylate-type siderophore staphyloferrin A and its derivatives to the piperazinyl nitrogen of ciprofloxacin and norfloxacin via amide bond formation. Four siderophore-drug conjugates were screened against a panel of bacteria associated with infection in humans. Whilst no activity was found against ciprofloxacin- or norfloxacin-resistant bacteria, one of the conjugates retained antibacterial activity against fluoroquinolone-susceptible strains although the structure of its lysine-based siderophore component differs from that of the natural siderophore staphyloferrin A. In contrast, three ornithine-based siderophore conjugates showed significantly reduced activity against strains that are susceptible to their respective parent fluoroquinolones, regardless of the type of fluoroquinolone attached or chirality at the ornithine Cα-atom. The loss of potency observed for the (R)- and (S)-ornithine-based ciprofloxacin conjugates correlates with their reduced inhibitory activity against the target enzyme DNA gyrase.

Evaluation in a porcine wound model and long-term clinical assessment of an autologous heterogeneous skin construct used to close full-thickness wounds.

Acute and chronic wounds involving deeper layers of the skin are often not adequately healed by dressings alone and require therapies such as skin grafting, skin substitutes, or growth factors. Here we report the development of an autologous heterogeneous skin construct (AHSC) that aids wound closure. AHSC is manufactured from a piece of healthy full-thickness skin. The manufacturing process creates multicellular segments, which contain endogenous skin cell populations present within hair follicles. These segments are physically optimized for engraftment within the wound bed. The ability of AHSC to facilitate closure of full thickness wounds of the skin was evaluated in a swine model and clinically in 4 patients with wounds of different etiologies. Transcriptional analysis demonstrated high concordance of gene expression between AHSC and native tissues for extracellular matrix and stem cell gene expression panels. Swine wounds demonstrated complete wound epithelialization and mature stable skin by 4 months, with hair follicle development in AHSC-treated wounds evident by 15 weeks. Biomechanical, histomorphological, and compositional analysis of the resultant swine and human skin wound biopsies demonstrated the presence of epidermal and dermal architecture with follicular and glandular structures that are similar to native skin. These data suggest that treatment with AHSC can facilitate wound closure.

Hypoxia and hypoxia-inducible factor in the burn wound.

The importance of hypoxia-inducible factor (HIF) in promoting angiogenesis and vasculogenesis during wound healing has been demonstrated. It is widely accepted that HIF activity can be promoted by many factors, including hypoxia in the wound or cytokines from inflammatory cells infiltrating the wound. However, there has not been a systematic exploration of the relationship between HIF activity and hypoxia in the burn wound. The location of the hypoxic tissue has not been clearly delineated. The time course of the appearance of hypoxia and the increased activity of HIF and appearance of HIF's downstream transcription products has not been described. The aim of this study was to utilize pimonidazole, a specific tissue hypoxia marker, to characterize the spatial and temporal course of hypoxia in a murine burn model and correlate this with the appearance of HIF-1α and its important angiogenic and vasculogenic transcription products vascular endothelial growth factor and SDF-1. Hypoxia was found in the healing margin of burn wounds beginning at 48 hours after burn and peaking at day 3 after burn. On sequential sections of the same tissue block, positive staining of HIF-1α, SDF-1, and vascular endothelial growth factor all occurred at the leading margin of the healing area and peaked at day 3, as did hypoxia. Immunohistochemical analysis was used to explore the characteristics of the hypoxic region of the wound. The localization of hypoxia was found to be related to cell growth and migration, but not to proliferation or inflammatory infiltration.

Barriers to recruitment to an orthopaedic randomized controlled trial comparing two surgical procedures for ankle arthritis : a qualitative study.

AIMS: A multicentre, randomized, clinician-led, pragmatic, parallel-group orthopaedic trial of two surgical procedures was set up to obtain high-quality evidence of effectiveness. However, the trial faced recruitment challenges and struggled to maintain recruitment rates over 30%, although this is not unusual for surgical trials. We conducted a qualitative study with the aim of gathering information about recruitment practices to identify barriers to patient consent and participation to an orthopaedic trial. METHODS: We collected 11 audio recordings of recruitment appointments and interviews of research team members (principal investigators and research nurses) from five hospitals involved in recruitment to an orthopaedic trial. We analyzed the qualitative data sets thematically with the aim of identifying aspects of informed consent and information provision that was either unclear, disrupted, or hindered trial recruitment. RESULTS: Recruiters faced four common obstacles when recruiting to a surgical orthopaedic trial: patient preferences for an intervention; a complex recruitment pathway; various logistical issues; and conflicting views on equipoise. Clinicians expressed concerns that the trial may not show significant differences in the treatments, validating their equipoise. However, they experienced role conflicts due to their own preference and perceived patient preference for an intervention arm. CONCLUSION: This study provided initial information about barriers to recruitment to an orthopaedic randomized controlled trial. We shared these findings in an all-site investigators' meeting and encouraged researchers to find solutions to identified barriers; this led to the successful completion of recruitment. Complex trials may benefit for using of a mixed-methods approach to mitigate against recruitment failure, and to improve patient participation and informed consent. Cite this article: Bone Jt Open 2021;2(8):631-637.

Combat Wound Initiative program.

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

Synthesis of citrate-ciprofloxacin conjugates.

Two regioisomeric citrate-functionalized ciprofloxacin conjugates have been synthesized and their antimicrobial activities against a panel of clinically-relevant bacteria have been determined. Cellular uptake mechanisms were investigated using wild-type and ompF deletion strains of Escherichia coli K-12.