Wound Bed Preparation 2024: Delphi Consensus on Foot Ulcer Management in Resource-Limited Settings.

GENERAL PURPOSE: To review a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Summarize issues related to wound assessment.2. Identify a class of drugs for the treatment of type II diabetes mellitus that has been shown to improve glycemia, nephroprotection, and cardiovascular outcomes.3. Synthesize strategies for wound management, including treatment in resource-limited settings.4. Specify the target time for edge advancement in chronic, healable wounds.

Chronic wound management in low-resource settings deserves special attention. Rural or underresourced settings (ie, those with limited basic needs/healthcare supplies and inconsistent availability of interprofessional team members) may not have the capacity to apply or duplicate best practices from urban or abundantly-resourced settings. The authors linked world expertise to develop a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. A group of 41 wound experts from 15 countries reached a consensus on wound bed preparation in resource-limited settings. Each statement of 10 key concepts (32 substatements) reached more than 88% consensus. The consensus statements and rationales can guide clinical practice and research for practitioners in low-resource settings. These concepts should prompt ongoing innovation to improve patient outcomes and healthcare system efficiency for all persons with foot ulcers, especially persons with diabetes.

'Granulitis': defining a common, biofilm-induced, hyperinflammatory wound pathology.

The hard-to-heal (chronic) wound condition, now believed to be inextricably linked to the presence of microbial biofilm, has posed challenges in translating scientific understanding to clinical practice in recent decades. During this time, multiple descriptive terms of the wound pathology have been described, including critical colonisation, biofilm infection and inflammatory stasis. However, the absence of naming this disease state as a specifically identified condition that is tangible to treat has led to some confusion and delay in possible therapeutic approaches. When there is clinical uncertainty of wound status, antibiotics are too often inappropriately administered as a precaution. We therefore propose that introducing the term 'granulitis' (inflamed, unhealthy granulation tissue) could be used to identify the biofilm-induced, persistent inflammatory wound condition. This will help to raise clinician and public awareness of the condition, guide appropriate and prompt local wound hygiene, and encourage allocation of adequate resources to improve wound healing outcomes globally.

Structure, processes, and initial outcomes of The Ottawa Hospital Multi-Specialist Limb-Preservation Clinic and Programme: A unique-in-Canada quality improvement initiative.

In 2017, The Ottawa Hospital initiated a unique-in-Canada quality improvement initiative by opening a novel, multi-specialist limb-preservation clinic. We sought to describe the structure, processes, and initial outcomes of the clinic and evaluate whether it is achieving its mandate of providing high-quality wound clinical care, education, and research. We conducted a descriptive prospective cohort study alongside a nested study of 162 clinic patients requiring serial assessments. There have been 1623 visits, mostly (72.2%) from outpatients. During 17.8% of visits, patients were evaluated by >1 specialist. Therapies provided most often included negative-pressure wound therapy (32.7%), biological wound dressings (21.6%), and total contact casting (18.5%). Furthermore, 1.2% underwent toe/ray amputations or skin grafting in clinic and 22.8% were initiated on antimicrobials. Mixed-effects models suggested that mean wound volumes for those requiring serial assessments decreased by 1.6 (95% confidence interval = -0.86 to -2.27) cm3 between visits. The clinic provided seven rotations to vascular surgery, infectious diseases, dermatology, and palliative care physicians; three nursing preceptorships; and two educational workshops. It also initiated provincial and national vascular health and wound care research initiatives. This study may be used to guide development of other limb-preservation clinics and programmes. Findings support that our programme is achieving its mandate.

Defying hard-to-heal wounds with an early antibiofilm intervention strategy: 'wound hygiene'.

Biofilm has been implicated as a barrier to wound healing and it is widely accepted that the majority of wounds not following a normal healing trajectory contain biofilm. Therefore, strategies that inform and engage clinicians to reduce biofilm and optimise the wound tissue environment to enable wound progression are of interest to wound care providers. In March 2019, an advisory board was convened where experts considered the barriers and opportunities to drive a broader adoption of a biofilm-based approach to wound care. Poor clarity and articulation of wound terminology were identified as likely barriers to clinical adoption of rigorous and proactive microbial decontamination that is supportive of wound healing advancement. A transition to an intuitive term such as 'wound hygiene' was proposed to communicate a comprehensive wound decontamination plan with an associated message of expected habitual routine. 'Wound hygiene', is a relatable concept that supports meticulous wound practice that addresses barriers to wound healing, such as biofilm, while aligning with antimicrobial stewardship programmes.

The effect of 22.5 kHz low-frequency contact ultrasound debridement (LFCUD) on lower extremity wound healing for a vascular surgery population: A randomised controlled trial.

The aim of this study was to compare changes in wound size and appearance and health complication rates in patients with vasculopathy and lower-extremity wounds treated with or without low-frequency contact ultrasound debridement (LFCUD) This study was a randomised controlled trial. The study was conducted in a vascular surgery service, including outpatient wound clinic and inpatient ward, in a tertiary care academic centre. In total, 70 patients with vasculopathy and lower-extremity wounds of mixed aetiology were enrolled in the trial; 68 completed the study. Patients were randomised to receive LFCUD plus usual care (n = 33) or usual care (n = 37) at 4 weekly visits, and were followed thereafter for up to 12 wk. The main outcome measures included closed wounds, change in wound surface area (WSA), and wound appearance by the revised Photographic Wound Assessment Tool (revPWAT). After 4 weekly LFCUD treatments, patients in the LFCUD group had significantly better wound appearance (total revPWAT score) compared with the control group treated only with usual care (P = <0.05). LFCUD-treated wounds also had a significant reduction in WSA over 4 wk that was not found in the UC group. LFCUD treatment was also associated with a greater number of healed wounds, odds ratio 5.00 (95% CI 1.24-20.25), and fewer instances of wound deterioration. Weekly LFCUD applications to patients with significant vasculopathy resulted in superior healing outcomes when compared with current usual wound care practice.

Multidisciplinary expert consensus statements and recommendations for use of hypochlorous acid as a solution for negative pressure wound therapy with instillation.

BACKGROUND: HOCl (eg, pHAp) preserved solutions have antimicrobial properties and are considered safe and effective for wound management. NPWTi-d (or NPWTi) is an established adjunctive wound modality for a variety of wound etiologies in various anatomic locations in which an instillate solution dwells on the surface of the wound to assist in wound bed preparation. A variety of solutions have been used, including 0.9% normal saline wound cleansers and antiseptics. pHAp is growing in popularity as the solution of choice for NPWTi-d. OBJECTIVE: To evaluate consensus statements on the use of NPWTi-d with pHAp. METHODS: A 15-member multidisciplinary panel of expert clinicians in the United States, Canada, and France convened in person in April 2023 in Washington, D.C. and/or corresponded later to discuss 10 statements on the use of pHAp with NPWTi-d. The panelists then replied "agree" or "disagree" to each statement and had the option to provide comments. RESULTS: Ten consensus statements are presented, along with the proportion of agreement or disagreement and summary comments. Although agreement with the statements on NPWTi-d with pHAp varied, the statements appear to reflect individual preferences for use rather than concerns about safety or efficacy. CONCLUSION: The consensus indicates that NPWTi-d with pHAp can have a beneficial effect in wound care.

Fostering the Next Generation of Researchers: a Sustainable Mentoring Program for Early Career Toxicologists in Scientific Abstract Review.

The presentation of abstracts at scientific meetings is an important step in the dissemination of scientific discovery. Most scientific meetings recruit volunteer experts to evaluate and score submitted abstracts to determine which ones qualify for presentation. Reviewing an abstract is an important service to one's specialty, but there is typically no formal training or required instruction during medical toxicology fellowship on scientific abstract scoring. In order to provide structured training in abstract review, the American College of Medical Toxicology (ACMT) Research Committee launched the Annual Scientific Meeting (ASM) Abstract Review Mentor program in 2021. The goals of this program were to train fellows how to score scientific abstracts and provide them with new mentor connections to toxicologists outside of their training program. After evaluating 3 years of data from participating fellows-in-training and faculty mentors, we conclude that ACMT's Abstract Review Mentor program was successful in training future reviewers and fostering external mentorship relationships. All participants reported their experience in this program will change how they submit future abstracts to scientific meetings, help their future service as an abstract reviewer, and motivate their involvement in other specialty-related research activities. Implementing an abstract review training program is sustainable and a vital strategy for enhancing the dissemination of scientific discovery and training the next generation of medical toxicology researchers.

Assessing Platelet Mitochondrial Dysfunction in a Murine Model of Acute Acetaminophen Toxicity.

INTRODUCTION: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity. METHODS: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation. RESULTS: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP. CONCLUSIONS: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC.

Reliability and predictive validity of Inlow's 60-Second Diabetic Foot Screen Tool.

OBJECTIVE: : The purpose of this study was to assess Inlow's 60-Second Diabetic Foot Screen Tool to ascertain consistency of risk recognition for development of ulceration independent of specific assessor and practice setting. Screening tools that assist clinicians in identifying risk require validation. The objectives were to determine the intrarater reliability, interrater reliability, and predictive validity of Inlow's 60-Second Diabetic Foot Screen Tool in 2 healthcare settings. DESIGN: : Following ethics board approval, a prospective observational study was completed. SETTING AND PARTICIPANTS: : A convenience sample of 69 persons with diabetes was recruited: n = 26 from an acute care setting (dialysis) and n = 43 from long-term-care (LTC) setting. MAIN OUTCOME MEASURES: : The screening tool was administered by 2 assessors independently to determine interrater reliability and later the same day by one of the assessors to determine intrarater reliability. Occurrence of foot ulcers or amputation was noted 1 to 5 months later to determine predictive validity. MAIN RESULTS: : Reliability is reported per setting using the intraclass correlation coefficient (2.1) and 95% confidence intervals. Intrarater reliability: LTC 0.96 (0.93-0.98) right foot, 0.97 (0.95-0.98) left foot; dialysis 1.00 right and 1.00 left foot. Interrater reliability: LTC 0.92 (0.86-0.96) right foot, 0.93 (0.87-0.96) left foot; dialysis 0.83 (0.65-0.92) right foot and left foot. Predictive validity: Two subjects had events-1 ulcer and 1 amputation-that were associated with high Inlow's screening tool scores. CONCLUSION: : This study demonstrates excellent interrater and intrarater reliability and provides preliminary information about predictive validity.

Staphylococcus aureus sortase A contributes to the Trojan horse mechanism of immune defense evasion with its intrinsic resistance to Cys184 oxidation.

Staphylococcus aureus is a Gram-positive bacterial pathogen that causes serious infections which have become increasingly difficult to treat due to antimicrobial resistance and natural virulence strategies. Bacterial sortase enzymes are important virulence factors and good targets for future antibiotic development. It has recently been shown that sortase enzymes are integral to bacterial survival of phagocytosis, an underappreciated, but vital, step in S. aureus pathogenesis. Of note, the reaction mechanism of sortases relies on a solvent-accessible cysteine for transpeptidation. Because of the common strategy of oxidative damage employed by professional phagocytes to kill pathogens, it is possible that this cysteine may be oxidized inside the phagosome, thereby inhibiting the enzyme. This study addresses this apparent paradox by assessing the ability of physiological reactive oxygen species, hydrogen peroxide and hypochlorite, to inhibit sortase A (SrtA) from S. aureus. Surprisingly, we found that SrtA is highly resistant to oxidative inhibition, both in vitro and in vivo. The mechanism of resistance to oxidative damage is likely mediated by maintaining a high reduction potential of the catalytic cysteine residue, Cys184. This is due to the unusual active site utilized by S. aureus SrtA, which employs a reverse protonation mechanism for transpeptidation, resulting in a high pK(a) as well as reduction potential for Cys184. The results of this study suggest that S. aureus SrtA is able to withstand the extreme conditions encountered in the phagosome and maintain function, contributing to survival of phagocytotic killing.

The Drosophila melanogaster Cajal body.

Cajal bodies (CBs) are nuclear organelles that are usually identified by the marker protein p80-coilin. Because no orthologue of coilin is known in Drosophila melanogaster, we identified D. melanogaster CBs using probes for other components that are relatively diagnostic for CBs in vertebrate cells. U85 small CB-specific RNA, U2 small nuclear RNA, the survival of motor neurons protein, and fibrillarin occur together in a nuclear body that is closely associated with the nucleolus. Based on its similarity to CBs in other organisms, we refer to this structure as the D. melanogaster CB. Surprisingly, the D. melanogaster U7 small nuclear RNP resides in a separate nuclear body, which we call the histone locus body (HLB). The HLB is invariably colocalized with the histone gene locus. Thus, canonical CB components are distributed into at least two nuclear bodies in D. melanogaster. The identification of these nuclear bodies now permits a broad range of questions to be asked about CB structure and function in a genetically tractable organism.

Tools for neuroanatomy and neurogenetics in Drosophila.

We demonstrate the feasibility of generating thousands of transgenic Drosophila melanogaster lines in which the expression of an exogenous gene is reproducibly directed to distinct small subsets of cells in the adult brain. We expect the expression patterns produced by the collection of 5,000 lines that we are currently generating to encompass all neurons in the brain in a variety of intersecting patterns. Overlapping 3-kb DNA fragments from the flanking noncoding and intronic regions of genes thought to have patterned expression in the adult brain were inserted into a defined genomic location by site-specific recombination. These fragments were then assayed for their ability to function as transcriptional enhancers in conjunction with a synthetic core promoter designed to work with a wide variety of enhancer types. An analysis of 44 fragments from four genes found that >80% drive expression patterns in the brain; the observed patterns were, on average, comprised of <100 cells. Our results suggest that the D. melanogaster genome contains >50,000 enhancers and that multiple enhancers drive distinct subsets of expression of a gene in each tissue and developmental stage. We expect that these lines will be valuable tools for neuroanatomy as well as for the elucidation of neuronal circuits and information flow in the fly brain.

Disability, pain, and wound-specific concerns self-reported by adults at risk of limb loss: A cross-sectional study using the World Health Organization Disability Assessment Schedule 2.0.

INTRODUCTION: There has been limited study of patient-reported outcomes (PROs) in patients at risk of limb loss. Our primary objective was to estimate the prevalence of disability in this patient population using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). MATERIALS AND METHODS: We recruited patients referred to a limb-preservation clinic. Patients self-reported their disability status using the 12-domain WHODAS 2.0. Severity of disability in each domain was scored from 1 = none to 5 = extreme and the total normalized to a 100-point scale (total score ≥25 = clinically significant disability). We also asked patients about wound-specific concerns and wound-related discomfort or distress. RESULTS: We included 162 patients. Reasons for clinic referral included arterial-insufficient (37.4%), postoperative (25.9%), and mixed etiology (10.8%) wounds. The mean WHODAS 2.0 disability score was 35.0 (standard deviation = 16.0). One-hundred-and-nineteen (73.5%) patients had clinically significant disability. Patients reported they had the greatest difficulty walking a long distance (mean score = 4.2), standing for long periods of time (mean score = 3.6), taking care of household responsibilities (mean score = 2.7), and dealing with the emotional impact of their health problems (mean score = 2.5). In the two-weeks prior to presentation, 87 (52.7%) patients expressed concern over their wound(s) and 90 (55.6%) suffered a moderate amount or great deal of wound-related discomfort or distress. In adjusted ordinary least squares regression models, although WHODAS 2.0 disability scores varied with changes in wound volume (p = 0.03) and total revised photographic wound assessment tool scores (p<0.001), the largest decrease in disability severity was seen in patients with less wound-specific concerns and wound-related discomfort and distress. DISCUSSION: The majority of people at risk of limb loss report suffering a substantial burden of disability, pain, and wound-specific concerns. Research is needed to further evaluate the WHODAS 2.0 in a multicenter fashion among these patients and determine whether care and interventions may improve their PROs.

Fatal pulmonary edema after acute occupational exposure to nitric acid.

BACKGROUND: Nitric acid (HNO(3)) is a solution of nitrogen dioxide (NO(2)) in water commonly used as an industrial chemical and cleaner. Oxides of nitrogen liberated as nitric acid interact with the environment to cause inhalation injuries. The coexistence of HNO(3) with varying oxides of nitrogen likely results in the large continuum of symptoms related to HNO(3) exposure and varying times of onset--acute, subacute, and delayed. Furthermore, dyspnea and evidence of acute lung injury may not occur for several hours after exposure and can lead to rapidly progressive acute respiratory distress syndrome (ARDS). OBJECTIVES: This case illustrates to physicians and occupational health personnel that HNO(3) inhalation may initially appear benign and that onset of severe effects may be delayed. CASE REPORT: A 66-year-old man developed delayed-onset pulmonary edema, ARDS, and fatal circulatory collapse 53 h after occupational exposure to HNO(3). CONCLUSION: This case serves to increase awareness among emergency physicians, as well as occupational health personnel, that patients exposed to HNO(3) may initially be asymptomatic. Patients should be evaluated and observed regardless of the severity or benign nature of symptoms, which occur immediately after exposure, as the most severe symptoms are often delayed in onset and rapidly progressive.

Biofilm exacerbates antibiotic resistance: Is this a current oversight in antimicrobial stewardship?

OBJECTIVE: To raise awareness of the role of environmental biofilm in the emergence and spread of antibiotic resistance and its consideration in antimicrobial stewardship. BACKGROUND: Antibiotic resistance is a major threat to public health. Overuse of antibiotics, increased international travel, and genetic promiscuity amongst bacteria have contributed to antibiotic resistance, and global containment efforts have so far met with limited success. Antibiotic resistance is a natural mechanism by which bacteria have adapted to environmental threats over billions of years and is caused either by genetic mutations or by horizontal gene transfer. Another ancient survival strategy involves bacteria existing within a self-produced polymeric matrix, which today is termed biofilm. Biofilm similarly enables bacterial tolerance to environmental threats, and also encourages the transfer of antibiotic resistance genes between bacterial species. This natural and ubiquitous mode of bacterial life has not been considered amongst strategies to tackle antibiotic resistance in healthcare facilities, despite its ability to significantly enhance bacterial survival and persistence, and to encourage antibiotic resistance. CONCLUSION: Biofilm must be considered synonymously with antibiotic resistance because of its proficiency in transferring resistance genes as well as its innate phenotypic tolerance to antibiotics. Although biofilm falls outside of the current definition of antimicrobial stewardship, greater awareness of the existence, ubiquity, and consequences of environmental biofilm amongst healthcare practitioners is crucial to improving hygiene practices and controlling the emergence and spread of antibiotic resistance in healthcare facilities.

Phenotypes Associated with 16p11.2 Copy Number Gains and Losses at a Single Institution.

Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1-BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs.

Virtual monitoring of suicide risk in the general hospital and emergency department.

OBJECTIVE: To determine whether continuous virtual monitoring, an intervention that facilitates patient observation through video technology, can be used to monitor suicide risk in the general hospital and emergency department (ED). METHOD: This was a retrospective analysis of a protocol in which select patients on suicide precautions in the general hospital and ED received virtual monitoring between June 2017 and March 2018. The primary outcome was the number of adverse events among patients who received virtual monitoring for suicide risk. Secondary outcomes were the percentage of patients for whom virtual monitoring was discontinued for behavioral reasons and the preference for observation type among nurses. RESULTS: 39 patients on suicide precautions received virtual monitoring. There were 0 adverse events (95% confidence interval (CI) = 0.000-0.090). Virtual monitoring was discontinued for behavioral reasons in 4/38 cases for which the reason for terminating was recorded (0.105, 95%CI = 0.029-0.248). We were unable to draw conclusions regarding preference for observation type among nurses due to a low response rate to our survey. CONCLUSIONS: Suicide risk can feasibly be monitored virtually in the general hospital or ED when their providers carefully select patients for low impulsivity risk.

Steady-state dynamics of Cajal body components in the Xenopus germinal vesicle.

Cajal bodies (CBs) are evolutionarily conserved nuclear organelles that contain many factors involved in the transcription and processing of RNA. It has been suggested that macromolecular complexes preassemble or undergo maturation within CBs before they function elsewhere in the nucleus. Most such models of CB function predict a continuous flow of molecules between CBs and the nucleoplasm, but there are few data that directly support this view. We used fluorescence recovery after photobleaching (FRAP) on isolated Xenopus oocyte nuclei to measure the steady-state exchange rate between the nucleoplasm and CBs of three fluorescently tagged molecules: U7 small nuclear RNA, coilin, and TATA-binding protein (TBP). In the nucleoplasm, the apparent diffusion coefficients for the three molecules ranged from 0.26 to 0.40 microm2 s-1. However, in CBs, fluorescence recovery was markedly slower than in the nucleoplasm, and there were at least three kinetic components. The recovery rate within CBs was independent of bleach spot diameter and could not be attributed to high CB viscosity or density. We propose that binding to other molecules and possibly assembly into larger complexes are the rate-limiting steps for FRAP of U7, coilin, and TBP inside CBs.

Biaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part I.

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).