Baloxavir marboxil (baloxavir) is a recently FDA-approved influenza virus polymerase acidic (PA) endonuclease inhibitor. Several PA substitutions have been demonstrated to confer reduced ...susceptibility to baloxavir; however, their impacts on measurements of antiviral drug susceptibility and replication capacity when present as a fraction of the viral population have not been established. We generated recombinant A/California/04/09 (H1N1)-like viruses (IAV) with PA I38L, I38T, or E199D substitutions and B/Victoria/504/2000-like virus (IBV) with PA I38T. These substitutions reduced baloxavir susceptibility by 15.3-, 72.3-, 5.4-, and 54.5-fold, respectively, when tested in normal human bronchial epithelial (NHBE) cells. We then assessed the replication kinetics, polymerase activity, and baloxavir susceptibility of the wild-type:mutant (WT:MUT) virus mixtures in NHBE cells. The percentage of MUT relative to WT virus necessary to detect reduced baloxavir susceptibility in phenotypic assays ranged from 10% (IBV I38T) to 92% (IAV E199D). While I38T did not alter IAV replication kinetics or polymerase activity, IAV PA I38L and E199D MUTs and the IBV PA I38T MUT exhibited reduced replication levels and significantly altered polymerase activity. Differences in replication were detectable when the MUTs comprised ≥90%, ≥90%, or ≥75% of the population, respectively. Droplet digital PCR (ddPCR) and next-generation sequencing (NGS) analyses showed that WT viruses generally outcompeted the respective MUTs after multiple replication cycles and serial passaging in NHBE cells when initial mixtures contained ≥50% of the WT viruses; however, we also identified potential compensatory substitutions (IAV PA D394N and IBV PA E329G) that emerged and appeared to improve the replication capacity of baloxavir-resistant virus in cell culture.
Baloxavir marboxil, an influenza virus polymerase acidic endonuclease inhibitor, represents a recently approved new class of influenza antivirals. Treatment-emergent resistance to baloxavir has been observed in clinical trials, and the potential spread of resistant variants could diminish baloxavir effectiveness. Here, we report the impact of the proportion of drug-resistant subpopulations on the ability to detect resistance in clinical isolates and the impact of substitutions on viral replication of mixtures containing both drug-sensitive and drug-resistant variants. We also show that ddPCR and NGS methods can be successfully used for detection of resistant subpopulations in clinical isolates and to quantify their relative abundance. Taken together, our data shed light on the potential impact of baloxavir-resistant I38T/L and E199D substitutions on baloxavir susceptibility and other biological properties of influenza virus and the ability to detect resistance in phenotypic and genotypic assays.
Early excision and autografting are standard care for deeper burns. However, donor sites are a source of significant morbidity. To address this, the ReCell
®
Autologous Cell Harvesting Device ...(ReCell) was designed for use at the point-of-care to prepare a noncultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin. A prospective study was conducted to evaluate the clinical performance of ReCell vs meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns. Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. At 4 weeks, 98% of the ASCS-treated sites were healed compared with 100% of the Controls. Pain and assessments of scarring at the treatment sites were reported to be similar between groups. Significant differences were observed between ReCell and Control donor sites. The mean ReCell donor area was approximately 40 times smaller than that of the Control (
P
< .0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (
P
= .04). Over the first 16 weeks, patients reported significantly less pain at the ReCell donor sites compared with Controls (
P
≤ .05 at each time point). Long-term patients reported higher satisfaction with ReCell donor site outcomes compared with the Controls. This study provides evidence that the treatment of deep partial-thickness burns with ASCS results in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG.
Radiation Injuries Kearns, Randy D; Hickerson, William L; Carter, Jeffery E
The Surgical clinics of North America
103, Številka:
3
Journal Article
Recenzirano
Radiation-related injuries are rare. Yet the consequences of an event involving a radiation source can be substantial. As with any clinical emergency that rarely occurs, we are typically less ...prepared to deal with the situation. Compounding the crisis will be the "worried well" population who may believe that they too are contaminated or suffering from radiation poisoning and report to the hospital for evaluation. Identifying and triaging those who are sick or injured, managing the surge of patients, and knowing where resources can be accessed are all essential.
While split-thickness autologous skin grafts remain the most common method of definitive burn wound closure, dermal substitutes have emerged as an attractive option. There are many advantages of ...utilizing a dermal substitute, notably reducing the need for donor tissue and subsequent iatrogenic creation of a secondary wound. However, there are disadvantages with each that most be weighed and factored into the decision. And most come at a high initial financial cost. There is little comparative literature of the various available and emerging products. This analysis was performed to objectively present risks and benefits of each option.
The goal of this study was to inform standards of best practice in the use of cultured epidermal autograft (CEA), manufactured in the United States, for treatment of patients with severe burns. The ...study was designed using the modified Delphi technique, a method for structuring group communication among experts to promote the development of consensus-based recommendations. Known areas of variability related to the stages of CEA treatment were identified by literature review prior to the study and were confirmed through qualitative interview with the experts. The areas included Preoperative Planning/Surgical Planning, Immediate Post-Operative Care, and Rehabilitation and Long-Term Care. A list of 22 questions was developed based on interviews with the experts, and a 3round Delphi technique was used to establish consensus (≥80% agreement). Following 3 rounds (quantitative, qualitative, and virtual roundtable meeting) of the Delphi study, important guidance for use of CEA treatment in severely burned patients gained consensus. Final key recommendations included minimum burn limit for CEA treatment (30%-50% TBSA), ideal biopsy timing (1-2 days), number of grafts (enough to cover; adjust 72 hours before application), use of dermal substrates (recommended) and wide meshed autograft underlay (recommended), optimal CEA drying time per day (open air >6 hours), slings used if CEA placed on extremities (recommended), dressing changes (performed every day, all at once, with all layers removed down to bridal veil), CEA backing removal (10-14 days post placement), heat lamps (can be used to aid the wound in drying, depending on clinical judgement), initial activity restrictions lifted (beginning 10 days after backing removal), compression garments (introduced at approximately 2 months post CEA surgery), lasers (CO2 laser can be introduced between 3 and 6 months post CEA surgery).
Abstract
This report summarizes the characteristics of 954 burned patients treated with cultured epidermal autografts (CEA), the largest number of patients to date. Data collected include patient ...demographics, survival, and final graft take. Source data were provided by the treating physician or attending burn team. Safety data were provided by the treating physician, attending burn team, and the pharmacovigilance database. In this dataset collected between 1989 and 2015, 954 patients were treated with cultured epidermal autographs for burns. Three hundred twenty-five (34%) were pediatric patients and 628 (66%) were adult (≥22 years of age); age unknown for one patient. The mean percentage total BSA (TBSA) burned was 67% (±17), median graft take at discharge was 75%, and overall survival at discharge was 84% (804/954). Survival rates were similar for pediatric and adult patients (89% vs 82%, respectively) and higher than the similar patient population reported in the National Burn Repository. Median graft take at discharge was also similar for pediatric and adult patients (80% vs 73%, respectively). The most frequently reported adverse reactions were infections in both pediatric and adult patients. There were no signals of increased risk of adverse reactions in pediatric compared with adult patients. When used as an adjunct to conventional split-thickness skin grafting for treatment of large burns in pediatric and adult patients, the analysis in this report shows an increased survival rate for patients treated with CEA compared with that reported for patients in the National Burn Repository with comparable burns.
To assess the association of burn size and community participation as measured by the LIBRE Profile.
Burn size is an established clinical predictor of survival after burn injury. It is often a factor ...in guiding decisions surrounding early medical interventions; however, literature is inconclusive on its relationship to quality of life outcomes.
This is a secondary data analysis of a cross-sectional survey of adult burn survivors. Self-reported data were collected between October 2014 and December 2015 from 601 burn survivors aged ≥18 years with ≥5% total body surface area (TBSA) or burns to critical areas. Sociodemographic characteristics were compared between participants with small burns (≤40% TBSA burned) and large burns (>40% TBSA burned). Ordinary least squares regression models examined associations between burn size and LIBRE Profile scale scores with adjustments for sex, current work status, burns to critical areas, and time since burn injury.
The analytic sample comprised 562 participants with data available for burn size. 42% of respondents had large burns (>40% TBSA burned) and 58% reported smaller burns (TBSA ≤40%). In adjusted regression models, patients with large burns tended to score lower on the Social Activities and Work & Employment scales ( P < 0.05) and higher on the Family & Friends scale ( P < 0.05). Participants with burns >40% TBSA scored lower for several individual items in the Social Activities scale and one item in the Work & Employment scale ( P < 0.05).
Increasing burn size was found to be negatively associated with selected items of Work & Employment and Social Activities, but positively associated with aspects of Family & Friend Relationships. Future longitudinal studies are necessary to assess and understand the long-term social impact of burn injuries on adult populations.
Lack of an accurate, publicly available database of burn/trauma resources creates challenges in providing burn care. In response to this gap, our group developed the National Injury Resource Database ...(NIRD), a comprehensive database of all US burn centers (BC) and trauma centers (TC) and their capabilities.
Lists of all national BC and TC were obtained from the American Burn Association (ABA), the American College of Surgeons, and every state department of health. Data was cross-checked and included BC/TC were linked with a 7-digit identification number using the American Hospital Association Quick Search guide. Each center’s resources and verification status were validated with electronic or telephonic communications.
The final database includes 135 BC and 617 TC, of which 18 are BC-only, 500 are TC-only, and 117 are combined BC/TC. ABA-verified BC (n = 76) are only found in Washington DC and 31 states, and 8 states have no BC. In the last 10 years, a net increase of 7 burn centers was found nationally. The ABA’s online BC directory is outdated.
NIRD represents the only up-to-date, comprehensive listing of BC and TC in existence. It categorizes all currently operating BC and TC across myriad classifications of designation and capabilities.
•National Injury Resource Database (NIRD) is a comprehensive listing of all US burn & trauma centers.•NIRD lists burn and trauma center resources, designations, & verifications.•The 76 ABA-verified burn centers are clustered in 31 states & DC.•Eight states have no burn centers, verified or unverified.
Our group previously reported a burn biopsy algorithm (BBA-V1) for categorizing burn wound depth. Here, we sought to promulgate a newer, simpler version of the BBA (BBA-V2).
Burn wounds undergoing ...excision underwent 4 mm biopsies procured every 25 cm2. Serial still photos were obtained at enrollment and at excision intraoperatively. Burn wounds assessed as likely to heal by 21 days were imaged within 72 h of injury and at 21 days. A sample of 798 burn wound biopsies were classified by both BBAV1 and BBAV2 algorithms. For nonoperative burn wounds, the proportion of healing versus nonhealing pixels at 21 days after injury were compared.
The 798 biopsies were classified by BBAV1 as 24% SPT, 47% DPT, 28% FT and by BBAV2 as 3% SPT, 67% DPT, and 30% FT (p < 0.0001). Overall, the proportion of biopsies whose wound reclassification changed from a nonoperative to operative pathway was 21% (95% CI: 18–24%). Nonoperative wounds judged at injury as being SPT contained 12.8 million pixels. Repeat 21-day imaging revealed 11.3 million healed pixels (accuracy = 89.6% (95% CI: 89.59–89.62)).
BBA-V2 was associated with a significantly higher concordance with visual assessment for burn wounds clinically judged as deep partial and full thickness.
•Burn surgeons clinically diagnosed burn wounds as DPT or FT with 97% accuracy.•Burn surgeons predicted spontaneous healing with 89% accuracy.•Our collection of 1192 burn wound biopsies is the largest in the literature.
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