SMOOTH protocol: A pilot randomised prospective intra-patient single-blinded observational study for examining the mechanistic basis of ablative fractional carbon dioxide laser therapy in treating hypertrophic scarring.

BACKGROUND: Burn injuries are the fourth most common type of trauma and are associated with substantial morbidity and mortality. The impact of burn injury is clinically significant as burn injuries often give rise to exuberant scarring. Hypertrophic scarring (HTS) is a particular concern as up to 70% of burns patients develop HTS. Laser therapy is used for treating HTS and has shown positive clinical outcomes, although the mechanisms remain unclear limiting approaches to improve its effectiveness. Emerging evidence has shown that fibroblasts and senescent cells are important modifiers of scarring. This study aims to investigate the cellular kinetics in HTS after laser therapy, with a focus on the association of scar reduction with the presence of senescent cells. METHODS: We will conduct a multicentre, intra-patient, single-blinded, randomised controlled longitudinal pilot study with parallel assignments to achieve this objective. 60 participants will be recruited to receive 3 interventional ablative fractional CO2 laser treatments over a 12-month period. Each participant will have two scars randomly allocated to receive either laser treatment or standard care. Biopsies will be obtained from laser-treated, scarred-no treatment and non-scarred tissues for immune-histological staining to investigate the longitudinal kinetics of p16INK4A+-senescent cells and fibroblast subpopulations (CD90+/Thy1+ and αSMA+). Combined subjective scar assessments including Modified Vancouver Scar Scale, Patient and Observer Scar Assessment Scale and Brisbane Burn Scar Impact Profile; and objective assessment tools including 3D-Vectra-H1 photography, DermaScan® Cortex, Cutometer® and ColoriMeter®DSMIII will be used to evaluate clinical outcomes. These will then be used to investigate the association between senescent cells and scar reduction after laser therapy. This study will also collect blood samples to explore the systemic biomarkers associated with the response to laser therapy. DISCUSSION: This study will provide an improved understanding of mechanisms potentially mediating scar reduction with laser treatment, which will enable better designs of laser treatment regimens for those living with HTS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04736251.

Efficacy and optimal dose of acetic acid to treat colonised burns wounds: protocol for a pilot randomised controlled trial.

INTRODUCTION: Despite of recent advancement in the burns wound management, burn wound infection (BWI) is still one of the major cause of burns mortality. Patients who survive their burns injury still suffers from BWI related complication like delayed wound healing and poor scarring. BWI has been treated by application of topical antimicrobial agents or systemic antibiotics. Due to the global risk of developing systemic antibiotics resistance, medical research focuses on identifying single topical agent which has effective antimicrobial activity, easily available and cost effective. One such agent is acetic acid (AA). AA has been used as a topical antibacterial agent for the treatment of burns wounds for many years and has shown to have activity against gram-negative organisms including Pseudomonas aeruginosa. So far there has been no consensus on optimal concentration that has effective antimicrobial activity, frequency of application, duration of treatment and most importantly good patient's tolerability. A randomised control study is required to answer all these questions. OBJECTIVE: To investigate the efficacy and tolerability of 0.5% and 2% of AA when applied to colonised burns wounds for 3 days after admittance to the Queen Elizabeth Hospital Birmingham. METHODS AND ANALYSIS: This is a double-blinded, prospective, randomised, controlled, single-centre trial. Patients will be screened for eligibility in the inpatient area and those who are found to be eligible will be randomly assigned to one of two treatment groups: group 1: 0.5% AA (10 patients); group 2: 2% AA (10 patients); total number: 20 patients. OUTCOME MEASURES: Primary outcome: Efficacy will be assessed by measuring the bacterial load from microbiology wound swabs for three consecutive days.Secondary outcomes: (1) The assessment of antimicrobial activity of AA and the minimum inhibitory concentrations. (2) Patient's tolerance by assessing Visual Analogue Scale pain score. (3) Time to 95% wound healing of treatment area. (4) Patient's perceived treatment allocation. ETHICS AND DISSEMINATION: AceticA trial protocol was approved by the National Research Ethics Service (West Midlands-Edgbaston Research Ethics Committee; 17/WM/0407; IRAS 234132). This article refers to protocol version 5.0 dated 6 July 2020. The analysed results will be presented at national and international conferences related to management of burn patients. The generated articles based on the trial results will be submitted to peer review journals for publication. TRIAL REGISTRATION NUMBER: ISRCTN11636684.

The role of biodegradable temporizing matrix in the management of a patient with major burns and anorexia nervosa.

Severe malnutrition secondary to anorexia nervosa results in deeper burns and significantly impacts wound healing, which represents a major challenge to burn management. The use of acellular dermal matrices, such as biodegradable temporizing matrix (BTM), is a valuable tool to overcome the surgical limitations. We describe a case of a 36-year-old female with a background of anorexia nervosa (body mass index of 12.3) presenting with a 30% total burns surface area (TBSA) burn. All of her burns were excised down to fascia due to the absence of subcutaneous fat. Her thin skin and depleted nutritional status significantly impacted reconstructive options. BTM was utilized to create a neodermis and provide adequate time to optimize the nutritional status before autologous skin resurfacing 3 weeks later, which yielded robust coverage with minimal donor site morbidity. Despite initial surgical and nutritional challenges, excellent outcomes were achieved in terms of wound healing, scar contractures and mobility.

Multicentre, longitudinal, observational cohort study to examine the relationship between neutrophil function and sepsis in adults and children with severe thermal injuries: a protocol for the Scientific Investigation of the Biological Pathways Following Thermal Injury-2 (SIFTI-2) study.

INTRODUCTION: Burn-induced changes in the phenotype and function of neutrophils, cells which provide front-line protection against rapidly dividing bacterial infections, are emerging as potential biomarkers for the early prediction of sepsis. In a longitudinal study of adult burns patients, we recently demonstrated that a combined measurement of neutrophil phagocytic capacity, immature granulocyte (IG) count and plasma cell-free DNA (cfDNA) levels on the day of injury gave good discriminatory power for the prediction of later sepsis development. However, limited by a small sample size, single-centre design and focus on adult burns patients, these biomarkers require prospective validation in a larger patient cohort. The Scientific Investigation of the Biological Pathways Following Thermal Injury-2 study aims to prospectively validate neutrophil phagocytic activity, IG count and plasma cfDNA levels as early prognostic biomarkers of sepsis in thermally injured adult and paediatric patients. METHODS AND ANALYSIS: This multicentre, longitudinal, observational cohort study will enrol 245 paediatric and adult patients with moderate to severe burns within 24 hours of injury. Blood samples will be obtained at 19 postinjury time points (days 1-14, day 28, months 3, 6, 12 and 24) and analysed for neutrophil phagocytic activity, IG count and cfDNA levels. Patients will be screened daily for sepsis using the 2007 American Burn Association diagnostic criteria for sepsis. In addition, daily multiple organ dysfunction syndrome and Sequential Organ Failure Assessment Scores will be recorded relationships between neutrophil phagocytic activity, IG count and plasma cfDNA levels on day 1 of injury and the development of sepsis will be examined using logistic regression models. ETHICS AND DISSEMINATION: This study received ethics approval from the West Midlands, Coventry and Warwickshire Research Ethics Committee (REC reference:16/WM/0217). Findings will be presented at national and international conferences, and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04693442.

Functional Maturation and In Vitro Differentiation of Neonatal Porcine Islet Grafts.

BACKGROUND: There is a strong rationale to pursue the use of neonatal porcine islets (NPIs) as an unlimited source of islets for clinical xenotransplantation. Because NPIs are composed of immature insulin producing beta (ß) cells and ductal precursor cells, they provide an ideal model to examine culture conditions to enhance ß cell proliferation and/or ß cell neoformation from ductal cells. In an attempt to optimize the potential of NPIs as a source of ß cell grafts, we used an in vitro differentiation protocol and measured its effect on the functional maturation and differentiation of NPIs. METHODS: Pancreata from 1- to 3-day-old neonatal pigs were digested and cultured in standard Ham's F10 media for 5 days. Each independent preparation was then further cultured in Dulbecco's modified Eagle medium nutrient mixture-F12 differentiation media containing growth factors added in a stepwise fashion, or cultured in control Ham's F10 media. After 20 days in culture, islets were assessed for insulin secretory capacity, cellular composition, gene expression, and metabolic activity after transplantation in immunodeficient mice with diabetes. RESULTS: Compared with control islets, differentiated islets exhibited a significantly higher proportion of endocrine cells, proliferating cell nuclear antigen double positive ß cells, and an enhanced glucose-stimulated insulin secretory activity. Mice transplanted with differentiated islets had significantly lower blood glucose values at weeks 18 and 20 compared with nondifferentiated controls and were shown to be more glucose tolerant. CONCLUSIONS: Culturing NPIs in a 20-day stepwise differentiation media increases the proportion of endocrine cells and augments both in vitro and in vivo function of the islets.

A New Grading System for the Management of Antenatal Hydronephrosis.

BACKGROUND AND OBJECTIVES: Standard clinical assessments do not predict surgical intervention in patients with a moderate degree of upper tract hydronephrosis. This study investigated whether combined measures of renal calyceal dilation and anteroposterior diameter (APD) of the renal pelvis at the first postnatal ultrasound better predict surgical intervention beyond standard assessments of the APD or Society of Fetal Urology (SFU) grading system. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort of 348 children with antenatal hydronephrosis followed from 2003 to 2013 were studied. Using Cox regression, the risk for surgery by APD, SFU, and combined grading on the basis of the first postnatal ultrasound was calculated. The predictive capability of each grading system for surgery was determined by calculating the positive likelihood ratio (LR+). RESULTS: The combination of APD≥6-9 mm and diffuse caliectasis had a hazard ratio (HR) of 19.5 (95% confidence interval [95% CI], 3.94 to 96.9) versus 0.59 (95% CI, 0.05 to 6.53) for APD≥6-9 mm alone and a similar risk of 8.9 for SFU grade 3 (95% CI, 3.84 to 20.9). The combination of APD≥9-15 mm and diffuse caliectasis had an HR of 18.7 (95% CI, 4.36 to 80.4) versus 1.75 (95% CI, 0.29 to 10.5) for APD≥9-15 mm alone. The LR+ for surgery for diffuse caliectasis and APD≥6-9 mm was higher than for APD≥6-9 mm alone (HR=2.62; 95% CI, 0.87 to 7.94 versus HR=0.04; 95% CI, 0.01 to 0.32) and was higher for APD≥9-15 mm and diffuse caliectasis than APD≥9-15 mm alone (HR=2.0; 95% CI, 1.15 to 3.45 versus HR=0.14; 95% CI, 0.04 to 0.43). Both combined groups of moderate hydronephrosis (APD≥6-9 mm or ≥9-15 mm with diffuse caliectasis) had only slightly higher LR+ than SFU grade 3 (HR=1.89; 95% CI, 1.17 to 3.05). CONCLUSIONS: These results suggest a grading system combining APD and diffuse caliectasis distinguishes those children with moderate degrees of upper tract hydronephrosis that are at higher risk of surgery.

A comprehensive review of pediatric urachal anomalies and predictive analysis for adult urachal adenocarcinoma.

PURPOSE: We examined the presentation, diagnosis and management of radiologically detected pediatric urachal anomalies and assessed the risk of malignant degeneration. MATERIALS AND METHODS: Our radiology database (2000 to 2012) was queried for all children younger than 18 years who were diagnosed with a urachal anomaly radiographically, and the operative database was used to determine those who underwent excision. Data collected included demographics, presenting symptoms, imaging modality and indication for excision. These data were compared to the Ontario Cancer Registry to determine the risk of malignancy. RESULTS: A total of 721 patients were radiographically diagnosed with a urachal anomaly (667 incidentally), yielding a prevalence of 1.03% of the general pediatric population. Diagnoses were urachal remnants (89% of cases), urachal cysts (9%) and patent urachus (1.5%). Ultrasonography was the most common imaging modality (92% of cases), followed by fluoroscopy/voiding cystourethrography (5%) and computerized tomography/magnetic resonance imaging (3%). A total of 61 patients (8.3%) underwent surgical excision. Indications for imaging and treatment were umbilical drainage (43% of patients), abdominal pain (28%), palpable mass (25%) and urinary tract infection (7%). Mean age at excision was 5.6 years and 64% of the patients were male. Based on provincial data, the number needed to be excised to prevent a single case of urachal adenocarcinoma was 5,721. CONCLUSIONS: Urachal anomalies are more common than previously reported. Children with asymptomatic lesions do not appear to benefit from prophylactic excision, as the risk of malignancy later in life is remote and a large number of urachal anomalies would need to be removed to prevent a single case of urachal adenocarcinoma.

Botulinum toxin A's expanding role in the management of pediatric lower urinary tract dysfunction.

Botulinum toxin A's (Onabotulinum toxin A - OnabotA) utility in the pediatric population is evolving, and is currently being used in the treatment of lower urinary tract dysfunction, both in children with neuropathic compromise, and non-neuropathic overactive bladders. The results of having OnabotA injected directly into the bladder wall cystoscopically are: a more compliant bladder with reduced bladder pressure, avoiding renal compromise and upper urinary tract deterioration; increased bladder capacity; and the ability for children to reach an improved degree of urinary continence through a minimally invasive approach. A growing body of research in patients with either neuropathic bladders or overactive bladders (OAB), have shown excellent results when looking at urodynamic parameters, patient satisfaction and improvement in symptomatology. One of the main indications for the use of OnabotA in children with neuropathic bladders is to delay or avoid the need for augmentation cystoplasty. By achieving the aforementioned results, some children can delay or avoid this more invasive and permanent procedure. Prospective studies are needed to answer questions regarding optimal dosage and frequency, ideal patient selection criteria and assessment of long-term outcomes and complications.