The Over-Irradiation Metabolite Derivative, 24-Hydroxylumister-ol3, Reduces UV-Induced Damage in Skin.

The hormonal form of vitamin D3, 1,25(OH)2D3, reduces UV-induced DNA damage. UV exposure initiates pre-vitamin D3 production in the skin, and continued UV exposure photoisomerizes pre-vitamin D3 to produce "over-irradiation products" such as lumisterol3 (L3). Cytochrome P450 side-chain cleavage enzyme (CYP11A1) in skin catalyzes the conversion of L3 to produce three main derivatives: 24-hydroxy-L3 [24(OH)L3], 22-hydroxy-L3 [22(OH)L3], and 20,22-dihydroxy-L3 [20,22(OH)L3]. The current study investigated the photoprotective properties of the major over-irradiation metabolite, 24(OH)L3, in human primary keratinocytes and human skin explants. The results indicated that treatment immediately after UV with either 24(OH)L3 or 1,25(OH)2D3 reduced UV-induced cyclobutane pyrimidine dimers and oxidative DNA damage, with similar concentration response curves in keratinocytes, although in skin explants, 1,25(OH)2D3 was more potent. The reductions in DNA damage by both compounds were, at least in part, the result of increased DNA repair through increased energy availability via increased glycolysis, as well as increased DNA damage recognition proteins in the nucleotide excision repair pathway. Reductions in UV-induced DNA photolesions by either compound occurred in the presence of lower reactive oxygen species. The results indicated that under in vitro and ex vivo conditions, 24(OH)L3 provided photoprotection against UV damage similar to that of 1,25(OH)2D3.

Codesigning informative resources for families of Aboriginal and Torres Strait Islander children who sustained a burn injury: a protocol for a participatory action research study.

INTRODUCTION: Parents of children hospitalised in a burn unit experience psychological trauma and later post-traumatic stress. Aboriginal and Torres Strait Islander families whose child has been admitted to a burn unit encounter additional burdens through a culturally unsafe healthcare system. Psychosocial interventions can help reduce anxiety, distress and trauma among children and parents. There remains a lack of interventions or resources that reflect Aboriginal and Torres Strait Islander people's perspective of health. The objective of this study is to codevelop a culturally appropriate informative resource to assist Aboriginal and Torres Strait Islander parents whose child has been hospitalised in a burn unit. METHODS: In this participatory research study, the development of a culturally safe resource will build on Aboriginal and Torres Strait Islander families' experiences and voices, complemented by the knowledge and expertise of an Aboriginal Health Worker (AHW) and burn care experts. Data will be collected through recorded yarning sessions with families whose child has been admitted to a burn unit, the AHW and burn care experts. Audiotapes will be transcribed and data will be analysed thematically. Analysis of yarning sessions and resource development will follow a cyclical approach. ETHICS AND DISSEMINATION: This study has been approved by the Aboriginal Health and Medical Research Council (AH&MRC) (1690/20) and the Sydney Children's Hospitals Network ethics committee (2020/ETH02103). Findings will be reported to all participants and will be disseminated with the broader community, the funding body and health workers at the hospital. Dissemination with the academic community will be through peer-reviewed publications and presentations in relevant conferences.

The CaSR Modulator NPS-2143 Reduced UV-Induced DNA Damage in Skh:hr1 Hairless Mice but Minimally Inhibited Skin Tumours.

The calcium-sensing receptor (CaSR) is an important regulator of epidermal function. We previously reported that knockdown of the CaSR or treatment with its negative allosteric modulator, NPS-2143, significantly reduced UV-induced DNA damage, a key factor in skin cancer development. We subsequently wanted to test whether topical NPS-2143 could also reduce UV-DNA damage, immune suppression, or skin tumour development in mice. In this study, topical application of NPS-2143 (228 or 2280 pmol/cm2) to Skh:hr1 female mice reduced UV-induced cyclobutane pyrimidine dimers (CPD) (p < 0.05) and oxidative DNA damage (8-OHdG) (p < 0.05) to a similar extent as the known photoprotective agent 1,25(OH)2 vitamin D3 (calcitriol, 1,25D). Topical NPS-2143 failed to rescue UV-induced immunosuppression in a contact hypersensitivity study. In a chronic UV photocarcinogenesis protocol, topical NPS-2143 reduced squamous cell carcinomas for only up to 24 weeks (p < 0.02) but had no other effect on skin tumour development. In human keratinocytes, 1,25D, which protected mice from UV-induced skin tumours, significantly reduced UV-upregulated p-CREB expression (p < 0.01), a potential early anti-tumour marker, while NPS-2143 had no effect. This result, together with the failure to reduce UV-induced immunosuppression, may explain why the reduction in UV-DNA damage in mice with NPS-2143 was not sufficient to inhibit skin tumour formation.

Paediatric pelvic fractures - an updated literature review.

BACKGROUND: Pelvic fractures in children are indicative of significant trauma. Patients will often have associated injuries - some of which require urgent intervention to prevent death and disability. Paediatric and adult pelvises respond to traumatic forces differently and distinct approaches are required for each population. Historically, pelvic fractures have been treated conservatively, but this trend is changing with a better understanding of the pelvis' inability to remodel significant deformity, as well as new techniques for operative fixation. METHODS: A comprehensive search of the literature was conducted for articles published between 2000 and 2020 on paediatric pelvic fractures using medical databases including PubMed, Embase and the Cochrane Library. RESULTS: We included 143 studies in our literature review and summarized the incidence, pathophysiology, assessment, management and complications associated with paediatric pelvic fractures. CONCLUSIONS: The rarity of paediatric pelvic fractures corresponds with a paucity of randomized clinical trials covering this topic. Trends such as the screening pelvic x-ray are derived from adult populations but are now questioned in children. Other aspects of assessment and management of these children warrant such levels of scrutiny.

Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D-Related Compounds.

The vitamin D hormone, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), and related compounds derived from vitamin D3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV-induced DNA damage with 20-hydroxyvitamin D3 or 24-hydroxylumisterol3, as previously shown for 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)2D3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)2D3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1α-hydroxylase and thus unable to make 1,25(OH)2D3 are not more susceptible. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Monocyte M1/M2 profile is altered in paediatric burn patients with hypertrophic scarring.

Hypertrophic scars (HTS) remain a common outcome of burn injury, particularly in children. They can arise from variations in the wound healing stages, such as an excessive inflammatory response or inefficient remodelling. Of the cells contributing to these healing stages, macrophages and fibrocytes are crucial. Specifically, the inflammatory phase is dominated by M1 macrophages, the proliferation/remodelling stages by M2 macrophages, and scar tissue contains numerous fibrocytes. As the progenitors to these cells, monocytes, can also exhibit M1- and M2-skewing, we proposed that their profile, or circulating fibrocyte counts, could be used to predict poor healing outcomes. To investigate this, we obtained blood samples from paediatric controls and burns patients, which were then divided into HTS and NoHTS groups upon scar assessment at 12 months. The samples were assessed by whole blood flow cytometry to quantify fibrocytes and monocyte subset proportions and to determine monocyte levels of M1 (CD86, CD120b, CD319) and M2 (CD93, CD163, CD200R) markers. Both burns groups had higher proportions of classical monocytes compared to controls, indicating increased cell turnover and/or entry of other subsets into the wound. In burns patients who took more than 21 days to heal, the HTS group had lower M2 (CD200R) expression with the ratio of M1/M2 (CD86/CD200R) being significantly higher. These results suggest an elevated early inflammatory monocyte response contributes to development of HTS. Correlations of marker expression with remaining healing time revealed a significant positive correlation with M1 (CD120b) and M1/M2 (CD120b/CD200R), suggesting a potential role for CD120b as an indicator of healing delay. Fibrocytes did not significantly differ between the groups. In conclusion, increased monocyte inflammation likely contributes to slower healing and development of scarring, but further studies are needed to determine the predictive power of monocyte inflammatory profile.

Paediatric adhesive bowel obstruction: a systematic review.

Adhesions following abdominal surgery remain a common cause of bowel obstruction. The incidence is between 1 and 12.6% in children who have had previous abdominal surgery. While conservative management is usually trialled in all patients (including children) suspected of having ASBO, the majority will require surgical intervention. New materials such as Seprafilm® have been studied in the paediatric population, with promising results of its use in index abdominal surgeries to prevent the formation of adhesions. In this article, we conducted a systematic review to present an overview of the current knowledge on the incidence, aetiology, pathophysiology, clinical presentation, and management of ASBO.

Holiday hazards: burns in children during school holidays.

BACKGROUND: Paediatric burns are preventable injuries that can have a permanent impact on a child's health and wellbeing. The Burns Unit at the Children's Hospital at Westmead appeared to experience an increase in paediatric burn injury referrals during the school holidays. The evaluation of the characteristics of burn injuries in the school holidays compared to the school term may improve the effectiveness of burn prevention programmes. METHODS: A retrospective review was performed of all school-aged children who were referred to our institution between January 2005 and January 2019. Patient details, burn aetiology, burn severity, length of stay and need for grafting were compared between burns sustained during the school holidays and burns sustained during school term. RESULTS: A total of 3020 children were referred to Children's Hospital at Westmead between January 2005 and January 2019. The mean number of burns sustained increased from 3.8 children per week during the school term to 5.4 children per week during school holidays (P < 0.0001). Contact burns were proportionally more common during school holidays than during the school term (26% versus 19.7%, P < 0.0001), whilst the proportion of scalds decreased significantly during the school holidays (43.5 versus 51.4%, P < 0.0001). There was no difference between mean age, % total body surface area, admission rates, length of stay or skin grafting rates. CONCLUSION: There is a significant increase in burn injuries among school-aged children during the school holidays. This highlights the need for targeted education and prevention campaigns in the periods immediately preceding the school holidays.

Comparison of Operative Logbook Experience of Australian General Surgical Trainees With Surgeons Deployed on Humanitarian Missions: What Can Be Learnt for the Future?

OBJECTIVE: General surgical training in Australia has undergone considerable change in recent years with less exposure to other areas of surgery. General surgeons from many high-income countries have played important roles in assisting with the provision of surgical care in low- and middle-income countries during sudden-onset disasters (SODs) as part of emergency medical teams (EMTs). It is not known if contemporary Australian general surgeons are receiving the broad surgical training required for work in EMTs. DESIGN: Logbook data on the surgical procedures performed by Australian general surgical trainees were obtained from General Surgeons Australia (GSA) for the time period February 2008 to February 2017. Surgical procedures performed by Médecins sans Frontières (MSF) surgeons during 5 projects in 3 SODs (the 2010 Haiti earthquake, the 2013 Philippines typhoon and the 2015 Nepal earthquake) were obtained from previously published data for 6 months following each disaster. SETTING AND PARTICIPANTS: This was carried out at the University of Sydney with input from MSF Operational Centre Brussels and GSA. RESULTS: Australian general surgical trainees performed a mean of 2107 surgical procedures (excluding endoscopy) during their training (10 6-month rotations). Common procedures included abdominal wall hernia repairs (268, 12.7%), cholecystectomies (247, 11.8%), and specialist colorectal procedures (242, 11.5%). MSF surgeons performed a total of 3542 surgical procedures across the 5 projects analyzed. Common procedures included Caesarean sections (443, 12.5%), wound debridement (1115, 31.5%), and other trauma-related procedures (472, 13.3%). CONCLUSIONS: Australian general surgical trainees receive exposure to both essential and advanced general surgery but lack exposure to specialty procedures including the obstetric and orthopedic procedures commonly performed by MSF surgeons after SODs. Further training in these areas would likely be beneficial for general surgeons prior to deployment with an EMT.

Balanitis xerotica obliterans: an update for clinicians.

Lichen sclerosus (LS) is a severe, chronic, dermatosis characterised by inflammatory, sclerotic, pruritic lesions that causes significant morbidity in patients of all genders and ages. In boys, the lesions typically affect the foreskin and glans (termed balanitis xerotica obliterans (BXO)), leading to phimosis and potentially meatal stenosis. The incidence of the disease is not well reported but the average age of affected boys is 8 years (range 1-16). Diagnosis can often be made clinically, although histological study remains important to rule out important differential diagnoses. Complications include genital scarring, urinary and sexual dysfunction as well as the development of carcinomas in adult life. Circumcision has been regarded as definitive management of BXO in boys, but this may be supplemented with medical therapies such as topical steroids, immune modulators, intralesional triamcinolone and ozonated olive oil. Supportive measures including emollients, avoidance of irritants, surveillance of complications and recurrence as well as education and counselling remain important.Conclusion: BXO remains an important cause of phimosis in boys. The frequency of this condition appears unclear but seems likely to be less than 1% of males. Treatment generally involves circumcision, with some evidence that topical steroids or immunomodulators may decrease the incidence of recurrent meatal stenosis.What is Known:• Surgical circumcision is considered the definitive management of BXO• Many aspects of BXO are still in contention or require further study including the epidemiology and aetiology.What is New:• There is increasing awareness of non-surgical modalities that may be used in adjunct to surgery including topical corticosteroids, immune modulators, intralesional triamcinolone and ozonated olive oil• Awareness of meatal stenosis-related BXO has led to the development of surgical techniques such as preputioplasty as well as buccal mucosal inlay grafts.

Australasian general surgical training and emergency medical teams: a review.

Emergency medical teams (EMTs) have provided surgical care in sudden-onset disasters in low- and middle-income countries. General surgeons have been heavily involved in many EMTs due to their traditional broad set of surgical skills and experience. With the increased subspecialization of general surgical training in many high-income countries, including Australia and New Zealand, finding general surgeons with adequately broad experience is becoming more challenging. Furthermore, it is now considered standard for EMTs deploying to a sudden-onset disaster to have undergone credentialing, demonstrating sufficient training of their deployed members. The purpose of this review was to highlight the challenges and potential solutions facing those involved in training and recruiting general surgeons for EMTs in Australasia.

Publishing trends in Journal of Paediatric Surgery, Pediatric Surgery International and European Journal of Pediatric Surgery over the past three decades.

The aim of this study was an analysis of the changing publication trends over the last three decades in the Journal of Pediatric Surgery (JPS), Pediatric Surgery International (PSI) and European Journal of Pediatric Surgery (EJPS) by studying the bibliometric variables, authorship, collaboration, and citation trends. A previously applied methodology using intermittent years was applied to review the archives of JPS, PSI and EJPS over the last 30 years. Citation data were collected from the Web of Science database. Statistical analysis was performed using SAS 9.4 software. A total of 1917 articles originating from 63 countries met the inclusion criteria. The number of articles published every year increased significantly in the last three decades from 336 in 1987 to 626 in 2017 (P < 0.0001). Multinational papers made up 5% of the total, of which 58% involved more than one continent. A majority of papers (75%) were single institution papers, there was strong evidence of an increase in multi-institution publications over time. There was a statistically significant increase in the number of female first and corresponding author. The publishing landscape of paediatric surgery has evolved to be more inclusive with increased collaboration, female authors and mentors and more publications from developing nations.

Surgical Procedures Performed by Emergency Medical Teams in Sudden-Onset Disasters: A Systematic Review.

BACKGROUND: Emergency medical teams (EMTs) frequently provide surgical care after sudden-onset disasters (SODs) in low- and middle-income countries. The purpose of this review is to describe the types of surgical procedures performed by EMTs with general surgical capability in order to aid the recruitment and training of surgeons for these teams. METHODS: A search of electronic databases (PubMed, MEDLINE, and EMBASE) was carried out to identify articles published between 1990 and 2018 that describe the type of surgical procedures performed by EMTs in the impact and post-impact phases of a SOD. Further relevant articles were obtained by hand searching reference lists. RESULTS: A total of 16 articles met the inclusion criteria. Articles reporting on EMTs from a number of different countries and responding to a variety of SODs were included. There was a high prevalence of procedures for extremity soft tissue injuries (46.8%) and fractures (28.3%), although a number of abdominal and genitourinary/obstetric procedures were also reported. CONCLUSIONS: Based upon this review, deployment of surgeons or teams with experience in the management of soft tissue wounds, orthopaedic trauma, abdominal surgery, and obstetrics is recommended.

Developmental outcome at 3 years of age of infants following surgery for infantile hypertrophic pyloric stenosis.

PURPOSE: The study compared neurodevelopmental outcome at 3 years of age of infants with infantile hypertrophic pyloric stenosis (IHPS) who underwent pyloromyotomy with healthy control infants in New South Wales, Australia. METHODS: Infants with IHPS as well as controls were recruited between August 2006 and July 2008. Developmental assessments were performed using the Bayley scales of infant and toddler development (version III) (BSITD-III) at 1 and 3 years of age. RESULTS: Of the 43 infants originally assessed at 1 year, 39 returned for assessment at 3 years (90%). The majority were term infants (77%). Assessments were also performed on 156 control infants. Infants with IHPS scored significantly lower on four of the five Bayley subsets (cognitive, receptive and expressive language and fine motor) compared to control infants. Analysis of co-variance showed statistically significant results in favour of the control group for these four subsets. CONCLUSION: Compared with the outcomes at 1 year, infants with IHPS at 3 years of age continue to score below controls in four of the BSITD-III subscales. This suggests they should have developmental follow-up with targeted clinical intervention. There is a need for further studies into functional impact and longer term outcomes.

Pathological prognostication of paediatric adrenocortical tumours: Is a gold standard emerging?

BACKGROUND: Criteria for the pathological classification of adult adrenocortical tumours (ACTs) have been found to overestimate the malignant potential of childhood ACTs. We sought to evaluate the accuracy and utility of criteria developed for paediatric ACT compared to current criteria for adults. METHODS: ACTs treated between January 2006 and December 2016 in two paediatric institutions were evaluated. Patients classified clinically as malignant (CM) had locally invasive disease at surgery requiring extensive en bloc resection to achieve clear margins, had local recurrence or distant metastasis. Slides were reviewed by pathologists blinded to the clinical outcome. A grade was assigned to each tumor according to the Weiss, Aubert, Wieneke and Dehner-Hill criteria. The pathological grade was compared to the clinical outcome. RESULTS: The median follow-up was 60 months (interquartile range 25-80 months). Based on clinical criteria, of 22 patients 14 (64%) had a benign course and eight (34%) behaved malignant. The malignant potential was overestimated by Weiss criteria in 23% and Aubert criteria in 27%. Wieneke and Dehner-Hill criteria showed good clinicopathological correlation; no child who had a benign course was classified as malignant. The Dehner-Hill criteria, however, classified five (23%) children as intermediate risk of which three had a clinically benign and two a CM course. CONCLUSION: The Wieneke criteria accurately predicts the clinical course in childhood ACTs and could be considered the gold standard in their pathological characterization.

Association between male genital anomalies and adult male reproductive disorders: a population-based data linkage study spanning more than 40 years.

BACKGROUND: The male genital anomalies hypospadias and undescended testes have been linked to adult male reproductive disorders, testicular cancer, and decreased fertility. Few population-based studies have evaluated their effects on adult fertility outcomes and, in the case of undescended testes, the importance of early corrective surgery (orchidopexy). METHODS: We did a population-based cohort study of all liveborn boys in Western Australia in 1970-99, and followed them up until 2016 via data linkage to registries for hospital admissions, congenital anomalies, cancer, and assisted reproductive technologies (ART). Study factors were hypospadias or undescended testes, and study outcomes were testicular cancer, paternity, and use of ART for male infertility. Cox regression was used to calculate hazard ratios (HRs) for the associations between genital anomalies and testicular cancer or paternity, and log-binomial regression was used to calculate relative risks (RRs) for the associations between genital anomalies and use of ART. FINDINGS: The cohort comprised 350 835 boys, of whom 2484 (0·7%) had been diagnosed with hypospadias and 7499 (2·1%) with undescended testes. There were 505 (0·1%) cases of testicular cancer, 109 471 (31·2%) men had fathered children, and 2682 (0·8%) had undergone fertility treatment with ART. Undescended testes was associated with a more than two times increase in risk of testicular cancer (HR 2·43, 95% CI 1·65-3·58) and hypospadias with an almost 40% increase (1·37, 0·51-3·67), although this increase was not significant. Both hypospadias and undescended testes were associated with a 21% reduction in paternity (adjusted HR 0·79 [95% CI 0·71-0·89] for hypospadias and 0·79 [0·74-0·85] for undescended testes). Undescended testes was associated with a two times increase in use of ART (adjusted RR 2·26, 95% CI 1·58-3·25). For every 6 months' delay in orchidopexy, there was a 6% increase in risk of testicular cancer (HR 1·06, 95% CI 1·03-1·08), a 5% increase in risk of future use of ART (1·05, 1·03-1·08), and a 1% reduction in paternity (RR 0·99, 95% CI 0·98-0·99). INTERPRETATION: Undescended testes is associated with an increased risk of testicular cancer and male infertility, and decreased paternity. We provide new evidence to support current guidelines for orchidopexy before age 18 months to decrease the risk of future testicular cancer and infertility. FUNDING: National Health and Medical Research Council and Sydney Medical School Foundation.

Influence of early childhood burns on school performance: an Australian population study.

OBJECTIVES: To determine the influence of burn injuries on childhood performance in national standardised curriculum-based school tests. DESIGN: Birth and health records of 977 children who were hospitalised with a burn injury between 2000 and 2006 in the state of New South Wales, Australia, were linked to performance scores in the National Assessment Program: Literacy and Numeracy test, a compulsory nationwide curriculum-based test (CBT) and compared with children who were not hospitalised for burns and who were matched for birth year, gender, gestation and socioeconomic status. MAIN OUTCOME MEASURES: Test scores in years 3 (ages 8-9), 5 (ages 10-11) and 7 (ages 13-14) in numeracy, writing, reading, spelling, grammar and punctuation. RESULTS: Mean age at first burn injury was 28 months (median: 20, range: 0-140). Children with burns were significantly more likely to have younger mothers (28.5 vs 29.6 years) (P<0.001), be indigenous (OR 2.5 (95% CI 2.1 to 3.1)) (P<0.001) and have siblings (OR 1.2 (95% CI 1.1 to 1.4)) (P<0.001). They were also less likely to meet national minimum standards in most domains of testing until year 5, even after adjustment for parental education levels, parental smoking, maternal age and indigenous status. Each 10% increase in total body surface area burnt was associated with a decrease in year 5 scores by 37.0% in numeracy and 71.9% in writing. CONCLUSIONS: Most childhood burn injuries occur before the start of formal schooling. Children who are hospitalised for burns perform more poorly in CBT even after accounting for family and socioeconomic disadvantage. Rehabilitation of children with burn injuries must address school performance to decrease any long-term negative societal impact of burns.