Paediatric surgical trials, their fragility index, and why to avoid using it to evaluate results.

BACKGROUND: The fragility index has been gaining ground in the evaluation of comparative clinical studies. Many scientists evaluated trials in their fields and deemed them to be fragile, although there is no consensus on the definition of fragility. We aimed to calculate the fragility index and its permutations for paediatric surgical trials. METHODS: We searched pubmed for prospectively conducted paediatric surgical trials with intervention and control group without limitations and calculated their (reverse) fragility indices and respective quotients along with posthoc-power. Relationships between variables were evaluated using Spearman's ρ. We also calculated S values by negative log transformation base-2 of P values. RESULTS: Of 516 retrieved records, we included 87. The median fragility index was 1.5 (interquartile range: 0-4) and the median reverse fragility index was 3 (interquartile range: 2-4), although they were statistically not different (Mood's test: χ2 = 0.557, df = 1, P = 0.4556). P values and fragility indices were strongly inversely correlated (ρ = - 0.71, 95% confidence interval: - 0.53 to - 0.85, P < 0.0001), while reverse fragility indices were moderately correlated to P values (ρ = 0.5, 95% confidence interval: 0.37-0.62, P < 0.0001). A fragility index of 1 resulted from P values between 0.039 and 0.003, which resulted in S values between 4 and 8. CONCLUSIONS: Fragility indices, reverse fragility indices, and their respective fragility quotients of paediatric surgical trials are low. The fragility index can be viewed as no more than a transformed P value with even more substantial limitations. Its inherent penalisation of small studies irrespective of their clinical relevance is particularly harmful for paediatric surgery. Consequently, the fragility index should be avoided.

Inguinal hernia repair in inpatient children: a nationwide analysis of German administrative data.

BACKGROUND: Contrary to adult inguinal hernia surgery, large-scale investigations using registries or administrative data are missing in paediatric surgery. We aimed to fill this gap by analysing German administrative hospital data to describe the current reality of inpatient hernia surgery in children. METHODS: We analysed aggregated data files bought from the German federals statistics office on hospital reimbursement data separately for principal diagnoses of inguinal hernia in children and for herniotomies in inpatients. Developments over time were assessed via regression and differences between groups with nonparametric comparisons. RESULTS: Principal diagnoses of hernias were decreasing over time with the exception of male bilateral and female bilateral incarcerated hernias in the first year of life which increased. The vast majority of operations were conducted via the open approach and laparoscopy was increasingly only used for females older than 1 year of age. Recurrent hernia repair was scarce. Rates of inguinal hernia repair were higher in both sexes the younger the patient was, but were also decreasing in all age groups despite a population growth since 2012. The amount of inguinal hernia repairs by paediatric surgeons compared to adult surgeons increased by 1.5% per year. CONCLUSIONS: Our results corroborate previous findings of age and sex distribution. It demonstrates that inpatient hernia repair is primarily open surgery with herniorrhaphy and that recurrences seem to be rare. We observed decreasing rates of hernia repairs over time and as this has been described before in England, future studies should try to elucidate this development. LEVEL OF EVIDENCE: III.

Meta-analyses in paediatric surgery are often fragile: implications and consequences.

PURPOSE: Meta-analyses occupy the highest level of evidence and thereby guide clinical decision-making. Recently, randomised-controlled trials were evaluated for the robustness of their findings by calculating the fragility index. The fragility index is the number of events that needs to be added to one treatment arm until the statistical significance collapses. We, therefore, aimed to evaluate the robustness of paediatric surgical meta-analyses. METHODS: We searched MEDLINE for paediatric surgical meta-analyses in the last decade. All meta-analyses on a paediatric surgical condition were eligible for analysis if they based their conclusion on a statistically significant meta-analysis. RESULTS: We screened 303 records and conducted a full-text evaluation of 60 manuscripts. Of them, 39 were included in our analysis that conducted 79 individual meta-analyses with significant results. Median fragility index was 5 (Q25-Q75% 2-11). Median fragility in relation to included patients was 0.77% (Q25-Q75% 0.29-1.87%). CONCLUSION: Paediatric surgical meta-analyses are often fragile. In almost 60% of results, the statistical significance depends on less than 1% of the included population. However, as the fragility index is just a transformation of the P value, it basically conveys the same information in a different format. It therefore should be avoided.

Comparing Aachen Minipigs and Pietrain Piglets as Models of Experimental Pediatric Urology to Human Reference Data.

INTRODUCTION: Swine had special roles in the development of minimally invasive procedures to treat vesicoureteral reflux, and minipigs have been gaining ground in recent years in experimental pediatric urology as they combine small size with less vulnerable adult physiology, but their suitability as a model has never been assessed. We therefore compared a landrace piglet with a juvenile minipig to elucidate comparability. METHODS: We evaluated five 3-week old Pietrain piglets and five 3-month old Aachen Minipigs as representatives of landrace and minipig models based on their expected bodyweight being similar to a newborn human. We compared renal weight, volume - via the ellipsoid formula - and ureteral length. In addition, we calculated porcine renal function via Gasthuys' formula. In order to compare the groups with previously published values for infants, we used resampling techniques to allow comparison to humans. RESULTS: Renal weight was higher in humans than in Pietrain piglets (ΔL = 7.6 g; ΔR = 5.4 g) and Aachen Minipigs (ΔL = 11 g; ΔR = 9.4 g). Renal volumes in humans were higher than in both Pietrain piglets (ΔL = 5.6 mL, p < 0.001; ΔR = 3.7 mL, p = 0.004) and Aachen Minipigs (ΔL = 8.1 mL; ΔR = 6.6 mL; both p < 0.001). Ureteral lengths in humans and both pig breeds were comparable as were estimated renal functions between both pig breeds. DISCUSSION AND CONCLUSION: Both landrace piglets and juvenile minipigs are suitable models for experimental pediatric urology as parameters did not differ between them. In addition, the anatomic parameters are comparable or smaller than in infants. This might facilitate translational research as technical failure is less likely in larger organs. Additional research is necessary to cover higher age ranges than those included in the present pilot study.

Using multidimensional scaling in model choice for congenital oesophageal atresia: similarity analysis of human autopsy organ weights with those from a comparative assessment of Aachen Minipig and Pietrain piglets.

Swine models had been popular in paediatric oesophageal surgery in the past. Although being largely replaced by rodent models, swine experienced a revival with the establishment of minipig models. However, none of them has ever been investigated for similarity to humans. We conducted a pilot study to determine whether three-week old Pietrain piglets and three-month old Aachen Minipigs are suitable for experimental paediatric oesophageal atresia surgery. We tested the operation's feasibility, performed a necropsy, weighed organs, measured organ length and calculated relative weights and lengths, and measured laboratory parameters. We used multidimensional scaling to assess the similarity of the swine breeds with previously published human data. Pietrain piglets had a higher a priori bodyweight than Aachen Minipigs (Δ = 1.31 kg, 95% confidence interval (CI): 0.37-2.23, p = 0.015), while snout-to-tail length was similar. Pietrain piglets had higher absolute and relative oesophageal lengths (Δ = 5.43 cm, 95% CI: 2.2-8.6; p = 0.0062, q1* = 0.0083 and Δ = 11.4%, 95% CI: 5.1-17.6; p = 0.0025, q3* = 0.0053). Likewise, absolute and relative small intestinal lengths were higher in Pietrains, but all other parameters did not differ, with the exception of minor differences in laboratory parameters. Multidimensional scaling revealed three-week old Pietrain piglets to be similar to two-month old humans based on their thoracoabdominal organ weights. This result indicates three-week old Pietrain piglets are a suitable model of paediatric oesophageal atresia surgery, because clinically many procedures are performed at around eight weeks age. Three-month old Aachen Minipigs were more dissimilar to eight-week old humans than three-week old Pietrain piglets.

Esophageal Biomechanics Revisited: A Tale of Tenacity, Anastomoses, and Suture Bite Lengths in Swine.

BACKGROUND: Anastomotic tension has repeatedly been associated with anastomotic leakages after esophagectomy for cancer or esophageal atresia repair. We therefore aimed to determine which anastomotic technique would come as close as possible to the native esophagus in sustaining traction forces. Constant traction for several minutes at esophageal remnants and large suture bites are also considered relevant in long-gap esophageal atresia repair. METHODS: Porcine esophagi were subjected to linear traction using a motorized horizontal test stand. We compared breaking strengths of native esophagi to simple continuous, simple interrupted, stapled, and barbed suture anastomoses. We also investigated the effects of suture bite length and phases of constant traction on breaking strengths and powered all experiments to at least 80% using exploratory investigations (n = 5 per group). RESULTS: Continuous suture anastomoses had a breaking strength comparable to native esophagi (Δ = -5.25 Newton, 95% confidence interval: -10.69 to 0.19 Newton, p = 0.058) and outperformed all other investigated anastomoses (Δ ≥14.01 Newton, p ≤ 0.02). Breaking strength correlated with suture bite length (R = 0.905) and predicted breaking strength for the simple stitch (adjusted R2 = 0.812, p < 0.0001), but not for anastomoses. Phases of incrementally increasing constant traction resulted in higher breaking strengths (Δ = 13.36 Newton, 95% confidence interval: 9.93 to 16.79 Newton, p < 0.0001) and higher length gain (Δ = 1.06 cm, 95% confidence interval: 0.65 to 1.48 cm, p < 0.0001) compared with controls. CONCLUSIONS: Only simple continuous anastomoses achieved the linear breaking strength of native tissue. Our study provides important insights in tolerance to traction forces, but its results have to be corroborated in living animals as anastomotic leakages are multifactorial processes.

Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients.

BACKGROUND & AIMS: Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA. METHODS: We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control). RESULTS: Livers from rhesus rota virus-infected mice with BA had 7-fold more Il17a messenger RNA than control mice (P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 µmol/L vs 78 µmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues (P = .02). CONCLUSIONS: In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.