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Background The optimal timing of repair for inguinal hernia in premature infants remains a controversial topic. Our objective was to assess the clinical effects of inguinal hernia repair done before or after neonatal intensive care unit (NICU) discharge. Methods MEDLINE, Embase, CINAHL, and CENTRAL were searched in July 2018. Publications comparing clinical outcomes of the premature infants with inguinal hernia repair before (early) and after (delayed) NICU discharge were identified. Two reviewers independently screened studies, extracted data, and assessed for quality. Results were pooled using random effects meta-analysis. Results Of 640 publications identified, six comparative studies assessing a total of 1761 premature infants were included. Meta-analysis indicated no statistically significant difference in incarceration rate (odds ratio (OR) 2.15, 95% confidence interval (CI) 0.83–5.58, I2 = 0%), surgical complications (OR 2.36, 95% CI 0.66–8.41, I2 = 0%) and other secondary complications. However, the odds of recurrence and respiratory difficulty was significantly increase in the early group compared to delayed (OR 4.12, 95% CI 1.17–14.45, I2 = 0%; OR 3.59, 95% CI 1.10–11.75, I2 = 42%). Conclusions Repair of inguinal hernia in premature infants before NICU discharge may increase the odds of recurrence, but not incarceration or surgical complications. Level of evidence Level III

Background The only curative treatment for Hirschsprung disease (HD) is surgical repair. However, some patients experience poor postoperative outcomes. We determined long-term outcomes of all HD patients in Ontario, Canada’s most populous province. Methods We conducted a retrospective cohort study including all children with HD born between April 1, 1991 and March 31, 2014 in Ontario using linked health administrative data. Each HD case was matched to five non-HD controls on sex, date of birth, region of residence and income and followed to March 31, 2016. Chronic diarrhea and constipation were identified using combinations of outpatient physician billing codes in both HD patients and non-HD residents of the province. We determined risk factors associated with diarrhea and constipation, including surgery type and sociodemographic characteristics, using multivariable conditional logistic regression, and reported adjusted odds ratios (aORs). Results There were 3,265,172 children born in the study period, of whom 673 had HD. Compared to controls, chronic constipation was more common in HD patients (27.5% versus 2.1%; aOR 17.2, 95% CI 12.6 to 23.4), as was chronic diarrhea (29.9% versus 6.9%, aOR 5.22, 95% CI 4.19 to 6.50). In HD patients, older age at surgery was associated with increased risk of chronic constipation (OR 2.71, 95% CI 1.75 to 4.20). Surgery type, sex, rural/urban residence and income were not associated with risk of chronic constipation or diarrhea. Conclusion Chronic constipation and diarrhea were common following surgery for HD. Older age at surgery was associated with subsequent risk of chronic constipation. Surgery type was not associated with increased risk of chronic constipation or diarrhea.

Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012–2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27–4·86; I2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70–1·91, 0·81–1·21, 0·67–1·95, 0·65–0·94, 0·60–1·45; I2 = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns. Interpretations: MSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events. Funding: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund Keywords: Mesenchymal stem cells, Safety, Adverse events, Systematic review

Acute kidney injury (AKI) is a significant contributing factor to the morbidity and mortality of critically ill adults, yet there remains controversy on the optimal renal replacement therapy mode for these patients. The aim of our systematic review was to determine the effect of sustained low-efficiency dialysis or continuous renal replacement therapy on patient outcomes in critically ill patients with AKI. A systematic search of Medline, Embase, CINAHL, and the Cochrane Library was conducted in February 2015. Identified citations were screened independently in duplicate and the methodological quality of included studies was evaluated. Data were extracted on study, patient, and intervention characteristics, as well as clinical outcomes. Results were pooled using inverse variance fixed and random effects meta-analysis. A total of 1564 patients in 18 studies were included. Meta-analysis indicated no statistically significant difference in our primary outcome, overall renal recovery (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.63-1.20, I2 66%). No significant difference was observed for the secondary outcome of time to renal recovery (mean difference 1.33, 95% CI 0.23-2.88, I2 0%). SLED was slightly favoured over CRRT in statistically significant manner for the secondary outcome of mortality (RR 1.21, 95% CI 1.02-1.43, I2 47%), however this diminished when sensitivity analysis of only RCTs was conducted (RR 1.25, 95% CI 1.00-1.57, I2 = 0%). There appears to be no clear for advantage continuous renal replacement in the hemodynamically unstable patient. Currently, both modalities are safe and effective means of treating AKI in the critically ill adult.

Despite evidence-based recommendations, adherence with secondary prevention medications post-myocardial infarction (MI) remains low. Taking medication requires behaviour change, and using behavioural theories to identify what factors determine adherence could help to develop novel adherence interventions.Compare the utility of different behaviour theory-based approaches for identifying modifiable determinants of medication adherence post-MI that could be targeted by interventions.Two studies were conducted with patients 0-2, 3-12, 13-24 or 25-36 weeks post-MI. Study 1: 24 patients were interviewed about barriers and facilitators to medication adherence. Interviews were conducted and coded using the Theoretical Domains Framework. Study 2: 201 patients answered a telephone questionnaire assessing Health Action Process Approach constructs to predict intention and medication adherence (MMAS-8).Study 1: domains identified: Beliefs about Consequences, Memory/Attention/Decision Processes, Behavioural Regulation, Social Influences and Social Identity. Study 2: 64, 59, 42 and 58% reported high adherence at 0-2, 3-12, 13-24 and 25-36 weeks. Social Support and Action Planning predicted adherence at all time points, though the relationship between Action Planning and adherence decreased over time.Using two behaviour theory-based approaches provided complimentary findings and identified modifiable factors that could be targeted to help translate Intention into action to improve medication adherence post-MI.

Study design Systematic review. Objectives To review the content and effectiveness of skin care self-management interventions for people with SCI. Setting International. Methods We searched electronic bibliographic databases, trial registers, and relevant reference lists. Eligibility criteria for the reviews of intervention content and effectiveness were identical with the exception of study design. The review of intervention content included non-randomized and randomized controlled trials (RCTs). The review of effectiveness included RCTs. A Behavior Change Technique (BCT) taxonomy of 93 BCTs was used to code intervention content. Intervention effects on outcomes of interest are summarized descriptively. Effect sizes were calculated, and the Cochrane risk of bias tool applied. Results In all, 15 studies testing 17 interventions were included in the review of intervention content. Interventions in these studies included 28 BCTs. The most common were “instructions on how to perform behavior” (16 interventions), “credible source” (12 interventions), and “social support (unspecified)” (9 interventions). Ten RCTs were included in the review of intervention effectiveness and they measured knowledge, self-efficacy, and skills relating to skin care/pressure ulcer (PU) prevention, skin care behaviors, skin status (PU prevalence, severity, and time to PU), and health-care utilization for skin problems. Evidence to support intervention effects on these outcomes was limited, particularly for clinical outcomes. Risk of bias assessments was often inconclusive due to poor reporting. Conclusions There is potential to design SCI skin care interventions that include currently untested BCTs. Further research and better consistency in outcome measurements and reporting are required to synthesize evidence on effectiveness.

Summary Refractory ulcerative colitis (UC) occurs in patients who experience a severe disease manifestation that is unresponsive to medical therapy. The assessment of upper endoscopic microscopic findings and its correlation with refractory UC has not been fully studied in pediatric patients and is the focus of this study. Medical records of UC patients treated at a tertiary pediatric center between 2000 and 2014 were reviewed. Endoscopic biopsies of the upper gastrointestinal (GI) tract of patients meeting a priori inclusion criteria were compared between refractory UC patients and nonrefractory UC patients for active inflammation. Statistically significant differences were determined between groups, and tissues shown to have significant differences were further evaluated for their diagnostic performance. A total of 52 patients were included, 26 in each group. Significant differences were observed in intraepithelial neutrophil infiltration and percentage involvement of crypts/glands for the antrum, body, and duodenal bulb ( P ≤ .001, .005, and .01 [intraepithelial neutrophil infiltration] and P = .001, .009, and .015 [% involvement], respectively). Microabscesses of mucosal glands/crypts were also experienced in a greater number of refractory UC patients in the stomach (ie, antrum and/or body of stomach; P = .005) and duodenum (ie, duodenum and/or duodenal bulb; P = .023). The sensitivity and specificity of upper GI tissues to predict refractory UC were moderate, with sensitivities ranging from 38% to 67% and specificities ranging from 81% to 100%. Our results suggest that children with refractory UC are more likely to have active inflammation in the upper GI tract, and thus, this may represent a predictor of responsiveness to current medical therapy.

Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18–0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies. DOI: http://dx.doi.org/10.7554/eLife.17850.001, eLife digest Most attempts to transform exciting findings from laboratories into clinical treatments are unsuccessful. One reason for this may be the failure to consider all of the laboratory work that has been performed before deciding to test a treatment on patients for the first time. In particular, negative findings (that suggest that a potential new treatment is ineffective) may be overlooked. Stem cells may help to treat life-threatening infections, but this has not been tested in human patients. However, the effectiveness of stem cell treatments has been tested in animals that act as models of human infection. Before deciding to begin a clinical trial of stem cell therapy for life-threatening infections, Lalu et al. performed an exhaustive search to find all the studies in which stem cells were used to treat animal models of infection. Combining the results of all of these studies using particular analysis techniques revealed that stem cell therapy increased the survival of these animals overall. These positive effects were seen over a range of different experimental conditions (for example, when treating the animals with different doses of stem cells, or giving the doses at different times). Lalu et al. also identified some limitations with most of the laboratory studies that had tested stem cell therapy for infections. Many of the studies used animal models that may not be the best representations of humans with severe infection. In addition, many of the scientists did not report that they had used methods (such as randomization) that would generate the most confidence in their results. Despite these limitations, there was a lot of consistency in the reported results. Overall, the results support the decision to proceed to a clinical trial that tests the effectiveness of stem cells for treating human infections. More generally, Lalu et al.’s analysis demonstrates a way of considering all laboratory evidence before deciding to proceed to a first clinical trial in humans. This may help researchers to identify promising therapies to further develop, and also to identify potential failures before they are tested in patients. DOI: http://dx.doi.org/10.7554/eLife.17850.002

Summary Background Patient-reported outcomes have the potential to provide invaluable information for evaluation of hypospadias patients, aid in decision-making, performance assessment, and improvement in quality of care. To appropriately measure patient-relevant outcomes, well-developed and validated patient-reported outcome (PRO) instruments are essential. Objective To identify and evaluate existing PRO instruments designed to measure quality of life and/or satisfaction of individuals with hypospadias that have been developed and validated in a hypospadias population. Methods A systematic search of MEDLINE, EMBASE, PsycINFO, CINAHL and Health and Psychosocial Instruments was conducted in April 2016. Two reviewers independently assessed studies and identified PRO instruments for inclusion. Data were extracted on study characteristics, instrument development and validation, and content domains. Results A total of 32 studies were included that used or described five PRO instruments: Hypospadias Objective Scoring Evaluation (HOSE), Pediatric Penile Perception Score (PPPS), Penile Perception Score (PPS), Genital Perception Scale (GPS) for adults, and GPS for children/adolescents. Instrument development and validation was limited. The majority of identified instruments focused on postoperative cosmetic satisfaction, with only one instrument considering urinary function, and no instruments evaluating sexual function and psychosocial sequelae. Conclusions While many hypospadias studies have acknowledged the necessity of a patient-reported element, few have used validated PRO instruments developed in a hypospadias population. Existing instruments to measure patient-reported outcomes in hypospadias require improvement in both the breadth of content and in their development and validation methodology.

Background In extrahepatic biliary atresia (EHBA) obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and death if left untreated in a timely manner. Infants with cholestasis may undergo many tests before EHBA diagnosis is reached. The role and place of preoperative liver biopsy in the diagnostic paradigm for EHBA have not been established. Methods We conducted a systematic review of MEDLINE, Embase, and CENTRAL to obtain all publications describing the sensitivity/specificity/accuracy/positive predictive value (PPV)/negative predictive value (NPV) of preoperative liver biopsy in infants with cholestasis. Screening, data extraction, and quality assessment were done in duplicate. Extracted data are described narratively and analyzed using forest plots and receiver operating characteristic curves. Results A total of 22 articles were included. Overall, the pooled accuracy of preoperative liver biopsy was 91.7%, with a sensitivity of 91.2%, specificity of 93.0% (n=1231), PPV of 91.2%, NPV of 92.5% (n=1182), and accuracy of 91.6% (n=1106). In patients who were 60days or less at time of presentation or diagnosis, the pooled sensitivity, specificity, PPV, NPV, and accuracy were 96.4%, 96.3%, 95.8%, 96.3%, and 94.9%, respectively. Conclusion Quantitative analysis demonstrated preoperative biopsy to be both highly specific and sensitive in diagnosing EHBA preoperatively. It is a highly reliable test that offers a means of arriving at an early definitive diagnosis of EHBA.

Wood frogs (Rana sylvatica) can endure weeks of subzero temperature exposure during the winter with up to 65% of their body water frozen as extracellular ice. Associated with freezing survival is elevated expression of a number of genes/proteins including the unidentified gene, li16, first described in liver. The current study undertakes a broad analysis of li16 expression in response to freezing in 12 tissues of wood frogs as well as expression responses to anoxia and dehydration. Transcript levels of li16 increased significantly after 24 h freezing (at −2.5 °C) demonstrating increases of approximately 3-fold in testes, greater than 2-fold in heart, ventral skin and lung, and over 1.5-fold in brain, liver and hind leg muscle as compared to unfrozen controls at 5 °C. Increased li16 transcript levels in brain, muscle and heart were mirrored by elevated Li16 protein in frozen frogs. Significant upregulation of li16 in response to both anoxia and dehydration (both components of freezing) was demonstrated in brain, kidney and heart. Overall, the results indicate that Li16 protein has a significant role to play in cell/organ responses to freezing in wood frogs and that its up-regulation may be linked with oxygen restriction that is a common element in the three stress conditions examined.

Many gastrointestinal (GI) disorders, including GI eosinophilia and inflammatory bowel disease, can be characterized by increased mucosal eosinophils (EOs) or mast cells (MCs). Normal mucosal cellular counts along the GI tract in healthy children have not been established for a Canadian pediatric population. To establish a benchmark reference, we quantified EO and MC from 356 mucosal biopsies of the GI tract obtained during upper and lower endoscopic biopsies of 38 pediatric patients in eastern Ontario. Mean total counts of EO varied for the 11 tissues we examined, from a low of 7.6±6.5/high-power field (HPF) (×40 [×400, 0.55mm(2)]) in the body of the stomach to a high of 50.3±17.4/HPF in the cecum. The lower GI tract (ileum, cecum, colon, sigmoid, and rectum) generally had higher total EO counts than the upper GI tract (antrum and body of stomach, duodenum, and duodenal cap) (combined average of 32.1±20.6 versus 19.3±15.8, respectively). Similarly, the number of mucosal MC was different in the various regions of the GI tract ranging from 0.04±0.2/HPF in the duodenal cap to 0.9±2.6/HPF in the ileum. Total counts for EO and MC in the lamina propria were not significantly different between sexes when adjusted for multiple testing. EO polarity was absent in many cases, irrespective of the GI region. These numeration and localization of EO and MC will provide normative data for upper and lower endoscopic GI biopsies in the pediatric population of Eastern Ontario.

Summary Introduction Historically, ureteroceles were surgically treated, as patients were diagnosed after developing symptoms. However, with the advance of fetal medicine, antenatal detection has provided an opportunity to look at the natural history of ureteroceles. Objectives With data derived from a retrospective chart review of patients with ureteroceles that were detected antenatally, the current study aimed to determine which group of children would be at risk for failure on active surveillance. It was hypothesized that single system ureteroceles (SSU) and male patients with duplex system ureteroceles (DSU) would be ideal for observation. Methods Outcomes were assessed by descriptive statistics. Kaplan–Meier curves were utilized to estimate median duration on active surveillance in both single and duplex cohorts. Breakthrough febrile urinary tract infection (fUTI) and surgery were determined by Cox regression in the duplex system cohort. Surgery was considered surveillance failure. Results A total of 102 patients (64 females/38 males) met the criteria: 78 (76.5%) had DSU and 24 (23.5%) SSU. The overall median observation was 1.2 years (range 0.7–3.1). Follow-up ranged from 0.3 to 11.7 years for SSU, and from 0.02 to 17.3 years for DSU. The predictors of failure of active surveillance (AS) in DSU (surgical intervention) were male gender (HR 1.8, 1.0–3.3, P = 0.037), or fUTI (HR 3.1, 1.7–5.8, P = 0.002). Predictors of fUTI were contralateral hydroureter or ipsilateral hydronephrosis ± hydroureter (OR 9.5, 1.2–71.7, P = 0.028). Interestingly, vesicoureteral reflux (VUR) was not a predictor of fUTI. The SSU patients were ideal for AS, while in DSU, surveillance was successful in 30% of patients who were primarily females without contralateral hydroureter or ipsilateral hydronephrosis ± hydroureter. However, in contradiction to the hypothesis, males were at higher risk for surgical intervention in the DSU cohort. Conclusion Active surveillance is an option for patients with antenatally detected ureteroceles, but careful long term follow up is mandatory. Parents should be advised that surgical intervention may still be necessary, particularly in males with DSU. Summary table . Patient characteristics Total, n = 102 SSU, n = 24 DSU, n = 78 Gender Female 6 58 Male 18 20 Circumcision Yes 5 4 No 11 13 Not reported 2 3 Interval on AS 252 days to 3.1 years 100 days to 11.2 years 7 days to 17.2 years Hydronephrosis of the lower moiety (ipsilateral to ureterocele) No N/A 11 Hydronephrosis only N/A 47 Hydroureteronephrosis N/A 20 Ipsilateral reflux (any grade) 4 34 Surgery Male 5 17 Female 0 36 AS, active surveillance; SSU, single system ureterocele; DSU, duplex system ureterocele; N/A, not available.

Wilms tumor (WT) is the most common malignant, solid renal tumor in children. Most recurrent or metastatic WT occur within the first 2 years after the primary diagnosis. Urethral metastases in WT are very unusual and to the best of our knowledge have been reported only twice within the English literature. Those two cases had a poor outcome suggesting that urethral metastasis in recurrent WT is an indicator of poor prognosis. We report a third case of urethral recurrence of WT and reviewed the two previously reported cases in details.

The J-pouch is a surgical procedure offered to children with refractory ulcerative colitis (UC) who have undergone subtotal colectomy to reconstruct a reservoir function with ileo-anal anastomosis. Unfortunately, post-operative complications may occur and can compromise the pouch function. We assessed rectal histopathology to determine whether severity of inflammation in the rectum prior to the creation of the J-Pouch was associated with post-operative complications. We retrospectively reviewed the histopathology of all J-pouch procedure specimens from paediatric patients during the period 2000-2013 using an objective grading system that assesses the chronicity and activity of the UC disease. We analysed the parameters for association with the post-operative complications. A classification tree algorithm was generated to predict the risk of complication based on histopathological parameters. A total of 28 paediatric patients were identified, among whom 10 developed post-operative complications (35%). The activity score at the recto-anal margin was higher among the patients with post-operative complications (mean 7.3±3.1 versus 4.8±3.1; p=0.04). The involvement of more than 5% colonic crypts with epithelial neutrophilic infiltration at the recto-anal margin was found to be an independent parameter that would stratify the patients into low-risk or high-risk group for developing complications (17% versus 64%; p=0.04). An association between UC disease activity at the recto-anal margin and post-operative J-pouch complications was determined. Potentially, this association suggests that a histopathological assessment of the recto-anal transitional zone may have value in guiding the surgeon on the risk of post-operative complications.

The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.

Mesoblastic nephroma (MN) is the most common renal tumour in the first 3 months of life and accounts for 3-5% of all paediatric renal neoplasms. To further understand the morphological variants of MN, we identified 19 cases of MN (five classic, eight cellular and six mixed) and examined each case for markers known to be important in urogenital embryological development (PAX8, WT1 and RCC), stem cell associated markers (Oct 4, CD34 and c-kit), muscle/myofibroblastic markers (muscle specific actin, calponin and h-caldesmon), aberrant transcription factors, cell cycle regulation and other oncogenic proteins (p16, cyclin D1 and beta-catenin). Fluorescence in situ hybridisation (FISH) testing for ETV6-NTRK3 gene fusion/rearrangement revealed further differentiation between the subtypes with ETV6-NTRK3 gene fusion detected in 0/5 of the classic MN, 8/8 of the cellular MN and 5/6 of the mixed MN cohorts, respectively. Our results conclude that cyclin D1 and beta-catenin may be useful markers for differentiating between cellular MN and classic MN when the histology is not conclusive. The absence of expression of stem cell markers and markers involved in urogenital development suggests that MN is not a nephroma and most likely represents a soft tissue tumour, with congenital infantile fibrosarcoma representing cellular MN with a predilection to arise in the kidney. In addition, the immunophenotype and genetic fingerprint of mixed MN most likely represents a heterogenous group of tumours that are mostly cellular type, with areas that are phenotypically less cellular.

Summary Introduction Renal stone disease diagnosed in the first year of life is relatively uncommon. While risk factors such as low birth weight, furosemide exposure, and metabolic disorders are well established, there exists little information regarding resolution rates and need for surgical intervention. Our study objective was to evaluate urolithiasis and renal calcification resolution rates, time to resolution, and need for surgical intervention in children diagnosed in their first year of life. Material and methods REB approved retrospective chart review of children younger than 12 months of age (corrected for prematurity) diagnosed with nephrolithiasis and/or nephrocalcinosis in a tertiary pediatric hospital between April 2000 and August 2015 with a minimum 1-year follow-up period. Exact logistic regression was performed to assess the relationship between size of the largest stone (on either side) and the need for surgical intervention. Kaplan–Meier curves were constructed to examine time to stone resolution among those not requiring surgical intervention. Results 62 patients (61% male) were diagnosed with stones or nephrocalcinosis by ultrasound at a median age of 2.9 months. Of these, 37% had been admitted to the NICU because of prematurity, low birth weight or comorbidities. A total of 45 patients were found to have stones ( Table ); 35 of these had a stone at initial ultrasound and 10 initially diagnosed as nephrocalcinosis were later confirmed to have a stone. 67% of all stones were asymptomatic on presentation. Metabolic anomalies were present in 56% (35/62), and 16% (10/62) required medical treatment. Seven patients ultimately required surgical intervention. Stone size was found to predict the eventual need for surgical intervention (OR 3.52, 95% CI 1.47–12.78) for each 0.1 mm increase in diameter). Among patients not requiring surgical intervention (n = 38), the estimated median time to spontaneous resolution of urolithiasis was 1.1 years (95% CI 0.89–1.53, range 2 months–6 years) and 1.2 years for nephrocalcinosis (95% CI 0.59–2.13). Conclusions Spontaneous resolution was a common outcome for newborns and infants diagnosed with urolithiasis in the first year of life, but high variability in time-to-resolution was observed. Only a small proportion who had confirmed stones on ultrasound required surgical intervention (15%), and large stone size was a predictive factor for surgery. Table . Clinical, radiographic, and renal stone or nephrocalcinosis outcomes of children younger than 12 months. Stones (n = 45) Nephrocalcinosis (n = 17) Sex, n male (%) 28 (62%) 10 (59%) Age at presentation, months, median (IQR) 2.9 (3.3) 2.1 (2.1) Symptomatic presentation, n (%) 15 (33%) 6 (36%) Premature, n (%) 26 (58%) 14 (82%) Metabolic anomalies (%) 22 (49%) 13 (76%) Stone size Under 3 mm 24 (53%) 3–5 mm 13 (29%) – Larger than 5 mm 8 (18%) Spontaneous resolution, n (%) 35 (78%) 16 (94%) Median time to resolution, years (CI) 1.1 (0.2–6) 1.2 (0.6–2.1) Required surgery/ESWL, n (%) 7 (15%) –

Freeze tolerance is a critical winter survival strategy for the wood frog, Rana sylvatica. In response to freezing, a number of genes are upregulated to facilitate the survival response. This includes fr10, a novel freeze-responsive gene first identified in R. sylvatica. This study analyzes the transcriptional expression of fr10 in seven tissues in response to freezing, anoxia, and dehydration stress, and throughout the Gosner stages of tadpole development. Transcription of fr10 increased overall in response to 24 h of freezing, with significant increases in expression detected in testes, heart, brain, and lung when compared to control tissues. When exposed to anoxia; heart, lung, and kidney tissues experienced a significant increase, while the transcription of fr10 in response to 40% dehydration was found to significantly increase in both heart and brain tissues. An analysis of the transcription of fr10 throughout the development of the wood frog showed a relatively constant expression; with slightly lower transcription levels observed in two of the seven Gosner stages. Based on these results, it is predicted that fr10 has multiple roles depending on the needs and stresses experienced by the wood frog. It has conclusively been shown to act as a cryoprotectant, with possible additional roles in anoxia, dehydration, and development. In the future, it is hoped that further knowledge of the mechanism of action of FR10 will allow for increased stress tolerance in human cells and tissues.