Transcriptomic convergence despite genomic divergence drive field cancerization in synchronous squamous tumors.

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence. Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors. Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors. Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity.

Presentation of Breast Cancer and Impact of Patient Navigation on Timeliness of Diagnosis and Treatment and on Adherence to Treatment Recommendations in a Multicenter Network in Malaysia.

PURPOSE: Breast cancer deaths disproportionately affect women living in low- and middle-income countries (LMICs). Patient navigation has emerged as a cost-effective and impactful approach to enable women with symptoms or suspicious mammogram findings to access timely diagnosis and patients with breast cancer to access timely and appropriate multimodality treatment. However, few studies have systematically evaluated the impact of patient navigation on timeliness of diagnosis and treatment in LMICs. METHODS: We established a nurse- and community-navigator-led navigation program in breast clinics of four public hospitals located in Peninsular and East Malaysia and evaluated the impact of navigation on timeliness of diagnosis and treatment. RESULTS: Patients with breast cancer treated at public hospitals reported facing barriers to accessing care, including having a poor recognition of breast cancer symptoms and low awareness of screening methods, and facing financial and logistics challenges. Compared with patients diagnosed in the previous year, patients receiving navigation experienced timely ultrasound (84.0% v 65.0%; P < .001), biopsy (84.0% v 78.0%; P = .012), communication of news (63.0% v 40.0%; P < .001), surgery (46% v 36%; P = .008), and neoadjuvant therapy (59% v 42%, P = .030). Treatment adherence improved significantly (98.0% v 87.0%, P < .001), and this was consistent across the network of four breast clinics. CONCLUSION: Patient navigation improves access to timely diagnosis and treatment for women presenting at secondary and tertiary hospitals in Malaysia.

Exploring Growth Failure in Neonates With Enterostomy.

AIM OF THE STUDY: Neonatal enterostomy is a known risk for growth failure. We hypothesized that episodes of inflammation may drive a catabolic state, exploring this by assessing serum biochemistry alongside growth trajectory in enterostomy patients. METHODS: A retrospective analysis of infants with histologically confirmed NEC from 01/2012-07/2021 in a tertiary neonatal surgical centre was performed. Change in weight-for-age Z-score (ΔZ) between stoma formation and closure was calculated. Serum CRP (C-reactive protein), urea, and creatinine levels were recorded and duration of elevated levels calculated as Area Under Curve (AUC). We examined for trends of serum levels rising together using intersecting moving averages. Spearman's correlation analysis was performed, while multivariable linear regression examined factors associated with ΔZ. RESULTS: 79 neonates were included. At stoma formation, median Z-score was -1.42 [range -4.73, +1.3]. Sixty-two patients (78 %) had a fall in Z-score during their time with a stoma, 16 (20 %) had a ΔZ less than -2. Urea AUC was significantly univariably correlated with ΔZ and remained statistically significant in a multivariable model (Exp(B) x 100 = -0.57[-1, -0.09]; p = 0.022). The number of biomarker peaks correlated significantly with ΔZ for urea (r = -0.25; p = 0.025) and CRP (r = -0.35; p = 0.0017) but not Creatinine (r = -0.21; p = 0.066). Analysing the number of peaks of any combination of variables coinciding was consistently significantly correlated negatively with ΔZ (r = -0.29 to -0.27; p ≤ 0.016 for all). CONCLUSION: Our data shows that infants who were more severely affected by growth failure had more frequent and severe uremia while they had a stoma (suggesting a catabolic state). Disturbances in urea were commonly associated with CRP, suggesting that inflammation is a significant factor in growth failure in these infants. These findings promote aggressive management of sepsis in these infants, as well as suggesting an earlier closure of stoma to minimise their "at-risk"' period.

Long-term urology outcomes of anorectal malformation.

INTRODUCTION: Urological problems are a recognised feature of anorectal malformation (ARM). Previous assumptions of favourable long-term urinary outcomes are being challenged. OBJECTIVE: We hypothesised that urinary tract problems are common in ARM and frequently persist into adulthood. We retrospectively reviewed long-term renal and bladder outcomes in ARM patients. STUDY DESIGN: Patients with ARM born between 1984-2005 were identified from electronic hospital databases. Their case notes were reviewed. Renal outcomes included serum creatinine and the need for renal replacement therapy. Bladder outcomes included symptom review, bladder medication, need for intermittent catheterisation, videourodynamics and whether the patient had undergone augmentation cystoplasty. RESULT (TABLE 1): The case notes of 50 patients were reviewed. The median age at last follow up was 18 years (range 12-34 years). The level of fistula was noted to be high in 17 patients, intermediate in eight, and low in 10. Four had cloaca. Congenital urological abnormalities were present in 25 (50%). An abnormal spinal cord was present in 22 (44%) patients. VACTERL association occurred in 27 (54%). Chronic kidney disease stage II or above was found in 14 (28%) patients, of whom four required a renal transplant. Abnormal bladder outcomes were found in 39 (78%) patients. Augmentation cystoplasty with Mitrofanoff had been performed in 12. Of those who had not undergone cystoplasty, 17 had urinary symptoms, including urinary incontinence in 12. Of the 39 patients with abnormal bladder outcome, 19 (49%) did not have a spinal cord abnormality. There was no significant statistical association between level of ARM and abnormal renal outcome or presence of bladder abnormality. DISCUSSION: Adverse renal and bladder outcomes are common in our cohort of young people with ARM with a significantly higher incidence compared with current literature. We did not demonstrate an association between level of ARM or presence of spinal cord anomaly with persistent bladder problems. Congenital urological anomalies are more common in those who later have an abnormal renal outcome. Although this difference is statistically significant, one fifth of patients born with anatomically normal upper tracts develop reduced renal function, implying an important acquired component. CONCLUSION: Bladder problems and reduced renal function affect a significant proportion of young adults with ARM. Neither adverse outcome is reliably predicted from ARM level, congenital urological anomaly or spinal cord anomaly. We advise continued long-term bladder and kidney follow-up for all patients with ARM.

Retroperitoneoscopic single-instrument horseshoe nephrectomy for dilated non-functioning right moiety.

Retroperitoneoscopic horseshoe nephrectomy is an uncommon procedure, in particular in the paediatric practice. We present a procedure carried out via a posterior approach with a single working port in a 20 months old boy. The video goes through the technical aspect, from the positioning of the patient and the port insertion, to the end of procedure. Highlighted are the critical steps of directing the initial fascial dissection more caudal and medial compared to a standard approach for nephrectomy, as well as tips to safely ligate and divide the very short right renal vein. The operative time was 90 min. The postoperative course was uneventful. The retroperitoneal access provides a good visualisation of the hylum (including the IVC in case of right side approach), the ureter and the isthmus and has the advantage to preserve the abdominal cavity. The retroperitoneal approach is safe also in horseshoe kidney.

Long-term outcome following cholecystocolostomy in 41 patients with progressive familial intrahepatic cholestasis.

PURPOSE: Progressive familial intrahepatic cholestasis (PFIC) is a cohort of autosomal recessive syndromes which presents with jaundice, severe pruritus and liver derangement. Without treatments, patients progress to liver failure in early childhood. Biliary diversion strategies have been deployed to interrupt enterohepatic circulation to alleviate symptoms and delay progression to cirrhosis. Cholecystocolostomy has been the diversion method of choice at our institution and we aim to evaluate its long-term outcome. METHODS: All patients with PFIC who underwent cholecystocolostomy between August 2003 to May 2019 were included. PFIC diagnosed by clinical course, serum liver biochemistry and genotyping excluding other causes of cholestasis. All patients received ursodeoxycholic acid prior to biliary diversion. Those without long-term follow-up were excluded. Long-term follow-up conducted with physical examination, abdominal ultrasonography, liver function tests, contrast enema studies and colonoscopies. Outcome analysis was performed with patients divided into three groups according to their postoperative responses. RESULTS: 58 children underwent cholecystocolostomy, 41 were included in the study. Overall survival rate was 73.2% without a liver transplant. Survival improved to 81.1% in those without cirrhosis. 83.3% of those without a transplant was to no longer need any medication after their cholecystocolostomy. Recurrent cholestasis was seen in those with constipation (n = 8), ascending cholangitis (n = 10), intrahepatic reflux from Y-loop (n = 3) and cystic duct stenosis (n = 4). CONCLUSION: Cholecystocolostomy is a safe and effective technique for treatment of cholestasis in PFIC patients without cirrhosis. Careful monitoring and proactive management of postoperative constipation and ascending cholangitis is required to prevent stenosis of the cystic duct leading to recurrent cholestasis.

Factors Associated With the Microbiome in Moderate-Late Preterm Babies: A Cohort Study From the DIAMOND Randomized Controlled Trial.

The gut microbiota of preterm infants is affected by perinatal factors and, in turn, may impact upon infant health. In this study, we collected fecal samples at Day-10 (D10) and 4-months corrected-age (4M) from 227 moderate-late preterm (MLPT) babies enrolled in a randomized controlled trial of nutritional management. A total of 320 samples underwent 16S amplicon sequencing, and shotgun metagenomic sequencing was performed on 94 samples from the 4M time point. The microbiome of babies whose families lived in lower socioeconomic status (SES) areas exhibited a significantly higher microbial alpha diversity at D10 (Wilcoxon test, p = 0.021), greater abundance of Bifidobacterium (linear model, q = 0.020) at D10 and Megasphaera (q = 0.031) at 4M. Hospital of birth explained 5.2% of the observed variance in 4M samples (PERMANOVA, p = 0.038), with Staphylococcus aureus more abundant in fecal samples from babies born in Middlemore hospital (linear model, q = 0.016). Maternal antibiotic (Wilcoxon test, p = 0.013) and probiotic (p = 0.04) usage within the four-week period before sample collection was associated with a reduction in the alpha diversity of D10 samples. Infant probiotic intake explained 2.1% (PERMANOVA, p = 0.021) of the variance in the D10 microbial profile with increased Lactobacillus (linear model, q = 1.1 × 10-10) levels. At 4M, the microbiome of infants who were breastmilk fed had reduced alpha diversity when compared to non-breastmilk fed infants (Wilcoxon test, p < 0.05). Although causality cannot be inferred within our study, we conclude that in MLPT babies, maternal socioeconomic factors, as well as the perinatal medical environment and nutrition impact on the development of the newborn microbiome.

The microbial biogeography of the gastrointestinal tract of preterm and term lambs.

Nutritional supplementation is a common clinical intervention to support the growth of preterm infants. There is little information on how nutritional supplementation interacts with the developing microbiome of the small intestine, the major site for nutrient metabolism and absorption. We investigated the effect of preterm birth and nutritional supplementation on the mucosal and luminal microbiota along the gastrointestinal tract (GIT) of preterm lambs. Preterm lambs (n = 24) were enterally supplemented with branched-chain amino acids (BCAAs), carbohydrate (maltodextrin), or water for two weeks from birth. Term lambs (n = 7) received water. Mucosal scrapings and luminal samples were collected from the duodenum, jejunum, ileum (small intestine) and colon at six weeks post-term age and analysed by 16S rRNA amplicon sequencing. Anatomical site explained 54% (q = 0.0004) of the variance and differences between the term and preterm groups explained 5.7% (q = 0.024) of the variance in microbial beta-diversities. The colon was enriched with Tenericutes and Verrucomicrobia compared to the small intestine, while Actinobacteria, and superphylum Patescibacteria were present in higher abundance in the small intestine compared to the colon. Our findings highlight that early-life short-term nutritional supplementation in preterm lambs does not alter the microbial community residing in the small intestine and colon.

Randomised Double-Blind Placebo-Controlled Trial of Inulin with Metronidazole in Non-Alcoholic Fatty Liver Disease (NAFLD).

Background: Non-alcoholic fatty liver disease (NAFLD) can be ameliorated by weight loss although difficult to maintain. Emerging evidence indicates that prebiotics and antibiotics improve NAFLD. Aim: To determine whether inulin supplementation after brief metronidazole therapy is effective in reducing alanine aminotransferase (ALT) and maintaining weight loss achieved through a very-low-calorie diet (VLCD) among people with NAFLD. Methods: Sixty-two people with NAFLD commenced 4-week VLCD using Optifast meal replacements (600 kcal/day). Sixty were then randomised into a 12-week double-blind, placebo-controlled, parallel three-arm trial: (1) 400 mg metronidazole twice daily in Week 1 then inulin 4 g twice daily OR (2) placebo twice daily in week one then inulin OR (3) placebo-placebo. Main outcomes were ALT and body weight at 12 weeks. Fecal microbiota changes were also evaluated. Results: Mean body mass index (BMI) and ALT reduced after VLCD by 2.4 kg/m2 and 11 U/L, respectively. ALT further decreased after metronidazole-inulin compared to after placebo-placebo (mean ALT change -19.6 vs. -0.2 U/L, respectively; p = 0.026); however, weight loss maintenance did not differ. VLCD treatment decreased the ratio of Firmicutes/Bacteroidetes (p = 0.002). Conclusion: Brief metronidazole followed by inulin supplementation can reduce ALT beyond that achieved after VLCD in patients with NAFLD.

Neonates living with enterostomy following necrotising enterocolitis are at high risk of becoming severely underweight.

Necrotising enterocolitis (NEC) is often managed with a temporary enterostomy. Neonates with enterostomy are at risk of growth retardation during critical neurodevelopment. We examined their growth using z-score. We identified all patients with enterostomy from NEC in two neonatal surgical units (NSU) during January 2012-December 2016. Weight-for-age z-score was calculated at birth, stoma formation and closure, noting severely underweight as z < - 3. We compared those kept in NSU until stoma closure with those discharged to local units or home (LU/H) with a stoma. A total of 74 patients were included. By stoma closure, 66 (89%) had deteriorated in z-score with 31 (42%) being severely underweight. There was no difference in z-score at stoma closure between NSU and LU/H despite babies sent to LU/H having a more distal stoma, higher birth weight and gestational age. Babies in LU/H spent a much shorter period on parenteral nutrition while living with their stoma for longer, many needing readmission.Conclusion: Growth failure is a common and severe problem in babies living with enterostomy following NEC. z-score allowed growth trajectory to be accounted for in nutrition prescription and timing of stoma closure. Care during this period should be focused on minimising harm.What is Known:• Necrotising enterocolitis (NEC) is a life-threatening condition affecting predominately premature and very low birth weight neonates. Emergency treatment with temporary enterostomy often leads to growth failure.• There is no consensus on the optimal timing for stoma reversal, hence prolonging impact on growth during crucial developmental periods. Both malnutrition and surgical NEC are independently associated with poor neurodevelopment outcome.What is New:• Our study found growth in 89% of babies deteriorated while living with a stoma, with 42% having a weight-for-age z-score < - 3, meeting the WHO criteria of being severely underweight, despite judicial use of parenteral nutrition. Applying z-score to weight measurements will allow growth trajectory to be accounted for in clinical decisions, including nutrition prescription (both enteral and parenteral), and guide timing of stoma closure.• Surgeons who target stoma closure at a certain weight risk waiting for an indefinite period of time, during which babies' growth may falter.

Factors Affecting Gastrointestinal Microbiome Development in Neonates.

The gut microbiome is established in the newborn period and is recognised to interact with the host to influence metabolism. Different environmental factors that are encountered during this critical period may influence the gut microbial composition, potentially impacting upon later disease risk, such as asthma, metabolic disorder, and inflammatory bowel disease. The sterility dogma of the foetus in utero is challenged by studies that identified bacteria, bacterial DNA, or bacterial products in meconium, amniotic fluid, and the placenta; indicating the initiation of maternal-to-offspring microbial colonisation in utero. This narrative review aims to provide a better understanding of factors that affect the development of the gastrointestinal (GI) microbiome during prenatal, perinatal to postnatal life, and their reciprocal relationship with GI tract development in neonates.

Registered Replication Report: Dijksterhuis and van Knippenberg (1998).

Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence ("professor") subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence ("soccer hooligans"). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%-3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and -0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the "professor" category and those primed with the "hooligan" category (0.14%) and no moderation by gender.

5 years after an ACE: what happens then?

PURPOSE: Antegrade continence enema (ACE) revolutionised the lives of children with chronic constipation and soiling. Parents often ask how long the ACE will be required. We looked at our patients 5 years after ACE formation to answer the question. METHODS: We reviewed clinical notes of all patients undergoing ACE procedure during January 1990 to December 2010. Only patients with >5 years follow-up were included. Data are given as median (range). RESULTS: 133 patients were included with >5 years of follow-up. Primary pathology was anorectal anomaly (ARA) 64 (48%); spinal dysraphism (SD) 40 (30%); functional constipation (FC) 14 (10%); Hirschsprung's Disease (HD) 10 (8%) and others 5 (4%). Median follow-up was 7 years (5-17 years). Overall 74% still use their ACE; whilst 26% no longer access their stoma, of whom 47% recovered normal colonic function. 50% of HD patient recover colonic function. FC has the highest failure rate at 21%. CONCLUSIONS: Overall 86% achieved excellent clinical outcome with 74% of patient still using their ACE at 5 years. HD has the highest recovery rate of 50%. FC has a more unreliable clinical outcome with 21% recovered colonic function and 21% failed. Outcome varied dependent on the background diagnosis.

A modified technique of laparoscopic mobilisation and transfer of intra-abdominal testis via inguinal canal.

Several techniques have been described for mobilising intra-abdominal testis (IAT) into the scrotum. Many are associated with significant morbidity. We hereby introduce our modification of the technique that is safe and reproducible. Surgical technique using a nylon tape to railroad instruments into the peritoneal cavity to minimise false passage and trauma is described in detail. Once the testis is delivered out of the scrotal wound, further division of restrictive bands to mobilise the testis is carried out laparoscopically. These steps are not previously described in the literature. A retrospective study of consecutive patients with IAT undergoing surgical intervention by a single surgeon over a period of 15 years has been included to demonstrate outcome. Twenty-five patients with unilateral IAT (10R, 15L) and 2 patients with bilateral IAT, a total of 29 IAT, underwent laparoscopic orchidopexy over the period 1997-2012. Median age of the patients was 3.0 years. One-stage testicular vessel preserving (VP) orchidopexy was performed in 20 testes, Fowler-Stephen (FS), vessel sacrificing orchidopexy (3 one-stage and 6 two-stage) was required in 9 testes. At follow-up, atrophy was detected in 1 (5.0 %) and 2 (22.2 %) patients of the VP and FS groups respectively. The railroading technique of transferring IAT into the scrotum via the inguinal canal under laparoscopic guidance minimises tissue trauma. It negates the need to create new tissue opening. It is reproducible with a testicular atrophy rate comparable to published literature.