Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Evaluation of Post-neonatal Intensive Care Unit Home Irrigations Prior to Pull-through: Implications for Hirschsprung Disease Management.

BACKGROUND: Pull-through procedures for Hirschsprung disease (HD) can be performed during the Neonatal Intensive Care Unit (NICU) stay or delayed until discharge following home irrigations. This study assesses the safety of a delayed pull-through as an alternative to neonatal reconstruction in infants with successful abdomen decompression with home irrigations based on Hirschsprung-associated enterocolitis (HAEC) development. METHODS: A single-institution retrospective review of neonates with HD who underwent delayed or neonatal pull-through from July 2018-July 2022. Endpoints included post-pull-through HAEC incidence, recurrence at an 18-month follow-up, time to the first HAEC episode, NICU length of stay (LOS), and HAEC-related LOS. RESULTS: Twenty-four neonates were included. Eighteen were discharged from the NICU with home irrigations. Of these, 3 (28%) developed enterocolitis preoperatively, 12 (67%) underwent a delayed pull-through. NICU LOS in the delayed cohort was 3 times shorter than in the neonatal (6 vs. 18 days, p < 0.01). The incidence of enterocolitis (82% vs. 80%), time to the first episode (43 vs. 57 days), and HAEC-related LOS (median of 3 days) were similar. CONCLUSIONS: Delayed HD pull-through is a viable neonatal reconstruction alternative that reduces NICU stay without increasing the risk of postoperative HAEC development. TYPE OF STUDY: Original Research Article. LEVEL OF EVIDENCE: III.

How enhanced recovery can boost patient outcomes.

The enhanced recovery approach aims to optimise patient outcomes and improve their experience. This article outlines its key principles and describes its benefits.

Single institution review of Mini-ACE® low-profile appendicostomy button for antegrade continence enema administration.

PURPOSE: Malone antegrade continence enemas (MACE) provide a conduit in which the patient can achieve improved continence, be clean of stool, and gain independence in maintaining bowel function. The Mini-ACE® is a low-profile balloon button that is used to facilitate the administration of antegrade enemas. We sought to describe our practice and short-term outcomes. METHODS: This work is a retrospective review of the Mini-ACE® appendicostomy button from April 2019 to March 2021, with follow-up concluding in October 2021. Patient demographics, colorectal diagnoses, and outcomes were examined. RESULTS: Forty-three patients underwent Mini-ACE® placement; 22 (51%) were male. The average age at Mini-ACE® insertion was 9.2 years (range 3-20 years). The most common diagnoses were functional constipation in 19 (44%), anorectal malformation in 15 (35%), and Hirschsprung disease in 3 (7%), spinal differences 3 (7%). There were no intra-operative complications, but 5 (12%) required prolapse resection. The median length of stay was two days (IQR 1, 4). Patients achieved self-catheterization at 4.5 [3,7] months from MACE creation, with 38 children (88%) reporting excellent success in remaining clean of stool. CONCLUSION: The Mini-ACE® appears to be a safe and low-profile option for antegrade continence enema access. Further research is needed directly comparing complications and patient satisfaction rates between different MACE devices and overall quality of life. LEVEL OF EVIDENCE: Level IV.

Optimizing intervention tools to improve nutrition and physical activity for colorectal cancer survivors (Tools To Be Fit): Study protocol of a randomized factorial experiment.

BACKGROUND: Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States. The American Cancer Society (ACS) Nutrition and Physical Activity Guidelines are associated with longer survival among CRC survivors, but few report behaviors consistent with the guidelines. METHODS: The Tools To Be Fit study, based on the Multiphase Optimization Strategy (MOST) framework, is a full factorial experimental to optimize a remotely delivered 48-week diet and physical activity intervention for non-metastatic CRC survivors. The intervention includes a core component (booklet and personal report). CRC survivors (N = 400) are additionally randomly assigned to one of 16 combinations of four candidate components, each with 2 options: 1) text messaging (on/off); 2) self-monitoring modality (digital/paper); 3) health coaching (on/off); and 4) support person coaching (on/off). OUTCOMES: Our primary outcome is adherence to the ACS guidelines after 48 weeks using a score that includes physical activity from accelerometers, dietary intake from a food frequency questionnaire, and body mass index (BMI) measured by a technician. Secondary outcomes include the ACS score after 24 weeks and score components at 24 and 48 weeks. Exploratory outcomes include adherence and change in Social Cognitive Theory constructs. We will explore moderation by sociodemographic, clinical, and psychological/behavioral factors; and change in the ACS score in relation to change in levels of insulin, insulin sensitivity, inflammation, gut microbiome structure, fatigue, depression, and sleep disturbance. DISCUSSION: The proposed study aims to inform a randomized controlled trial to determine whether an optimized intervention reduces risk of recurrence among CRC survivors.

Does exclusive enteral nutrition reduce the rate of stoma formation in patients requiring ileocolic resection for Crohn's disease? A single center experience.

BACKGROUND AND AIM: Nutrition has a role in achieving and maintaining remission in Crohn's disease. The aim of this study was to determine the impact of a strategy of steroid-avoidance and Exclusive Enteral Nutrition (EEN) for 6 weeks (with a minimum of 4 weeks) in adult patients presenting with acute small bowel Crohn's disease followed by an interval ileocolic resection 4-6 weeks later. METHODS: Retrospective review of prospectively collected data. Patients were administered exclusive enteral nutrition (EEN) for at least 4 weeks prior to surgery. RESULTS: 24 EEN patients included. Median age of 45 (range 23-73). 17/24 patients tolerated Modulen for at least 4 weeks, 5 were switched to Ensures and 2 a liquid diet. 6 patients underwent surgery earlier than planned. Prior to surgery, there was no change in the mean BMI, albumin increased from a mean of 36 g/L (range 25-43) to 40 g/L (range 30-48). CRP levels decreased by a mean of 35.8 mg/L overall. 19 (79%) of operations were performed laparoscopically. 6 of the cases were re-do operations. All but 3 patients avoided a stoma at the time of the original operation. There were 5 post-operative complications: 1 anastomotic leak in a patient with a BMI of 42, 3 cases of paralytic ileus and 2 wound infections. Median length of stay was 7 days (range 3-76 days). Only 2 patients were readmitted within the 30-day post-operative period. CONCLUSION: The pre-operative use of EEN appears to avoid unnecessary stoma formation with acceptable clinical outcomes.

Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing.

An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.

Cryopreservation of human embryos at the morula stage and outcomes after transfer.

OBJECTIVE: To evaluate the survival rate of human morula embryo freezing and the morphological alterations during freezing, during and after thawing, and their applications in embryo selection. DESIGN: Retrospective observational study. SETTING: Private infertility clinic. PATIENT(S): Consecutive patients under age 39 undergoing frozen morula embryo transfers from December 1999 to May 2003. INTERVENTION(S): Embryo freezing was performed at the morula stage. Embryo thaw and post-thaw ETs were conducted on the same day, which is equivalent to a day 4 ET. MAIN OUTCOME MEASURE(S): Morphological alterations during freezing and thawing and after thawing. Post-thaw embryo survival rates, transferable rates, pregnancy rates, and implantation rates. RESULT(S): Morula embryos showed reversed morphological alterations during the freezing process; these alterations were recovered during thawing or shortly after the thawing. Post-thaw survival rates showed no significant difference between any of the morula substages. However, embryos scored as grade 3, which represented good quality, had significantly higher post-thaw survival and transferable rates than grade 2 and 1 embryos. Patients who received at least one grade 3 embryo had significantly higher pregnancy rates, implantation rates, and ongoing/live birth rates than other groups. CONCLUSION(S): An acceptable survival rate can be achieved after cryopreservation of human morula embryos, and morphological alterations that occur during and shortly after an embryo thaw can be a feasible index for determining viable embryos.