Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn's disease (CD): protocol of a pilot study.

INTRODUCTION: Early relapse in Crohn's disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles. METHODS AND ANALYSIS: This is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10

Environment and shipping drive environmental DNA beta-diversity among commercial ports.

The spread of nonindigenous species by shipping is a large and growing global problem that harms coastal ecosystems and economies and may blur coastal biogeographical patterns. This study coupled eukaryotic environmental DNA (eDNA) metabarcoding with dissimilarity regression to test the hypothesis that ship-borne species spread homogenizes port communities. We first collected and metabarcoded water samples from ports in Europe, Asia, Australia and the Americas. We then calculated community dissimilarities between port pairs and tested for effects of environmental dissimilarity, biogeographical region and four alternative measures of ship-borne species transport risk. We predicted that higher shipping between ports would decrease community dissimilarity, that the effect of shipping would be small compared to that of environment dissimilarity and shared biogeography, and that more complex shipping risk metrics (which account for ballast water and stepping-stone spread) would perform better. Consistent with our hypotheses, community dissimilarities increased significantly with environmental dissimilarity and, to a lesser extent, decreased with ship-borne species transport risks, particularly if the ports had similar environments and stepping-stone risks were considered. Unexpectedly, we found no clear effect of shared biogeography, and that risk metrics incorporating estimates of ballast discharge did not offer more explanatory power than simpler traffic-based risks. Overall, we found that shipping homogenizes eukaryotic communities between ports in predictable ways, which could inform improvements in invasive species policy and management. We demonstrated the usefulness of eDNA metabarcoding and dissimilarity regression for disentangling the drivers of large-scale biodiversity patterns. We conclude by outlining logistical considerations and recommendations for future studies using this approach.

Sex-Specific Pathways Lead to Statural Growth Impairment in Children with Crohn's Disease.

OBJECTIVES: To examine the underlying mechanisms that lead growth impairment to occur more commonly in males than females with Crohn's disease (CD). STUDY DESIGN: Children and adolescents with CD were enrolled in a prospective multicenter longitudinal cohort study. Height Z-score difference was computed as height Z-score based on chronological age (height chronological age-Z-score) minus height Z-score based on bone age (height bone age-Z-score) using longitudinal data. Specific serum cytokines were measured, hormone Z-scores were calculated based on bone age (bone age-Z), and their longitudinal associations were examined. RESULTS: There were 122 children with CD (63% male) who completed 594 visits. The mean ± SD chronological age was 11.70 ± 1.79 years. The mean ± SD height chronological age-Z-score was -0.03 ± 0.99 in males and -0.49 ± 0.87 in females. The mean ± SD height bone age-Z-score was 0.23 ± 0.93 in males and 0.37 ± 0.96 in females. The magnitude of the mean height Z-score difference was greater in females (-0.87 ± 0.94) than males (-0.27 ± 0.90; P = .005), indicating growth was better in females than males. The following negative associations were identified: in females, interleukin (IL)-8 (P < .001) and IL-12p70 (P = .035) with gonadotropin-bone age-Z-scores; IL-8 (P = .010), IL-12p70 (P = .020), and interferon-γ (P = .004) with sex hormone-bone age-Z-scores, and IL-8 (P = .044) and interferon-γ (P < .001) with insulin-like growth factor 1-bone age-Z-scores; in males, IL-1 beta (P = .019) and IL-6 (P = .025) with insulin-like growth factor 1-bone age-Z-scores. CONCLUSIONS: Our data suggest that sex-specific molecular pathways lead to growth impairment in children with CD (primarily growth hormone/insulin-like growth factor-1 axis in males and primarily hypothalamic-pituitary-gonadal axis in females). Mapping these sex-specific molecular pathways may help in the development of sex-specific treatment approaches targeting the underlying inflammation characteristic of CD.

Vedolizumab Experience in Children and Adolescents With Inflammatory Bowel Disease: A Multicenter Observational Study.

Background: Vedolizumab is increasingly used off-label to treat children and adolescents with inflammatory bowel disease (IBD). In the absence of rigorous clinical trial experience, multicenter observational data are important to establish expectations for efficacy and safety. We examined 1-year outcomes following vedolizumab therapy in a large multicenter pediatric IBD cohort. Methods: We performed a retrospective study of 159 pediatric patients (4-17 years old) with IBD [78, Crohn disease (CD); 81, ulcerative colitis/IBD-unspecified (UC/IBD-U)] treated with vedolizumab for 1 year at 8 pediatric medical centers in the United States. Demographics, clinical outcomes, laboratory data, and vedolizumab dosing were recorded. The primary outcome was corticosteroid (CS)-free clinical remission at 1 year. Other measured outcomes were clinical remission at 12 and/or 24 weeks, laboratory outcomes at 1 year, and endoscopy/histology results at 1 year. Results: Among the 159 patients (mean age, 14.5 ± 2.4 years; 86% anti-TNF experienced), 68/159 (43%) achieved CS-free clinical remission at 1 year (CD, 35/78, 45%; UC/IBD-U, 33/81, 40%). Vedolizumab therapy failed and was discontinued in 33/159 (21%) patients prior to 1 year (CD, 18/78, 23%; UC/IBD-U, 15/81, 19%). While week 12 clinical remission was not predictive of 1-year clinical remission in either CD or UC/IBD-U, week 24 clinical remission was predictive of 1-year clinical remission only in CD patients. No infusion reactions or serious side effects were noted. Conclusions: Vedolizumab was safe and effective in this pediatric population with approximately 43% achieving CS-free clinical remission at 1 year. Similar efficacy was noted in both CD and UC.

Clinical Variables Associated With Statural Growth in Pediatric Crohn's Disease Differ by Sex (The Growth Study).

BACKGROUND: Statural growth impairment is more common in male patients with Crohn's disease (CD). We identified clinical variables associated with height z score differences by sex in children participating in the Growth Study, a prospective multicenter longitudinal study examining sex differences in growth impairment in pediatric CD. METHODS: Patients with CD (female patients with bone age [BA] ≥4 years 2 months and ≤12 years; male patients with BA ≥5 years and ≤14 years at screening) who had completed study visit 1 qualified. The height z score difference was computed as height z score based on chronological age minus height z score based on BA. RESULTS: One hundred thirteen patients with CD (36% female) qualified. The mean chronological age was 12.0 ± 1.8 (SD) years. The magnitude of the mean height z score difference was significantly greater in female patients (-0.9 ± 0.8) than in male patients (-0.5 ± 0.9; P = 0.021). An initial classification of inflammatory bowel disease as CD (P = 0.038) and perianal disease behavior at diagnosis (P = 0.009) were associated with higher standardized height gain with BA progression, and arthralgia at symptom onset (P = 0.016), azathioprine/6-merpcaptopurine (P = 0.041), and probiotics (P ≤ 0.021) were associated with lower standardized height gain with BA progression in female patients. Patient-reported poor growth at symptom onset (P = 0.001), infliximab (P ≤ 0.025), biologics (P ≤ 0.015), methotrexate (P = 0.042), and vitamin D (P ≤ 0.010) were associated with higher standardized height gain with BA progression, and initial classification as CD (P = 0.025) and anorexia (P = 0.005) or mouth sores (P = 0.004) at symptom onset were associated with lower standardized height gain with BA progression in male patients. CONCLUSIONS: Different clinical variables were associated with statural growth in male patients vs female patients, suggesting that sex-specific molecular pathways lead to statural growth impairment in CD.

Spanish-Speaking Parents' Experiences Accessing Academic Medical Center Care: Barriers, Facilitators and Technology Use.

BACKGROUND AND OBJECTIVE: Children of Spanish-speaking caregivers face multiple barriers to care in academic medical centers. This study identified barriers and facilitators of health care and described use of health information technology in order to guide interventions and optimize services. METHODS: In-depth, audiotaped interviews were conducted with monolingual Spanish-speaking caregivers (N = 28) of children receiving care in academic medical center clinics using a structured interview guide. Interviews were transcribed in Spanish, and key themes were identified using thematic analysis. Illustrative quotes for each theme were translated into English. RESULTS: Language-specific barriers included arrival/registration occurring in English, lack of bilingual personnel, heavy reliance on interpreters, long wait times, and challenging phone communication. Non-language-specific barriers included medical center size and complexity, distance to services, lack of convenient and coordinated appointments, missing work/school, and financial barriers including insurance coverage or lack of citizenship. Caregivers identified interpreters, bilingual physicians and staff, and written materials in Spanish as facilitators of care. Most caregivers had internet access and expressed interest in health information technology, including patient portals, to communicate about their children's health. CONCLUSIONS: Caregivers of Spanish-speaking children encounter many language-specific barriers, which are compounded by non-language-specific barriers arising from complex health systems and social needs. Caregivers with limited resources described working hard to meet children's complex health care needs despite these barriers. Most caregivers had internet access and interest in patient portals. Academic medical centers may need multifaceted interventions that improve the availability of bilingual staff and interpreters and also address caregivers' social and informational needs.

Outcomes of pediatric liver transplant are unaffected by the time or day of surgery.

BACKGROUND: In adults, the time of day for LT does not affect post-transplant outcomes. Whether this is true or not in children is unknown. In this study, we aimed to evaluate if weekend and weeknight liver transplants are associated with worse patient and graft survival in children. METHODS: We interrogated the UNOS database for outcomes of pediatric liver transplants that occurred between 1988 and 2018. We excluded liver transplants in patients >17 years as well as all multiple organ transplants. We compared weeknight and weekday, as well as weekend transplant operations. We used Cox proportional hazard ratios to determine patient and graft survival by 7, 30, 90, and 365 days post-transplant after controlling for confounding factors. RESULTS: In total, 12,610 pediatric liver transplants were included in the analysis. A total of 4590 transplants occurred during weekdays, 3671 transplants occurred during weeknights, and 4349 occurred during weekends. After controlling for confounding variables, 1-year patient survival was not associated with worse outcomes if the transplant occurred on the weeknight (HR 0.94, 95%CI 0.74-1.21) or weekend (HR 0.95, 95%CI 0.75-1.20) compared to the weekday. One-year graft survival was also not associated with worse outcomes if the transplant occurred on the weeknight (HR 0.91, 95%CI 0.76-1.09) or weekend (HR 0.91, 95%CI 0.77-1.09) compared to the weekday. CONCLUSION: Weekday, weeknight, and weekend procedures resulted in similar 1-year survival rates. Pediatric patient and graft survival outcomes are not affected by the time or day of surgery.

Cloning of ground-state intestinal stem cells from endoscopic biopsy samples.

'Adult' or 'somatic' stem cells harbor an intrinsic ability to regenerate tissues. Heterogeneity of such stem cells along the gastrointestinal tract yields the known segmental specificity of this organ and may contribute to the pathology of certain enteric conditions. Here we detail technology for the generation of 'libraries' of clonogenic cells from 1-mm-diamter endoscopic biopsy samples from the human gastrointestinal tract. Each of the 150-300 independent clones in a typical stem cell library can be clonally expanded to billions of cells in a few weeks while maintaining genomic stability and the ability to undergo multipotent differentiation to the specific epithelia from which the sample originated. The key to this methodology is the intrinsic immortality of normal intestinal stem cells (ISCs) and culture systems that maintain them as highly immature, ground-state ISCs marked by a single-cell clonogenicity of 70% and a corresponding 250-fold proliferative advantage over spheroid technologies. Clonal approaches such as this enhance the resolution of molecular genetics, make genome editing easier, and may be useful in regenerative medicine, unravelling heterogeneity in disease, and facilitating drug discovery.

Introduction to and Screening Visit Results of the Multicenter Pediatric Crohn's Disease Growth Study.

BACKGROUND: Statural growth impairment is more common in males with Crohn's disease (CD). We assessed sex differences in height Z score differences and bone age (BA) Z scores and characterized age of menarche in a novel contemporary cohort of pediatric CD patients undergoing screening for enrollment in the multicenter longitudinal Growth Study. METHODS: Crohn's disease patients (females with chronological age [CA] 5 years and older and younger than 14 years; males with CA 6 years and older and younger than 16 years) participated in a screening visit for the Growth Study. Height BA-Z scores are height Z scores calculated based on BA. Height CA-Z scores are height Z scores calculated based on CA. The height Z score difference equals height CA-Z score minus height BA-Z score. RESULTS: One hundred seventy-one patients (60% male) qualified for this analysis. Mean CA was 12.2 years. Mean height CA-Z score was -0.4, and mean height BA-Z score was 0.4 in females. Mean height CA-Z score was -0.1, and mean height BA-Z score was 0.2 in males. The absolute value of the mean height Z score difference was significantly greater in females (0.8) than males (0.3; P = 0.005). The mean BA-Z score in females (-1.0) was significantly lower than in males (-0.2; P = 0.002). The median CA at menarche was 13.6 (95% CI, 12.6-14.6) years. CONCLUSIONS: Our screening visit data suggest that standardized height gain is lower in males with skeletal maturation and delayed puberty is common in females in CD. We are investigating these findings in the ongoing Growth Study.

Continued Statural Growth in Older Adolescents and Young Adults With Crohn's Disease and Ulcerative Colitis Beyond the Time of Expected Growth Plate Closure.

BACKGROUND: Cessation of statural growth occurs with radiographic closure of the growth plates, radiographically defined as bone age (BA) 15 years in females and 17 in males. METHODS: We determined the frequency of continued growth and compared the total height gain beyond the time of expected growth plate closure and the chronological age at achievement of final adult height in Crohn's disease (CD) vs ulcerative colitis (UC) and described height velocity curves in inflammatory bowel disease (IBD) compared with children in the National Health and Nutrition Examination Survey (NHANES). We identified all females older than chronological age (CA) 15 years and males older than CA 17 years with CD or UC in the ImproveCareNow registry who had height documented at ≥3 visits ≥6 months apart. RESULTS: Three thousand seven patients (48% female; 76% CD) qualified. Of these patients, 80% manifested continued growth, more commonly in CD (81%) than UC (75%; P = 0.0002) and in females with CD (83%) than males with CD (79%; P = 0.012). Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025). Height velocity curves were shifted to the right in patients with IBD vs NHANES. CONCLUSIONS: Pediatric patients with IBD frequently continue to grow beyond the time of expected growth plate closure. Unexpectedly, a high proportion of patients with UC exhibited continued growth, indicating delayed BA is also common in UC. Growth, a dynamic marker of disease status, requires continued monitoring even after patients transition from pediatric to adult care.

Improving Satisfaction and Appointment Attendance Through Navigation for Spanish-Speaking Families.

OBJECTIVE: Monolingual Spanish-speaking families face linguistic barriers to care. Volunteer bilingual navigation (VBN) may increase appointment attendance and satisfaction. METHODS: Volunteer bilingual navigation was implemented in a children's multispecialty clinic and included way-finding, non-medical interpretation, and pre-visit phone calls. Outcome measures were: 1) Appointment attendance, measured by no-show percentages; 2) Mean Press-Ganey® patient satisfaction ratings. No-show percentages were evaluated using segmented linear regression. Mean patient satisfaction ratings were compared during baseline, intervention, and follow-up phases using t-tests. RESULTS: Trained VBNs provided navigation during the nine-month intervention. In-person navigation was associated with non-significantly decreased no-shows (-0.95%; [-2.43, 0.53]) from baseline (9.32%). Addition of pre-visit phone calls was associated with no-show decrease of -2.82% (-3.97, -1.66). Mean satisfaction ratings increased non-significantly (84.0 to 92.9; p=.18) and remained increased at two-year follow-up. CONCLUSION: Bilingual navigation is an effective complement to formal medical interpretation, may improve Spanish-speaking families' appointment attendance and satisfaction, and can be implemented sustainably.

Inestabilidad posterior de hombro. Resultados de la reconstrucción artroscópica en pacientes sin defectos óseos significativos / Posterior shoulder instability. Arthroscopic reconstruction in patients without significant bone defects

Presentamos los resultados de una serie de casos de pacientes con inestabilidad posterior de hombro, sin defectos óseos ni retroversión glenoidea significativos, tratados con técnica artroscópica de reparación cápsulolabral con anclajes. Entre 2010 y 2019, dieciocho pacientes con inestabilidad posterior de hombro fueron tratados con una reparación cápsulolabral artroscópica con anclajes, en el mismo centro quirúrgico y por el mismo cirujano. Fueron dieciséis hombres y dos mujeres con una edad promedio de 30.5 años (en un rango de diecinueve a cuarenta y cuatro años). Con un seguimiento promedio de 64.4 meses (en un rango entre trece y ciento dieciséis meses) los pacientes fueron evaluados clínicamente con el test de Kim, Jerk y test de aprehensión. También utilizamos los scores de WOSI, ASES, Rowe, radiografía, tomografía computada y resonancia magnética, para las evaluaciones pre y postoperatorias. Tipo de estudio: Serie de casos. Nivel de evidencia: IV

Objective: We present the results of a case series of patients with posterior shoulder instability without significant bone defects or excessive glenoid retroversion treated with arthroscopic capsule-labral repair with suture anchors.Methods: Between 2010 and 2019, 18 patients with posterior shoulder instability underwent an arthroscopic capsule-labral repair with suture anchors. All the cases were operated on at the same surgical center by the same surgeon. The patients were 16 men and two women with an average age of 30.5 years (range 19 to 44 years). With a mean follow up of 64.4 months (range 13-116 months), the patients were clinically evaluated by the Kim, Jerk, and Apprehension tests. Furthermore, the WOSI, ASES, and ROWE scores, X Rays, CT Scans, and MRIs were also used for pre and postoperative assessment. Results: We did not find any case of recurrence of instability. At the final follow up, the Kim's, Jerk, and Apprehension tests were negative in all the patients. The posterior drawer test decreased translation at an average of 2 pluses. The mean WOSI Score risen from 35.2 to 86.5, the ASES from 33.3 to 85.3, and the Rowe from 20.3 to 91.1. Two patients showed moderate to severe degenerative changes at the final X-Rays. The postoperative MRIs of 12 patients demonstrated an anatomic reduction and adequate healing of the posterior labrum.Conclusions: The arthroscopic repair of the labrum with anchors is a reliable, reproducible, and effective technique that warrants satisfactory results in selected posterior shoulder instability cases without significant glenoid bone loss or excessive retroversion. Type of study: Case series. Level of evidence: IV

Impact of a Quality Improvement Initiative to Optimize the Discharge Process of Pediatric Gastroenterology Patients at an Academic Children's Hospital.

Discharge is an important and complex process that can be optimized to reduce inpatient healthcare inefficiency and waste. This study aimed to increase the percentage of patients discharged before 1 pm by 20% from an academic inpatient pediatric gastroenterology service (IPGS), over 6 months. METHODS: We conducted a preintervention and postintervention study of patients discharged from IPGS. Patients discharged from January to June 2016, and those following our intervention from June to December 2016, were studied. Interventions included (1) implementation of the electronic medical record medical and logistical discharge criteria checklists for the 4 most common IPGS discharge diagnoses, (2) standardization of the rounds process to prioritize discharge, (3) education of nursing staff and families about the role they played in discharge. Process, outcome, and balancing measures were analyzed. RESULTS: Three hundred fifty-five total discharges were studied. Between the preintervention and postintervention groups, there were no significant improvements in discharge order time, physical discharge time, discharge response time, or discharges before 1 pm. The balancing measure of 30-day readmission was unaffected. However, length of stay (LOS) index, calculated as the ratio of actual to expected LOS, improved; when translated into days, LOS declined by 1 day, with potential associated savings of $373,000. CONCLUSIONS: Interventions to improve discharge timeliness on IPGS service demonstrated mixed effectiveness. Only LOS index improved. Further iterative quality improvement interventions are needed to continue optimizing discharge timeliness and change the culture of pediatric discharge on inpatient subspecialty services in academic children's hospitals.

Unlimited expansion of intestinal stem cells from a wide range of ages.

The recent technical advance in cloning and culturing ground-state intestinal stem cells (ISC) provides us an opportunity of accurate assessment of age-related impact on the function of highly proliferative intestinal stem cells. Our ability of indefinitely and robustly expanding single-stem-cell derived pedigrees in vitro allows us to study intestinal stem cells at the clonal level. Interestingly, comparable number of ISC clones was yielded from 1mm endoscopic biopsy of all donors despite the age. They were passaged in vitro as pedigrees and expanded to 1 billion cells in approximately sixty days without changes in stemness demonstrated by clonogenicity and multipotency. Therefore, our study shows that ISCs from a wide range of ages can be cloned and expanded to unlimited number in vitro with similar efficiency and stability. These patient-derived ISCs harbor intrinsic immortality and are ideal for autologous transplantation, supporting the promise of adult-stem-cell based personalized medicine.