What "First, Do No Harm" Means in Pediatrics.

This Viewpoint describes the multiple layers of meaning in the maxim "first, do no harm" applied in the pediatric setting.

The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines.

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

Neuromonitoring in Children with Cerebrovascular Disorders.

BACKGROUND: Cerebrovascular disorders are an important cause of morbidity and mortality in children. The acute care of a child with an ischemic or hemorrhagic stroke or cerebral sinus venous thrombosis focuses on stabilizing the patient, determining the cause of the insult, and preventing secondary injury. Here, we review the use of both invasive and noninvasive neuromonitoring modalities in the care of pediatric patients with arterial ischemic stroke, nontraumatic intracranial hemorrhage, and cerebral sinus venous thrombosis. METHODS: Narrative review of the literature on neuromonitoring in children with cerebrovascular disorders. RESULTS: Neuroimaging, near-infrared spectroscopy, transcranial Doppler ultrasonography, continuous and quantitative electroencephalography, invasive intracranial pressure monitoring, and multimodal neuromonitoring may augment the acute care of children with cerebrovascular disorders. Neuromonitoring can play an essential role in the early identification of evolving injury in the aftermath of arterial ischemic stroke, intracranial hemorrhage, or sinus venous thrombosis, including recurrent infarction or infarct expansion, new or recurrent hemorrhage, vasospasm and delayed cerebral ischemia, status epilepticus, and intracranial hypertension, among others, and this, is turn, can facilitate real-time adjustments to treatment plans. CONCLUSIONS: Our understanding of pediatric cerebrovascular disorders has increased dramatically over the past several years, in part due to advances in the neuromonitoring modalities that allow us to better understand these conditions. We are now poised, as a field, to take advantage of advances in neuromonitoring capabilities to determine how best to manage and treat acute cerebrovascular disorders in children.

Maxillomandibular osteotomy healing in a patient with hypophosphatemic rickets.

Hypophosphatemic rickets is a hereditary disease of childhood that affects bone metabolism. Patients with this disease can have poor bony healing at growth centers due to impaired mineralization of the cartilaginous bone plates. The orthopedic literature has shown appropriate long bone healing in patients with rickets who are undergoing concurrent medical management. However, there has never been a report of successful osteotomy or fracture of the maxillomandibular skeleton in a patient with rickets with documented radiographic and clinical resolution. This report describes a case of successful Le Fort I osteotomy with bilateral mandibular sagittal split osteotomies with concurrent medical management in an 18-year-old female with hypophosphatemic rickets. Before surgery the patient was consented and understood that because there has never been a documented case such as this, she might especially risk complications including non-union, malunion, or unfavorable osteotomy splits. The intraoperative quality of the patient's bone was of normal caliber and allowed routine osteotomy creation and internal fixation with no complications. She was followed for over 3 years and showed uneventful healing. While this disease is especially rare, practitioners should be aware that acceptable healing alongside appropriate medical management has been documented.

COVID-19 and Kawasaki Disease: Novel Virus and Novel Case.

In the midst of the coronavirus disease 2019 (COVID-19) pandemic, we are seeing widespread disease burden affecting patients of all ages across the globe. However, much remains to be understood as clinicians, epidemiologists, and researchers alike are working to describe and characterize the disease process while caring for patients at the frontlines. We describe the case of a 6-month-old infant admitted and diagnosed with classic Kawasaki disease, who also screened positive for COVID-19 in the setting of fever and minimal respiratory symptoms. The patient was treated per treatment guidelines, with intravenous immunoglobulin and high-dose aspirin, and subsequently defervesced with resolution of her clinical symptoms. The patient's initial echocardiogram was normal, and she was discharged within 48 hours of completion of her intravenous immunoglobulin infusion, with instruction to quarantine at home for 14 days from the date of her positive test results for COVID-19. Further study of the clinical presentation of pediatric COVID-19 and the potential association with Kawasaki disease is warranted, as are the indications for COVID-19 testing in the febrile infant.

The electrospinning of a thermo-responsive polymer with peptide conjugates for phenotype support and extracellular matrix production of therapeutically relevant mammalian cells.

Current cell expansion methods for tissue engineering and regenerative medicine applications rely on the use of enzymatic digestion passaging and 2D platforms. However, this enzymatic treatment significantly reduces cell quality, due to the destruction of important cell-surface proteins. In addition, culture in 2D results in undesired de-differentiation of the cells caused by the lack of 3D similarity to the natural extracellular matrix (ECM) environment. Research has led to the development of thermo-responsive surfaces for the continuous culture of cells. These thermo-responsive materials properties can be used to passage cells from the surface when the cell culture temperature is reduced. Here we report the development of a PLA/thermo-responsive (PDEGMA) blend 3D electrospun fibre-based scaffold to create an enzymatic-free 3D cell culture platform for the expansion of mammalian cells with the desired phenotype for clinical use. Human corneal stromal cells (hCSCs) were used as an exemplar as they have been observed to de-differentiate to an undesirable myo-fibroblastic phenotype when cultured by conventional 2D cell culture methods. Scaffolds were functionalised with a cell adherence peptide sequence GGG-YIGSR by thiol-ene chemistry to improve cell adherence and phenotype support. This was obtained by functionalising the thermo-responsive polymer with a thiol (PDEGMA/PDEGSH) by co-polymerisation. These incorporated thiols react with the norbornene acid functionalised peptide (Nor-GGG-YIGSR) under UV exposure. Presence of the thiol in the scaffold and subsequent peptide attachment on the scaffolds were confirmed by fluorescence labelling, ToF-SIMS and XPS analysis. The biocompatibility of the peptide containing scaffolds was assessed by the adhesion, proliferation and immuno-staining of hCSCs. Significant increase in hCSC adherence and proliferation was observed on the peptide containing scaffolds. Immuno-staining showed maintained expression of the desired phenotypic markers ALDH, CD34 and CD105, while showing no or low expression of the undesired phenotype marker α-SMA. This desired expression was observed to be maintained after thermo-responsive passaging and higher when cells were cultured on PLA scaffolds with 10 wt% PDEGMA/4 mol% PDEGS-Nor-GGG-YIGSR. This paper describes the fabrication and application of a first generation, biocompatible peptide conjugated thermo-responsive fibrous scaffold. The ease of fabrication, successful adherence and expansion of a therapeutically relevant cell type makes these scaffolds a promising new class of materials for the application of cell culture expansion platforms in the biomaterials and tissue engineering field.

The Renew® anal insert for passive faecal incontinence: a retrospective audit of our use of a novel device.

AIM: The Renew® anal insert is a recent treatment for patients who suffer from passive faecal incontinence (FI). Our aim was to assess the effectiveness of the insert and patients' satisfaction with it. METHOD: A retrospective audit of patients who were treated with the Renew® anal insert was undertaken. The St Mark's Incontinence Score was used to evaluate clinical outcome. Renew® size, the number of inserts used per day and per week had also been recorded. Subjective assessment of symptoms, how beneficial Renew® was and how satisfied patients were with the device were all recorded. Major events and side effects were also noted. RESULTS: Thirty patients received Renew® as a treatment for passive incontinence in 2016. The median St Mark's Incontinence Score was 15 (range 7-18) at baseline and 10 (range 2-18) at first follow-up (P < 0.0001) at a median of 11 (range 8-14) weeks. Eleven (37%) patients used the regular size and 19 (63%) the large size. Patients used an average of 1.67 inserts per day (range 1-3) on an average of 3.58 days per week (1-7). Three patients reported a deterioration in symptoms, seven (23%) had no change and 20 (67%) showed a significant improvement. Six patients (20%) did not like the device while 24 (80%) liked it. Seventeen patients (57%) wanted to continue this treatment in the long term. CONCLUSION: The Renew® device seems to be an acceptable and effective therapeutic option for passive FI. Further work is needed to compare it with other treatments and establish its position in the treatment pathway.

Acceptability, effectiveness and safety of a Renew® anal insert in patients who have undergone restorative proctocolectomy with ileal pouch-anal anastomosis.

INTRODUCTION: Restorative proctocolectomy has gained acceptance in the surgical management of medically refractive ulcerative colitis and cancer prevention in familial adenomatous polyposis. Incontinence following restorative proctocolectomy occurs in up to 25% of patients overnight. The Renew® insert is an inert single-use device which acts as an anal plug. The aim of this study was to assess the acceptability, effectiveness and safety of the Renew® insert in patients who have undergone restorative proctocolectomy. The device has yet to be assessed in patients who have undergone restorative proctocolectomy. METHOD: This was a prospective study exploring the acceptability, effectiveness and safety of the Renew® insert in improving incontinence in patients who had undergone restorative proctocolectomy. A total of 15 patients with incontinence were asked to use the Renew® insert for 14 days following their standard care. The Incontinence Questionnaire-Bowels was used pre- and posttreatment to assess response and patients were asked to report the perceived acceptability, effectiveness and safety of the device at the end of the trial. RESULTS: The device was acceptable to 8/15 (53%) of patients and was effective in 6/15 (40%). Only 2/15 (13%) of patients raised any safety concerns, and these were minor. The device was associated with a significant reduction in night seepage (P = 0.034). CONCLUSION: In a small study, the Renew® insert can be both acceptable and effective and is also associated with few safety concerns. It is also associated with significant reductions in night-time seepage.

Indications and outcomes of home parenteral nutrition in patients with an ileoanal pouch.

INTRODUCTION: Restorative proctocolectomy is a surgical treatment for patients with medically refractory ulcerative colitis and some cases of familial adenomatous polyposis. Intestinal failure, defined as an inability to maintain adequate hydration and micronutrient balances when on a conventionally accepted normal diet, is a rare complication of restorative proctocolectomy. We describe our experience of patients with restorative proctocolectomy who have developed intestinal failure requiring parenteral support. MATERIAL AND METHODS: This was a retrospective analysis using a database of patients referred to our intestinal failure unit from January 1998 to January 2016. We analysed the records of all those patients who had restorative proctocolectomy who developed intestinal failure. RESULTS: 807 patient records analysed, 35 patients were found to have had a restorative proctocolectomy (13 male and 22 female). Ninety-one percent (n = 32) of patients developed IF as a consequence of unpredictable complications which occurred after RPC formation. Potentially predictable complications were noted in 9% (n = 3) of patients. DISCUSSION AND CONCLUSIONS: Most cases of intestinal failure in restorative proctocolectomy were unpredictable. In a small number of patients, accurate assessment and measurement of the small intestine may have better predicted the adverse outcome of intestinal failure allowing improved pre-operative counseling of patients.

Design and fabrication of a hybrid alginate hydrogel/poly(ε-caprolactone) mold for auricular cartilage reconstruction.

The aim of this study was to design and manufacture an easily assembled cartilage implant model for auricular reconstruction. First, the printing accuracy and mechanical properties of 3D-printed poly-ε-caprolactone (PCL) scaffolds with varying porosities were determined to assess overall material properties. Next, the applicability of alginate as cell carrier for the cartilage implant model was determined. Using the optimal outcomes of both experiments (in terms of (bio)mechanical properties, cell survival, neocartilage formation, and printing accuracy), a hybrid auricular implant model was developed. PCL scaffolds with 600 µm distances between strands exhibited the best mechanical properties and most optimal printing quality for further exploration. In alginate, chondrocytes displayed high cell survival (~83% after 21 days) and produced cartilage-like matrix in vitro. Alginate beads cultured in proliferation medium exhibited slightly higher compressive moduli (6 kPa) compared to beads cultured in chondrogenic medium (3.5 kPa, p > .05). The final auricular mold could be printed with 300 µm pores and high fidelity, and the injected chondrocytes survived the culture period of 21 days. The presented hybrid auricular mold appears to be an adequate model for cartilage tissue engineering and may provide a novel approach to auricular cartilage regeneration for facial reconstruction. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1711-1721, 2019.

Management of early pouch-related septic complications in ulcerative colitis: a systematic review.

AIM: It is well established that ileo-anal pouch-related septic complications (PRSC) increase the risk of pouch failure. There are a number of publications that describe the management of early PRSC in ulcerative colitis (UC) in small series. This article aims to systematically review and summarize the relevant current data on this subject and provide an algorithm for the management of early PRSC. METHOD: A systematic review was undertaken in accordance with PRISMA guidelines. Studies published between 2000 and 2017 describing the clinical management of PRSC in patients with UC within 30 days of primary ileo-anal pouch surgery were included. A qualitative analysis was undertaken due to the heterogeneity and quality of studies included. RESULTS: A total of 1157 abstracts and 266 full text articles were screened. Twelve studies were included for analysis involving a total of 207 patients. The studies described a range of techniques including image-guided, endoscopic, surgical and endocavitational vacuum methods. Based on the evidence from these studies, an algorithm was created to guide the management of early PRSC. CONCLUSION: The results of this review suggest that although successful salvage of early PRSC is improving there is little information available relating to methods of salvage and outcomes. Novel techniques may offer an increased chance of salvage but comparative studies with longer follow-up are required.

Systematic review: ileoanal pouch microbiota in health and disease.

BACKGROUND: The resident gut microbiota is essential for physiological processes; the disturbance of its balance is linked to intestinal inflammation. The ileoanal pouch is a model for the study of intestinal inflammation, as inflammation of the pouch is common and mostly develops within 12 months following ileostomy closure. This allows the longitudinal study of the microbiota, giving insight into the microbiota changes during transition from a normal to an inflamed pouch. AIM: To explore the literature on the microbiota of the ileoanal pouch in health and disease. METHODS: A systematic computer search of the on-line bibliographic databases MEDLINE and EMBASE was performed between 1966 and February 2017. Randomised controlled trials, cohort studies and observational studies were included. Studies were included if they reported microbiota analysis on faecal samples or tissue from the ileoanal pouch. RESULTS: Twenty-six papers were eligible. Following ileostomy closure, anaerobic bacteria are the abundant species in the ileoanal pouch with presence of a diverse microbiota key to maintaining a healthy ileoanal pouch. Acute pouchitis is associated with an increase in Clostridia species, while chronic pouchitis is associated with an increase in Staphylococcus aureus. In the treatment of pouchitis, a decrease in Clostridia species appears to be associated with treatment response. CONCLUSION: The microbiota plays an important role in both the inflamed and the healthy ileoanal pouch. A direct causal relationship between individual microbiota changes and inflammation has not yet been established, but manipulation of the ileoanal pouch microbiota may be a novel therapeutic avenue to explore.

A design of experiments approach to identify the influencing parameters that determine poly-D,L-lactic acid (PDLLA) electrospun scaffold morphologies.

Electrospun fibrous materials have increasing applications in regenerative medicine due to the similarity of fibre constructs to the morphology of certain extracellular matrices. Although experimentally the electrospinning method is relatively simple, at the theoretical level the interactions between process parameters and their influence on the fibre morphology is not yet fully understood. Here, we hypothesised that a design of experiments (DoE) model could determine combinations of process parameters that result in significant effects on poly-D,L-lactic acid (PDLLA) fibre morphology. The process parameters used in this study were applied voltage, needle-to-collector distance, flow rate and polymer concentration. Data obtained for mean fibre diameter, standard deviation (SD) of the fibre diameter (measure of fibre morphology) and presence of 'beading' on the fibres (beads per µm2) were evaluated as a measure of PDLLA fibre morphology. Uniform fibres occurred at SDs of ≤500 nm, 'beads-on-string' morphologies were apparent between ±500 and 1300 nm and large beads were observed at ±1300-1800 nm respectively. Mean fibre diameter was significantly influenced by the applied voltage and interaction between flow rate and polymer concentration. Fibre morphology was mainly influenced by the polymer concentration, while bead distribution was significantly influenced by the polymer concentration as well as the flow rate. The resultant DoE model regression equations were tested and considered suitable for the prediction of parameters combinations needed for desired PDLLA fibre diameter and additionally provided information regarding the expected fibre morphology.

National trends in the treatment of diabetic nephropathy in the United States.

WHAT IS KNOWN AND OBJECTIVE: The prevalence of diabetic nephropathy continues to rise and it remains a strong predictor of morbidity and mortality in diabetic patients. Patients diagnosed with diabetic nephropathy are actively excluded from most trials involving diabetic medications and it is important to understand the prescription patterns in this subset of patients with diabetes. METHODS: Using the IMS Health's National Disease and Therapeutic Index, we analysed the medication prescription patterns for six classes of medications from 2010 to 2014 among patients, 35 years or older, with diabetic nephropathy. RESULTS: Annual office visits increased from 772 860 (95% confidence interval (CI), 755, 470-790, 249) in 2010 to 1 868 618 (95% CI, 1 834 422-1 902 814) in 2013 and declined to 830 596 (95% CI, 809 167-852 025) in 2014. Sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were the most frequently used of the four classes of diabetic medications included in this study. DPP-4 inhibitors use increased gradually and was used in 54% (95% CI 49-58) of treatment visits by the last quarter of 2014. Across these years, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs and ARBs) were prescribed in the majority of treatment visits with peaks above 90%. However, there were some periods when utilization of these antihypertensives was low. WHAT IS NEW AND CONCLUSIONS: Significant increases occurred in the uptake of new diabetic medications; DPP-4 inhibitors and SGLT-2 inhibitors and in the utilization of ACEIs and ARBs compared to the findings reported in other studies with increased complexity in the treatment of patients with diabetic nephropathy. Improved and continued used of these medications may be beneficial in improving patient outcomes.

Systematic review with meta-analysis: the management of chronic refractory pouchitis with an evidence-based treatment algorithm.

BACKGROUND: Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is considered the procedure of choice in patients with ulcerative colitis (UC) refractory to medical therapy. The incidence of pouchitis is 40% at 5 years. Ten to 15% of patients with pouchitis experience chronic pouchitis. AIM: To determine the efficacy of medical therapies for the treatment of chronic refractory pouchitis in patients undergoing IPAA for UC. METHODS: A systematic computer-assisted search of the on-line bibliographic database MEDLINE and EMBASE was performed between 1966 and February 2016. All original studies reporting remission rates following medical treatment for chronic pouchitis were included. All study designs were considered. Remission was defined according to the individual study. Remission endpoints ranged from 15 days to 10 weeks. Chronic pouchitis was defined by each study. RESULTS: Twenty-one papers were considered eligible. Results from all studies combined suggested that overall remission was obtained in 59% of patients (95% CI: 44-73%). Antibiotics significantly induced remission in patients with chronic pouchitis with 74% remission rate (95% CI:56-93%), (P < 0.001). Biologics significantly induced remission in patients with chronic pouchitis with 53% remission rate (95% CI:30-76%), (P < 0.001). Steroids, bismuth, elemental diet and tacrolimus all can induce remission but failed to achieve significance. Faecal microbiota transplantation in a single study was not found to achieve remission. CONCLUSIONS: Treatment of chronic refractory pouchitis remains difficult and is largely empirical. Larger randomised controlled trials will help aid the management of chronic pouchitis.

Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical Students: A Systematic Review and Meta-Analysis.

Importance: Medical students are at high risk for depression and suicidal ideation. However, the prevalence estimates of these disorders vary between studies. Objective: To estimate the prevalence of depression, depressive symptoms, and suicidal ideation in medical students. Data Sources and Study Selection: Systematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language restriction for studies on the prevalence of depression, depressive symptoms, or suicidal ideation in medical students published before September 17, 2016. Studies that were published in the peer-reviewed literature and used validated assessment methods were included. Data Extraction and Synthesis: Information on study characteristics; prevalence of depression or depressive symptoms and suicidal ideation; and whether students who screened positive for depression sought treatment was extracted independently by 3 investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. Main Outcomes and Measures: Point or period prevalence of depression, depressive symptoms, or suicidal ideation as assessed by validated questionnaire or structured interview. Results: Depression or depressive symptom prevalence data were extracted from 167 cross-sectional studies (n = 116 628) and 16 longitudinal studies (n = 5728) from 43 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of depression or depressive symptoms was 27.2% (37 933/122 356 individuals; 95% CI, 24.7% to 29.9%, I2 = 98.9%). Summary prevalence estimates ranged across assessment modalities from 9.3% to 55.9%. Depressive symptom prevalence remained relatively constant over the period studied (baseline survey year range of 1982-2015; slope, 0.2% increase per year [95% CI, -0.2% to 0.7%]). In the 9 longitudinal studies that assessed depressive symptoms before and during medical school (n = 2432), the median absolute increase in symptoms was 13.5% (range, 0.6% to 35.3%). Prevalence estimates did not significantly differ between studies of only preclinical students and studies of only clinical students (23.7% [95% CI, 19.5% to 28.5%] vs 22.4% [95% CI, 17.6% to 28.2%]; P = .72). The percentage of medical students screening positive for depression who sought psychiatric treatment was 15.7% (110/954 individuals; 95% CI, 10.2% to 23.4%, I2 = 70.1%). Suicidal ideation prevalence data were extracted from 24 cross-sectional studies (n = 21 002) from 15 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of suicidal ideation was 11.1% (2043/21 002 individuals; 95% CI, 9.0% to 13.7%, I2 = 95.8%). Summary prevalence estimates ranged across assessment modalities from 7.4% to 24.2%. Conclusions and Relevance: In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among medical students was 27.2% and that of suicidal ideation was 11.1%. Further research is needed to identify strategies for preventing and treating these disorders in this population.