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Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer. They develop mammary tumors with comparable histopathology to humans and exhibit differences in resistance or susceptibility to mammary cancer depending on strain. While some rat strains (e.g., Sprague-Dawley) readily form mammary tumors following treatment with the chemical carcinogen, 7,12-dimethylbenz[a]-anthracene (DMBA), other strains (e.g., Copenhagen) are resistant to DMBA-induced mammary carcinogenesis. Genetic linkage in inbred strains has identified strain-specific quantitative trait loci (QTLs) affecting mammary tumors, via mechanisms that act together to promote or attenuate, and include 24 QTLs controlling the outcome of chemical induction, 10 QTLs controlling the outcome of estrogen induction, and 4 QTLs controlling the outcome of irradiation induction. Moreover, and based on shared factors affecting mammary cancer etiopathogenesis between rats and humans, including orthologous risk regions between both species, rats have served as useful models for identifying methods for breast cancer prediction and treatment. These studies in rats, combined with alternative animal models that more closely mimic advanced stages of breast cancer and/or human lifestyles, will further improve our understanding of this complex disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG., Objective: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients., Methods: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates., Results: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported., Conclusion: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prader-Willi syndrome (PWS) is a complex genetic disorder with three genetic classes. Patients with PWS are characterized by severe hypotonia, developmental delay, behavioral problems, learning disabilities and morbid obesity in early childhood if untreated. Data were collected through Rare Disease Clinical Research Network (RDCRN) from four study centers which evaluated patients with PWS. The Behavior Assessment System for Children 2nd edition (BASC-2) was chosen to provide behavioral assessment. Data from 330 participants ((64% 15q11-q13 deletion (DEL), 36% maternal disomy 15 (UPD)) were separated into three age groups and analyzed, 68% of whom were still actively receiving recombinant human growth hormone (rhGH) treatment. When comparing the BASC results by molecular subtype, parent-reported aggression was higher for the deletion than for the UPD cohort ( p = 0.007). Participants who were on rhGH treatment showed lower scores for parent-reported hyperactivity and aggression ( p = 0.04, 0.04, respectively), and a trend for anger control ( p = 0.06) and teacher-reported attention problems and aggression ( p = 0.01, 0.004, respectively). Additional adjusted analyses were undertaken and significant differences were noted in the GH versus non-GH treated groups for only teacher-reported aggression, which increased in the No GH treated patient group ( p = 0.03). This study showed documented differences in PWS behavior by molecular class and rhGH treatment. RhGH therapy may be beneficial for certain behaviors in patients with PWS; however, observed differences need more studies for confirmation in the future.

Ampicillin is frequently used in neonates for early- and late-onset group B streptococcal (GBS) disease. In 2019, the American Academy of Pediatrics (AAP) published guidelines for GBS which included updated dosing recommendations for ampicillin for bacteremia and provided specific dosing recommendations for meningitis. The dosing recommendations in the guidelines were based off the 2018 Report of the Committee on Infectious Diseases (i.e., Red Book), which differed from the 2015 Red Book. For bacteremia, no dosing changes were recommended for ampicillin dosing in neonates ≤ 7 days of postnatal age (PNA), but less frequent dosing intervals were recommended for neonates > 7 days PNA. For meningitis, increased dosing recommendations were provided in the update. However, the rationale and supporting evidence for these changes were not provided. A literature search was performed to review articles pertaining to the pharmacokinetics (PK), pharmacodynamics (PD) and safety of ampicillin in neonates. The ampicillin dosing recommendations in the AAP guidelines were mainly supported by a 2014 publication that evaluated the PK and PD of ampicillin in neonates with gestational age (GA) of 24 to 41 weeks and PNA of 0 to 25 days. The proposed dosing from this study for bacteremia is included in the 2018 Red Book and 2019 guidelines. For meningitis, no supporting evidence was identified for the dosing recommendations in the 2018 Red Book and 2019 guidelines. Only one study has evaluated ampicillin concentrations in cerebrospinal fluid, but proposed dosing from this study was much lower than that included in the guidelines. The high ampicillin doses for GBS meningitis should be used with caution, as high ampicillin concentrations have been associated with seizures and no studies have evaluated efficacy of this dosing strategy. The purpose of this review is to identify key pieces of literature regarding dosing recommendations and safety of ampicillin in neonates. KEY POINTS: · Recent guidelines provide dosing recommendations for ampicillin, but the supporting evidence is not included.. · Literature supporting evidence for ampicillin dosing for bacteremia is available, but not for dosing for meningitis.. · Recommended meningitis dose may result in supratherapeutic concentrations and increase seizure risk.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Depressive symptoms are substantial among stroke survivors and their caregivers in poststroke management. Optimism and social support are known to protect against depressive symptoms. However, little is known about how optimism and social support contribute to depressive symptoms among stroke survivor-caregiver dyads. The study's purpose was to examine actor and partner effects of optimism on depressive symptoms through perceived social support among stroke survivors and caregiver dyads in the chronic stage of rehabilitation., Methods: Stroke survivors and caregivers (N = 105 dyads) completed the survey at 2 years of follow-up after the first stroke. Depressive symptoms, optimism, and perceived social support were assessed using the Center for Epidemiologic Studies-Depression, the Life Orientation Test, and the Interpersonal Support Evaluation List. The Actor-Partner Interdependence Model Extended to Mediation analysis was used to test the indirect effect of optimism on depressive symptoms through perceived social support., Results: Higher optimism was significantly associated with lower depressive symptoms for caregivers (direct actor effect, -0.6844; 95% confidence interval [CI], -0.9844 to -0.3844) and stroke survivors (direct partner effect, -0.4189; 95% CI, -0.0789 to -0.0889). Perceived social support availability significantly mediated the association between optimism and depressive symptoms for stroke survivors (indirect effect, -0.1957; 95% CI, -0.3923 to -0.0670). Caregiver perceived social support availability was also a significant mediator between caregivers' optimism and stroke survivors' depressive symptoms (indirect effect, 0.1658; 95% CI, 0.0559-0.3128)., Conclusions: Intervention improving dyad members' optimism and social support would be beneficial to improve depressive symptoms of the stroke survivors and caregivers in chronic stroke management., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Neonicotinoid mixtures are common in streams worldwide, but corresponding ecological responses are poorly understood. We combined experimental and observational studies to narrow this knowledge gap. The mesocosm experiment determined that concentrations of the neonicotinoids imidacloprid and clothianidin (range of exposures, 0 to 11.9 μg/liter) above the hazard concentration for 5% of species (0.017 and 0.010 μg/liter, respectively) caused a loss in taxa abundance and richness, disrupted adult emergence, and altered trophodynamics, while mixtures of the two neonicotinoids caused dose-dependent synergistic effects. In 85 Coastal California streams, neonicotinoids were commonly detected [59% of samples ( n = 340), 72% of streams], frequently occurred as mixtures (56% of streams), and potential toxicity was dominated by imidacloprid (maximum = 1.92 μg/liter) and clothianidin (maximum = 2.51 μg/liter). Ecological responses in the field were consistent with the synergistic effects observed in the mesocosm experiment, indicating that neonicotinoid mixtures pose greater than expected risks to stream health.

Aims: Patients with heart failure (HF) and their family caregivers commonly experience depressive symptoms associated with low quality of life (QOL) at the individual level. However, there is a lack of knowledge about how QOL and family function are associated with depressive symptoms at the dyad level. The aim of this article is to compare QOL and family function among dyads stratified by depressive symptoms., Methods and Results: Outpatients with HF and their primary caregivers completed the Beck Depression Inventory-II for depressive symptoms, the Short Form 36 for physical and mental QOL, and the McMaster Family Assessment Device for a family function. Analysis of variance was used to compare QOL and family function among the four dyad groups. A total of 91 dyads were categorized into four groups: neither member having depressive symptoms (43.9%), only the caregiver having depressive symptoms (13.2%), only the patient having depressive symptoms (23.1%), and both members having depressive symptoms (20.9%). Dyads without depressive symptoms had the highest levels of physical and mental QOL among the groups. The dyads with both members having depressive symptoms had the lowest levels of physical and mental QOL (P < 0.001) and the lowest levels of general family functioning, problem-solving ability, and communication ability (P < 0.001). Intermediate levels of QOL were seen in dyads with only one member having depressive symptoms, and a similar pattern of intermediate scores was found in all three subscales of family function., Conclusion: Dyads with both members having depressive symptoms may be at greatest risk of having poor QOL and low family functioning., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Individuals with Prader-Willi syndrome (PWS) may be at higher risk of developing blood clots as compared to the typical population, but this risk is poorly understood. It is also unclear if laboratory testing of D-dimer concentration might be useful to screen for thrombosis in PWS. Here, we surveyed the thrombosis history of 883 individuals with PWS and evaluated the D-dimer concentration in a subset of 214 asymptomatic individuals, ages 5-55. A history of at least one blood clot was reported by 3.6% of respondents. Thrombosis increased with age, but no significant difference was found on the basis of sex or family history. Genetic subtype was a significant factor when considering only those with a known subtype, and individuals with a history of edema had significantly more blood clots. In the D-dimer sub-study, ≈15% of participants had high D-dimer concentrations, and 3.7% had D-dimer values more than twice the normal upper limit. One participant with a high D-dimer result was found to have a blood clot. No significant differences in D-dimer results were found on the basis of age, sex, genetic subtype, family history of blood clots, edema history, or BMI. The D-dimer test does not appear to be a sensitive and specific screening tool for blood clots in asymptomatic individuals with PWS.

Purpose: To summarize recently published research reports and practice guidelines deemed to be significantly impactful for pediatric pharmacy practice., Summary: Our author group was composed of 8 board-certified pediatric pharmacists. Eight major themes were identified: critical care, hematology/oncology, medication safety, general pediatrics, infectious diseases, neurology/psychiatry, gastrointestinal/nutrition, and neonatology. The author group was assigned a specific theme(s) based on their practice expertise and were asked to identify articles using MEDLINE and/or searches of relevant journal articles pertaining to each theme that were published from January 2019 through December 2020 that they felt were "significant" for pediatric pharmacy practice. A final list of compiled articles was distributed to the authors, and an article was considered significant if it received a vote from 5 of the 8 authors. Thirty-two articles, including 16 clinical practice guidelines or position statements and 16 review or primary literature articles, were included in this review. For each of these articles, a narrative regarding its implications for pediatric pharmacy practice is provided., Conclusion: Given the heterogeneity of pediatric patients, it is difficult for pediatric pharmacists to stay up to date with the most recent literature, especially in practice areas outside their main expertise. Over the last few years, there has been a significant number of publications impacting the practice of pediatric pharmacists. This review of articles that have significantly affected pediatric pharmacy practice may be helpful in staying up to date on key articles in the literature., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

Background: Throughout 2020, the coronavirus disease 2019 (COVID-19) has become a threat to public health on national and global level. There has been an immediate need for research to understand the clinical signs and symptoms of COVID-19 that can help predict deterioration including mechanical ventilation, organ support, and death. Studies thus far have addressed the epidemiology of the disease, common presentations, and susceptibility to acquisition and transmission of the virus; however, an accurate prognostic model for severe manifestations of COVID-19 is still needed because of the limited healthcare resources available., Objective: This systematic review aims to evaluate published reports of prediction models for severe illnesses caused COVID-19., Methods: Searches were developed by the primary author and a medical librarian using an iterative process of gathering and evaluating terms. Comprehensive strategies, including both index and keyword methods, were devised for PubMed and EMBASE. The data of confirmed COVID-19 patients from randomized control studies, cohort studies, and case-control studies published between January 2020 and May 2021 were retrieved. Studies were independently assessed for risk of bias and applicability using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). We collected study type, setting, sample size, type of validation, and outcome including intubation, ventilation, any other type of organ support, or death. The combination of the prediction model, scoring system, performance of predictive models, and geographic locations were summarized., Results: A primary review found 445 articles relevant based on title and abstract. After further review, 366 were excluded based on the defined inclusion and exclusion criteria. Seventy-nine articles were included in the qualitative analysis. Inter observer agreement on inclusion 0.84 (95%CI 0.78-0.89). When the PROBAST tool was applied, 70 of the 79 articles were identified to have high or unclear risk of bias, or high or unclear concern for applicability. Nine studies reported prediction models that were rated as low risk of bias and low concerns for applicability., Conclusion: Several prognostic models for COVID-19 were identified, with varying clinical score performance. Nine studies that had a low risk of bias and low concern for applicability, one from a general public population and hospital setting. The most promising and well-validated scores include Clift et al., 15 and Knight et al., 18 which seem to have accurate prediction models that clinicians can use in the public health and emergency department setting., (© 2022 Society for Academic Emergency Medicine.)

Hyperpolarised magnetic resonance imaging (HP  13 C-MRI) is an emerging clinical technique to detect [1- 13 C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1- 13 C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1- 13 C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP  13 C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1- 13 C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP  13 C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments., (© 2022. The Author(s).)

Numerous hydride-abstracting agents generate the same cationic intermediate, but substrate features such as intermediate cation stability, oxidation potential, and steric environment can influence reaction rates in an oxidant-dependent manner. This manuscript provides experimental data to illustrate the role that structural features play in the kinetics of hydride abstraction reactions with commonly used quinone-, oxoammonium ion-, and carbocation- based oxidants. Computational studies of the transition state structures and energies explain these results and energy decomposition analysis calculations reveal unique sensitivities to electrostatic attraction and steric repulsions. Rigorous rate studies of select reactions validated the capacity of the calculations to predict reactivity trends. Additionally, kinetics studies demonstrate the potential for product inhibition in DDQ-mediated reactions. These studies provide a clear guide to select the optimal oxidant for structurally disparate substrates and lead to predictions of reactivity that were validated experimentally., (© 2021 Wiley-VCH GmbH.)

Purpose: Caring for a family member with chronic illness increases cardiovascular disease (CVD) risk by 82%, and rurality imparts additional CVD disparities. The purpose of this study was to describe a profile of rural caregivers of patients with chronic illnesses to determine the prevalence of CVD risk factors, and psychosocial and socioeconomic burden, as well as to compare these variables across gender., Methods: Baseline data from a trial of CVD risk reduction in rural caregivers of patients with chronic illnesses were used. We measured depression and anxiety with the PHQ-9 and Brief Symptom Inventory; social, economic, and environmental factors using the MOS-Social Support and Economic and Environmental surveys; body mass index (BMI); blood pressure (BP); and lipid profile., Results: Of 181 caregivers (age 53±14 years, 80% female), 69% were married; 88% were caring for a family member, including 46% caring for a spouse and 18% for a parent. A total of 51% were anxious, 25% depressed, and 25% reported lack of social support. Most (51%) caregivers had one or more types of CVD; and 49% were smokers. By examination, 76% had elevated BP; 35% had total cholesterol >200; 50% low-density lipoprotein >100; 56% triglycerides >150; and 79% high-density lipoprotein <60. Based on BMI, 91.5% were overweight or obese. Gender comparisons revealed that women reported higher levels of depressive symptoms than men., Conclusions: Rural caregivers, regardless of gender, are at increased risk of CVD and struggle with factors that make caregiving burdensome and contribute to their own poor cardiac health., (© 2021 National Rural Health Association.)

Objective: Limited reports have described ketamine's role as an adjunct sedative. The purpose was to describe ketamine's role as an adjunct to achieve goal sedation in mechanically ventilated children., Design: Retrospective, descriptive study., Setting: Thirteen-bed pediatric intensive care unit (ICU) and 12-bed pediatric cardiovascular ICU., Participants: Seventy-three ketamine courses were included, representing 62 mechanically ventilated children <18 years receiving ketamine for ≥12 hours., Main Outcome Measure(s): The primary outcome was to determine the median dose and time to achieve goal sedation (80 percent of State Behavioral Scale scores between 0 and -1) based on ketamine's place in therapy as an adjunct in the sedation regimen. Secondary outcomes included a comparison of sedative dosing pre- and post-ketamine initiation between place in therapy groups and paralyzed/nonparalyzed patients, and identification of ketamine-attributed adverse drug event (ADEs) or iatrogenic withdrawal syndrome (IWS)., Results: The median age was 1.0 years (interquartile range: 0.4-4.9). Ketamine was initiated as first-line (n = 7; 9.6 percent), second-line (n = 39; 53.4 percent), third-line (n = 26; 35.6 percent), or fourth-line (n = 1; 1.4 percent) sedation. The median initial and peak doses were 0.6 mg/kg/h (0.3-0.6) and 0.9 mg/kg/h (0.9-1.2), respectively. The median dose and time to achieve goal sedation was 0.8 mg/kg/h (0.6-1.1) and 2 hours (1-7), respectively. ADEs were noted during three courses (4.1 percent) and IWS after discontinuation of one course (1.4 percent)., Conclusions: The majority were initiated on ketamine as a second- or third-line adjunct sedative. The median initial dose was 0.6 and dose to achieve goal sedation was 0.8 mg/kg/h. Ketamine-attributed ADEs and IWS episodes were rare.

Objective: To determine the incidence of cytomegalovirus (CMV) DNAemia and disease, identify potential risk factors, and assess the safety and efficacy of weight-based valganciclovir dosing in pediatric post-renal transplant patients., Methods: This single-center, retrospective study included patients ≤21 years who received a kidney transplant between January 1, 2011, and November 1, 2019, with 3 to 24 months of follow-up data. Demographics and clinical characteristics were collected to assess for potential risk factors. Descriptive statistics and logistic regressions were used to determine rates of CMV DNAemia considering clinical characteristics and chemoprophylaxis., Results: Fifty-seven patients were included. The incidence of CMV DNAemia was 43.9%. Cytomegalovirus seropositive status was associated with increased risk of CMV DNAemia. Patients receiving valganciclovir for <150 days had 8.33 (95% CI, 1.68-41.29) greater odds of developing CMV DNAemia than patients receiving valganciclovir for 180 ± 30 days, p = 0.01. The median time to detectable CMV PCR after transplant was 140 days (range, 12-511 days). Cytomegalovirus DNAemia was not statistically different between those receiving weight-based vs FDA-approved valganciclovir dosing; however, patients receiving the FDA-approved dosing were more likely to develop neutropenia. Among the intermediate-risk group, the adjusted relative risk of CMV DNAemia was 0.62 (95% CI, 0.36-1.09) for those not receiving chemoprophylaxis compared with those who did., Conclusions: Risk of CMV DNAemia is higher among patients receiving valganciclovir for <150 days. Further exploration of weight-based valganciclovir dosing for CMV chemoprophylaxis in high- and intermediate-risk post-renal transplant patients is needed to minimize adverse drug effects while maintaining efficacy., Competing Interests: Disclosures. The authors declare no conflicts of financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2022.)

Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.

Background: The multicenter randomized controlled trial Management of Myelomeningocele Study demonstrated that prenatal repair of open spina bifida by hysterotomy, compared with postnatal repair, decreases the need for ventriculoperitoneal shunting and increases the chances of independent ambulation. However, the hysterotomy approach is associated with risks that are inherent to the uterine incision. Fetal surgeons from around the world embarked on fetoscopic open spina bifida repair aiming to reduce maternal and fetal/neonatal risks while preserving the neurologic benefits of in utero surgery to the child., Objective: This study aimed to report the main obstetrical, perinatal, and neurosurgical outcomes in the first 12 months of life of children undergoing prenatal fetoscopic repair of open spina bifida included in an international registry and to compare these with the results reported in the Management of Myelomeningocele Study and in a subsequent large cohort of patients who received an open fetal surgery repair., Study Design: All known centers performing fetoscopic spina bifida repair were contacted and invited to participate in a Fetoscopic Myelomeningocele Repair Consortium and enroll their patients in a registry. Patient data entered into this fetoscopic registry were analyzed for this report. Fisher exact test was performed for comparison of categorical variables in the registry with both the Management of Myelomeningocele Study and a post-Management of Myelomeningocele Study cohort. Binary logistic regression analyses were used to assess the registry data for predictors of preterm birth at <30 weeks' gestation, preterm premature rupture of membranes, and need for postnatal cerebrospinal fluid diversion in the fetoscopic registry., Results: There were 300 patients in the fetoscopic registry, 78 in the Management of Myelomeningocele Study, and 100 in the post-Management of Myelomeningocele Study cohort. The 3 data sets showed similar anatomic levels of the spinal lesion, mean gestational age at delivery, distribution of motor function compared with upper anatomic level of the lesion in the neonates, and perinatal death. In the Management of Myelomeningocele Study (26.16±1.6 weeks) and post-Management of Myelomeningocele Study cohort (23.3 [20.2-25.6] weeks), compared with the fetoscopic registry group (23.6±1.4 weeks), the gestational age at surgery was lower (comparing fetoscopic repair group with the Management of Myelomeningocele Study; P<.01). After open fetal surgery, all patients were delivered by cesarean delivery, whereas in the fetoscopic registry approximately one-third were delivered vaginally (P<.01). At cesarean delivery, areas of dehiscence or thinning in the scar were observed in 34% of cases in the Management of Myelomeningocele Study, in 49% in the post-Management of Myelomeningocele Study cohort, and in 0% in the fetoscopic registry (P<.01 for both comparisons). At 12 months of age, there was no significant difference in the number of patients requiring treatment for hydrocephalus between those in the fetoscopic registry and the Management of Myelomeningocele Study., Conclusion: Prenatal and postnatal outcomes up to 12 months of age after prenatal fetoscopic and open fetal surgery repair of open spina bifida are similar. Fetoscopic repair allows for having a vaginal delivery and eliminates the risk of uterine scar dehiscence, therefore protecting subsequent pregnancies of unnecessary maternal and fetal risks., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Opioid rotations from fentanyl to hydromorphone may reduce opioid/sedative exposure in critically ill children., Objective: The primary objective was to determine the conversion percentage from fentanyl to hydromorphone infusions using equianalgesic conversions (0.1 mg fentanyl = 1.5 mg hydromorphone). Secondary objectives included identification of the median time and hydromorphone rate at stabilization (defined as the first 24-hour period no hydromorphone rates changed, 80% of State Behavioral Scale [SBS] scores between 0 and -1, and <3 hydromorphone boluses administered). Additional outcomes included a comparison of opioid/sedative requirements on the day of conversion versus the three 24-hour periods prior to conversion., Methods: This retrospective study included children <18 years old converted from fentanyl to hydromorphone infusions over 6.3 years. Linear mixed models were used to determine if the mean cumulative opioid/sedative dosing differed from the day of conversion versus three 24-hour periods prior to conversion., Results: A total of 36 children were converted to hydromorphone. The median conversion percentage of hydromorphone was 86% of their fentanyl dose (interquartile range [IQR] = 67-100). The median hydromorphone rate at stabilization was 0.08 mg/kg/h (IQR = 0.05-0.1). Eight (22%) were stabilized on their initial hydromorphone rate; 8 (22%) never achieved stabilization. Patients had a significant decrease in opioid dosing on the day of conversion versus the 24-hour period prior to conversion but no changes in sedative dosing following conversion., Conclusion and Relevance: A median 14% fentanyl dose reduction was noted when transitioning to hydromorphone. Further exploration is needed to determine if opioid rotations with hydromorphone can reduce opioid/sedative exposure.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD., Competing Interests: Declaration of interests David L.A. Wood and Lutz Krause are employees of Microba Life Sciences. Gene W. Tyson is a co-founder and director of Microba Life Sciences. Gerald Holtmann is on the advisory board of Servatus Biopharmaceuticals. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad-spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen-stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis-related inflammatory disorders associated with excess cytokine secretion., (© 2021 The Authors. Immunology published by John Wiley & Sons Ltd.)

Objectives: To compare the performance of the TEG 5000 and TEG 6S Global Hemostasis cartridge., Methods: We reviewed validation data of the TEG 5000 and TEG 6S Global Hemostasis cartridge. The specimens were analyzed in parallel according to the manufacturer's operating instructions., Results: Fifty-four healthy donors and 13 donors with known hemostatic abnormalities were included. The correlations between instrument types were only moderate-the Spearman rank correlations were 0.55, 0.62, 0.64, and 0.72, respectively, for CK R, K, angle, and maximum amplitude (MA) parameters. Using the manufacturer's device-specific reference ranges to classify results as normal/abnormal, there was weak agreement in the qualitative interpretation of all parameters (Cohen's κ for agreement for CK R, K, angle, and MA was 0.418, 0.154, -0.083, and 0.127, respectively). This could lead to discordant transfusion decisions., Conclusions: These findings indicate that the TEG 5000 and TEG 6S may not be used interchangeably., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls., Methods: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale., Results: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes., Conclusions: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Injured patients with traumatic hemorrhagic shock often require resuscitation with transfusion of red blood cells, plasma, and platelets. Resuscitation with whole blood (WB) has been used in military settings, and its use is increasingly common in civilian practice. We provide an overview of the benefits and challenges, guidelines, and unanswered questions related to the use of WB in the treatment of civilian trauma-related hemorrhage. Implications for advanced practice nurses and nursing staff are also discussed., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.

Ketamine is an N -methyl-D-aspartate receptor antagonist that has been used as an adjunct analgesic and sedative in critically ill children. Previous reports noted that ketamine has been used for a variable duration of 12 to 408 hours for this indication. We report on the use of ketamine infusions for >720 hours as a second-line sedative in addition to an opioid and dexmedetomidine infusion in a 2-month old and 17-month old. The purpose of this case report and review of the literature is to highlight the prolonged ketamine exposure of these two patients and to provide awareness to clinicians on the potential of withdrawal with extended ketamine administration. These children were started on initials doses of 5 and 15 µg/kg/min and titrated to peak doses of 20 and 25 µg/kg/min, respectively. They were continued for a total of 987 and 792 hours, respectively. No adverse events were noted during the ketamine infusions. One patient developed possible withdrawal symptoms 17 hours after ketamine discontinuation despite tapering of the infusion. These symptoms resolved with administration of as needed intravenous opioids and benzodiazepines, and the agitation normalized within 24 hours after ketamine discontinuation. Clinicians should consider tapering ketamine infusions in children receiving >72 hours of a continuous infusion by 5 µg/kg/min every 8 to 12 hours. Patients should be monitored for potential withdrawal symptoms including anxiety, allodynia, hyperalgesia, sweating, and drowsiness., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background: There is a relative lack of information on the incidence and treatment of vision problems in Prader-Willi syndrome (PWS). Using data from the Global PWS Registry, we performed a cross-sectional study of vision problems in PWS., Methods: Data, reported by caregivers who completed the Vision Survey in the Global PWS Registry between May of 2015 and March of 2020, were analyzed using descriptive statistics., Results: There were 908 participants in this survey, with a mean age of 14.5 years (range 0-62 years). The prevalence of strabismus in this population was 40 %, with no statistically significant difference in prevalence by genetic subtype. Ninety-one percent of participants with strabismus were diagnosed before 5 years of age. Of those with strabismus, 42 % went on to have strabismus surgery, with 86 % of those having their first strabismus surgery before 5 years of age and 10.1 % having more than one strabismus surgery. Additional vision issues reported included myopia (41 %), hyperopia (25 %), astigmatism (25 %), and amblyopia (16 %)., Conclusions: The prevalence of strabismus, amblyopia, and hyperopia are considerably higher in the PWS population represented in the Global PWS Registry as compared to the general population. People with PWS should be screened early and regularly for vision problems., (© 2021. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Background: Few studies have compared clinical outcomes and medication use between obese and nonobese children in the pediatric intensive care unit (PICU). Objectives: The primary objective was to compare clinical outcomes including mortality, PICU length of stay (LOS), and mechanical ventilation (MV) requirement between obese and nonobese children. Secondary objectives included analysis of factors associated with these outcomes and medication use between groups. Methods: This retrospective study included children 2 to 17 years old admitted to the PICU over a 1-year time frame. Patients were categorized as obese, body mass index (BMI) ≥ 95th percentile, and nonobese (BMI < 95th percentile). Three binary regression models assessed the impact of obesity on clinical outcomes. Results : There were 834 admissions, with 22.1% involving obese children. There was no difference in mortality, MV requirement, or PICU LOS between groups. There were no associations with obesity and clinical outcomes found, but an association was noted for medication classes and receipt of continuous infusions on clinical outcomes. There was no difference noted in the median number (interquartile range [IQR]) of medications between obese and nonobese children, 8 (6-13) versus 9 (6-15), P = .38, but there was a difference in patients receiving a continuous infusion between obese and nonobese children, 24.4% versus 8.8%, P < .01. The 15 most used medications in both groups included analgesics, antimicrobials, corticosteroids, bronchodilators, and gastrointestinal agents. Conclusions : One-fifth of all admissions included obese children. Obesity was not associated with mortality, PICU LOS, and MV requirement, but the number of medication classes and continuous infusions were associated with these outcomes., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objectives: Adolescents of color are underrepresented in behavioral health research. Study aims were to quantify the amount and types of outreach effort needed to recruit young Black adolescents with type 1 diabetes and their primary caregiver into a clinical trial evaluating a parenting intervention and to determine if degree of recruitment difficulty was related to demographic, diabetes-related, or family characteristics., Methods: Data were drawn from a multi-center clinical trial. Participants (N = 155) were recruited from seven pediatric diabetes clinics. Contact log data were used to quantify both number/type of contacts prior to study enrollment as well as length of time to enrollment. Families were coded as having expedited recruitment (ER) or prolonged recruitment (PR). Baseline study data were used to compare ER and PR families on sociodemographic factors, adolescent diabetes management and health status and family characteristics such as household organization and family conflict., Results: Mean length of time to recruit was 6.6 months and mean number of recruitment contacts was 10.3. Thirty-nine percent of the sample were characterized as PR. These families required even higher levels of effort (mean of 9.9 months to recruit and 15.4 contacts). There were no significant between-group differences on any baseline variable for ER and PR families, with the exception of family income., Conclusions: Researchers need to make persistent efforts in order to successfully enroll adolescents of color and their caregivers into clinical trials. Social determinants of health such as family resources may differentiate families with prolonged recruitment within such samples., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low-anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair-haired (p < 0.001). Participants in both genetic groups receiving GH were taller (p = 0.005), had larger HCs (p = 0.005), and longer hands (p = 0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose, and genitalia., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Since the completion of the Management of Myelomeningocoele Study, maternal-fetal surgery for spina bifida has become a valid option for expecting parents. More recently, multiple groups are exploring a minimally invasive approach and recent outcomes have addressed many of the initial concerns with this approach. Based on a previously published framework, we attempt to delineate the developmental stage of the surgical techniques. Furthermore, we discuss the barriers of performing randomized controlled trials comparing two surgical interventions and suggest that data collection through registries is an alternative method to gather high-grade evidence., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Aims: The association of delay in seeking medical care to subsequent cardiac events remains unknown in patients with worsening heart failure (HF) symptoms. The aims of this study were to (i) identify factors predicting care-seeking delay and (ii) examine the impact of care-seeking delay on subsequent cardiac rehospitalization or death., Methods and Results: We studied 153 patients hospitalized with an exacerbation of HF. Potential predictors of delay including demographic, clinical, psychosocial, cognitive, and behavioural variables were collected. Patients were followed for 3 months after discharge to determine time to the first cardiac rehospitalization or death. The median delay time was 134 h (25th and 75th percentiles 49 and 364 h). Non-linear regression showed that New York Heart Association functional class III/IV (P = 0.001), worse depressive symptoms (P = 0.004), better HF knowledge (P = 0.003), and lower perceived somatic awareness (P = 0.033) were predictors of delay time from patient perception of worsening HF to subsequent hospital admission. Cox regression revealed that patients who delayed longer (more than 134 h) had a 1.93-fold higher risk of experiencing cardiac events (P = 0.044) compared to non-delayers., Conclusions: Care-seeking delay in patients with worsening HF symptoms was significantly associated with an increased risk of rehospitalization and mortality after discharge. Intervention strategies addressing functional status, psychological state, cognitive and behavioural factors are essential to reduce delay and thereby improve outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study was undertaken to explore the feasibility of assessing platelet dense granule release in response to platelet stimuli, using less than 1 mL of whole blood (WB)., Methods: Optimization of the luciferin-luciferase (LL) assay for ATP release, together with additional modifications, was applied to 1:10 diluted WB., Results: LL assay optimization using nonstirred 1:10 diluted WB resulted in dense granule ATP release in response to thrombin receptor-activating peptide (TRAP) of similar magnitude to that observed using stirred platelet-rich plasma. Stirring of the 1:10 diluted WB restored collagen-induced dense granule secretion. Addition of lyophilized, formalin-fixed platelets, together with stirring, restored dense granule secretion responsiveness to ADP. TRAP, ADP, and collagen all stimulated ATP release in 1:10 diluted WB under the optimized conditions of this study at levels close to those observed using platelet-rich plasma. Blood sample reconstitution experiments offer hope that this assay may prove robust down to WB platelet counts as low as 50 × 103/μL., Conclusions: Platelet dense granule release in response to a number of classic stimuli, including ADP, was accomplished from less than 1 mL WB with minimal specimen processing, using widely available reagents and instrumentation., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A nested longitudinal study within theAsymptomatic novel CORonavirus iNFfection study followed participants with positive nasopharyngeal swab to query for development of symptoms and assess duration of positive reverse transcription-polymerase chain reaction (RT-PCR) test results. Of the 91 participants initially testing positive, 86 participated in follow-up approximately 14 days after study enrollment; of those 86 participants, 19 (22.1%) developed at least one symptom at any time after the initial positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. The median number of days to symptom development after their initial positive test result was 6 (range 1-29 days). No participants reported a SARS-CoV-2-related hospitalization. The most frequently reported symptoms were fatigue or muscle aches (10.5%), headache (9.3%), fever (5.8%), and shortness of breath (5.8%). Of the 78 participants who submitted a nasopharyngeal swab for repeat RT-PCR testing, 17 (21.8%) remained positive at Day 14, 4 of which continued to test positive at Day 28. These findings reinforce the probable role of silent SARS-CoV-2 infections in community transmission, and that reliance on symptom development will miss a large proportion of infections. Broad testing programs not limited to individuals presenting with symptoms are critical for identifying persons with SARS-CoV-2 infection and ultimately slowing transmission., (© 2021 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Background: The purpose of this study was to identify patterns of depressive symptom trajectory and examine the associations of the symptom trajectory with caregiving burden, family function, social support, and perceived health status of caregivers of stroke survivors during the first year of caregiving after discharge from rehabilitation center., Methods: Caregivers of stroke survivors completed a survey of depressive symptoms, caregiving burden, family function, perceived availability of social support, and perceived health status at postdischarge and 1 year. Patterns of depressive symptom trajectory (ie, symptom-free, symptom relieved, symptom developed, and persistent symptom groups) were identified by grouping depressive symptoms based on 2 assessments using the Center for Epidemiologic Studies-Depression. Repeated-measures analysis of variance and multinomial logistic regression were used to examine the associations., Results: Of the 102 caregivers, 57.8% were symptom-free, 20.6% experienced persistent depressive symptoms, 11.8% relieved depressive symptoms, and 9.8% developed depressive symptoms. There were significant changes in family function (Wilks λ = 0.914, P = .038) and perceived health status (Wilks λ = 0.914, P = .033) among the groups during the first year of caregiving. The persistent symptom group reported the highest level of burden and the lowest level of family function and perceived availability of social support at both assessment times. Compared with symptom-free caregivers, caregivers with persistent depressive symptoms were 7 times more likely to have fair/poor health rather than excellent/very good health at 1 year (odds ratio, 7.149; P = .012)., Conclusion: Caregivers with persistent depressive symptoms are the most vulnerable to negative psychosocial outcomes and poor perceived health status during the first year of caregiving from discharge for stroke survivors., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

While individual and family risk factors that contribute to health disparities in children with type 1 diabetes have been identified, studies on the effects of neighborhood risk factors on glycemic control are limited, particularly in minority samples. This cross-sectional study tested associations between family conflict, neighborhood adversity and glycemic outcomes (HbA1c) in a sample of urban, young Black adolescents with type 1 diabetes(mean age = 13.4 ± 1.7), as well as whether neighborhood adversity moderated the relationship between family conflict and HbA1c. Participants (N = 128) were recruited from five pediatric diabetes clinics in two major metropolitan US cities. Diabetes-related family conflict was measured via self-report questionnaire (Diabetes Family Conflict Scale; DFCS). Neighborhood adversity was calculated at the census block group level based on US census data. Indictors of adversity were used to calculate a neighborhood adversity index (NAI) for each participant. Median family income was $25,000, suggesting a low SES sample. In multiple regression analyses, DFCS and NAI both had significant, independent effects on glycemic control (β = 0.174, P = 0.034 and β = 0.226 P = 0.013, respectively) after controlling for child age, family socioeconomic status and insulin management regimen. Tests of effects of the NAI and DFCS interaction on HbA1c found no significant moderating effects of neighborhood adversity. Even within contexts of significant socioeconomic disadvantage, variability in degree of neighborhood adversity predicts diabetes-related health outcomes in young Black adolescents with type 1 diabetes. Providers should assess social determinants of health such as neighborhood resources that may impact adolescents' ability to maintain optimal glycemic control., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Twin to twin transfusion syndrome (TTTS) is a common complication that typically presents in the second trimester of pregnancy in 10-15% of monochorionic twins due to net transfer of volume and hormonal substances from one twin to the other across vascular anastomoses on the placenta. Without recognition and treatment, TTTS is the greatest contributor to fetal loss prior to viability in 90-100% of advanced cases. Ultrasound diagnosis of monochorionicity is most reliable in the first trimester and sets the monitoring strategy for this type of twins. The diagnosis of TTTS is made by ultrasound with the findings of polyhydramnios due to volume overload and polyuria in one twin and oligohydramnios due to oliguria of the co-twin. Assessment of bladder filling as well as arterial and venous Doppler patterns are required for staging disease severity. Assessment of fetal cardiac function also provides additional insight into the fetal cardiovascular impacts of the disease as well as help identify fetuses that may require postnatal follow up. Fetoscopic laser ablation of the communicating vascular anastomoses between the twins is the standard treatment for TTTS. It aims to cure the condition by interrupting the link between their circulations and making them independent of one another. Contemporary outcome data after laser surgery suggests survival for both fetuses can be anticipated in up to 65% of cases and survival of a single fetus in up to 88% of cases. However, preterm birth remains a significant contributor to postnatal morbidity and mortality. Long term outcomes of TTTS survivors indicate that up to 11% of children may show signs of neurologic impairment. Strategies to minimize preterm birth after treatment and standardized reporting by laser centers are important considerations to improve overall outcomes and understand the long-term impacts of TTTS., Competing Interests: Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-264). The series “Fetal Surgery” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare., (2021 Translational Pediatrics. All rights reserved.)

Introduction: Fentanyl pharmacokinetic and pharmacodynamic data are limited in mechanically ventilated children. This study aimed to assess the fentanyl pharmacokinetics (PK), the sedation outcome, and the development of tolerance in children receiving fentanyl continuous infusion., Methods: This study included children admitted to the pediatric or cardiovascular intensive care unit between January 1 and October 31, 2016, who were >30 days to <18 years of age, receiving ventilatory support via endotracheal tube or tracheostomy, and receiving a fentanyl infusion. Population PK analysis was performed using a nonlinear mixed-effects model. The relationship between initial sedation outcome using State Behavioral Scale (SBS) and fentanyl exposure was assessed, and the observations consistent with tolerance were described., Results: Seventeen children, with a median age of 0.83 years (range: 0.1-12) and weight of 8.7 kg (range: 3.4-52), were included. The fentanyl PK was adequately described by a weight-based allometry model with the power of 0.75 for clearance (CL=89.8 L/hr/70 kg) and distributional CL, and 1 for volumes of distribution. In infants <6.6 months, age was an additional factor for CL (31.4 L/h/70 kg) to account for age-related maturation. Seven of twelve nonparalyzed patients achieved goal sedation, defined as >80% of SBS scores ≤0 per 24 h, on the first day of fentanyl infusion with a median plasma concentration of 1.29 ng/ml (interquartile range: 0.78-2.05). Eight of the nine tolerant patients developed tolerance within a day of reaching goal sedation., Conclusion: Different weight-based fentanyl dosing rates may be required for infants and children of different ages to achieve similar plasma concentrations. Using SBS scores may guide the dosing titration of fentanyl that resulted in plasma concentrations within the therapeutic range of 1-3 ng/ml. For those who developed tolerance to fentanyl and/or a sedative, it was noted one day after goal sedation was achieved., (© 2021 Pharmacotherapy Publications, Inc.)

Objectives: Pulmonary platelet deposition and microangiopathy are increasingly recognized components of coronavirus disease 2019 (COVID-19) infection. Thrombosis is a known component of sepsis and disseminated intravascular coagulation. We sought to compare the level of platelet deposition in the pulmonary vasculature in cases of confirmed COVID-19 infection to other lung injuries and infections., Methods: Immunohistochemistry was performed on 27 autopsy cases and 2 surgical pathology cases targeting CD61. Multiple cases of normal lung, diffuse alveolar damage, COVID-19, influenza, and bacterial and fungal infections, as well as one case of pulmonary emboli, were included. The levels of CD61 staining were compared quantitatively in the autopsy cases, and patterns of staining were described., Results: Nearly all specimens exhibited an increase in CD61 staining relative to control lung tissue. The area of CD61 staining in COVID-19 infection was higher than influenza but still comparable to many other infectious diseases. Cases of aspiration pneumonia, Staphylococcus aureus infection, and blastomycosis exhibited the highest levels of CD61 staining., Conclusions: Platelet deposition is a phenomenon common to many pulmonary insults. A spectrum of staining patterns was observed, suggestive of pathogen-specific mechanisms of platelet deposition. Further study into the mechanisms driving platelet deposition in pulmonary injuries and infections is warranted., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Adults with Prader-Willi syndrome (PWS) require less energy intake to maintain body weight than the general adult population. This, combined with their altered gastrointestinal transit time, may impact microbiota composition. The aim of the study was to determine if the fecal microbiota composition of adults with PWS differed from non-affected adults. Using usual diet/non-interventional samples, fecal microbiota composition was analyzed using 16S rRNA gene amplicon sequencing and data from adults with PWS were merged with four other adult cohorts that differed by geographical location and age. QIIME 2™ sample-classifier, machine learning algorithms were used to cross-train the samples and predict from which dataset the taxonomic profiles belong. Taxa that most distinguished between all datasets were extracted and a visual inspection of the R library PiratePlots was performed to select the taxa that differed in abundance specific to PWS., Results: Fecal microbiota composition of adults with PWS showed low Blautia and enhanced RF39 (phyla Tenericutes), Ruminococcaceae, Alistipes, Erysipelotrichacaea, Parabacteriodes and Odoribacter. Higher abundance of Tenericutes, in particular, may be a signature characteristic of the PWS microbiota although its relationship, if any, to metabolic health is not yet known.

Background: Neonates are susceptible to postoperative wound complications (POWCs), as prematurity, hypoxia, steroid use, immunosuppression, and malnutrition are all common comorbidities. Critically ill infants, dependent on parenteral nutrition, are at even further risk of developing essential fatty acid deficiency (EFAD). We hypothesized that POWC severity and EFAD were associated because of increased susceptibility to infections and impaired wound healing seen with EFAD., Methods: Institutional review board-approved (OUHSC10554), retrospective review from our academic Level IV Neonatal Intensive Care Unit. Infants aged <1 y who underwent a fascial-compromising gastrointestinal surgery from June 1, 2015, to March 15, 2019, and who had essential fatty acids (EFAs) measured ±2 wk from surgery were included. Three blinded investigators independently categorized POWC using the World Union of Wound Healing Society Surgical Wound Grading System. Infants were categorized into three groups: no POWC, POWC Grades 1 and 2 (superficial tissue nonintegrity), and POWC Grades 3 and 4 (deep tissue nonintegrity and complete dehiscence). EFA status and other possible POWC-associated factors were analyzed to determine any association with wound severity., Results: Fifty infants met the inclusion criteria. Half (25/50) had no POWC, 30% (15/50) had Grade 1 or 2, and 20% (10/50) had Grade 3 or 4. We found no association between EFAD and POWC severity., Conclusions: In our cohort, EFA status did not predict POWC severity. At this time, we cannot suggest delaying elective surgical procedures to correct EFAD as an approach to preventing POWC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This report describes the development and maintenance of a table to present an assessment of evidence for treatments used in patients with coronavirus disease 2019 (COVID-19)., Summary: AHFS Drug Information (AHFS DI) (American Society of Health-System Pharmacists, Bethesda, MD) is ASHP's evidence-based drug compendium that contains drug monographs written for pharmacists and other healthcare professionals. The professional editorial and analytical staff of pharmacists critically evaluate published evidence to develop drug monographs for AHFS DI. In response to the global COVID-19 pandemic, these skills were applied to assess emerging evidence for COVID-19-related treatments, and the information was compiled into a new resource for pharmacists and other healthcare professionals to use at the point of care. A list of therapies was developed and prioritized based on review of scientific and public discussions on the use of these therapies in patients with COVID-19; certain therapies used for supportive care and therapies that might theoretically be harmful to patients with COVID-19 also were considered for inclusion. Potential treatments were identified, and the evidence for use in patients with COVID-19 was assessed and summarized in a table format. Information presented for each therapy included the rationale for use, summaries of clinical trials or experience, trial registry numbers, and dosage regimens. Comments on safety and efficacy, including limitations of available data, were presented along with recommendations from recognized authorities. The editorial team continued to add new therapies to the table and update existing entries as new evidence emerged., Conclusion: A comprehensive table that summarized available evidence for potential treatments for patients with COVID-19 was developed. The table format enabled the drug information editorial staff to provide ongoing updates as new information emerged during the pandemic., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)