Low-risk pneumatosis intestinalis in the pediatric surgical population.

BACKGROUND: Pneumatosis intestinalis (PI, presence of air in bowel wall) develops in a variety of settings and due to a variety of insults which is then characterized by varying severity and clinical course. Anecdotally, many of these cases are benign with few clinical sequelae; however, we lack evidence-based guidelines to help guide management of such lower-risk cases. We aimed to describe the clinical entity of low-risk PI, characterize the population of children who develop this form of PI, determine if management approach or clinical outcomes differed depending on the managing physician's field of practice, and finally determine if a shortened course of NPO and antibiotics was safe in the population of children with low-risk PI. METHODS: We performed a retrospective review of all children over age 1 year treated at Children's Hospital Colorado (CHCO), between 2009 and 2019 with a diagnosis of PI who did not also have a diagnosis of cancer or history of bone marrow transplant (BMT). Data including demographic variables, clinical course, and outcomes were obtained from the electronic medical record. Low-risk criteria included no need for ICU admission, vasopressor use, or urgent surgical intervention. RESULTS: Ninety-one children were treated for their first episode of PI during the study period, 72 of whom met our low-risk criteria. Among the low-risk group, rates of complications including hemodynamic decompensation during treatment, PI recurrence, Clostridium difficile colitis, and death did not differ between those who received 3 days or less of antibiotics and those who received more than 3 days of antibiotics. Outcomes also did not differ between children cared for by surgeons or pediatricians. CONCLUSIONS: Here, we define low-risk PI as that which occurs in children over age 1 who do not have a prior diagnosis of cancer or prior BMT and who do not require ICU admission, vasopressor administration, or urgent surgical intervention. It is likely safe to treat these children with only 3 days of antibiotic therapy and NPO. LEVEL OF EVIDENCE: Level III.

Fertility concerns and outcomes in females with anorectal malformations.

PURPOSE: To assess fertility concerns and to describe pregnancy outcomes in patients with anorectal malformations (ARM). METHODS: This is an IRB approved, cross-sectional study of patients in the Adult Colorectal Research Registry who completed reproductive health surveys between November 2021 and August 2022. Patients assigned female at birth with age 18 or older and ARM were included. RESULTS: Sixty-four patients with ARM, age 18 or older, were included. Fertility concerns were reported in 26 (40.6%) patients, 11 of which had seen a fertility specialist, including four who had not yet tried to conceive. Fertility concerns were highest amongst cloaca patients who had not yet tried to conceive (37.5%). 26 (40.6%) patients had tried to conceive, of which 16 (25%) reported fertility problems, most frequently uterine abnormalities and damaged or blocked fallopian tubes. 22 (34.4%) participants were able to conceive and 18 (28.1%) had at least one live birth. Patients with ARM who had concerns of fertility, had better FertiQoL when compared to published reference scores for patients experiencing fertility issues. CONCLUSION: Providers should be aware of fertility concerns in patients with ARM. Proactive counseling with referrals to a fertility specialist should be considered in patients who desire future fertility.

Gastrointestinal quality of life and bowel function in adults born with anorectal malformation and hirschsprung disease.

PURPOSE: To assess the quality of life and disease-specific functioning of adults with anorectal malformations (ARM) or Hirschsprung disease (HD) compared to healthy reference scores. METHODS: Patients with the diagnosis of ARM or HD from the Adult Colorectal Research Registry completed the Short Form 36 Health Survey (SF-36), the Gastrointestinal Quality of Life Index (GIQoLI), and the Bowel Function Score (BFS) between October 2019 and August 2022. One-sample Wilcoxon test compared the results to reported healthy references with a significance level of < 0.05. RESULTS: The response rate was 67%. All three surveys were completed by 133 adults with a slight preponderance of males (51%). Median age was 31 years, 117 were born with ARM and 16 with HD. All subgroups had significantly lower BFS than healthy references. ARM patients scored significantly lower than the healthy reference population when assessed for GIQoL. All showed significant impairment with the mental component summary (MCS) of SF-36. Patients with a successful bowel management had significantly higher scores on all three questionnaires than those with fecal accidents. CONCLUSION: Our results emphasize the importance of a successful bowel management and its impact on the quality of life and bowel function. Long-term follow-up is recommended with attention to mental health.

What is the role of neutropenia in pediatric cancer patients with pneumatosis intestinalis?

BACKGROUND: We aimed to identify prognostic indicators in pneumatosis intestinalis (PI) in a pediatric oncology population. We hypothesized that neutropenia would be an independent risk factor for adverse outcomes, including the need for abdominal operation to treat PI and for the development of recurrent PI. METHODS: We performed a retrospective review of all patients treated for PI between 2009 and 2019 with a diagnosis of cancer or history of bone marrow transplant (BMT). RESULTS: Sixty-eight children were treated for their first episode of PI; 15 (22%) were not neutropenic at presentation; eight underwent urgent abdominal operation (12%). Patients with neutropenia were more likely to receive TPN, had a longer course of NPO, and received a longer course of antibiotics. Neutropenia at presentation was associated with a decreased risk of PI recurrence (40% vs 13%, p = 0.03). Children who required an abdominal operation were more likely to require vasopressors at diagnosis (50% vs 10%, p = 0.013). CONCLUSIONS: Among pediatric cancer patients, need for vasopressors at the time of PI is a marker of severe PI, with increased likelihood of requiring operative intervention. The presence of neutropenia is associated with lower rates of PI recurrence. LEVEL OF EVIDENCE: Level III.

A National Survey of U.S. Adolescent Sleep Duration, Timing, and Social Jetlag During the COVID-19 Pandemic.

OBJECTIVES: To assess changes in duration, timing, and social jetlag in adolescent sleep during the COVID-19 pandemic and evaluate the impact of mood, physical activity, and social interactions on sleep. STUDY DESIGN: An online survey queried adolescents' sleep before (through retrospective report) and during the initial phase of COVID-19 in May 2020. Adolescents (N = 3,494), 13-19 years old, in the United States (U.S.) answered questions about their current and retrospective (prior to COVID-19) sleep, chronotype, mood, and physical and social activities. Linear regression models were fit for time in bed, reported bed and wake times, and social jetlag during COVID-19, accounting for pre-COVID-19 values. RESULTS: Total reported time in bed (a proxy for sleep duration) increased on weekdays by an average of 1.3 ± 1.8 hours (p < .001) during COVID-19, compared to retrospective report of time in bed prior to COVID-19. During COVID-19, 81.3% of adolescents reported spending 8 hours or more in bed on weekdays compared to only 53.5% prior to COVID-19. On weekdays, bedtimes were delayed on average by 2.5 hours and wake times by 3.8 hours during COVID-19 compared to prior to COVID-19. On weekends, bedtimes were delayed on average by 1.6 hours and waketimes by 1.5 hours (all p's < 0.001). Social jetlag of >2 hours decreased to 6.3% during COVID-19 compared to 52.1% prior to COVID-19. Anxiety and depression symptoms and a decline in physical activity during COVID-19 were associated with delayed bed and wake times during COVID-19. CONCLUSIONS: During COVID-19, adolescents reported spending more time in bed, with most adolescents reporting 8 hours of sleep opportunity and more consistent sleep schedules. As schools return to in-person learning, additional research should examine how sleep schedules may change due to school start times and what lessons can be learned from changes that occurred during COVID-19 that promote favorable adolescent sleep.

Longitudinal assessment of anxiety and depression symptoms in U.S. adolescents across six months of the coronavirus pandemic.

BACKGROUND: The present study aimed to describe anxiety and depression symptoms at two timepoints during the coronavirus pandemic and evaluate demographic predictors. METHODS: U.S. high school students 13-19 years old completed a self-report online survey in May 2020 and November 2020-January 2021. The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Depression and Anxiety short forms queried depression and anxiety symptoms. RESULTS: The final sample consisted of 694 participants (87% White, 67% female, 16.2 ± 1.1 years). Nearly 40% of participants reported a pre-pandemic depression diagnosis and 49% reported a pre-pandemic anxiety diagnosis. Negative affect, defined as both moderate to severe depression and anxiety PROMIS scores, was found in ~ 45% of participants at both timepoints. Female and other gender identities and higher community distress score were associated with more depression and anxiety symptoms. Depression symptoms T-score decreased slightly (- 1.3, p-value ≤ 0.001). CONCLUSION: Adolescent mental health screening and treatment should be a priority as the pandemic continues to impact the lives of youth.

Altered Immunoglobulin Repertoire and Decreased IgA Somatic Hypermutation in the Gut during Chronic HIV-1 Infection.

Humoral immune perturbations contribute to pathogenic outcomes in persons with HIV-1 infection (PWH). Gut barrier dysfunction in PWH is associated with microbial translocation and alterations in microbial communities (dysbiosis), and IgA, the most abundant immunoglobulin (Ig) isotype in the gut, is involved in gut homeostasis by interacting with the microbiome. We determined the impact of HIV-1 infection on the antibody repertoire in the gastrointestinal tract by comparing Ig gene utilization and somatic hypermutation (SHM) in colon biopsies from PWH (n = 19) versus age and sex-matched controls (n = 13). We correlated these Ig parameters with clinical, immunological, microbiome and virological data. Gene signatures of enhanced B cell activation were accompanied by skewed frequencies of multiple Ig Variable genes in PWH. PWH showed decreased frequencies of SHM in IgA and possibly IgG, with a substantial loss of highly mutated IgA sequences. The decline in IgA SHM in PWH correlated with gut CD4+ T cell loss and inversely correlated with mucosal inflammation and microbial translocation. Diminished gut IgA SHM in PWH was driven by transversion mutations at A or T deoxynucleotides, suggesting a defect not at the AID/APOBEC3 deamination step but at later stages of IgA SHM. These results expand our understanding of humoral immune perturbations in PWH that could have important implications in understanding mucosal immune defects in individuals with chronic HIV-1 infection. IMPORTANCE The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4+ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation. To date, the consequences of microbial translocation on the mucosal humoral immune response (or vice versa) remains poorly integrated into the panoply of mucosal immune defects in PWH. We utilized next-generation sequencing approaches to profile the Ab repertoire and ascertain frequencies of somatic hypermutation in colon biopsies from antiretroviral therapy-naive PWH versus controls. Our findings identify perturbations in the Ab repertoire of PWH that could contribute to development or maintenance of dysbiosis. Moreover, IgA mutations significantly decreased in PWH and this was associated with adverse clinical outcomes. These data may provide insight into the mechanisms underlying impaired Ab-dependent gut homeostasis during chronic HIV-1 infection.

Acute vaping in a golden Syrian hamster causes inflammatory response transcriptomic changes.

E-cigarette vaping is a major aspect of nicotine consumption, especially for children and young adults. Although it is branded as a safer alternative to cigarette smoking, murine and rat models of subacute and chronic e-cigarette vaping exposure have shown many proinflammatory changes in the respiratory tract. An acute vaping exposure paradigm has not been demonstrated in the golden Syrian hamster, and the hamster is a readily available small animal model that has the unique benefit of becoming infected with and transmitting respiratory viruses, including SARS-CoV-2, without genetic alteration of the animal or virus. Using a 2-day, whole body vaping exposure protocol in male golden Syrian hamsters, we evaluated serum cotinine, bronchoalveolar lavage cells, lung, and nasal histopathology, and gene expression in the nasopharynx and lung through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Depending on the presence of nonnormality or outliers, statistical analysis was performed by ANOVA or Kruskal-Wallis tests. For tests that were statistically significant (P < 0.05), post hoc Tukey-Kramer and Dunn's tests, respectively, were performed to make pairwise comparisons between groups. In nasal tissue, RT-qPCR analysis revealed nicotine-dependent increases in gene expression associated with type 1 inflammation (CCL-5 and CXCL-10), fibrosis [transforming growth factor-ß (TGF-ß)], nicotine-independent increase oxidative stress response (SOD-2), and a nicotine-independent decrease in vasculogenesis/angiogenesis (VEGF-A). In the lung, nicotine-dependent increases in the expression of genes involved in the renin-angiotensin pathway [angiotensin-converting enzyme (ACE), ACE2], coagulation (tissue factor, Serpine-1), extracellular matrix remodeling (MMP-2, MMP-9), type 1 inflammation (IL-1ß, TNF-α, and CXCL-10), fibrosis (TGF-ß and Serpine-1), oxidative stress response (SOD-2), neutrophil extracellular traps release (ELANE), and vasculogenesis and angiogenesis (VEGF-A) were identified. To our knowledge, this is the first demonstration that the Syrian hamster is a viable model of e-cigarette vaping. In addition, this is the first report that e-cigarette vaping with nicotine can increase tissue factor gene expression in the lung. Our results show that even an acute exposure to e-cigarette vaping causes significant upregulation of mRNAs in the respiratory tract from pathways involving the renin-angiotensin system, coagulation, extracellular matrix remodeling, type 1 inflammation, fibrosis, oxidative stress response, neutrophil extracellular trap release (NETosis), vasculogenesis, and angiogenesis.

Granzyme B+ CD4 T cells accumulate in the colon during chronic HIV-1 infection.

Chronic HIV-1 infection results in the sustained disruption of gut homeostasis culminating in alterations in microbial communities (dysbiosis) and increased microbial translocation. Major questions remain on how interactions between translocating microbes and gut immune cells impact HIV-1-associated gut pathogenesis. We previously reported that in vitro exposure of human gut cells to enteric commensal bacteria upregulated the serine protease and cytotoxic marker Granzyme B (GZB) in CD4 T cells, and GZB expression was further increased in HIV-1-infected CD4 T cells. To determine if these in vitro findings extend in vivo, we evaluated the frequencies of GZB+ CD4 T cells in colon biopsies and peripheral blood of untreated, chronically infected people with HIV-1 (PWH). Colon and blood GZB+ CD4 T cells were found at significantly higher frequencies in PWH. Colon, but not blood, GZB+ CD4 T cell frequencies were associated with gut and systemic T cell activation and Prevotella species abundance. In vitro, commensal bacteria upregulated GZB more readily in gut versus blood or tonsil-derived CD4 T cells, particularly in inflammatory T helper 17 cells. Bacteria-induced GZB expression in gut CD4 T cells required the presence of accessory cells, the IL-2 pathway and in part, MHC Class II. Overall, we demonstrate that GZB+ CD4 T cells are prevalent in the colon during chronic HIV-1 infection and may emerge following interactions with translocated bacteria in an IL-2 and MHC Class II-dependent manner. Associations between GZB+ CD4 T cells, dysbiosis and T cell activation suggest that GZB+ CD4 T cells may contribute to gut HIV-1 pathogenesis.

Why Delay? Early Enteral Nutrition in Pediatric Burn Patients Improves Outcomes.

Children who sustain moderate to large surface area burns present in a hypermetabolic state with increased caloric and protein requirements. A policy was implemented at our institution in 2017 to initiate enteral nutrition (EN) in pediatric burn patients within 4 hours of admission. The authors hypothesize that early EN (initiated within 4 hours of admission) is more beneficial than late EN (initiated ≥ 4 hours from admission) for pediatric burn patients and is associated with decreased rates of pneumonia, increased calorie and protein intake, fewer feeding complications, a shorter Intensive Care Unit (ICU) length of stay (LOS), and a reduced hospital LOS. Children who sustained a total body surface area (TBSA) burn injury ≥ 10% between 2011 and 2018 were identified in a prospectively maintained burn registry at Children's Hospital Colorado. Patients were stratified into two groups for comparison: early EN and late EN. The authors identified 132 pediatric burn patients who met inclusion criteria, and most (60%) were male. Approximately half (48%) of the study patients were in the early EN group. The early EN group had lower rates of underfeeding during the first week (P = .014) and shorter ICU LOS (P = .025). Achieving and sustaining adequate nutrition in pediatric burn patients with moderate to large surface area burn injuries are critical to recovery. Early EN in pediatric burn patients is associated with decreased underfeeding and reduced ICU LOS. The authors recommend protocols to institute feeding for patients with burns ≥ 10% TBSA within 4 hours of admission at all pediatric burn centers.

Qualitative Differences Between the IFNα subtypes and IFNß Influence Chronic Mucosal HIV-1 Pathogenesis.

The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNß that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNα subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNß in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNα subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNα subtypes. Notably, IFNß induced a broader interferome than the individual IFNα subtypes. Since IFNß, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNß-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNß levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNß-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNß and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNß may drive HIV-1 pathogenesis in the gut.