Bacterial heat shock protein genes during induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

Background: Heat shock proteins (HSP) protect cancer cells. Gastrointestinal bacteria contain HSP genes and can release extracellular vesicles which act as biological shuttles. Stress from treatment may result in a microbial community with more HSP genes, which could contribute to circulating HSP levels. Methods: The authors examined the abundance of five bacterial HSP genes pre-treatment and during induction in stool sequences from 30 pediatric acute lymphoblastic leukemia patients. Results: Decreased mean HTPG counts (p = 0.0024) pre-treatment versus induction were observed. During induction, HTPG, Shannon diversity and Bacteroidetes decreased (p = 7.5e-4; 1.1e-3; 8.6e-4), while DNAK and Firmicutes increased (p = 6.9e-3; 9.2e-4). Conclusion: Understanding microbial HSP gene community changes with treatment is the first step in determining if bacterial HSPs are important to the tumor microenvironment and leukemia treatment.

Metabolome Changes With Diet-Induced Remission in Pediatric Crohn's Disease.

BACKGROUND & AIMS: The Crohn's disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN) both induce remission in pediatric CD. CDED+PEN is better tolerated and able to sustain remission. We characterized the changes in fecal metabolites induced by CDED+PEN and EEN and their relationship with remission. METHODS: A total of 216 fecal metabolites were measured in 80 fecal samples at week (W) 0, W6, and W12, of children with mild to moderate CD in a prospective randomized trial comparing CDED+PEN vs EEN. The metabolites were measured using liquid chromatography coupled to mass spectrometry. Metagenome Kyoto Encyclopedia of Genes and Genomes Orthology analysis was performed to investigate the differential functional gene abundance involved in specific metabolic pathways. Data were analyzed according to clinical outcome of remission (W6_rem), no remission (W6_nr), sustained remission (W12_sr), and nonsustained (W12_nsr) remission. RESULTS: A decrease in kynurenine and succinate synthesis and an increase in N-α-acetyl-arginine characterized CDED+PEN W6_rem, whereas changes in lipid metabolism characterized EEN W6_rem, especially reflected by lower levels in ceramides. In contrast, fecal metabolites in EEN W6_nr were comparable to baseline/W0 samples. CDED+PEN W6_rem children maintained metabolome changes through W12. In contrast, W12_nsr children in the EEN group, who resumed a free diet after week 6, did not. The metabolome of CDED+PEN differed from EEN in the purine, pyrimidine, and sphingolipid pathways. A significant differential abundance in several genes involved in these pathways was detected. CONCLUSION: CDED+PEN- and EEN-induced remission are associated with significant changes in inflammatory bowel disease-associated metabolites such as kynurenine, ceramides, amino acids, and others. Sustained remission with CDED+PEN, but not EEN, was associated with persistent changes in metabolites. CLINICALTRIALS: gov, Number NCT01728870.

The impact of the host intestinal microbiome on carcinogenesis and the response to chemotherapy.

The microbiome consists of all microbes present on and within the human body. An unbalanced, or 'dysbiotic' intestinal microbiome is associated with inflammatory bowel disease, diabetes and some cancer types. Drug treatment can alter the intestinal microbiome composition. Additionally, some chemotherapeutics interact with microbiome components, leading to changes in drug safety and/or efficacy. The intestinal microbiome is a modifiable target, using strategies such as antibiotic treatment, fecal microbial transplantation or probiotic administration. Understanding the impact of the microbiome on the safety and efficacy of cancer treatment may result in improved treatment outcome. The present review seeks to summarize relevant research and look to the future of cancer treatment, where the intestinal microbiome is recognized as an actionable treatment target.

Lay abstract The microbiome describes all of the microorganisms (including bacteria, viruses and fungi) that are normally present on and inside the human body. Some diseases, including cancer, can be caused or worsened by an 'unbalanced' or 'unhealthy' gut microbiome. Some drugs that are given to people who have cancer can change the microbiome. Importantly, components of the gut microbiome can also change how a cancer drug will work in someone. We can change the microbiome in certain ways, like by giving someone antibiotics. Understanding how the microbiome influences the way anticancer drugs work is important because it could help us understand how to make cancer treatment safer and more effective. This review article summarizes available research on the impact of the microbiome on cancer treatment.

Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. METHODS: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. RESULTS: Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68-115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34-10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. CONCLUSION: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

Improved inference of site-specific positive selection under a generalized parametric codon model when there are multinucleotide mutations and multiple nonsynonymous rates.

BACKGROUND: An excess of nonsynonymous substitutions, over neutrality, is considered evidence of positive Darwinian selection. Inference for proteins often relies on estimation of the nonsynonymous to synonymous ratio (ω = dN/dS) within a codon model. However, to ease computational difficulties, ω is typically estimated assuming an idealized substitution process where (i) all nonsynonymous substitutions have the same rate (regardless of impact on organism fitness) and (ii) instantaneous double and triple (DT) nucleotide mutations have zero probability (despite evidence that they can occur). It follows that estimates of ω represent an imperfect summary of the intensity of selection, and that tests based on the ω > 1 threshold could be negatively impacted. RESULTS: We developed a general-purpose parametric (GPP) modelling framework for codons. This novel approach allows specification of all possible instantaneous codon substitutions, including multiple nonsynonymous rates (MNRs) and instantaneous DT nucleotide changes. Existing codon models are specified as special cases of the GPP model. We use GPP models to implement likelihood ratio tests for ω > 1 that accommodate MNRs and DT mutations. Through both simulation and real data analysis, we find that failure to model MNRs and DT mutations reduces power in some cases and inflates false positives in others. False positives under traditional M2a and M8 models were very sensitive to DT changes. This was exacerbated by the choice of frequency parameterization (GY vs. MG), with rates sometimes > 90% under MG. By including MNRs and DT mutations, accuracy and power was greatly improved under the GPP framework. However, we also find that over-parameterized models can perform less well, and this can contribute to degraded performance of LRTs. CONCLUSIONS: We suggest GPP models should be used alongside traditional codon models. Further, all codon models should be deployed within an experimental design that includes (i) assessing robustness to model assumptions, and (ii) investigation of non-standard behaviour of MLEs. As the goal of every analysis is to avoid false conclusions, more work is needed on model selection methods that consider both the increase in fit engendered by a model parameter and the degree to which that parameter is affected by un-modelled evolutionary processes.

A Robust ANOVA Approach to Estimating a Phylogeny from Multiple Genes.

In this article, we address the issue of estimating the phylogenetic tree based on sequence data across a set of genes. Recognizing that the individual gene trees may not all share the same evolutionary history due to lateral gene transfer or differences in rates of evolution for instance, we develop a robust algorithm for tree estimation based on pairwise distances computed gene by gene. A robust analysis of variance (ANOVA) is used to combine the distances across all genes giving a summary distance for all genes. The tree can then be constructed using any distance method such as BIONJ. Using the weights from the robust ANOVA, we can then identify the outlying genes and taxa for further examination. As the method is based on distances, computation is much faster than maximum likelihood on the concatenated genes. It is also very straightforward to carry out a bootstrap analysis using standard methods for regression models. We test our methods in a comprehensive simulation study and apply them to three data sets recently analyzed in the literature.

Seasonal assemblages and short-lived blooms in coastal north-west Atlantic Ocean bacterioplankton.

Temperate oceans are inhabited by diverse and temporally dynamic bacterioplankton communities. However, the role of the environment, resources and phytoplankton dynamics in shaping marine bacterioplankton communities at different time scales remains poorly constrained. Here, we combined time series observations (time scales of weeks to years) with molecular analysis of formalin-fixed samples from a coastal inlet of the north-west Atlantic Ocean to show that a combination of temperature, nitrate, small phytoplankton and Synechococcus abundances are best predictors for annual bacterioplankton community variability, explaining 38% of the variation. Using Bayesian mixed modelling, we identified assemblages of co-occurring bacteria associated with different seasonal periods, including the spring bloom (e.g. Polaribacter, Ulvibacter, Alteromonadales and ARCTIC96B-16) and the autumn bloom (e.g. OM42, OM25, OM38 and Arctic96A-1 clades of Alphaproteobacteria, and SAR86, OM60 and SAR92 clades of Gammaproteobacteria). Community variability over spring bloom development was best explained by silicate (32%)--an indication of rapid succession of bacterial taxa in response to diatom biomass--while nanophytoplankton as well as picophytoplankton abundance explained community variability (16-27%) over the transition into and out of the autumn bloom. Moreover, the seasonal structure was punctuated with short-lived blooms of rare bacteria including the KSA-1 clade of Sphingobacteria related to aromatic hydrocarbon-degrading bacteria.

BiomeNet: a Bayesian model for inference of metabolic divergence among microbial communities.

Metagenomics yields enormous numbers of microbial sequences that can be assigned a metabolic function. Using such data to infer community-level metabolic divergence is hindered by the lack of a suitable statistical framework. Here, we describe a novel hierarchical Bayesian model, called BiomeNet (Bayesian inference of metabolic networks), for inferring differential prevalence of metabolic subnetworks among microbial communities. To infer the structure of community-level metabolic interactions, BiomeNet applies a mixed-membership modelling framework to enzyme abundance information. The basic idea is that the mixture components of the model (metabolic reactions, subnetworks, and networks) are shared across all groups (microbiome samples), but the mixture proportions vary from group to group. Through this framework, the model can capture nested structures within the data. BiomeNet is unique in modeling each metagenome sample as a mixture of complex metabolic systems (metabosystems). The metabosystems are composed of mixtures of tightly connected metabolic subnetworks. BiomeNet differs from other unsupervised methods by allowing researchers to discriminate groups of samples through the metabolic patterns it discovers in the data, and by providing a framework for interpreting them. We describe a collapsed Gibbs sampler for inference of the mixture weights under BiomeNet, and we use simulation to validate the inference algorithm. Application of BiomeNet to human gut metagenomes revealed a metabosystem with greater prevalence among inflammatory bowel disease (IBD) patients. Based on the discriminatory subnetworks for this metabosystem, we inferred that the community is likely to be closely associated with the human gut epithelium, resistant to dietary interventions, and interfere with human uptake of an antioxidant connected to IBD. Because this metabosystem has a greater capacity to exploit host-associated glycans, we speculate that IBD-associated communities might arise from opportunist growth of bacteria that can circumvent the host's nutrient-based mechanism for bacterial partner selection.

The Challenge of Clinical Research and Suicidality: Participant Feedback on a Safety Protocol.

Objective: Clinical studies of depression have historically excluded participants with suicidal ideation. Research participant safety protocols are critical to allow for the much-needed study of suicide risk. This report summarizes participant feedback about the safety protocol used in a national, remote study of perinatal women with suicidal ideation.Methods: Upon completion of the study, participants who had triggered the suicidality safety protocol during the study were invited to complete a brief survey with questions about their experiences with the protocol. The survey included 4 Likert-scale questions and 1 open text question where participants could provide feedback, suggestions, and comments to the research team. Participant feedback survey data were collected between October 2021 and April 2022, and this research was funded by the National Institute of Mental Health.Results: Of the 45 participants enrolled in the UPWARD-S study, 16 triggered the safety protocol. All eligible participants (N = 16) completed the survey. Among respondents, most were at least neutral to very comfortable with the call from the study psychiatrist (75% [n = 12]) and reported that the call had a "positive impact" on their well-being (69% [n = 11]). After the call with the study psychiatrist, 50% of participants (n = 8) reported that they increased engagement with treatment for depression, and the other 50% reported no change in treatment. We also report on themes from the qualitative feedback regarding suggestions of how to modify or improve the safety protocol.Conclusions: Learning from the experiences of research participants will provide unique insight into satisfaction with, and impact of, the implemented suicidality safety protocol. Findings from this study could inform the refinement and implementation of safety protocols used in depression studies as well as future research on the impact of such protocols.

The gastrointestinal antibiotic resistome in pediatric leukemia and lymphoma patients.

Introduction: Most children with leukemia and lymphoma experience febrile neutropenia. These are treated with empiric antibiotics that include ß-lactams and/or vancomycin. These are often administered for extended periods, and the effect on the resistome is unknown. Methods: We examined the impact of repeated courses and duration of antibiotic use on the resistome of 39 pediatric leukemia and lymphoma patients. Shotgun metagenome sequences from 127 stool samples of pediatric oncology patients were examined for abundance of antibiotic resistance genes (ARGs) in each sample. Abundances were grouped by repeated courses (no antibiotics, 1-2 courses, 3+ courses) and duration (no use, short duration, long and/or mixed durationg) of ß-lactams, vancomycin and "any antibiotic" use. We assessed changes in both taxonomic composition and prevalence of ARGs among these groups. Results: We found that Bacteroidetes taxa and ß-lactam resistance genes decreased, while opportunistic Firmicutes and Proteobacteria taxa, along with multidrug resistance genes, increased with repeated courses and/or duration of antibiotics. Efflux pump related genes predominated (92%) among the increased multidrug genes. While we found ß-lactam ARGs present in the resistome, the taxa that appear to contain them were kept in check by antibiotic treatment. Multidrug ARGs, mostly efflux pumps or regulators of efflux pump genes, were associated with opportunistic pathogens, and both increased in the resistome with repeated antibiotic use and/or increased duration. Conclusions: Given the strong association between opportunistic pathogens and multidrug-related efflux pumps, we suggest that drug efflux capacity might allow the opportunistic pathogens to persist or increase despite repeated courses and/or duration of antibiotics. While drug efflux is the most direct explanation, other mechanisms that enhance the ability of opportunistic pathogens to handle environmental stress, or other aspects of the treatment environment, could also contribute to their ability to flourish within the gut during treatment. Persistence of opportunistic pathogens in an already dysbiotic and weakened gastrointestinal tract could increase the likelihood of life-threatening blood borne infections. Of the 39 patients, 59% experienced at least one gastrointestinal or blood infection and 60% of bacteremia's were bacteria found in stool samples. Antimicrobial stewardship and appropriate use and duration of antibiotics could help reduce morbidity and mortality in this vulnerable population.

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

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

Successful Dietary Therapy in Paediatric Crohn's Disease is Associated with Shifts in Bacterial Dysbiosis and Inflammatory Metabotype Towards Healthy Controls.

BACKGROUND AND AIMS: Nutritional therapy with the Crohn's Disease Exclusion Diet + Partial Enteral Nutrition [CDED+PEN] or Exclusive Enteral Nutrition [EEN] induces remission and reduces inflammation in mild-to-moderate paediatric Crohn's disease [CD]. We aimed to assess if reaching remission with nutritional therapy is mediated by correcting compositional or functional dysbiosis. METHODS: We assessed metagenome sequences, short chain fatty acids [SCFA] and bile acids [BA] in 54 paediatric CD patients reaching remission after nutritional therapy [with CDED + PEN or EEN] [NCT01728870], compared to 26 paediatric healthy controls. RESULTS: Successful dietary therapy decreased the relative abundance of Proteobacteria and increased Firmicutes towards healthy controls. CD patients possessed a mixture of two metabotypes [M1 and M2], whereas all healthy controls had metabotype M1. M1 was characterised by high Bacteroidetes and Firmicutes, low Proteobacteria, and higher SCFA synthesis pathways, and M2 was associated with high Proteobacteria and genes involved in SCFA degradation. M1 contribution increased during diet: 48%, 63%, up to 74% [Weeks 0, 6, 12, respectively.]. By Week 12, genera from Proteobacteria reached relative abundance levels of healthy controls with the exception of E. coli. Despite an increase in SCFA synthesis pathways, remission was not associated with increased SCFAs. Primary BA decreased with EEN but not with CDED+PEN, and secondary BA did not change during diet. CONCLUSION: Successful dietary therapy induced correction of both compositional and functional dysbiosis. However, 12 weeks of diet was not enough to achieve complete correction of dysbiosis. Our data suggests that composition and metabotype are important and change quickly during the early clinical response to dietary intervention. Correction of dysbiosis may therefore be an important future treatment goal for CD.

Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense.

Due to decreased immunity, both antibiotics and antifungals are regularly used in pediatric hematologic-cancer patients as a means to prevent severe infections and febrile neutropenia. The general effect of antibiotics on the human gut microbiome is profound, yielding decreased diversity and changes in community structure. However, the specific effect on pediatric oncology patients is not well-studied. The effect of antifungal use is even less understood, having been studied only in mouse models. Because the composition of the gut microbiome is associated with regulation of hematopoiesis, immune function and gastrointestinal integrity, changes within the patient gut can have implications for the clinical management of hematologic malignancies. The pediatric population is particularly challenging because the composition of the microbiome is age dependent, with some of the most pronounced changes occurring in the first three years of life. We investigated how antibiotic and antifungal use shapes the taxonomic composition of the stool microbiome in pediatric patients with leukemia and lymphoma, as inferred from both 16S rRNA and metagenome data. Associations with age, antibiotic use and antifungal use were investigated using multiple analysis methods. In addition, multivariable differential abundance was used to identify and assess specific taxa that were associated with multiple variables. Both antibiotics and antifungals were linked to a general decline in diversity in stool samples, which included a decrease in relative abundance in butyrate producers that play a critical role in host gut physiology (e.g., Faecalibacterium, Anaerostipes, Dorea, Blautia),. Furthermore, antifungal use was associated with a significant increase in relative abundance of opportunistic pathogens. Collectively, these findings have important implications for the treatment of leukemia and lymphoma patients. Butyrate is important for gastrointestinal integrity; it inhibits inflammation, reinforces colonic defense, mucosal immunity. and decreases oxidative stress. The routine use of broad-spectrum anti-infectives in pediatric oncology patients could simultaneously contribute to a decline in gastrointestinal integrity and colonic defense while promoting increases in opportunistic pathogens within the patient gut. Because the gut microbiome has been linked to both short-term clinical outcomes, and longer-lasting health effects, systematic characterization of the gut microbiome in pediatric patients during, and beyond, treatment is warranted.

Gut bacterial gene changes following pegaspargase treatment in pediatric patients with acute lymphoblastic leukemia.

Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene (iaaA) with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.

Investigating the gut microbial community and genes in children with differing levels of change in serum asparaginase activity during pegaspargase treatment for acute lymphoblastic leukemia.

Asparaginase (ASNase) is an effective treatment of pediatric acute lymphoblastic leukemia (ALL). Changes in ASNase activity may lead to suboptimal treatment and poorer outcomes. The gut microbiome produces metabolites that could impact ASNase therapy, however, remains uninvestigated. We examined gut-microbial community and microbial-ASNase and asparagine synthetase (ASNS) genes using 16SrRNA and metagenomic sequence data from stool samples of pediatric ALL patients. Comparing ASNase activity between consecutive ASNase-doses, we found microbial communities differed between decreased- and increased-activity samples. Escherichia predominated in the decreased-activity community while Bacteroides and Streptococcus predominated in the increased-activity community. In addition microbial ASNS was significantly (p=.004) negatively correlated with change in serum ASNase activity. These preliminary findings suggest microbial communities prior to treatment could affect serum ASNase levels, although the mechanism is unknown. Replication in an independent cohort is needed, and future research on manipulation of these communities and genes could prove useful in optimizing ASNase therapy.

Reconciling ecological and genomic divergence among lineages of listeria under an "extended mosaic genome concept".

There is growing evidence for a discontinuity between genomic and ecological divergence in several groups of bacteria. This evidence is difficult to reconcile with the traditional concept that ecologically divergent species maintain a cohesive gene pool isolated from other gene pools by barriers to homologous recombination (HR). There have been several innovative models of bacterial divergence that permit such discontinuity; we refer to these, collectively, as "mosaic genome concepts" (MGCs). These concepts remain a point of contention. Here, we undertake an investigation among ecologically divergent lineages of genus Listeria, and report our assessment of both niche-specific selection pressure and HR in their core genome. We find evidence of a mosaic Listeria core genome. Some core genes appear to have been free to recombine across ecologically divergent lineages or across named species. In contrast, other core genes have histories consistent with the expected organism relationships and have evolved under niche-specific selective pressures. The products of some of those genes can even be linked to metabolic phenotypes with ecological significance. This finding indicates a potentially strong connection between ecological divergence and core-genome evolution, even among lineages that also experience frequent recombination. Based on these findings, we propose an expanded role for natural selection in core-genome evolution under the MGC.

Neurosurgery Resident Wellness and Recovery from Burnout: A 39-Year Single-Institution Experience.

OBJECTIVE: Physician burnout in neurosurgery is highly prevalent and occurs most severely during residency. Although earlier assessments have identified stressors contributing to neurosurgery resident burnout, recovery interventions have not been studied extensively. We aimed to characterize burnout patterns and factors contributing to recovery through a single-institution assessment of neurosurgery residents across 4 decades. METHODS: We administered a 59-item questionnaire to all living current and former residents of a large neurosurgical training institution (n = 96). Respondents indicated the timeline of burnout or hardship during residency and evaluated burnout stressors and recovery factors through a 5-point Likert scale and free-text response. RESULTS: The survey response rate was 67% (64 of 96). The overall self-reported burnout rate was 30% (19 of 64). Recent trainees were significantly more likely to report burnout (P < 0.05). Postgraduate year 2 was cited by 66% of respondents as the onset of burnout or hardship. The most common stressors included work-life imbalance (55%) and imbalance of resident duties (33%). The highest-impact recovery factors were end of a rotation or postgraduate year (80%), increased sleep (48%), and meaningful relationships with colleagues (42%). Institution-specific factors, such as outdoor activities (52%) and intraprogram social events (34%), were also influential in recovery. In free-text responses, respondents identified a strong sense of mission in neurosurgical training as a central driver of recovery to wellness. CONCLUSIONS: Institutional support structures promoting mentorship and camaraderie are actionable methods to encourage resident burnout recovery. This study serves as a model for other programs to identify their "critical periods" of burnout and effective wellness interventions.

The relationship between fecal bile acids and microbiome community structure in pediatric Crohn's disease.

Gut microbiome community structure is associated with Crohn's disease (CD) development and response to therapy. Bile acids (BAs) play a central role in modulating intestinal immune responses, and changes in gut bacterial communities can profoundly alter the intestinal BA pool. The liver synthesizes and conjugates primary bile acids (priBAs) that are then deconjugated, epimerized, and dehydroxylated by gut bacteria to produce secondary bile acids (secBAs). We investigated the relationship between the gut microbiome and the fecal BA pool in stool samples obtained from a well-characterized cohort of pediatric CD patients undergoing nutritional therapy to induce disease remission. We found that fecal BA composition was altered in a sub-group of CD patients who did not sustain remission. The microbial community structures associated with priBA and secBA-dominant profiles were distinct. In addition, the fecal BA concentrations were correlated with the abundance of distinct bacterial taxonomic groups. Finally, priBA dominant samples were associated with community-level decreases in enzymes for dehydroxylation but not deconjugation.

Subclavian Artery to Internal Carotid Artery Interpositional Bypass for Carotid Artery Occlusion: Technical Case Report.

BACKGROUND AND IMPORTANCE: Conventional microsurgical treatment for symptomatic internal carotid artery (ICA) occlusion is revascularization with superficial temporal artery (STA) to middle cerebral artery bypass. However, in rare cases where the common carotid artery, external carotid artery (ECA), or both are also occluded, other microsurgical treatment options must be considered. CLINICAL PRESENTATION: We present the case of a 52-yr-old woman with common carotid artery occlusion and weak ICA flow from collateral connections between the vertebral artery, occipital artery, and ECA. She had ischemic symptoms and a history of stroke. The patient's STA was unsuitable as a donor vessel due to its small caliber and poor flow, and we instead performed an interpositional bypass from the subclavian artery to the ICA using a radial artery graft. CONCLUSION: This case illustrates the successful use of the subclavian artery to ICA bypass technique with an interpositional radial artery graft. The surgical anatomy of the subclavian arteries is reviewed, and the technical details of subclavian artery to radial artery graft to ICA interpositional bypass are presented.

Bacterial Taxa and Functions Are Predictive of Sustained Remission Following Exclusive Enteral Nutrition in Pediatric Crohn's Disease.

BACKGROUND: The gut microbiome is extensively involved in induction of remission in pediatric Crohn's disease (CD) patients by exclusive enteral nutrition (EEN). In this follow-up study of pediatric CD patients undergoing treatment with EEN, we employ machine learning models trained on baseline gut microbiome data to distinguish patients who achieved and sustained remission (SR) from those who did not achieve remission nor relapse (non-SR) by 24 weeks. METHODS: A total of 139 fecal samples were obtained from 22 patients (8-15 years of age) for up to 96 weeks. Gut microbiome taxonomy was assessed by 16S rRNA gene sequencing, and functional capacity was assessed by metagenomic sequencing. We used standard metrics of diversity and taxonomy to quantify differences between SR and non-SR patients and to associate gut microbial shifts with fecal calprotectin (FCP), and disease severity as defined by weighted Pediatric Crohn's Disease Activity Index. We used microbial data sets in addition to clinical metadata in random forests (RFs) models to classify treatment response and predict FCP levels. RESULTS: Microbial diversity did not change after EEN, but species richness was lower in low-FCP samples (<250 µg/g). An RF model using microbial abundances, species richness, and Paris disease classification was the best at classifying treatment response (area under the curve [AUC] = 0.9). KEGG Pathways also significantly classified treatment response with the addition of the same clinical data (AUC = 0.8). Top features of the RF model are consistent with previously identified IBD taxa, such as Ruminococcaceae and Ruminococcus gnavus. CONCLUSIONS: Our machine learning approach is able to distinguish SR and non-SR samples using baseline microbiome and clinical data.