Antibiotics damage the colonic mucus barrier in a microbiota-independent manner.

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1ß.

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1ß (IL-1ß). However, the role of IL-1ß in intestinal defense against Salmonella remains unclear. Here, we show that IL-1ß production is detrimental during Salmonella infection. Mice lacking IL-1ß (IL-1ß -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1ß -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1ß induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1ß loss prevented mortality in Salmonella-infected IL-1ß -/- mice. Finally, we found that IL-1ß expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1ß signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1ß signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

Leukemic Optic Neuropathy in Pediatric Patients: A Case Series.

PURPOSE: To characterize the presentation, clinical course, and treatment of a series of children with leukemic optic neuropathy. METHODS: Patients with leukemia who were treated at a tertiary children's hospital for optic nerve infiltration were included (n = 11). Demographic information, cancer history, ophthalmologic examination findings, treatment, and outcomes were retrospectively collected. RESULTS: Mean age was 10.0 ± 4.8 years, and 63.6% were male and 36.4% were female. The most common underlying oncologic diagnosis was B-precursor acute lymphoblastic leukemia (n = 7, 63.6%). Notably, the majority presented with optic nerve infiltration during presumed remission (n = 9, 81.8%), but 2 patients (18.2%) presented with optic nerve infiltration at their initial leukemia diagnosis. Cerebrospinal fluid was positive for leukemic cells in 36.4% of patients. Magnetic resonance imaging demonstrated optic nerve enhancement and/or enlargement in only 8 patients (72.7%). In addition to other leukemia-directed treatment, 8 patients (72.7%) received emergent local radiation within 1.5 ± 1.2 days of initial ophthalmology examination. CONCLUSIONS: The largely negative cerebrospinal fluid results and variable magnetic resonance imaging findings in this study emphasize the importance of clinical context for this diagnosis. Clinicians should consider optic nerve infiltration in patients with leukemia and visual or ocular complaints, because urgent treatment is required to preserve vision and manage systemic disease. [J Pediatr Ophthalmol Strabismus. 2024;61(1):67-72.].

Neurophysiological MEG markers of cognitive impairment and performance validity in multiple sclerosis.

BACKGROUND: Suboptimal performance during neuropsychological testing frequently occurs in multiple sclerosis (MS), leading to unreliable cognitive outcomes. Neurophysiological alterations correlate with MS-related cognitive impairment, but studies have not yet considered performance validity. OBJECTIVES: To investigate neurophysiological markers of cognitive impairment in MS, while explicitly addressing performance validity. METHODS: Magnetoencephalography recordings, neuropsychological assessments, and performance validity testing were obtained from 90 MS outpatients with cognitive complaints. Spectral and resting-state functional connectivity (rsFC) properties were compared between cognitively impaired (CI), cognitively preserved (CP), and suboptimally performing (SUB) patients using regression models and permutation testing. RESULTS: CI had higher power in low-frequency bands and lower power in high bands compared to CP, indicating neuronal slowing. CI also showed lower beta power compared to SUB. Overall power spectra visually differed between CI and CP, and SUB showed overlap with both groups. CI had lower rsFC than CP and SUB patients. CP and SUB patients showed no differences. CONCLUSION: Neuronal slowing and altered rsFC can be considered cognitive markers in MS. Patients who performed suboptimally showed resemblance with patients with and without cognitive impairments, and although their overall neurophysiological profile was more similar to patients without impairments, it suggests heterogeneity regarding their pathophysiology.

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress.

Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.

Lasting Effects of Helicobacter pylori Infection on the Microbial Communities of Patients with and without Small Intestinal Bacterial Overgrowth.

Gastrointestinal (GI) microbial populations are important in maintaining normal functioning of the GI by preventing disorders. Dysbiotic microbiota may increase the likelihood of small intestinal bacterial overgrowth (SIBO), a syndrome associated with significant morbidity. We aimed to inves- tigate the microbiota populations of patients with SIBO. Patients with symptoms of SIBO were consecutively enrolled; they underwent a SIBO hydrogen breath test and stool was collected for microbiome analysis by sequencing of the 16S rRNA. Of the 55 patients recruited, 42 (76.4%) were positive for SIBO. When visualizing the bacterial ß-di- versity, a sub-cluster of patients was identified. Further examination of these patients' records re- vealed previous treatment for Helicobacter pylori (HP). Microbiome analysis of these patients demonstrated a significant decrease in ß-diversity (p-value<0.001) compared to patients without previous HP therapy. Furthermore, ß-diversity was significantly different in this subgroup, and sev- eral bacterial taxa were differentially expressed, including one from the genus Methanobrevibacter, which was reduced in patients that previously underwent HP treatment. Our findings suggest that while symptoms associated with SIBO may cause dysbiosis, there was no differentiation in fecal microbiome composition based on SIBO diagnosis. Furthermore, our results support previous observations regarding antibiotic-altered microbiota with effects extending two and three years post-treatment.

Neuro-ophthalmic manifestations of cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Neuro-ophthalmic manifestations of cancer are vast and early recognition of a serious ocular condition due to either cancer or its therapy is important for both vision preservation as well as providing valuable treatment and prognostic information regarding the underlying malignancy. This review focuses on direct and indirect effects of cancer on the eye and its adnexa, hematologic malignancy, complications of traditional and novel oncologic therapies, and paraneoplastic syndromes as they relate to the eye as these disorders can lead to potentially devastating or irreversible vision loss. METHODS: PubMed was searched primarily for the following topics: optic nerve infiltration, primary vitreoretinal lymphoma (PVRL), ocular paraneoplastic disorders, and ophthalmic complications of cancer therapeutics. Literature was selected based on historical significance and landmark studies (e.g., Cross et al. series of paraneoplastic optic neuritis patients; Chan's textbook on primary intraocular lymphoma) as well as publications published after 2000. References from select studies were additionally included. Given the sparsity of literature on many subjects, most publications were included during this time frame in our review. KEY CONTENT AND FINDINGS: There are several ophthalmic entities that the oncologist should be aware of including leukemic optic nerve infiltration, PVRL, paraneoplastic syndromes as they related to the eye, and adverse effects of therapeutics. Unfortunately, given the rarity of some of these entities [e.g., paraneoplastic optic neuropathy (PON), cancer-associated retinopathy (CAR)], diagnosis can be difficult and treatment options are often limited. CONCLUSIONS: Oncologists can develop a set of basic ophthalmology examination skills that will help to triage and manage patient eye complaints. In certain instances, oncologists have the potential to avert devastating vision loss with early recognition of neuro-ophthalmic complications.

Ontogeny of the B Cell Receptor Repertoire and Microbiome in Mice.

The immune system matures throughout childhood to achieve full functionality in protecting our bodies against threats. The immune system has a strong reciprocal symbiosis with the host bacterial population and the two systems co-develop, shaping each other. Despite their fundamental role in health physiology, the ontogeny of these systems is poorly characterized. In this study, we investigated the development of the BCR repertoire by analyzing high-throughput sequencing of their receptors in several time points of young C57BL/6J mice. In parallel, we explored the development of the gut microbiome. We discovered that the gut IgA repertoires change from birth to adolescence, including an increase in CDR3 lengths and somatic hypermutation levels. This contrasts with the spleen IgM repertoires that remain stable and distinct from the IgA repertoires in the gut. We also discovered that large clones that germinate in the gut are initially confined to a specific gut compartment, then expand to nearby compartments and later on expand also to the spleen and remain there. Finally, we explored the associations between diversity indices of the B cell repertoires and the microbiome, as well as associations between bacterial and BCR clusters. Our results shed light on the ontogeny of the adaptive immune system and the microbiome, providing a baseline for future research.

Utilizing a Professionalism Mentor to Address Sexual Harassment in Academic Ophthalmology.

Objective This study assesses a new departmental role-a professionalism mentor-who receives sexual harassment reporting, liaisons with campus resources, and organizes educational sessions. Study Design Multicenter randomized controlled survey study. Methods Academic ophthalmology departments in the United States were randomized to a professionalism mentor group ( n = 9) and a control group ( n = 7). Among both pre- and postsurveys, 605 faculty and trainee responses were received and 546 were complete. The intervention group was assigned a professionalism mentor with educational session for a 6- to 10-month period. Sexual harassment and reporting rate change over time were compared between the two groups. Results Among 546 anonymous responses, 16% experienced workplace sexual harassment during the prior 10 months. Location in the South or Midwest was a risk factor ( p < 0.001). Victims were mostly women (76%), including residents/fellows (46%) and academic attendings (49%); perpetrators included patients (35%) and academic attendings (35%). Departments with and without a professionalism mentor had stable harassment from pre- to postsurvey ( p = 0.95 comparing change). The professionalism mentor group had an increase in reporting to an authority from pre- to postsurvey (7-23%), whereas the control group had a decrease (27-12%; p = 0.07 comparing change). Most faculty and trainees in the interventional arm of this study recommended instituting a professionalism mentor with educational session (66% presurvey and 68% postsurvey), compared with educational session alone (25% presurvey and 23% postsurvey), or neither (9% presurvey and 9% postsurvey). Residency program directors in the professionalism mentor group even more strongly supported instituting both a professionalism mentor and educational program (100% presurvey and 100% postsurvey) as opposed to educational program alone (0% presurvey and 0% postsurvey) or neither (0% presurvey and 0% postsurvey). Conclusion This study identified a high sexual harassment rate in academic ophthalmology departments over a brief period. The presence of a professionalism mentor was viewed favorably and may lead to increased reporting.

Retinal disease in the neurology clinic.

PURPOSE OF REVIEW: Retinal disease can manifest with visual symptoms similar to those which result from central nervous system disorders. We provide a framework for considering retinal causes of common visual complaints presenting to a neurology clinic. RECENT FINDINGS: Technological advances have afforded quicker detection and a more thorough understanding of these retinal entities and are crucial to consider when evaluating visual complaints in the neurology clinic. SUMMARY: It is essential to maintain a working knowledge of common retinal conditions that symptomatically overlap with common neurologic conditions. Furthermore, the ophthalmoscopic exam and retinal imaging modalities can both aid in the diagnosis and workup of visual complaints and neurologic disease.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

In utero human intestine harbors unique metabolome, including bacterial metabolites.

Symbiotic microbial colonization through the establishment of the intestinal microbiome is critical to many intestinal functions, including nutrient metabolism, intestinal barrier integrity, and immune regulation. Recent studies suggest that education of intestinal immunity may be ongoing in utero. However, the drivers of this process are unknown. The microbiome and its byproducts are one potential source. Whether a fetal intestinal microbiome exists is controversial, and whether microbially derived metabolites are present in utero is unknown. Here, we aimed to determine whether bacterial DNA and microbially derived metabolites can be detected in second trimester human intestinal samples. Although we were unable to amplify bacterial DNA from fetal intestines, we report a fetal metabolomic intestinal profile with an abundance of bacterially derived and host-derived metabolites commonly produced in response to microbiota. Though we did not directly assess their source and function, we hypothesize that these microbial-associated metabolites either come from the maternal microbiome and are vertically transmitted to the fetus to prime the fetal immune system and prepare the gastrointestinal tract for postnatal microbial encounters or are produced locally by bacteria that were below our detection threshold.

Idiopathic bilateral central artery occlusion in a young woman.

Central retinal artery occlusion (CRAO) is uncommon among children and young adults. Bilateral CRAO before the age of 18 years are extremely rare. We present a case of an idiopathic bilateral CRAO in a young healthy female.

IMPACT OF RETINOPATHY SCREENINGS FOR PROSPECTIVE HEART TRANSPLANT CANDIDATES.

PURPOSE: To determine the prevalence of retinopathy among patients undergoing heart transplantation screening and to determine the impact of this finding on eligibility for transplantation. METHODS AND PATIENTS: A retrospective case series was collected to perform an institutional review of all inpatient consults for dilated eye examinations on potential heart transplant candidates over 5.5 years-from March 27, 2008 to October 10, 2014. Measured outcomes included the presence or absence of retinopathy and the effect of retinopathy, if present, on a patient's eligibility for cardiac transplantation. RESULTS: A total of 155 heart transplant candidates underwent bedside ophthalmologic examination as part of their heart transplant candidacy workup. Retinopathy was found in 16 (10%) of these patients: diabetic retinopathy in 13 (8.4%) and hypertensive retinopathy in 3 (1.9%). None of these patients were excluded from the transplant candidacy based on the presence of retinopathy. CONCLUSION: On bedside ophthalmologic examination, retinopathy is an uncommon finding among cardiac transplant candidates. Retinopathy did not preclude transplantation in these patients. We question the utility of the present system of bedside ophthalmic consultation of heart transplant candidates. This may not be an optimal allocation of provider resources. Further studies are warranted to determine an appropriate protocol for ocular evaluation of these patients.

Achieving target refraction after cataract surgery.

PURPOSE: To evaluate the difference between target and actual refraction after phacoemulsification and intraocular lens implantation at an academic teaching institution's Comprehensive Ophthalmology Service. DESIGN: Retrospective study. PARTICIPANTS: We examined 1275 eye surgeries for this study. METHODS: All consecutive cataract surgeries were included if they were performed by an attending or resident surgeon from January through December 2010. Postoperative refractions were compared with preoperative target refractions. Patients were excluded if they did not have a preoperative target refraction documented or if they did not have a recorded postoperative manifest refraction within 90 days. MAIN OUTCOME MEASURES: The main outcome measure was percentage of cases achieving a postoperative spherical equivalent ± 1.0 diopter (D) of target spherical equivalent. RESULTS: We performed 1368 cataract surgeries from January through December of 2010. Of these, 1275 (93%) had sufficient information for analysis. Of the included cases, 94% (1196 of 1275) achieved ± 1.0 D of target refraction by 90 days after cataract surgery. CONCLUSIONS: This paper establishes a new benchmark for a teaching hospital, where 94% of patients achieved within 1.0 D of target refraction after cataract surgery. The refractive outcomes after cataract surgery at this academic teaching institution were higher than average international benchmarks.