Intersection of the microbiome and immune metabolism in lupus.

Systemic lupus erythematosus is a complex autoimmune disease resulting from a dysregulation of the immune system that involves gut dysbiosis and an altered host cellular metabolism. This review highlights novel insights and expands on the interactions between the gut microbiome and the host immune metabolism in lupus. Pathobionts, invasive pathogens, and even commensal microbes, when in dysbiosis, can all trigger and modulate immune responses through metabolic reprogramming. Changes in the microbiota's global composition or individual taxa may trigger a cascade of metabolic changes in immune cells that may, in turn, reprogram their functions. Factors contributing to dysbiosis include changes in intestinal hypoxia, competition for glucose, and limited availability of essential nutrients, such as tryptophan and metal ions, all of which can be driven by host metabolism changes. Conversely, the accumulation of some host metabolites, such as itaconate, succinate, and free fatty acids, could further influence the microbial composition and immune responses. Overall, mounting evidence supports a bidirectional relationship between host immunometabolism and the microbiota in lupus pathogenesis.

Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation.

Tryptophan modulates disease activity and the composition of microbiota in the B6.Sle1.Sle2.Sle3 (TC) mouse model of lupus. To directly test the effect of tryptophan on the gut microbiome, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated non-autoimmune B6 mice that were fed with a high or low tryptophan diet. The recipient mice with TC microbiota and high tryptophan diet had higher levels of immune activation, autoantibody production and intestinal inflammation. A bloom of Ruminococcus gnavus (Rg), a bacterium associated with disease flares in lupus patients, only emerged in the recipients of TC microbiota fed with high tryptophan. Rg depletion in TC mice decreased autoantibody production and increased the frequency of regulatory T cells. Conversely, TC mice colonized with Rg showed higher autoimmune activation. Overall, these results suggest that the interplay of genetic and tryptophan can influence the pathogenesis of lupus through the gut microbiota.

Immune-mediated resolution of a herniated lumbar disc prolapse aided by motor control exercises-a case report.

Low back pain is the global leading cause of disability. Herniated intervertebral discs are a common cause of lower back pain. The natural history of the herniated intervertebral disc is that it can resorb spontaneously through an immune-mediated mechanism. Despite this favourable natural history, there is an increasing reliance on surgical intervention. A 64-year-old presented with a left L3/4 disc prolapse. With reassurance, simple analgesics, and motor control exercises, the MRI scan confirmed the complete resolution of the disc prolapse within 3 months. Patients with disc prolapses should be reassured that disc prolapses will naturally resolve and advised to remain active. Surgical intervention should only be considered with the presence of red flags, progressive neurology, or when clear evidence exists that all non-interventional techniques have been exhausted. With such a favourable natural history, caution should be exercised before surgical intervention is recommended.

TLR7/TLR8 activation and susceptibility genes synergize to breach gut barrier in a mouse model of lupus.

Background: Mounting evidence suggests that increased gut permeability, or leaky gut, and the resulting translocation of pathobionts or their metabolites contributes to the pathogenesis of Systemic Lupus Erythematosus. However, the mechanisms underlying the induction of gut leakage remain unclear. In this study, we examined the effect of a treatment with a TLR7/8 agonist in the B6.Sle1.Sle2.Sle3 triple congenic (TC) mouse, a spontaneous mouse model of lupus without gut leakage. Materials and methods: Lupus-prone mice (TC), TC.Rag1-/- mice that lack B and T cells, and congenic B6 healthy controls were treated with R848. Gut barrier integrity was assessed by measuring FITC-dextran in the serum following oral gavage. Claudin-1 and PECAM1 expression as well as the extent of CD45+ immune cells, B220+ B cells, CD3+ T cells and CD11b+ myeloid cells were measured in the ileum by immunofluorescence. NKp46+ cells were measured in the ileum and colon by immunofluorescence. Immune cells in the ileum were also analyzed by flow cytometry. Results: R848 decreased gut barrier integrity in TC but not in congenic control B6 mice. Immunofluorescence staining of the ileum showed a reduced expression of the tight junction protein Claudin-1, endothelial cell tight junction PECAM1, as well as an increased infiltration of immune cells, including B cells and CD11b+ cells, in R848-treated TC as compared to untreated control mice. However, NKp46+ cells which play critical role in maintaining gut barrier integrity, had a lower frequency in treated TC mice. Flow cytometry showed an increased frequency of plasma cells, dendritic cells and macrophages along with a decreased frequency of NK cells in R848 treated TC mice lamina propria. In addition, we showed that the R848 treatment did not induce gut leakage in TC.Rag1-/- mice that lack mature T and B cells. Conclusions: These results demonstrate that TLR7/8 activation induces a leaky gut in lupus-prone mice, which is mediated by adaptive immune responses. TLR7/8 activation is however not sufficient to breach gut barrier integrity in non-autoimmune mice.

Patient understanding of pharmacogenomic test results in clinical care.

OBJECTIVE: Previous research has not objectively assessed patients' comprehension of their pharmacogenomic test results. In this study we assessed understanding of patients who had undergone cytochrome P450 2C19 (CYP2C19) pharmacogenomic testing. METHODS: 31 semi-structured interviews with patients who underwent CYP2C19 testing after cardiac catheterization and had been sent a brochure, letter, and wallet card explaining their results. Answers to Likert and binary questions were summarized with descriptive statistics. Qualitative data were analyzed using a grounded theory approach, with particular focus on categorization. RESULTS: No participants knew the name of the gene tested or their metabolizer status. Seven participants (23%) knew whether the testing identified any medications that would have lower effectiveness or increased adverse effects for them at standard doses ("Adequate Understanding"). Four participants (13%) read their results from the letter or wallet card they received but had no independent understanding ("Reliant on Written Materials"). Ten participants remembered receiving the written materials (32%). CONCLUSION: A majority of participants who had undergone CYP2C19 PGx testing did not understand their results at even a minimal level and would be unable to communicate them to future providers. PRACTICE IMPLICATIONS: Further research is necessary to improve patient understanding of PGx testing and their results, potentially through improving patient-provider communication.

Biobank Participants' Attitudes toward Requiring Understanding for Biobank Consent.

Biobank participants often do not understand the information they are provided during the informed consent process. Ethicists and other stakeholders have disagreed, however, on the appropriate response to these failures in understanding. This paper describes an attempt to address this issue by conducting knowledge tests with 22 recent biobank enrollees, followed by in-depth, semistructured interviews about the goal of understanding in biobank consent. The interviews revealed that while biobank enrollees thought the information on the knowledge test was important, they did not think that performance on the test should affect whether individuals are permitted to enroll in a biobank. Three main themes emerged from the interviews: helping others by contributing to research is more important than understanding consent forms, less understanding is required because biobank-based research is low risk, and only a small amount of information in the consent form is really essential. These perspectives should be considered in discussing the ethics and governance of biobank consent processes.

The complete mitochondrial genome of the strawberry aphid Chaetosiphon fragaefolii Cockerell, 1901 (Hemiptera: Aphididae) from California, USA.

The aphid Chaetosiphon fragaefolii Cockerell, 1901 is an agricultural pest and known vector of strawberry viruses. To better understand its biology and systematics, we performed a genomic analysis on C. fragaefolii collected from Quinalt strawberry plants from Pacific Grove, Monterey county, California, USA using Oxford Nanopore and Illumina sequencing. The resulting data were used to assemble the aphids complete mitogenome. The mitogenome of C. fragaefolii is 16,108 bp in length and contains 2 rRNA, 13 protein-coding, and 22 tRNA genes (GenBank accession number LC590896). The mitogenome is similar in content and organization to other Aphididae. Phylogenetic analysis of the C. fragaefolii mitogenome resolved it in a fully supported clade in the tribe Macrosiphini. Analysis of the cox1 barcode sequence of C. fragaefolii from California found exact and nearly identical sequences to C. fragaefolii and Chaetosiphon thomasi Hille Ris Lambers, 1953, suggesting the two species are conspecific.

Lethal Effects of a Silica Gel + Pyrethrins (Drione) on Amblyomma americanum (Ixodida: Ixodidae) Larvae and Nymphs.

Ixodids (hard ticks) ingest blood from host animals, and they can transmit pathogenic organisms that induce medical and veterinary diseases. As resistance to synthetic conventional acaricides becomes more common, alternative tactics are coming under heightened scrutiny. Laboratory bioassays were used to assess the efficacy of CimeXa, a commercially available silica gel desiccant dust product, and Drione, a commercial product containing silica gel + pyrethrins and a synergist, piperonyl butoxide, against lone star tick, Amblyomma americanum (L.) (Ixodida: Ixodidae), larvae and nymphs. Both life stages were completely killed by CimeXa by 24 h, and Drione caused total larval mortality within 1 h when they were briefly immersed in the dusts and when they crawled across dust-treated substrate; nymphs were completely killed by 4 h after the same kinds of exposure. Mortality of A. americanum larvae and nymphs occurred after the pests crawled across dried aqueous suspensions of the products, but this was not as efficient and fast-acting as when the immature life stages were exposed to dry dusts. Further, dried aqueous suspensions of Drione were not substantially more lethal than dried aqueous suspensions of CimeXa. CimeXa and Drione will provide prophylactic control on vegetation and animals for as long as the silica gel remains without being physically removed. Both of the dust-based products will likely also be effective against other problematic ixodid species. Advantages and disadvantages, and potential uses, of desiccant dust-based acaricides are discussed.

Evaluating Clinical Outcomes for Determining the Optimal Delay to Skin Incision under WALANT: A Prospective Series of 34 Patients from a Low-Resource Tertiary Setting.

BACKGROUND: Additional studies on clinical outcomes to determine the optimal time delay from injection of local anesthesia to skin incision for WALANT surgeries are needed. The authors aimed to propose the optimal time delay from local injection to skin incision for WALANT surgeries of the hand and wrist by analyzing intraoperative blood loss, postoperative pain scores, and complication rates. METHODS: Thirty-four patients were consecutively recruited and allocated by either 7-min or 30-min delay for skin incision from local injection of epinephrine with lidocaine. Intraoperative bleeding and postoperative pain scores were analyzed between both groups by Mann-Whitney U-test, while complication rates were compared using Fisher's exact test. RESULTS: The present study did not find significant differences in mean intraoperative blood loss (8 ± 5.8 mL vs. 5 ± 2.2 mL, p=0.074), complication rates (18% vs. 0%, p=0.227), and mean pain scores (1.2 ± 0.5 vs. 1.4 ± 0.5, p=0.307) between the 7-min and 30-min groups. CONCLUSION: The authors conclude that a waiting time of 7 min from the injection of local anesthesia is sufficient to achieve comparable clinical outcomes for minor hand and wrist surgeries under WALANT.

Parents of healthy children assign lower quality of life measure to scenarios labeled as cancer than to identical scenarios not labeled as cancer.

BACKGROUND: While it is commonly understood that a cancer diagnosis evokes feelings of fear, the effect of labeling a child's illness as "cancer" remains unstudied. We hypothesized that lower health utility scores would be assigned to disease states labeled as cancer compared to identical disease states without the mention of cancer. METHODS: In this randomized study, caregivers of healthy children were asked to assign health utility values to different scenarios written as improving, stable, or worsening. Participants from general pediatric clinics at Eskenazi Health were randomly assigned to either the scenarios labeled as "cancer" or "a serious illness". Participants then rated the scenarios using the Standard Gamble, with laddering of health utilities between 0 (a painless death) and 1 (perfect health). We also gathered subject demographics and assessed the subject's numeracy. RESULTS: We approached 319 subjects and 167 completed the study. Overall median health utilities of "cancer" scenarios were lower than "serious illness" scenarios (0.61 vs. 0.72, p = 0.018). Multivariate regression (with an outcome of having a utility above the 75th percentile) showed no significant effects by race, ethnicity, numeracy, or income level. "Cancer" scenarios remained significantly lower after adjustment for confounders using logistic regression, but only for the more serious scenarios (OR 0.92, p = 0.048). CONCLUSIONS: On average, caregivers with healthy children were shown to take more risk with their treatment options and view their child as having a worse quality of life when they knew the disease was cancer. Awareness of this bias is important when discussing treatments with families, particularly when a risk of cancer is present.