ABX test

Abstract: We present a new framework for the evaluation of speech rep- resentations in zero-resource settings, that extends and complements previous work by Carlin, Jansen and Hermansky [1]. In particular, we replace their Same/Different discrimination task by several Minimal-Pair ABX (MP-ABX) tasks. We explain the analytical advantages of this new framework and apply it to de- compose the standard signal processing pipelines for computing PLP and MFC coefficients. This method enables us to confirm and quantify a variety of well-known and not-so-well-known results in a single framework.

Abstract: Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1–α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance. Description Editor’s summary Immune checkpoint blockade therapy for the treatment of cancer can have reduced efficacy when antibiotics are administered and then discontinued before the start of therapy. Fidelle et al. investigated whether bacteria that rebound may affect the treatment response (see the Perspective by Pratt and Milner). Enterocloster species that recolonized the guts of mice treated with antibiotics down-regulated the expression of MAdCAM-1, the ligand for integrin α4β7 that helps to retain an immunosuppressive subset of T cells (Tr17 cells) within the gut. This leads to transit of Tr17 cells to tumors and tumor-draining lymph nodes, where they compromise immune checkpoint blockade therapy. In cancer patients undergoing immunotherapy, low levels of serum-soluble MAdCAM-1 correlated with intestinal dysbiosis and poor clinical outcomes for renal, bladder, and lung tumors. —Priscilla N. Kelly & Seth Thomas Scanlon The MAdCAM-1– α4β7 interaction is a gut immune checkpoint for cancer immunosurveillance. INTRODUCTION Resistance of cancers to immune checkpoint inhibitors (ICIs) can result from antibiotic (ABX) treatment, likely as a result of a deviated gut microbiota. ABX compromise clinical outcome when administered before, rather than during, ICI administration, suggesting that bacterial recolonization following ABX discontinuation may be deleterious. Gut commensals induce the differentiation of an immunosuppressive subset of FoxP3+ retinoic acid receptor–related orphan receptor-γt (RORγt+) regulatory (Treg17) cells. Lymphocytes primed in the mesenteric lymph nodes (mLNs) or homing to the intestinal lamina propria express the α4β7 integrin interacting with its counter-receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed in high endothelial venules (HEVs). RATIONALE We hypothesized that disruption of the MAdCAM-1–α4β7 interaction that retains Treg17 cells might cause their migration from the gut to tumors and thereby compromise the anticancer effects of ICIs. We used two complementary methods to visualize the exodus of intestinal T cells to subcutaneous tumors and tumor-draining lymph nodes (tdLNs): (i) Kaede mice expressing a fluorescent protein that is photoconverted upon ultraviolet light illumination of the ileum and (ii) the injection of carboxyfluorescein succinimidyl ester into mLNs. Moreover, we used transgene-enforced Madcam1 expression in the liver to locally intercept Treg17 cells during their migration. RESULTS Several classes of ABX down-regulated Madcam1 expression in ileal venules, Peyer’s patches and mLNs, coinciding with the ileal exodus of α4β7+ T helper (Th17) and Treg17 cells toward extraintestinal tumors and tdLNs. This ABX-induced reduction in MAdCAM-1 could be explained by the recolonization of the gut by the genus Enterocloster (encompassing the E. clostridioformis species), because its oral administration was sufficient to down-regulate MAdCAM-1 expression through its effects on bile acid metabolism. Genetic or antibody-mediated neutralization of MAdCAM-1 or α4β7 integrin phenocopied the immunosuppressive effects of ABX, promoting resistance to ICIs targeting programmed cell death protein 1 (PD-1) and inducing a surge in gut-derived α4β7+ Treg17 cells in tdLNs and tumors. Restoration of MAdCAM-1 on ileal HEV by fecal microbial transplantation or blockade of IL-17A reversed the inhibitory effects of ABX. Ectopic expression of MAdCAM-1 in the liver caused the local retention of enterotropic α4β7+ Treg17 cells, reducing their accumulation in tumor beds and improving immunotherapy outcomes in mice. Finally, low-serum-soluble MAdCAM-1 was identified as a proxy of intestinal dysbiosis and a robust predictor of shorter overall and progression-free survival of renal, bladder, and lung cancer patients under immunotherapy with antibodies targeting PD-1 or PD-L1. In non-small-cell lung cancer patients, the prognostic value of soluble MAdCAM-1 was independent of PD-L1 expression. CONCLUSION The relocation of enterotropic and immunosuppressive Treg17 cells to cancerous tissue (tumors and tdLNs) is repressed by the molecular interaction between the HEV addressin MAdCAM-1 and the integrin α4β7 expressed by Treg17 cells. Disruption of the MAdCAM-1 expression by ABX or gut dysbiosis causes the relocation of Treg17 cells into tumors, consequently compromising cancer immunosurveillance and the therapeutic efficiency of ICIs in mice and patients. MAdCAM-1 as a gut immune checkpoint for cancer immunosurveillance. Bacteria from the genus Enterocloster, for example, after discontinuation of ABX, induce the down-regulation of MAdCAM-1 in the ileal lamina propria and mLNs, inducing the exodus of the immunosuppressive α4β7+ Treg17 cells from the gut to cancers and tdLNs. Disruption of the MAdCAM-1–α4β7 axis compromises the efficacy of immunotherapy in mice and patients.

Abstract: Although most respiratory tract infections (RTIs) are due to viral infections, they cause the majority of antibiotic (Abx) prescriptions in primary care. This systematic review summarises the evidence on the effectiveness of interventions in primary care aiming to reduce Abx prescriptions in patients ≥ 13 years for acute RTI. We searched the databases “MEDLINE/PubMed” and “Cochrane Library” for the period from January 1, 2005, to August 31, 2016, for randomised controlled trials (RCTs) in primary care aiming at the reduction of Abx prescriptions for patients suffering from RTI. Out of 690 search results, 67 publications were retrieved and 17 RCTs were included. We assumed an absolute change of 10% as minimal important change. Twelve out of 17 included RCTs showed statistically significant lower Abx prescription rates in the intervention groups, but only six of them reported a clinically relevant reduction according to our definition. Communication skills training (CST) and point-of-care testing (POCT) were the most effective interventions. Pre-intervention Abx prescription rates varied between 13.5% and 80% and observed reductions ranged from 1.5 to 23.3%. Studies with post-intervention rates lower than 20% had no significant effects. Post-intervention observation periods ranged from 2 weeks up to 3.5 years. The design of the trials was heterogeneous precluding calculation of pooled effect size. The reporting of many RCTs was poor. CST and POCT alone or as adjunct can reduce antibiotic prescriptions for RTI. Eleven out of 17 trials were not successfully reducing Abx prescription rates according to our definition of minimal important change. However, five of them reported a statistically significant reduction. Trials with initially lower prescription rates were less likely to be successful. Future trials should investigate sustainability of intervention effects for a longer time period. The generalisability of findings was limited due to heterogeneous designs and outcome measures. Therefore, a consensus of designing and reporting of studies aiming at reducing antibiotic prescriptions is urgently needed to generate meaningful evidence.