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are respiratory pathogens comprised of three classical species: , and . With recent surges in spp. cases and antibiotics becoming less effective to combat infectious diseases, there is an imperative need for novel antimicrobial therapies. Our goal is to investigate the possible targets of host immunomodulatory mechanisms that can be exploited to promote clearance of spp. infections. Vasoactive intestinal peptide (VIP) is a neuropeptide that promotes Th2 anti-inflammatory responses through VPAC1 and VPAC2 receptor binding and activation of downstream signaling cascades. We used classical growth assays to evaluate the effects of VIP on spp. growth and survival. Using the three classical spp. in combination with different mouse strains we were able to evaluate the role of VIP/VPAC2 signaling in the infectious dose 50 and infection dynamics. Finally using the murine model we determine the suitability of VPAC2 antagonists as possible therapy for spp. infections. Under the hypothesis that inhibition of VIP/VPAC2 signaling would promote clearance, we found that VPAC2 mice, lacking a functional VIP/VPAC2 axis, hinder the ability of the bacteria to colonize the lungs, resulting in decreased bacterial burden by all three classical species. Moreover, treatment with VPAC2 antagonists decrease lung pathology, suggesting its potential use to prevent lung damage and dysfunction caused by infection. Our results indicate that the ability of spp. to manipulate VIP/VPAC signaling pathway appears to be mediated by the type 3 secretion system (T3SS), suggesting that this might serve as a therapeutical target for other gram-negative bacteria. Taken together, our findings uncover a novel mechanism of bacteria-host crosstalk that could provide a target for the future treatment for whooping cough as well as other infectious diseases caused primarily by persistent mucosal infections.

Eosinophils are granulocytes primarily associated with TH2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers TH2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote TH17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.

Eosinophils were once viewed mainly as effectors of type 2 inflammation, such as allergy and immunity to helminths. Their role in bacterial lung infection has been less clear. In the lung, eosinophils maintain tissue balance and organize immune responses that shape outcomes. Using Bordetella bronchiseptica as a model, this work examines how eosinophils drive iBALT formation, under the context of Bordetella spp. infection.Chapter II identifies a host–pathogen axis in which a BtrS-regulated type III secretion system promotes colonization by engaging VIP–VPAC2 signaling. Loss of VPAC2 reduces colonization and persistence, linking this pathway to the T3SS and establishing VIP–VPAC2 as a target exploited by Bordetella. Chapter III shows that deleting btrS reveals a suppressed host program. A ΔbtrS mutant induces iBALT by day 7 only in the presence of eosinophils. Eosinophil-deficient mice fail to form iBALT and clear ΔbtrS more slowly. Wildtype B. bronchiseptica infection obscures this requirement, consistent with BtrS-dependent suppression of eosinophil function. Eosinophils are required for iBALT establishment but not maintenance. Early XCL1 signaling also proves critical, as eosinophils localize with XCL1 and a blockade of XCL1 prevents iBALT formation. Chapter IV uses 3D imaging and spatial analysis to show that GL7⁺ B and T cells cluster within iBALT after ΔbtrS priming and rapidly reassemble on recall, correlating with clearance.Together, these findings highlight eosinophils as key coordinators of adaptive immunity and potential targets for therapies or adjuvants that stimulate iBALT and enhance mucosal defense.

A characteristic that differentiates pathogenic and opportunistic bacteria is that pathogens have been selected by their ability to suppress host inflammatory responses allowing colonization and persistence. Bordetella spp. are respiratory pathogens characterized for the arsenal of mechanisms they use to manipulate host immune responses. We have previously characterized a B. bronchiseptica mutant, RB50DbtrS, that is not able to suppress host immune responses, resulting not only in rapid clearance of the infection but also long-term lung sterilizing immunity against reinfection with the three classical Bordetella spp. Interestingly, this strong immune response requires eosinophils. In this work our results indicate that wildtype B. bronchiseptica, RB50, blocks eosinophil pro-inflammatory functions to prevent the rapid recruitment of B and T cells to the lung that results in iBALT formation. Moreover, eosinophils promote a TH17 microenvironment within the iBALT that might be responsible for the long-term robust protective immunity generated by infection with this mutant. Overall, this work provides a novel role for eosinophils as promoters of adaptive immune responses and protective immunity, while also indicating that bacteria actively manipulate those cells to promote long-term persistence and reinfection. Competing Interest Statement The authors have declared no competing interest.

Bordetella pertussis releases the monomeric peptidoglycan (PGN) fragment tracheal cytotoxin (TCT) due to inefficient recycling by the permease AmpG. Releasing this PGN is metabolically costly and potentially immune alarming and the benefits to B. pertussis are unclear. While TCT has been characterized as a potent NOD1 agonist capable of causing the extrusion of ciliated cells, in vitro, the consequences of its release have yet to be studied in vivo. Here we show that selective PGN release by B. pertussis biases host PGN sensing toward NOD1 and away from NOD2, suppressing IL-1β-driven inflammation and blunting adaptive immune recruitment. Mice infected with a TCT over-releasing strain (TCT(+)) exhibit reduced pulmonary immunopathology relative to wild type (WT) and a TCT-under-releasing strain (TCT(-)), despite similar bacterial burdens. NOD reporter assays demonstrate that TCT release enhances NOD1 activation and inversely correlates with NOD2 activation. Bulk transcriptomic analysis of infected lungs shows that B. pertussis PGN release dampens pro-inflammatory transcriptional programs. Single-cell transcriptomic determined Nod2 expression is limited to inflammatory myeloid subsets. IL-1 family genes were highly enriched in Nod2- but not Nod1 expressing alveolar macrophages. Upstream regulator analysis predicted IL-1β as a major driver of B. pertussis inflammation, which was enhanced by the absence of PGN release. Flow cytometry shows that PGN release skews macrophages polarization toward M2 and away from M1 in a NOD1 dependent manner. Finally, extracellular release of PGN and subsequent reduced IL-1 production facilitated the suppression fibroblast chemokine programs (e.g., CXCL13, CCL19), diminished recruitment of B and T cells, reduced iBALT formation, and limited immune memory development. Conversely, IL-1R1 deficiency impairs adaptive recruitment and bacterial clearance despite similar innate infiltration. Together, these data suggest PGN release by B. pertussis is an immune-evasion strategy, favoring NOD1 activation over NOD2, reducing IL-1–dependent fibroblast reprogramming, and curtailing chemokine-driven adaptive responses. Graphic Abstract B. pertussis can produce both NOD1 and NOD2 activating PGNs. Release of TCT promotes NOD1 activation and diminishes NOD2 activation. NOD2 activation in myeloid cells drives M1 polarization of macrophages and IL-1 family cytokine production. IL-1 family cytokines skew fibroblasts towards an inflammatory phenotype, leading to chemokine release, extracellular remodeling, and recruitment of lymphocytes. Therefore, TCT release tempers long-term immunity to B. pertussis.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

In a large study comparing different strategies for screening for Down's syndrome, first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin [fβhCG]) at 11 weeks was better than second-trimester quadruple screening (measurement of alpha-fetoprotein, hCG, unconjugated estriol, and inhibin A). Strategies combining first-trimester and second-trimester screening provide high detection rates at acceptable false positive rates. These findings will help guide the choice of screening strategies for Down's syndrome. In a large study comparing different strategies for screening for Down's syndrome, first-trimester combined screening at 11 weeks was better than second-trimester quadruple screening. Strategies combining first-trimester and second-trimester screening provide high detection rates at acceptable false positive rates. First-trimester screening for Down's syndrome that includes the use of ultrasonography to assess nuchal translucency has become widespread since its introduction by Nicolaides and colleagues in the early 1990s. 1 – 4 The largest U.S. study of first-trimester screening to date, involving 8514 pregnancies, reported a 79 percent detection rate at a 5 percent false positive rate. 5 Second-trimester screening remains the most common approach to assessing the risk of Down's syndrome in the United States. 6 When inhibin A is included in second-trimester quadruple screening, the estimated detection rate for Down's syndrome is 81 percent with a 5 percent false positive rate. 7 However, . . .

In this randomized trial involving 454 patients with pleural infections that required antibiotic therapy and chest-tube drainage, there was no benefit from the use of intrapleural streptokinase in terms of survival, the need for surgery, the length of the hospital stay, or the resolution of radiographic abnormalities. In this trial involving 454 patients with pleural infections, there was no benefit from the use of intrapleural streptokinase in terms of survival, the need for surgery, the length of the hospital stay, or the resolution of radiographic abnormalities. Pleural infection develops in about 65,000 patients each year in the United States and the United Kingdom. 1 Approximately 15 percent of patients die, 2 which is similar to the death rate among patients hospitalized with pneumonia, 3 , 4 and 15 to 40 percent require surgical drainage of the infected pleural space. 2 , 5 The median duration of inpatient care is 15 days, with 20 percent of patients remaining in the hospital for a month or longer. 2 Apart from antibiotic therapy, treatment in patients with pleural infection consists mainly of drainage of the infected pleural fluid, and the intrapleural administration of fibrinolytic drugs is . . .

Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation. In the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, β-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (<13.6 nmol/L), 7.5% and 82.0% for riboflavin (<5 nmol/L and ≤26.5 nmol/L, respectively), 9.1% for vitamin B12 (<221 pmol/L), and 48.7% for vitamin D (<50 nmol/L); these proportions were balanced between the groups. Over 90% of all participants had low or marginal status for one or more of these vitamins at recruitment. Among participants in the control group, plasma concentrations of riboflavin declined through early and late pregnancy, whereas concentrations of 25-hydroxyvitamin D were unchanged in early pregnancy, and concentrations of vitamin B6 and B12 declined throughout pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate <20 nmol/L). After 1 month of supplementation, plasma concentrations of supplement components were substantially higher among participants in the intervention group than those in the control group: riboflavin by 0.77 SDS (95% CI 0.68 to 0.87, p < 0.0001), vitamin B6 by 1.07 SDS (0.99 to 1.14, p < 0.0001), vitamin B12 by 0.55 SDS (0.46 to 0.64, p < 0.0001), and vitamin D by 0.51 SDS (0.43 to 0.60, p < 0.0001), with higher levels in the intervention group maintained during pregnancy. Markers of vitamin insufficiency/deficiency were reduced in the intervention group, and the proportion of participants with vitamin D insufficiency (<50 nmol/L) during late pregnancy was lower in the intervention group (35.1% versus 8.5%; p < 0.0001). Plasma vitamin B12 remained higher in the intervention group than in the control group 6 months postdelivery (by 0.30 SDS (0.14, 0.46), p = 0.0003). The main limitation is that generalizability to the global population is limited by the high-resource settings and the lack of African and Amerindian women in particular. Over 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period. ClinicalTrials.gov NCT02509988; U1111-1171-8056.

Large Language Models have advanced clinical Natural Language Generation, creating opportunities to manage the volume of medical text. However, the high-stakes nature of medicine requires reliable evaluation, which remains a challenge. In this narrative review, we assess the current evaluation state for clinical summarization tasks and propose future directions to address the resource constraints of expert human evaluation.