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We present 2 cases of Aspergillus endocarditis occurring in lung transplant recipients, both of whom were treated with early surgical intervention and triazole anti-fungal agents. Neither had evidence of airway colonization/infection with Aspergillus post-transplant, suggesting hematogenous spread of fungi at the time of surgery as a possible mechanism of infection. One case was successfully treated and discharged from the hospital, but, despite initial recovery, death occurred 10 months later due to a recurrence of Aspergillus endocarditis. Aspergillus endocarditis should be considered a relapsing disease and survivors of the condition should receive ongoing anti-fungal therapy. [Copyright &y& Elsevier]

• Oral ixazomib therapy was associated with decreased treatment failure compared with a historical benchmark in a national phase II trial. • The 2014 National Institutes of Health response criteria-defined overall response rate was 40% at 6 months in a cohort with advanced chronic graft-versus-host disease. New interventions are needed in advanced chronic graft-versus-host disease (GVHD). In a phase II, single-arm, multicenter trial, we examined the efficacy of ixazomib in patients with chronic GVHD who had progressed after at least 1 previous line of systemic immunosuppressive (IS) therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic IS therapy. A total of 50 subjects were enrolled at 6 institutions. The median time from the onset of chronic GVHD to enrollment was 2.8 years (interquartile range, 1.5 to 4.3 years). The degree of chronic GVHD at enrollment was National Institutes of Health (NIH)-defined moderate (16%) or severe (84%), predominantly classic (80% versus 20% overlap), with 52% of patients having involvement of 4 or more organs. The patients were heavily pretreated, with 39 (78%) receiving 3 or more previous lines of systemic therapy for chronic GVHD. Of the 50 patients treated, 26 completed 6 months of planned therapy. The 6-month treatment failure rate was significantly lower than the historical benchmark (28% versus 44%; P =.01) previously established in second-line therapy for chronic GVHD. No patient, transplantation, or chronic GVHD variables were significantly associated with 6-month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival was 92% at 6 months and 90% at 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months, the NIH-defined rate of complete/partial response was 40%, and 52% of patients remained on ixazomib therapy, suggesting that the low treatment failure rate was due in part due to prevention of progressive disease that would have required additional treatment. [ABSTRACT FROM AUTHOR]

Key points: Enteroids are a physiologically relevant model to examine the human intestine and its functions.Previously, the measurable cytokine response of human intestinal enteroids has been limited following exposure to host or microbial pro‐inflammatory stimuli.Modifications to enteroid culture conditions facilitated robust human cytokine responses to pro‐inflammatory stimuli.This new human enteroid culture methodology refines the ability to study microbiome:human intestinal epithelium interactions in the laboratory. The intestinal epithelium is the primary interface between the host, the gut microbiome and its external environment. Since the intestinal epithelium contributes to innate immunity as a first line of defence, understanding how the epithelium responds to microbial and host stimuli is an important consideration in promoting homeostasis. Human intestinal enteroids (HIEs) are primary epithelial cell cultures that can provide insights into the biology of the intestinal epithelium and innate immune responses. One potential limitation of using HIEs for innate immune studies is the relative lack of responsiveness to factors that stimulate epithelial cytokine production. We report technical refinements, including removal of extracellular antioxidants, to facilitate enhanced cytokine responses in HIEs. Using this new method, we demonstrate that HIEs have distinct cytokine profiles in response to pro‐inflammatory stimuli derived from host and microbial sources. Overall, we found that host‐derived cytokines tumour necrosis factor and interleukin‐1α stimulated reactive oxygen species and a large repertoire of cytokines. In contrast, microbial lipopolysaccharide, lipoteichoic acid and flagellin stimulated a limited number of cytokines and histamine did not stimulate the release of any cytokines. Importantly, HIE‐secreted cytokines were functionally active, as denoted by the ability of human blood‐derived neutrophil to migrate towards HIE supernatant containing interleukin‐8. These findings establish that the immune responsiveness of HIEs depends on medium composition and stimuli. By refining the experimental culture medium and creating an environment conducive to epithelial cytokine responses by human enteroids, HIEs can facilitate exploration of many experimental questions pertaining to the role of the intestinal epithelium in innate immunity. Key points: Enteroids are a physiologically relevant model to examine the human intestine and its functions.Previously, the measurable cytokine response of human intestinal enteroids has been limited following exposure to host or microbial pro‐inflammatory stimuli.Modifications to enteroid culture conditions facilitated robust human cytokine responses to pro‐inflammatory stimuli.This new human enteroid culture methodology refines the ability to study microbiome:human intestinal epithelium interactions in the laboratory. [ABSTRACT FROM AUTHOR]

Details research concerned with how the ETR1 receptor from the plant Arabidopsis binds the gaseous hormone ethylene, and how copper ions in the ethylene-binding domain are involved. Mutations that eliminate ethylene binding and copper/receptor interaction; Comparison of a homologous genome sequence in the cyanobacterium Synechocystis; A structural model for the copper-based ethylene sensor domain based on the comparison and the mutagenesis of ETR1.

In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. [ABSTRACT FROM AUTHOR]

Abstract: The origin of alluvial diamonds from the four main diamond mining districts in Kalimantan was studied through characterisation of their properties, and determination of PT and age of formation of representative collections of diamonds from four localities of the island. The diamonds are mostly colourless, yellow or pale brown, shiny surfaced, dodecahedroids, octahedron/dodecahedroids, and more rarely cube combination forms. They are intensively resorbed. They have surface radiation damage and show abrasion features indicative of fluvial transportation and crustal recycling. The diamonds were polished down to expose internal structures and mineral inclusions. The majority of the diamonds are internally homogeneous or have simple octahedral zonation and show plastic deformation. Analysis by Fourier transform infra red spectroscopy of their N content and aggregation characteristics shows that many diamonds are well-aggregated type IaB implying a long-term, mantle residence time and/or high temperatures of formation. Identified inclusion parageneses are 68% peridotitic and 32% eclogitic. The peridotitic inclusions are represented by olivine, chromite, garnet, orthopyroxene and pentlandite. Olivines (Fo92–93) belong to the dunite–harzburgite paragenesis, with one at Fo90 identified as lherzolitic. Chromite inclusions with 65–66 wt.% Cr2O3 and <1 wt.% TiO2 are typical of chromite diamond inclusions world-wide. Two garnet inclusions identified are a subcalcic high chrome harzburgite “G10” and a mildly subcalcic type transitional between “G9” and “G10”. The eclogitic inclusions are represented by omphacite, rutile, kyanite and coesite. Re/Os dating of a high Ni sulphide inclusion from one peridotitic diamond gave an Archean model age of 3.1 Ga±0.2 (2 sigma). In terms of their external and internal morphology, N aggregation characteristics and paragenesis the Kalimantan diamonds resemble those transported to surface by kimberlite or lamproite from sources in the subcontinental lithospheric mantle. Five distinctive genetic groups of diamond have been recognised but occur mixed in each of the four diamond mining districts due to a presumed long history of sedimentary recycling and alluvial transportation. Thermobarometry calculations from diamond inclusion chemistry (930 °C to 1250 °C; >4.2 GPa) are consistent with a paleo-heat flow of 38 to 40 mW/m2 and derivation from 120 to 160 km depth, i.e. subcontinental mantle lithosphere conditions similar to diamonds from African and Yakutian cratonic situations. [Copyright &y& Elsevier]

Abstract: To verify a previously reported three-dimensional (3D) ultrasound method for the measurement of time-average volumetric blood flow, experiments were performed under pulsatile flow conditions, including in vivo investigations, and results were compared with accepted, but invasive, “gold standard” techniques. Results showed that volume averaging results in the correct time-average volume flow without the need for cardiac gating. Unlike other currently employed methods, this method is independent of Doppler angle, flow profile and vessel geometry. A GE Logiq 9 ultrasound system (GE Medical Systems, Milwaukee, WI, USA) and a four-dimensional (4D) 10L and 4D 16L probe were used to acquire 3D Doppler measurements in the femoral and carotid arteries of four canines. Two invasive blood flow meters were used (electromagnetic for one canine and ultrasonic for three canines) as the gold standard techniques. Transcutaneous color flow measurements were taken to obtain 3D volume data sets encompassing the vessel. Constant depth planes were used to integrate color flow pixels encompassing the entire vessel cross-section. Power Doppler data were used to correct for partial volume effects. An artificial stenosis was induced to vary the ambient volume flow. Unrestricted, bidirectional flow was measured as high as 400mLmin-1. Several flow restrictions were imposed that decreased the measured volumetric flow rate to as low as 30mLmin-1. All flow rate estimates (n =38) were plotted against results obtained via the gold standards. A general line fit resulted in y = 0.926 x - 0.87 (r2 = 0.95), which corresponds to a 0.6% flow offset relative to the average flow rate of 142mLmin-1, as well as a 7.4% error in the linearity of our estimate. A secondary curve fit was performed that required the slope to be 1 and the intercept to be 0, which yielded an r 2-value of 0.93. The percent-error distribution was computed and fitted to a Gaussian function, which yielded μ =-7.04% and σ =9.52%. Theoretical studies were conducted to estimate the expected error in our volume flow measurements as a function of number of samples (N) used for averaging pulsatile waveforms. Experiments showed the same dependence as theory. Direct comparisons of volume flow rate estimates using volumetric color Doppler and independent standards showed that our method has good accuracy under in vivo pulsatile blood flow conditions. (E-mail: greentom@umich.edu) [Copyright &y& Elsevier]

New therapeutic approaches are needed to improve outcomes of patients with advanced chronic graft vs. host disease (GVHD). Pre-clinical and clinical data suggest proteasome inhibition may modulate GVHD. In a phase II, single-arm, multi-center trial conducted by the Chronic GVHD Consortium, we examined the efficacy of ixazomib in advanced chronic GVHD treatment. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. An amendment permitted additional cycles beyond 6 for those with responsive chronic GVHD. The primary endpoint was 6 month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immune suppressive (IS) therapy, compared with a historical 6 month treatment failure rate of 44% based on 312 patients treated with secondary therapy. Key eligibility criteria included age ≥ 18, NIH Consensus defined chronic GVHD, failure of at least one prior line of systemic IS therapy, and adequate hematologic parameters, hepatic, and renal function. A total of 50 subjects were enrolled at 6 institutions. Median age was 58 years. Median time from transplant to enrollment was 3.6 years (IQR 2.6-5.5), and from chronic GVHD onset to enrollment 2.8 years (IQR 1.5-4.3). Chronic GVHD was NIH moderate (16%) or severe (84%), predominantly classic (80% vs. overlap 20%), with 52% having 4 or more involved organs. Patients were heavily pretreated with 39 (78%) having 3 or more prior lines of systemic therapy for chronic GVHD. Of the 50 treated subjects, 26 completed all 6 months of planned therapy. Dose reductions most commonly occurred for thrombocytopenia, fatigue, diarrhea, and infection. SAEs occurred in 38% of subjects, and 5 deaths occurred in study participants (2 deemed possibly related to ixazomib). The 6 month treatment failure rate was significantly improved vs. the historical benchmark (28% vs. 44%, p=0.01), Figure 1. No patient, transplant, or chronic GVHD variables were significantly associated with 6 month treatment failure. NIH response rates at 3, 6, and 12 months are presented in Figure 2; the ORR was 34% (17/50) at 6 months. Overall survival at 6 and 12 months was 92% and 90%. No subjects completely discontinued IS by 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months the ORR rate was 34% and 50% remained on ixazomib suggesting the low treatment failure rate was in part due to prevention of progressive disease that would have required additional treatment. Randomized studies are warranted. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF., Methods: Experimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth., Results: Accurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased., Conclusion: Applications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels., Competing Interests: Conflict of interest Pinter, SZ: Equipment support, General Electric Healthcare Company. Rubin, JM: Research and equipment support, General Electric Healthcare Company. Hall, AL: At time of data acquisition, Employee, General Electric Healthcare Company. Fowlkes, JB: Research and equipment support, General Electric Healthcare Company. Kripfgans, OD: Research and equipment support, General Electric Healthcare Company., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the relationships between social and environmental factors and parenting self-efficacy (PSE) among mothers of preterm infants hospitalized in neonatal intensive care units (NICUs) using a social determinants of health (SDoH) framework., Method: We analyzed data from a prospective cohort study that included 187 mother-infant dyads admitted to four NICUs in the Mountain West region between June 2017 and December 2019. We used multivariable linear regression models to assess the independent associations between maternal and infant characteristics and PSE., Results: Our final multiple linear regression model predicting the efficacy score including maternal race/ethnicity, age, insurance, employment status before giving birth, gestational age, depression, and having other children was significant (F(12,160) = 3.17, p = .0004, adjusted R¬2 = .131). Significant predictors of PSE were race/ethnicity (β= 3.3, p = .022), having another child/children (β= 4.2, p = .005), and depression (β= -4.2, p = .004)., Conclusions: Findings suggest that social workers and medical practitioners should consider SDoH, such as insurance type, household income, and employment, along with traditional clinical indicators when assessing families' infant care needs. Social workers, medical practitioners, and researchers should be mindful of how implicit bias may influence the allocation of care and parental supports., Competing Interests: Conflict of Interest None declared.

Objectives: Evaluate the association between maternal social factors and maternal time spent in the NICU for very preterm infants admitted to 4 level III and IV NICUs., Methods: In this prospective observational cohort study, we enrolled mother-infant dyads whose infants were born <32 weeks' gestation. Enrollment occurred after 2 weeks of NICU exposure, when maternal social factors and demographic information was collected. Maternal time spent in the NICU was abstracted from the electronic medical record and was dichotomized into 0 to 6 days and ≥6 days per week. Demographic differences between the 2 groups were compared by using χ 2 tests. Logistic regression was used to assess the independent association between maternal social factors and the average number of days per week spent in the NICU., Results: A total of 169 mother-infant dyads were analyzed. Maternal social factors associated with more time spent in the NICU included an annual household income of >$100 000, compared with those with an annual household income of <$50 000 (adjusted odds ratio [aOR]: 5.68; 95% confidence interval [CI] 1.77-18.19), a travel time <30 minutes to the NICU (compared with those who traveled >60 minutes [aOR: 7.85; 95% CI 2.81-21.96]), and the lack of other children in the household, compared with women with other children (aOR: 3.15; 95% CI 1.39-7.11)., Conclusions: Maternal time spent in the NICU during a prolonged birth hospitalization of a very preterm infant differed by socioeconomic status, travel time, and presence of other dependents. Strategies to better identify and reduce these disparities to optimize engagement and, subsequently, improve infant health outcomes is needed., Competing Interests: POTENTIAL CONFLICTS OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background & Aims: The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood., Methods: Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT-receptor expression in the brain, and 5-HT-receptor-dependent behavior was evaluated using the marble burying test., Results: B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium-secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT-receptor 2a in B dentium-treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT-receptor 2a., Conclusions: These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To decrease the average length of stay (LOS) of opioid-exposed newborns (OENs) by 20% from baseline from April 2017 to December 2019., Methods: The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative is a consortium of neonatal providers, public health experts, and legislative experts that provides infrastructure and resources for Colorado birthing hospitals to undertake initiatives focused on improving the care of OENs. The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative was started in September 2017 and includes 19 birthing hospitals in Colorado, with 12 contributing data to the centralized database. The interventions were focused on (1) hospital engagement and (2) increasing nonpharmacologic care (by using the Eat, Sleep, Console assessment tool; developing guidelines for breastfeeding eligibility; employing comfort measures before pharmacologic therapy; and administering opiate therapy on an as-needed basis)., Results: From April 2017 to December 2019, 787 OENs were identified. Among infants ≥35 weeks' gestational age without other medical diagnoses ( n = 647), statistical process control charts revealed significant reduction in the primary outcome of interest, average hospital LOS, from 14.8 to 5.9 days. For all OENs, receipt of pharmacologic therapy declined from 61% to 23%. Among OENs who received pharmacologic therapy (and were ≥35 weeks' gestational age without other medical diagnoses), average LOS also declined from 21.9 to 8.0 days., Conclusions: Through standardization of OEN care focused on family engagement and nonpharmacologic care, this statewide collaborative reduced average LOS, the percentage of OENs requiring opiate therapy, and average LOS for OENs requiring opiate therapy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Purpose: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD., Methods: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD., Results: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants., Conclusions: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.

Background: Living with Parkinson disease (PD) is complicated by an unpredictable disease course which can delay planning for future needs. This study explores patient and care partner needs related to future planning using a palliative care framework with physical, psychological, social, cultural, end-of-life, and ethical aspects of care in PD to guide analysis., Methods: Secondary analysis of patient and care partner interviews from a randomized clinical trial comparing interdisciplinary outpatient palliative care versus standard care for individuals with PD and care partners in an academic setting. Sixty participants were interviewed (30 patients and 30 care partners) about needs related to future planning. Team-based thematic analysis was used to identify key themes., Results: Many care partners and patients living with PD described a desire for information about what to expect and how to plan for the future. Participants posed multiple questions about PD progression and devised the metaphor of a "roadmap" as a guide for decision making and planning. When exploring the concept of a PD roadmap, five themes emerged: (I) desire for a comprehensive tool for future planning, such as a roadmap, (II) care partner preferences for specific future planning, (III) PD-related life changes as opportunity for future planning and decision-making, (IV) cues from family, peers, and medical professionals about "location" on the roadmap, and (V) opportunities and challenges to integrating a PD roadmap into patient-centered care., Conclusions: Patients and care partners described key needs related to future planning that can inform a comprehensive roadmap to assist with education, communication, and decision making. A roadmap tool can promote individualized anticipatory guidance and multidimensional shared decision-making discussions between patients, care partners, and the healthcare team related to PD progression.

Background: Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. In L. reuteri, histamine synthesis and secretion requires L-histidine decarboxylase and a L-histidine/histamine exchanger. Chloride channel (ClC)-family proton/chloride antiporters have been proposed to act as electrochemical shunts in conjunction with amino acid decarboxylase systems, correcting ion imbalances generated by decarboxylation through fixed ratio exchange of two chloride ions for one proton. This family is unique among transporters by facilitating ion flux in either direction. Here we examine the histidine decarboxylase system in relation to ClC antiporters in the probiotic organism Lactobacillus reuteri., Results: In silico analyses reveal that L. reuteri possesses two ClC transporters, EriC and EriC2, as well as a complete histidine decarboxylase gene cluster (HDC) for the synthesis and export of histamine. When the transport activity of either proton/chloride antiporter is disrupted by genetic manipulation, bacterial histamine output is reduced. Using fluorescent reporter assays, we further show that ClC transporters affect histamine output by altering intracellular pH and membrane potential. ClC transport also alters the expression and activity of two key HDC genes: the histidine decarboxylase (hdcA) and the histidine/histamine exchanger (hdcP)., Conclusions: Histamine production is a potentially beneficial feature for intestinal microbes by promoting long-term colonization and suppression of inflammation and host immune responses. ClC transporters may serve as tunable modulators for histamine production by L. reuteri and other gut microbes.

The fitness effect of a mutation can depend on both its genetic background, known as epistasis, and the prevailing external environment. Many examples of these dependencies are known, but few studies consider both aspects in combination, especially as they affect mutations that have been selected together. We examine interactions between five coevolved mutations in eight diverse environments. We find that mutations are, on average, beneficial across environments, but that there is high variation in their fitness effects, including many examples of mutations conferring a cost in some, but not other, genetic background-environment combinations. Indeed, even when global interaction trends are accounted for, specific local mutation interactions are common and differed across environments. One consequence of this dependence is that the range of trade-offs in genotype fitness across selected and alternative environments are contingent on the particular evolutionary path followed over the mutation landscape. Finally, although specific interactions were common, there was a consistent pattern of diminishing returns epistasis whereby mutation effects were less beneficial when added to genotypes of higher fitness. Our results underline that specific mutation effects are highly dependent on the combination of genetic and external environments, and support a general relationship between a genotype's current fitness and its potential to increase in fitness., (© 2019 The Author(s). Evolution © 2019 The Society for the Study of Evolution.)

Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived species Bifidobacterium dentium would increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans. In silico data revealed that B. dentium lacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating that B. dentium could not use naive mucin glycans as primary carbon sources in vitro To examine B. dentium mucus modulation in vivo , Swiss Webster germfree mice were monoassociated with live or heat-killed B. dentium Live B. dentium -monoassociated mice exhibited increased colonic expression of goblet cell markers Krüppel-like factor 4 ( Klf4 ), Trefoil factor 3 ( Tff3 ), Relm -β, Muc2 , and several glycosyltransferases compared to both heat-killed B. dentium and germfree counterparts. Likewise, live B. dentium -monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining. In vitro , B. dentium -secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified that B. dentium -secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates that B. dentium is capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production. IMPORTANCE Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium , which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier., (Copyright © 2019 Engevik et al.)

Objective: Advance care planning (ACP) is a core quality measure in caring for individuals with Parkinson disease (PD) and there are no best practice standards for how to incorporate ACP into PD care. This study describes patient and care partner perspectives on ACP to inform a patient- and care partner-centered framework for clinical care., Methods: This is a qualitative descriptive study of 30 patients with PD and 30 care partners within a multisite, randomized clinical trial of neuropalliative care compared to standard care. Participants were individually interviewed about perspectives on ACP, including prior and current experiences, barriers to ACP, and suggestions for integration into care. Interviews were analyzed using theme analysis to identify key themes., Results: Four themes illustrate how patients and care partners perceive ACP as part of clinical care: (1) personal definitions of ACP vary in the context of PD; (2) patient, relationship, and health care system barriers exist to engaging in ACP; (3) care partners play an active role in ACP; (4) a palliative care approach positively influences ACP. Taken together, the themes support clinician initiation of ACP discussions and interdisciplinary approaches to help patients and care partners overcome barriers to ACP., Conclusions: ACP in PD may be influenced by patient and care partner perceptions and misperceptions, symptoms of PD (e.g., apathy, cognitive dysfunction, disease severity), and models of clinical care. Optimal engagement of patients with PD and care partners in ACP should proactively address misperceptions of ACP and utilize clinic teams and workflow routines to incorporate ACP into regular care., (© 2019 American Academy of Neurology.)

Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apc min/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

Adequate nutrition during the pre- and early-postnatal periods plays a critical role in programming early neurodevelopment. Disruption of neurodevelopment by nutritional deficiencies can result not only in lasting functional deficits, but increased risk of neuropsychiatric disease in adulthood. Historical periods of famine such as the Dutch Hunger Winter and the Chinese Famine have provided foundational evidence for the long-term effects of developmental malnutrition on neuropsychiatric outcomes. Because neurodevelopment is a complex process that consists of many nutrient- and brain-region-specific critical periods, subsequent clinical and pre-clinical studies have aimed to elucidate the specific roles of individual macro- and micronutrient deficiencies in neurodevelopment and neuropsychiatric pathologies. This review will discuss developmental iron deficiency (ID), the most common micronutrient deficiency worldwide, as a paradigm for understanding the role of early-life nutrition in neurodevelopment and risk of neuropsychiatric disease. We will review the epidemiologic data linking ID to neuropsychiatric dysfunction, as well as the underlying structural, cellular, and molecular mechanisms that are thought to underlie these lasting effects. Understanding the mechanisms driving lasting dysfunction and disease risk is critical for development and implementation of nutritional policies aimed at preventing nutritional deficiencies and their long-term sequelae.

Intrauterine growth restricted (IUGR) infants are at increased risk for neurodevelopmental deficits that suggest the hippocampus and cerebral cortex may be particularly vulnerable. Evaluate regional neurochemical profiles in IUGR and normally grown (NG) 7-day old rat pups using in vivo 1 H magnetic resonance (MR) spectroscopy at 9.4 T. IUGR was induced via bilateral uterine artery ligation at gestational day 19 in pregnant Sprague-Dawley dams. MR spectra were obtained from the cerebral cortex, hippocampus and striatum at P7 in IUGR (N = 12) and NG (N = 13) rats. In the cortex, IUGR resulted in lower concentrations of phosphocreatine, glutathione, taurine, total choline, total creatine (P < 0.01) and [glutamate]/[glutamine] ratio (P < 0.05). Lower taurine concentrations were observed in the hippocampus (P < 0.01) and striatum (P < 0.05). IUGR differentially affects the neurochemical profile of the P7 rat brain regions. Persistent neurochemical changes may lead to cortex-based long-term neurodevelopmental deficits in human IUGR infants.

Ethylene signaling in plants is mediated by a family of receptors related to bacterial two-component histidine kinases. Of the five members of the Arabidopsis ethylene receptor family, members of subfamily I (ETR1 and ERS1) contain completely conserved histidine kinase domains, whereas members of subfamily II (ETR2, EIN4, and ERS2) lack conserved residues thought to be necessary for kinase activity. To examine the role of the conserved histidine kinase domain in receptor signaling, ers1;etr1 loss-of-function double mutants were generated. The double mutants exhibited a severe constitutive ethylene response phenotype consistent with the negative regulator model for receptor function. The adult ers1-2;etr1-6 and ers1-2;etr1-7 phenotypes included miniature rosette size, delayed flowering, and both male and female sterility, whereas etiolated-seedling responses were less affected. Chimeric transgene constructs in which the ETR1 promoter was used to drive expression of cDNAs for each of the five receptor isoforms were transferred into the ers1-2;etr1-7 double-mutant plants. Subfamily I constructs restored normal growth, whereas subfamily II constructs failed to rescue the double mutant, providing evidence for a unique role for subfamily I in receptor signaling. However, transformation of either the ers1-2;etr1-6 or ers1-2;etr1-7 mutant with a kinase-inactivated ETR1 genomic clone also resulted in complete restoration of normal growth and ethylene responsiveness in the double-mutant background, leading to the conclusion that canonical histidine kinase activity by receptors is not required for ethylene receptor signaling.