Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in PSC-IBD.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunological, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs). METHODS: Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n=22), PSC-IBD (n=45) and control individuals (n=27) was performed to detect OMVs in the systemic circulation and liver. RESULTS: In both, preclinical model systems and in human PSC-IBD patients, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on TLR4 and NLRP3-GSDMD. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort. CONCLUSION: This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier, and thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.

Biodegradable-Polymer or Durable-Polymer Stents in Patients at High Bleeding Risk: A Randomized, Open-Label Clinical Trial.

BACKGROUND: Limited information is available on the comparative efficacy and safety of different stent platforms in patients at high bleeding risk undergoing an abbreviated dual antiplatelet therapy duration after percutaneous coronary intervention (PCI). The aim of this study was to compare the safety and effectiveness of the biodegradable-polymer sirolimus-eluting stent with the durable-polymer zotarolimus-eluting stent in patients at high bleeding risk receiving 1 month of dual antiplatelet therapy after PCI. METHODS: The Bioflow-DAPT Study is an international, randomized, open-label trial conducted at 52 interventional cardiology hospitals in 18 countries from February 24, 2020, through September 20, 2021. Patients with a clinical indication to PCI because of acute or chronic coronary syndrome who fulfilled 1 or more criteria for high bleeding risk were eligible for enrollment. Patients were randomized to receive either biodegradable-polymer sirolimus-eluting stents or durable-polymer, slow-release zotarolimus-eluting stents after successful lesion preparation, followed by 1 month of dual antiplatelet therapy and thereafter single antiplatelet therapy. The primary outcome was the composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year, and was powered for noninferiority, with an absolute margin of 4.1% at 1-sided 5% alpha. RESULTS: A total of 1948 patients at high bleeding risk were randomly assigned (1:1) to receive biodegradable-polymer sirolimus-eluting stents (969 patients) or durable-polymer zotarolimus-eluting stents (979 patients). At 1 year, the primary outcome was observed in 33 of 969 patients (3.6%) in the biodegradable-polymer sirolimus-eluting stent group and in 32 of 979 patients (3.4%) in the durable-polymer zotarolimus-eluting stent group (risk difference, 0.2 percentage points; upper boundary of the 1-sided 95% CI, 1.8; upper boundary of the 1-sided 97.5% CI, 2.1; P<0.0001 for noninferiority for both tests). CONCLUSIONS: Among patients at high risk for bleeding who received 1 month of dual antiplatelet therapy after PCI, the use of biodegradable-polymer sirolimus-eluting stents was noninferior to the use of durable-polymer zotarolimus-eluting stents with regard to the composite of death from cardiac causes, myocardial infarction, or stent thrombosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04137510.

Plant diversity and community age stabilize ecosystem multifunctionality.

It is well known that biodiversity positively affects ecosystem functioning, leading to enhanced ecosystem stability. However, this knowledge is mainly based on analyses using single ecosystem functions, while studies focusing on the stability of ecosystem multifunctionality (EMF) are rare. Taking advantage of a long-term grassland biodiversity experiment, we studied the effect of plant diversity (1-60 species) on EMF over 5 years, its temporal stability, as well as multifunctional resistance and resilience to a 2-year drought event. Using split-plot treatments, we further tested whether a shared history of plants and soil influences the studied relationships. We calculated EMF based on functions related to plants and higher-trophic levels. Plant diversity enhanced EMF in all studied years, and this effect strengthened over the study period. Moreover, plant diversity increased the temporal stability of EMF and fostered resistance to reoccurring drought events. Old plant communities with shared plant and soil history showed a stronger plant diversity-multifunctionality relationship and higher temporal stability of EMF than younger communities without shared histories. Our results highlight the importance of old and biodiverse plant communities for EMF and its stability to extreme climate events in a world increasingly threatened by global change.

Plant growth strategy determines the magnitude and direction of drought-induced changes in root exudates in subtropical forests.

Root exudates are an important pathway for plant-microbial interactions and are highly sensitive to climate change. However, how extreme drought affects root exudates and the main components, as well as species-specific differences in response magnitude and direction, are poorly understood. In this study, root exudation rates of total carbon (C) and its components (e.g., sugar, organic acid, and amino acid) were measured under the control and extreme drought treatments (i.e., 70% throughfall reduction) by in situ collection of four tree species with different growth rates in a subtropical forest. We also quantified soil properties, root morphological traits, and mycorrhizal infection rates to examine the driving factors underlying variations in root exudation. Our results showed that extreme drought significantly decreased root exudation rates of total C, sugar, and amino acid by 17.8%, 30.8%, and 35.0%, respectively, but increased root exudation rate of organic acid by 38.6%, which were largely associated with drought-induced changes in tree growth rates, root morphological traits, and mycorrhizal infection rates. Specifically, trees with relatively high growth rates were more responsive to drought for root exudation rates compared with those with relatively low growth rates, which were closely related to root morphological traits and mycorrhizal infection rates. These findings highlight the importance of plant growth strategy in mediating drought-induced changes in root exudation rates. The coordinations among root exudation rates, root morphological traits, and mycorrhizal symbioses in response to drought could be incorporated into land surface models to improve the prediction of climate change impacts on rhizosphere C dynamics in forest ecosystems.

Regional transplant rates depend more on physician-dependent variables than on proximity to transplant center.

PURPOSE: The objective of this work was to uncover inequalities in access to liver transplantation in Bavaria, Germany. METHODS: For this purpose, the annual transplantation rate per 1 million inhabitants for the respective districts was determined from the aggregated postal codes of the place of residence of transplanted patients. The variables examined were proximity and travel time to the nearest transplant center, as well as the care category of the regional hospital. In addition, we assessed whether the head of gastroenterology at the regional hospital through which liver transplant candidates are referred was trained at a liver transplant center. RESULTS: We could not demonstrate a direct relationship between proximity or travel time to the nearest transplant center and access to liver transplantation. Multivariate regression analysis shows that liver transplant training (p < 0.0001) of the chief physician (gastroenterologist) of the regional hospital was the most decisive independent factor for access to liver transplantation within a district. CONCLUSION: We show that the transplant training experience of the head of gastroenterology at a regional hospital is an independent factor for the regional transplantation rate. Therefore, it appears important to maintain some liver transplant expertise outside the transplant centers in order to properly identify and assign potential transplant candidates for transplantation.

Four-and-a-Half LIM-Domain Protein 2 (FHL2) Induces Neuropeptide Y (NPY) in Macrophages in Visceral Adipose Tissue and Promotes Diet-Induced Obesity.

Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage-adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.

Role of Fibroblast Growth Factors in the Crosstalk of Hepatic Stellate Cells and Uveal Melanoma Cells in the Liver Metastatic Niche.

Hepatic metastasis is the critical factor determining tumor-associated mortality in different types of cancer. This is particularly true for uveal melanoma (UM), which almost exclusively metastasizes to the liver. Hepatic stellate cells (HSCs) are the precursors of tumor-associated fibroblasts and support the growth of metastases. However, the underlying mechanisms are widely unknown. Fibroblast growth factor (FGF) signaling is dysregulated in many types of cancer. The aim of this study was to analyze the pro-tumorigenic effects of HSCs on UM cells and the role of FGFs in this crosstalk. Conditioned medium (CM) from activated human HSCs significantly induced proliferation together with enhanced ERK and JNK activation in UM cells. An in silico database analysis revealed that there are almost no mutations of FGF receptors (FGFR) in UM. However, a high FGFR expression was found to be associated with poor survival for UM patients. In vitro, the pro-tumorigenic effects of HSC-CM on UM cells were abrogated by a pharmacological inhibitor (BGJ398) of FGFR1/2/3. The expression analysis revealed that the majority of paracrine FGFs are expressed by HSCs, but not by UM cells, including FGF9. Furthermore, the immunofluorescence analysis indicated HSCs as a cellular source of FGF9 in hepatic metastases of UM patients. Treatment with recombinant FGF9 significantly enhanced the proliferation of UM cells, and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398. Our study indicates that FGF9 released by HSCs promotes the tumorigenicity of UM cells, and thus suggests FGF9 as a promising therapeutic target in hepatic metastasis.

Effects of plant species diversity on nematode community composition and diversity in a long-term biodiversity experiment.

Diversity loss has been shown to change the soil community; however, little is known about long-term consequences and underlying mechanisms. Here, we investigated how nematode communities are affected by plant species richness and whether this is driven by resource quantity or quality in 15-year-old plant communities of a long-term grassland biodiversity experiment. We extracted nematodes from 93 experimental plots differing in plant species richness, and measured above- and belowground plant biomass production and soil organic carbon concentrations (Corg) as proxies for resource quantity, as well as C/Nleaf ratio and specific root length (SRL) as proxies for resource quality. We found that nematode community composition and diversity significantly differed among plant species richness levels. This was mostly due to positive plant diversity effects on the abundance and genus richness of bacterial-feeding, omnivorous, and predatory nematodes, which benefited from higher shoot mass and soil Corg in species-rich plant communities, suggesting control via resource quantity. In contrast, plant-feeding nematodes were negatively influenced by shoot mass, probably due to higher top-down control by predators, and were positively related to SRL and C/Nleaf, indicating control via resource quality. The decrease of the grazing pressure ratio (plant feeders per root mass) with plant species richness indicated a higher accumulation of plant-feeding nematodes in species-poor plant communities. Our results, therefore, support the hypothesis that soil-borne pathogens accumulate in low-diversity communities over time, while soil mutualists (bacterial-feeding, omnivorous, predatory nematodes) increase in abundance and richness in high-diversity plant communities, which may contribute to the widely-observed positive plant diversity-productivity relationship.

A Comparison of Six Transport Models of the MADE-1 Experiment Implemented With Different Types of Hydraulic Data.

Six conceptually different transport models were applied to the macrodispersion experiment (MADE)-1 field tracer experiment as a first major attempt for model comparison. The objective was to show that complex mass distributions in heterogeneous aquifers can be predicted without calibration of transport parameters, solely making use of structural and flow data. The models differ in their conceptualization of the heterogeneous aquifer structure, computational complexity, and use of conductivity data obtained from various observation methods (direct push injection logging, DPIL, grain size analysis, pumping tests and flowmeter). They share the same underlying physical transport process of advection by the velocity field solely. Predictive capability is assessed by comparing results to observed longitudinal mass distributions of the MADE-1 experiment. The decreasing mass recovery of the observed plume is attributed to sampling and no physical process like mass transfer is invoked by the models. Measures like peak location and strength are used in comparing the modeled and measured plume mass distribution. Comparison of models reveals that the predictions of the solute plume agree reasonably well with observations, if the models are underlain by a few parameters of close values: mean velocity, a parameter reflecting log-conductivity variability, and a horizontal length scale related to conductivity spatial correlation. The robustness of the results implies that conservative transport models with appropriate conductivity upscaling strategies of various observation data provide reasonable predictions of plumes longitudinal mass distribution, as long as key features are taken into account.

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance.

OBJECTIVE: Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC. DESIGN: Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model. RESULTS: Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis. CONCLUSIONS: KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.

ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis.

OBJECTIVE: Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown. DESIGN: Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients. RESULTS: Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers. CONCLUSIONS: Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.

Is mesenteric defect closure needed in urologic surgery using ileum?

INTRODUCTION: Classic surgical teaching advocates for closure of the mesenteric defect (MD) after bowel anastomosis but the necessity is controversial. We sought to evaluate the necessity of MD closure at the time of harvest of ileum for genitourinary reconstructive surgery (GURS) by analyzing the incidence of early and late gastrointestinal adverse events (GIAE) in patients with and without MD closure. MATERIALS AND METHODS: A retrospective review was conducted on patients undergoing urologic reconstruction with ileum to identify incidence of ileus, small bowel obstruction (SBO), gastrointestinal (GI) fistula and stoma complications. Patient and procedure variables were analyzed to identify risk factors for GIAE. RESULTS: A total of 288 patients met inclusion criteria and 93% of GURS was for urinary diversion following cystectomy. MD was closed in 194 cases (67%). Median follow up was 19 months. Early (< 30 day) GIAE rates were 16.5% (n = 32) and 21.3% (n = 20) in the closure and non-closure groups, respectively (p = 0.22). The rate of early ileus/SBO requiring nasogastric tube decompression or laparotomy were similar after closure (15.0%) and non-closure (21.3%) (p = .18). The late GIAE rates were 5.7% (n = 11) and 6.4% (n = 6) in the closure and non-closure cohorts, respectively (p = 0.56). The rate of late SBO were similar and no cases of early or late SBO in either cohort were due to internal herniation. On multivariate analysis, increasing BMI was associated with both early and late GIAE. CONCLUSIONS: After harvesting ileum for urologic reconstruction, the MD can safely be left open as we found no association between non-closure and early or late GIAE..

Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets.

The novel CKLF-like Marvel Transmembrane Domain-containing gene family (CMTM) consists of 8 members (CMTM1-8). As little is known about the oncogenic impact of these genes, we aimed to systematically investigate the relevance of CMTMs to glioblastoma pathogenesis. We performed mRNA expression analyses and survival correlations in glioblastoma patients. Moreover, we analyzed the impact of RNAi-based silencing and overexpression of CMTM family genes on tumor cell proliferation and invasion in vitro. CMTMs appeared to be widely regulated in the group of glioblastomas relative to non-neoplastic brain (NB) tissue (significant upregulation for CMTM2, 3, and 6 and significant downregulation for CMTM 4 and 8). For CMTM1, 5 and 7, we found aberrant expression levels in individual tumors. Functionally, CMTM1, 3, and 7 promoted tumor cell invasion, while CMTM1 additionally enhanced cell proliferation. In a large clinically annotated dataset, higher CMTM1 and 3 expression was significantly correlated with shorter overall survival. Our data thus suggest CMTM1 and 3 as priority targets in glioblastomas. Using a human phosphokinase protein expression profiling assay, we can provide first insights into signalling of these two genes that might be conveyed by growth factor receptor, Src family kinase and WNT activation.

Neuropeptide Y restores non-receptor-mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension.

BACKGROUND & AIMS: Vascular hyporeactivity to vasoconstrictors contributes to splanchnic arterial vasodilatation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY), a sympathetic cotransmitter, has been shown to improve adrenergic vascular contractility in portal hypertensive rats and markedly attenuate hyperdynamic circulation. To further characterize the NPY-effects in portal hypertension, we investigated its role for non-receptor-mediated vasoconstriction in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham-operated rats. METHODS: Ex vivo SMA perfusion of PVL and sham rats was used to analyse the effects of NPY on pressure response to non-receptor-mediated vasoconstriction. Dose-response curves to KCl (30-300 mM) were used to bypass G protein-coupled receptor mechanisms. Potential involvement of the cyclooxygenase-pathway was tested by non-selective cyclooxygenase-inhibition using indomethacin. RESULTS: KCl-induced vascular contractility but not vascular sensitivity was significantly attenuated in PVL rats as compared with sham rats. Administration of NPY resulted in an augmentation of KCl-evoked vascular sensitivity being not different between study groups. However, KCl-induced vascular contractility was markedly more enhanced in PVL rats, thus, vascular response was no more significantly different between PVL and sham rats after addition of NPY. Administration of indomethacin abolished the NPY-induced enhancement of vasoconstriction. CONCLUSIONS: Receptor-independent vascular contractility is impaired in mesenteric arteries in portal hypertension. NPY improves non-receptor mediated mesenteric vasoconstriction more effective in portal hypertension than in healthy conditions correcting splanchnic vascular hyporesponsiveness. This beneficial vasoactive action of NPY adds to its well known more pronounced effects on adrenergic vasoconstriction in portal hypertension making it a promising therapeutic agent in portal hypertension.

Clinical Pharmacist Counselling Improves Long-term Medication Safety and Patient-reported Outcomes in Anti-TNF-treated Patients With Inflammatory Bowel Diseases: The Prospective, Randomized AdPhaNCED Trial.

BACKGROUND: Antitumor necrosis factor (anti-TNF) antibody treatment has led to marked improvements in the management of patients with inflammatory bowel diseases (IBDs). Nevertheless, anti-TNF therapy is associated with potential adverse drug reactions (ADRs). Our prospective, randomized trial investigated the effect of intensified clinical pharmacist counselling in a multidisciplinary team on medication safety in anti-TNF-treated IBD patients. METHODS: Patients with IBD with ongoing anti-TNF treatment were enrolled in our tertiary center AdPhaNCED trial and randomized to either receive conventional standard of care (control group) or additional clinical pharmacist counselling (intervention group) over 12 months. The primary end point consisted of the number and severity of ADRs associated with anti-TNF therapy. Secondary end points included patient satisfaction with medication information and medication safety. RESULTS: One hundred twenty-seven IBD patients were included in this study. Anti-TNF-related ADRs were significantly lower in the intervention compared with the control group (0.20 vs 0.32 [mean] ADR/patient/month, P = .006) after 12 months. The risk of more severe ADRs (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥2) was significantly higher in the control compared with the intervention group (hazard ratio, 0.34; P = .001). The probability of ADR resolution (hazard ratio, 2.02; P < .001) and patient satisfaction with medication information (14.82 vs 11.60; P < .001) were significantly higher in the intervention group compared with the control group. CONCLUSIONS: Our study results demonstrate that intensified pharmacist counselling significantly reduces the occurrence and severity of therapy-related ADRs and improves patient satisfaction. Clinical pharmacists should therefore be part of a holistic approach to IBD care delivered by a multidisciplinary team.

The prospective, randomized AdPhaNCED trial demonstrated that anti-TNF-treated IBD patients had diminished and less severe drug-related adverse reactions and higher patient satisfaction when they received intensified pharmacist counselling in comparison with conventional standard of care over 12 months.

Linking plant diversity-productivity relationships to plant functional traits of dominant species and changes in soil properties in 15-year-old experimental grasslands.

Positive plant diversity-productivity relationships are known to be driven by complementary resource use via differences in plant functional traits. Moreover, soil properties related to nutrient availability were shown to change with plant diversity over time; however, it is not well-understood whether and how such plant diversity-dependent soil changes and associated changes in functional traits contribute to positive diversity-productivity relationships in the long run. To test this, we investigated plant communities of different species richness (1, 2, 6, and 9 species) in a 15-year-old grassland biodiversity experiment. We determined community biomass production and biodiversity effects (net biodiversity [NEs], complementarity [CEs], and selection effects [SEs]), as well as community means of plant functional traits and soil properties. First, we tested how these variables changed along the plant diversity gradient and were related to each other. Then, we tested for direct and indirect effects of plant and soil variables influencing community biomass production and biodiversity effects. Community biomass production, NEs, CEs, SEs, plant height, root length density (RLD), and all soil property variables changed with plant diversity and the presence of the dominant grass species Arrhenatherum elatius (increase except for soil pH, which decreased). Plant height and RLD for plant functional traits, and soil pH and organic carbon concentration for soil properties, were the variables with the strongest influence on biomass production and biodiversity effects. Our results suggest that plant species richness and the presence of the dominant species, A. elatius, cause soil organic carbon to increase and soil pH to decrease over time, which increases nutrient availability favoring species with tall growth and dense root systems, resulting in higher biomass production in species-rich communities. Here, we present an additional process that contributes to the strengthening positive diversity-productivity relationship, which may play a role alongside the widespread plant functional trait-based explanation.

Tree diversity effects on productivity depend on mycorrhizae and life strategies in a temperate forest experiment.

Tree species are known to predominantly interact either with arbuscular mycorrhizal (AM) or ectomycorrhizal (EM) fungi. However, there is a knowledge gap regarding whether these mycorrhizae differently influence biodiversity-ecosystem functioning (BEF) relationships and whether a combination of both can increase community productivity. In 2015, we established a tree-diversity experiment by growing tree communities with varying species richness levels (one, two, or four species) and either with AM or EM tree species or a combination of both. We investigated basal area and annual basal area increment from 2015 to 2020 as proxies for community productivity. We found significant positive relationships between tree species richness and community productivity, which strengthened over time. Further, AM and EM tree species differently influenced productivity; however, there was no overyielding when AM and EM trees grew together. EM tree communities were characterized by low productivity in the beginning but an increase of increment over time and showed overall strong biodiversity effects. For AM tree communities the opposite was true. Although young trees did not benefit from the presence of the other mycorrhizal type, dissimilar mechanisms underlying BEF relationships in AM and EM trees indicate that maximizing tree and mycorrhizal diversity may increase ecosystem functioning in the long run.

Evidence Based Estimation of Macrodispersivity for Groundwater Transport Applications.

The scope of this work is to discuss the proper choice of macrodispersion coefficients in modeling contaminant transport through the advection dispersion equation (ADE). It is common to model solute concentrations in transport by groundwater with the aid of the ADE. Spreading is quantified by macrodispersivity coefficients, which are much larger than the laboratory observed pore-scale dispersivities. In the frame of stochastic theory, longitudinal macrodispersivity is related to the hydraulic conductivity spatial variability via its statistical moments (mean, variance, integral scales), which are generally determined by geostatistical analysis of field measurements. In many cases, especially for preliminary assessment of contaminant spreading, these data are not available and ad hoc values are adopted by practitioners. The present study aims at recommending dispersivity values based on a thorough analysis of tens of field experiments. Aquifers are classified as of weak, medium, and high heterogeneity and for each class a range of macrodispersivity values is recommended. Much less data are available for the transverse macrodispersivities, which are significantly smaller than the longitudinal one. Nevertheless, a few realistic values based on field data, are recommended for applications. Transport models using macrodispersivities can predict mean concentrations, different from the local ones. They can be used for estimation of robust measures, like plumes spatial moments, longitudinal mass distribution and breakthrough curves at control planes.

Vasectomy Regret Among Childless Men.

OBJECTIVE: To address historical concerns surrounding vasectomy in childless men, we sought to evaluate for the level of regret in this unique cohort. METHODS: The records of patients who underwent vasectomy via single surgeon between 2006 and 2021 were retrospectively reviewed and those who had not fathered children in any capacity at time of vasectomy were selected. We devised a 6-question survey inquiring about regret and thoughts on vasectomy reversal and assisted reproductive technology (ART). The questions are listed in Table 1. Patients were queried via a telephone call to rate their level of regret, both immediately after vasectomy and present day. The cohort was analyzed via age at time of vasectomy, time since vasectomy and marital status. RESULTS: There were 4812 overall patients who underwent vasectomy in this interval, with 205 (4.3%) who were childless. The response rate was 33.2% (68/205). Average age was 36.6 years with average time since vasectomy at time of phone call was 5.51 years. Regret rate was 4.4% immediately following vasectomy and 7.4% at time of telephone interview. A confirmatory, second consultation before vasectomy was present in 6.8% (14/205). The majority of patients 150/205 (73.1%) were married. When patients were stratified by marital status, there was no significant difference in any of the questions. The majority of patients were satisfied with their decision, with few contemplating or pursuing reversal or ART (Table 1). CONCLUSION: Regret in childless patients who undergo vasectomy is very rare, with the majority of patients feeling that their life was improved.