Rinse K Weersma

University of Groningen, Groningen, Groningen, Netherlands

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Publications (120)1148.17 Total impact

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    ABSTRACT: Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease. The currently known IBD risk loci show an almost 75% overlap with genetic risk loci for other immune mediated diseases. Current studies are focused on the translation of the identified risk loci to clinical practice. The first steps towards this translation are being taken with the identification of genetic risk factors for drugs toxicity, specific disease course and response to therapy. In this review we will discuss how the IBD genetic risk loci were identified and how this knowledge can be translated towards clinical practice.
    Expert Review of Clinical Immunology 12/2014; · 2.89 Impact Factor
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    ABSTRACT: Crohn's disease (CD) is caused by a complex interplay among genetic, microbial and environmental factors. ATG16L1 is an important genetic factor involved in innate immunity, including autophagy and phagocytosis of microbial components from the gut. We investigated the effect of inflammation on the composition of microbiota in the ileal mucosa of CD patients in relation to the ATG16L1 risk status.
    Gut 09/2014; · 10.73 Impact Factor
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    ABSTRACT: In up to 30 percent of small bowel capsule endoscopy procedures, the capsule does not reach the cecum within recording time. A prolonged gastric transit time has been recognized as a risk factor for incomplete capsule endoscopy. The aim of this study was to analyze if a single dose of orally administered erythromycin prior to capsule endoscopy results in a higher completion rate compared to orally administered domperidone.
    BMC Gastroenterology 09/2014; 14(1):162. · 2.11 Impact Factor
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    ABSTRACT: Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
    Nature Genetics 09/2014; · 35.21 Impact Factor
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    ABSTRACT: Over 100 ulcerative colitis (UC) loci have been identified by genome-wide association studies (GWASs) primarily in Caucasians (CEUs). Many of them have weak effects on disease susceptibility, and the bulk of the heritability cannot be ascribed to these loci. Very little is known about the genetic background of UC in non-CEU groups. Here we report the first GWAS on UC in a genetically distinct north Indian (NI) population.
    Gut 05/2014; · 10.73 Impact Factor
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    Gut 04/2014; · 10.73 Impact Factor
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    ABSTRACT: In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.
    Science translational medicine 04/2014; 6(233):233ra53. · 10.76 Impact Factor
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    ABSTRACT: The clinical presentation of the inflammatory bowel diseases (IBD) is extremely heterogenous and is characterized by various extraintestinal manifestations and complications (EIM). Increasing genetic insight for IBD and EIM shows multiple shared susceptibility loci. We hypothesize that, next to these overlapping genetic risk loci, distinct disease pathways are shared between IBD and EIM. The overlapping genetic risk loci for IBD and its EIM were searched in literature. We assessed shared disease pathways by performing an extensive pathway analysis by protein-protein interaction and cotranscriptional analysis, using both publicly available and newly developed databases. Reliable genetic data were available for primary sclerosing cholangitis, ankylosing spondylitis, decreased bone mineral density, colorectal carcinoma, gallstones, kidney stones, and deep venous thrombosis. We found an extensive overlap in genetic risk loci, especially for IBD and primary sclerosing cholangitis and ankylosing spondylitis. We identified 370 protein-protein interactions, of which 108 are statistically specific. We identified 446 statistically specific cotranscribed gene pairs. The interactions are shown to cluster in specific biological pathways. We show that the pathogenetic overlap between IBD and its EIM extends beyond shared risk genes to distinctive shared biological pathways. We define genetic background as a risk factor for IBD-EIM alongside known mechanisms such as malabsorption and medication. Clustering patients based on distinctive pathways may enable stratification of patients to predict development of EIM.
    Inflammatory Bowel Diseases 04/2014; · 5.12 Impact Factor
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    ABSTRACT: To investigate the incidence of non-small-bowel abnormalities in patients referred for small bowel capsule endoscopy, this single center study was performed. Small bowel capsule endoscopy is an accepted technique to investigate obscure gastrointestinal bleeding. This is defined as bleeding from the digestive tract that persists or recurs without an obvious etiology after a normal gastroduodenoscopy and colonoscopy. Nevertheless, capsule endoscopy sometimes reveals findings outside the small bowel, i.e., within reach of conventional endoscopes. In this retrospective single center study, 595 patients undergoing capsule endoscopy between 2003 and 2009 were studied. The incidence of non-small bowel abnormalities was defined as visible abnormalities detected by capsule endoscopy that are located within reach of conventional endoscopes. In 595 patients, referred for obscure gastrointestinal bleeding or for suspected Crohn's disease, abnormalities were found in 306 (51.4%). Of these 306 patients, 85 (27.7%) had abnormalities within reach of conventional endoscopes; 63 had abnormalities apparently overlooked at previous conventional endoscopies, 10 patients had not undergone upper and lower endoscopy prior to capsule endoscopy and 12 had abnormalities that were already known prior to capsule endoscopy. The most common type of missed lesions were vascular lesions (n = 47). Non-small-bowel abnormalities were located in the stomach (n = 15), proximal small bowel (n = 22), terminal ileum (n = 21), colon (n = 19) or at other or multiple locations (n = 8). Ten patients with abnormal findings in the terminal ileum had not undergone examination of the ileum during colonoscopy. A significant proportion of patients undergoing small bowel capsule endoscopy had lesions within reach of conventional endoscopes, indicating that capsule endoscopy was unnecessarily performed.
    World Journal of Gastroenterology 04/2014; 20(14):4025-9. · 2.55 Impact Factor
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    ABSTRACT: & Aims: Activation of the transcription factor NFκB has been associated with development of inflammatory bowel disease (IBD). COMMD1, a regulator of various transport pathways, has been shown to limit NFκB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in humans. We created mice with specific disruption of Commd1 in myeloid cells (Mye-K/O mice); we analyzed immune cell populations and functions and expression of genes regulated by NFκB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate (DSS), and colitis-associated cancer was induced by administration of DSS and azoxymethane. We measured levels of COMMD1 mRNA in colon biopsies from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed reduced expression of COMMD1 in colon biopsies and circulating leukocytes from patients with IBD. We associated single nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.
    Gastroenterology 04/2014; · 12.82 Impact Factor
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    ABSTRACT: The Th17/IL23 pathway has both genetically and biologically been implicated in the pathogenesis of the inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis. So far, it is unknown whether and how associated risk variants affect expression of the genes encoding for Th17/IL23 pathway proteins. Ten IBD-associated SNPs residing near Th17/IL23 genes were used to construct a genetic risk model in 753 Dutch IBD cases and 1045 controls. In an independent cohort of 40 Crohn's disease, 40 ulcerative colitis, and 40 controls, the genetic risk load and presence of IBD were correlated to quantitative PCR-generated messenger RNA (mRNA) expression of 9 representative Th17/IL23 genes in both unstimulated and PMA/CaLo stimulated peripheral blood mononuclear cells. In 1240 individuals with various immunological diseases with whole genome genotype and mRNA-expression data, we also assessed correlation between genetic risk load and differential mRNA expression and sought for SNPs affecting expression of all currently known Th17/IL23 pathway genes (cis-expression quantitative trait locus). The presence of IBD, but not the genetic risk load, was correlated to differential mRNA expression for IL6 in unstimulated peripheral blood mononuclear cells and to IL23A and RORC in response to stimulation. The cis-expression quantitative trait locus analysis showed little evidence for correlation between genetic risk load and mRNA expression of Th17/IL23 genes, because we identified for only 2 of 22 Th17/IL23 genes a cis-expression quantitative trait locus single nucleotide polymorphism that is also associated to IBD (STAT3 and CCR6). Our results suggest that only the presence of IBD and not the genetic risk load alters mRNA expression levels of IBD-associated Th17/IL23 genes.
    Inflammatory Bowel Diseases 03/2014; · 5.12 Impact Factor
  • E.A.M. Festen, R.K. Weersma
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    ABSTRACT: Inflammatory bowel disease, consisting of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies.
    Best Practice & Research Clinical Gastroenterology. 01/2014;
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    ABSTRACT: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.
    Gut 10/2013; · 10.73 Impact Factor
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    ABSTRACT: Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
    PLoS Genetics 09/2013; 9(9):e1003723. · 8.52 Impact Factor
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    ABSTRACT: Extensive population-based studies are much needed to accurately establish the epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population-based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on site verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until liver transplantation or PSC-related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n=422)(P<0.0001). Colorectal carcinoma (CRC) risk was 10-fold increased as compared to ulcerative colitis controls and developed at a much younger age (39 yrs[range 26-64]) compared to IBD controls (59 yrs[range 34-73])(P=0.019). Colonoscopic surveillance was associated with significantly better outcome. Conclusion: This study exemplifies that for relatively rare diseases it is paramount to collect observational data from large population-based cohorts, because incidence and prevalence rates of PSC are markedly lower and survival much longer than previously reported. The selection bias-free population-based cohort showed a significantly longer survival compared to the tertiary referral cohort. CRC can develop at an early age, warranting surveillance from time of PSC diagnosis. (HEPATOLOGY 2013.).
    Hepatology 06/2013; · 12.00 Impact Factor
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    ABSTRACT: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling. To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT. Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up. Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC. Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.
    Liver international: official journal of the International Association for the Study of the Liver 06/2013; · 3.87 Impact Factor
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    ABSTRACT: BACKGROUND& AIMS: Genome-wide association studies (GWASs) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with Crohn's disease (CD) and 5 healthy individuals (controls), and then filtered single-nucleotide variants by incorporating association results from meta-analyses of CD GWASs and in silico mutation effect prediction algorithms. We then genotyped 9348 patients with CD, 2868 with ulcerative colitis, and 14,567 controls, and associated variants analyzed in functional studies using materials from patients and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing1 (PRDM1) and associated these with CD. These increased proliferation of T cells and secretion of cytokines upon activation, and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWASs, correlated with reduced expression of PRDM1 in ileal biopsies and peripheral blood mononuclear cells (combined P=1.6×0(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P=4.83×10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit NFκB activation of genes that regulate inflammation and affect stability of proteins in toll-like receptor pathways. CONCLUSIONS: We have extended GWAS results and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWASs and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role for autophagy in pathogenesis of CD.
    Gastroenterology 04/2013; · 12.82 Impact Factor
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    ABSTRACT: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
    Nature Genetics 04/2013; · 35.21 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Benign anastomotic strictures are often difficult to treat. We assessed the efficacy of adding corticosteroid injections to endoscopic dilation therapy with Savary bougienage. METHODS: In a multicenter, double-blind trial, 60 patients (mean age 63±9 y, 78% male) with an untreated cervical anastomotic stricture after esophagectomy with gastric tube reconstruction and dysphagia for at least solid food were randomly assigned to groups given either 4 quadrant injections of 0.5 ml triamcinolone (40 mg/ml, n=29) or saline (controls, n=31) into the stricture, followed by Savary dilation to 16 mm. Dysphagia, complications, and quality of life were assessed after 1 and 2 weeks and 1, 3, and 6 months. The primary endpoint was a dysphagia-free period of 6 months. RESULTS: In the corticosteroid group, 45% of the patients remained dysphagia-free for 6 months, compared with 36% of controls (relative risk [RR], 1.26; 95% confidence interval [CI], 0.68-2.36;P =.46). Median time to repeat dilation was 108 days (range, 15-180 days) in the corticosteroid group vs 42 days (range, 17-180 days) for controls ( P =.11). A median number of 2 dilations (range 1-7) was performed in the corticosteroid group vs 3 dilations (range 1-9) in controls (RR, 0.76; 95% CI, 0.42-1.38; P =.36). Two major intervention-related complications occurred: 1 submucosal laceration in the corticosteroid group and 1 hemorrhage in the control group. Four patients in the corticosteroid group, but none of the controls, developed candida esophagitis ( P =.03). CONCLUSIONS: Corticosteroid injections do not provide a statistically significant decrease in frequency of repeat dilations or prolongation of the dysphagia-free period in patients with benign anastomotic esophagogastric strictures. Dutch Trial Registration number 2236.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2013; · 5.64 Impact Factor
  • Liver International. 01/2013;

Publication Stats

4k Citations
1,148.17 Total Impact Points

Institutions

  • 2004–2014
    • University of Groningen
      • • Department of Gastroenterology and Hepatology
      • • Department of Genetics
      Groningen, Groningen, Netherlands
  • 2013
    • Montreal Heart Institute
      • Research Centre
      Montréal, Quebec, Canada
  • 2012
    • Christian-Albrechts-Universität zu Kiel
      • Institute of Clinical Molecular Biology
      Kiel, Schleswig-Holstein, Germany
  • 2010–2012
    • Oslo University Hospital
      • Department of Transplantation Medicine
      Oslo, Oslo, Norway
  • 2011
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
    • Peking Union Medical College Hospital
      Peping, Beijing, China
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2005–2011
    • Universitair Medisch Centrum Groningen
      • • Department of Genetics
      • • Department of Gastroenterology and Hepatology
      Groningen, Groningen, Netherlands
  • 2008
    • University Medical Center Utrecht
      • Department of Medical Genetics
      Utrecht, Provincie Utrecht, Netherlands