H S Markus

University of Cambridge, Cambridge, England, United Kingdom

Are you H S Markus?

Claim your profile

Publications (170)1090.23 Total impact

  • Neurology 05/2015; DOI:10.1212/WNL.0000000000001606 · 8.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background To investigate potential cardiovascular and other eff ects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of infl ammation.
  • The Lancet Neurology 01/2015; 14(4):361-7. · 21.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to evaluate whether treatment with sodium valproate (SV) was associated with reduced risk of stroke or myocardial infarction (MI).
    Pharmacoepidemiology and Drug Safety 07/2014; 23(7). DOI:10.1002/pds.3651 · 3.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and Purpose-Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. Methods-Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. Results-One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. Conclusions-This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.
    Stroke 06/2014; 45(7):1920-1924. DOI:10.1161/STROKEAHA.114.005208 · 6.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.
    JAMA Psychiatry 05/2014; DOI:10.1001/jamapsychiatry.2014.528 · 12.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Personalized medicine is increasingly being employed across many areas of clinical practice, as genes associated with specific diseases are discovered and targeted therapies are developed. Mobile apps are also beginning to be used in medicine with the aim of providing a personalized approach to disease management. In some areas of medicine, patient-tailored risk prediction and treatment are applied routinely in the clinic, whereas in other fields, more work is required to translate scientific advances into individualized treatment. In this forum article, we asked specialists in oncology, neurology, endocrinology and mobile health technology to discuss where we are in terms of personalized medicine, and address their visions for the future and the challenges that remain in their respective fields.
    BMC Medicine 02/2014; 12(1):37. DOI:10.1186/1741-7015-12-37 · 7.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
    Nature Genetics 10/2013; DOI:10.1038/ng.2742 · 29.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
    Circulation 08/2013; DOI:10.1161/CIRCULATIONAHA.113.002251 · 14.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are small non-coding RNAs that are detectable in plasma and serum. Circulating levels of microRNAs have been measured in various studies related to cardiovascular disease. Heparin is a potential confounder of microRNA measurements due to its known interference with polymerase chain reactions. In this study, platelet-poor plasma was obtained from patients undergoing cardiac catheterisation for diagnostic coronary angiography, or for percutaneous coronary intervention, both before and after heparin administration. Heparin had pronounced effects on the assessment of the exogenous C. elegans spike-in control (decrease by >3 cycles), which disappeared 6 hours after the heparin bolus. Measurements of endogenous microRNAs were less sensitive to heparin medication. Normalization of individual microRNAs with the average cycle threshold value of all microRNAs provided a suitable alternative to normalisation with exogenous C. elegans spike-in control in this setting. Thus, both the timing of blood sampling relative to heparin dosing and the normalisation procedure are critical for reliable microRNA measurements in patients receiving intravenous heparin. This has to be taken into account when designing studies to investigate the relation of circulating microRNAs to acute cardiovascular events or coronary intervention.
    Thrombosis and Haemostasis 06/2013; 110(3). DOI:10.1160/TH13-05-0368 · 5.76 Impact Factor
  • Source
    PLoS Medicine 06/2013; · 14.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
    Stroke 05/2013; DOI:10.1161/strokeaha.113.679936 · 6.02 Impact Factor
  • Heart (British Cardiac Society) 05/2013; 99(Suppl 2):A139-A140. DOI:10.1136/heartjnl-2013-304019.265 · 6.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Short course of dual antiplatelet therapy for early secondary prevention is a promising treatment for patients with minor stroke or transient ischemic attack at high risk of recurrence. METHODS: We examined the efficacy and safety of dual antiplatelets in patients with transient ischemic attack or minor stroke, defined as National Institute of Health Stroke Scale scores 0-3, in a subgroup analysis of Clopidogrel plus aspirin versus Aspirin alone for Reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR) study. Microembolic signals on transcranial Doppler monitoring was used as surrogate marker for recurrent stroke risk. Patients with ≥1 microembolic signals at baseline were randomized to receive dual therapy (aspirin 75-160 mg daily and clopidogrel 300 mg day 1 then 75 mg daily) or monotherapy (aspirin 75-160 mg daily) for seven-days. RESULTS: Sixty-five of 100 patients recruited had transient ischemic attack or minor stroke: 30 received dual therapy and 35 received monotherapy. Mean onset-to-randomization was 2·3 days in dual therapy group and 3·2 days in monotherapy group (P = 0·03). At day 7, the proportion of patients with ≥1 microembolic signals was 9 of 29 patients in dual therapy group and 18 of 34 patients in monotherapy group (adjusted relative risk reduction 41·4%, 95% CI 29·8-51·1, P < 0·001). The median number of microembolic signals on day 7 was 0 in dual therapy group and 1·0 in monotherapy group (P = 0·046). No patients had intracranial or severe systemic hemorrhage. CONCLUSIONS: Early dual therapy with clopidogrel and aspirin reduces microembolic signals in patients with minor ischemic stroke or transient ischemic attack, without causing significant bleeding complications.
    International Journal of Stroke 03/2013; DOI:10.1111/ijs.12003 · 4.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: MicroRNA biomarkers are attracting considerable interest. Effects of medication, however, have not been investigated thus far. Objective: To analyse changes in plasma microRNAs in response to anti-platelet therapy. Methods and Results: Profiling for 377 microRNAs was performed in platelets, platelet microparticles, platelet-rich plasma, platelet-poor plasma and serum. Platelet-rich plasma showed markedly higher levels of microRNAs than serum and platelet-poor plasma. Few abundant platelet microRNAs, such as miR-24, miR-197, miR-191, and miR-223, were also increased in serum compared to platelet-poor plasma. In contrast, anti-platelet therapy significantly reduced microRNA levels. Using custom-made qPCR plates, 92 microRNAs were assessed in a dose-escalation study in healthy volunteers at four different time points: at baseline without therapy, at 1 week with 10mg prasugrel, at 2 weeks with 10mg prasugrel+75mg aspirin and at 3 weeks with 10mg prasugrel+300mg aspirin. Findings in healthy volunteers were confirmed by individual TaqMan qPCR assays (n=9). Validation was performed in an independent cohort of patients with symptomatic atherosclerosis (n=33) who received low dose aspirin at baseline. Plasma levels of platelet microRNAs, such as miR-223, miR-191 and others, i.e. miR-126 and miR-150, decreased upon further platelet inhibition. Conclusions: Our study demonstrated a substantial platelet contribution to the circulating microRNA pool and identified microRNAs responsive to anti-platelet therapy. It also highlights that anti-platelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma microRNAs to cardiovascular disease.
    Circulation Research 01/2013; 112(4). DOI:10.1161/CIRCRESAHA.111.300539 · 11.09 Impact Factor
  • Alice King, Martin Shipley, Hugh Markus
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND PURPOSE: Recent evidence suggests current best medical treatment may be sufficient to prevent stroke in patients with asymptomatic carotid stenosis. If this is the case, then it is important to determine risk reduction provided by treatments. Using Asymptomatic Carotid Emboli Study (ACES) prospective data, the effect of current treatment and risk factors on future stroke and transient ischemic attack risk were determined. METHODS: Four-hundred seventy-seven patients with asymptomatic carotid stenosis were followed-up every 6 months for 2 years. Changes in risk factors and stroke prevention therapies were reviewed at each visit. Using time-dependent Cox regression, the relationship between current treatment over time was determined and presented as hazard ratios and 95% confidence intervals for risk of stroke, transient ischemic attack, and cardiovascular death end points. RESULTS: On multivariate analysis, antiplatelets (P=0.001) and lower mean blood pressure (P=0.002) were independent predictors of reduced risk of ipsilateral stroke and transient ischemic attack. Antiplatelets (P<0.0001) and antihypertensives (P<0.0001) were independent predictors of a lower risk of any stroke or cardiovascular death. CONCLUSIONS: Antiplatelet therapy and blood pressure control are the most important factors in reducing short-term stroke and cardiovascular risk in patients with asymptomatic carotid stenosis. More prospective data are required for medical treatments in asymptomatic carotid stenosis in particular for current statin usage.
    Stroke 11/2012; 44(2). DOI:10.1161/STROKEAHA.112.673608 · 6.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND:Adequate control of blood pressure reduces the risk of recurrent stroke. We conducted a randomized controlled study to determine whether home blood pressure monitoring with nurse-led telephone support would reduce blood pressure in patients with hypertension and a history of stroke. METHODS:We recruited 381 participants (mean age 72 years) from outpatient and inpatient stroke clinics between Mar. 1, 2007, and Aug. 31, 2009. Nearly half (45%, 170) of the participants had some disability due to stroke. Participants were visited at home for a baseline assessment and randomly allocated to home blood pressure monitoring (n = 187) or usual care (n = 194). Those in the intervention group were given a monitor, brief training and telephone support. Participants who had home blood pressure readings consistently over target (target < 130/80 mm Hg) were advised to consult their family physician. The main outcome measure was a fall in systolic blood pressure after 12 months, measured by an independent researcher unaware of group allocation. RESULTS:Despite more patients in the intervention group than in the control group having changes to antihypertensive treatment during the trial period (60.1% [98/163] v. 47.6% [78/164], p = 0.02), the fall in systolic blood pressure from baseline did not differ significantly between the groups (adjusted mean difference 0.3 mm Hg, 95% confidence interval -3.6 to 4.2 mm Hg). Subgroup analysis showed significant interaction with disability due to stroke (p = 0.03 at 6 months) and baseline blood pressure (p = 0.03 at 12 months). INTERPRETATION:Overall, home monitoring did not improve blood pressure control in patients with hypertension and a history of stroke. It was associated with a fall in systolic pressure in patients who had uncontrolled blood pressure at baseline and those without disability due to stroke. Trial registration: ClinicalTrials.gov registration NCT00514800.
    Canadian Medical Association Journal 11/2012; 185(1). DOI:10.1503/cmaj.120832 · 5.81 Impact Factor
  • Source
    Hugh S Markus
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome wide association study approach, are transforming what we know about the genetics of multifactorial stroke and are identifying novel stroke genes. Current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However the already identified genetic variants explain only a small proportion of overall stroke risk and therefore are not currently useful in predicting risk in the individual patient. This may become a reality as we identify a greater number of stroke risk variants which explain the majority of genetic risk, and perhaps when information on rare variants, identified by whole genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of "personalized genetic " medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side effects, but these approaches have not yet been widely adopted in clinical practice.
    BMC Medicine 09/2012; 10(1):113. DOI:10.1186/1741-7015-10-113 · 7.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Barrett's esophagus is an increasingly common disease that  is strongly associated with reflux of stomach acid and usually  a hiatus hernia, and it strongly predisposes to esophageal  adenocarcinoma (EAC), a tumor with a very poor prognosis.  We report the first genome-wide association study on Barrett's  esophagus, comprising ,852 UK cases and 5,72 UK controls  in the discovery stage and 5,986 cases and 2,825 controls in  the replication stage. Variants at two loci were associated with  disease risk: chromosome 6p2, rs9257809 (P combined  =   4.09 × 0 −9 ; odds ratio (OR) = .2, 95% confidence interval  (CI) =.3–.28), within the major histocompatibility complex  locus, and chromosome 6q24, rs9936833 (P combined  =   2.74 × 0 −0 ; OR = .4, 95% CI = .0–.9), for which the  closest protein-coding gene is FOXF1, which is implicated in  esophageal development and structure. We found evidence that  many common variants of small effect contribute to genetic  susceptibility to Barrett's esophagus and that SNP alleles  predisposing to obesity also increase risk for Barrett's esophagus. Barrett's esophagus is one of the most common premalignant lesions in the western world. It affects over 2% of the adult population and, unlike bowel polyps, lacks any proven effective therapy 1 . In the major-ity of cases, Barrett's esophagus is associated with chronic gastro-esophageal reflux disease (GERD), including esophagitis 2,3 . Over 80% of affected individuals have a hiatus hernia in the lower esophagus that facilitates the reflux of acid and bile into the esophagus 4 . The measured annual risk of EAC in individuals with Barrett's esophagus varies widely but is approximately 0.4–1% (refs. 5–7). Notably, the incidence of EAC has been rising by 3% each year for the last 30 years; it is now the fifth most common cancer in the UK 8 . Despite modern multimodality therapy, the prog-nosis for EAC remains poor, with a 9–15% 5-year survival rate 9,10 . The etiology of Barrett's esophagus is not well characterized. Environmental factors, such as diet, are weakly associated with GERD, Barrett's esophagus and EAC, and obesity is a known risk factor for all three conditions 11 . There is also evidence implicating genetic factors: relative risks are increased by 2-to 4-fold for GERD, Barrett's esophagus and EAC when one first-degree relative is affected 12–17 . A segregation analysis of 881 pedigrees of familial Barrett's esophagus supports an incompletely dominant inheritance model with a polygenic component 18 . Extensive candidate gene and linkage searches have to date been unsuccessful in identifying genetic variants that are associated with risk of Barrett's esophagus 19 . As part of the Wellcome Trust Case Control Consortium 2 (WTCCC2) study of 15 common disorders and traits, we present the results of the first genome-wide association study of Barrett's esophagus susceptibility. Using a discovery cohort from the UK (with case samples from the Aspirin and Esomeprazole Chemoprevention Trial of Cancer in Barrett's esophagus (AspECT)) 20 and five repli-cation cohorts (including case samples from CHemoprevention Of Premalignant Intestinal Neoplasia (ChOPIN) and Esophageal Adenocarcinoma GenEtics Consortium (EAGLE) studies 9,20), we identified two variants associated with Barrett's esophagus, each with combined evidence at P < 5 × 10 −8 . The analysis workflow is outlined in Supplementary Figure 1, and characteristics of the case and con-trol samples that were included can be found in the Online Methods and Supplementary Table 1. For the discovery analysis, cases with histologically confirmed Barrett's esophagus (Online Methods) were recruited from sites across the UK (Supplementary Table 2). Population controls were taken from the WTCCC2 common set of 1958 Birth Cohort (58C) and National Blood Service (UKBS) samples as previously described 21 .
    Nature Genetics 09/2012; · 29.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia.

Publication Stats

7k Citations
1,090.23 Total Impact Points


  • 2014
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
  • 1995–2013
    • St George's, University of London
      • • Stroke and Dementia Research Centre
      • • Division of Biomedical Sciences
      Londinium, England, United Kingdom
  • 1995–2011
    • University of London
      Londinium, England, United Kingdom
  • 2004
    • Sharif University of Technology
      Teheran, Tehrān, Iran
    • Imperial College London
      • Department of Computing
      Londinium, England, United Kingdom
  • 2002
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
    • St George Hospital
      Sydney, New South Wales, Australia
  • 2000
    • London Research Institute
      Londinium, England, United Kingdom
    • St. George's School
      Middletown, Rhode Island, United States
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 1999
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 1997–1999
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom
  • 1996–1999
    • King's College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
  • 1998
    • University of Münster
      • Department of Neurology
      Münster, North Rhine-Westphalia, Germany