An update of the Mayo Clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients

Primary central nervous system vasculitis (PCNSV) is an uncommon condition in which lesions are limited to vessels of the brain and spinal cord. Because the clinical manifestations are not specific, the diagnosis is often difficult, and permanent disability and death are frequent outcomes. This study is based on a cohort of 163 consecutive patients with PCNSV who were examined at the Mayo Clinic over a 29-year period from 1983 to 2011. The aim of the study was to define the characteristics of these patients, which represents the largest series in adults reported to date. A total of 105 patients were diagnosed by angiographic findings and 58 by biopsy results. The patients diagnosed by biopsy more frequently had at presentation cognitive dysfunction, greater cerebrospinal fluid total protein concentrations, less frequent cerebral infarcts, and more frequent leptomeningeal gadolinium-enhanced lesions on magnetic resonance imaging (MRI), along with less mortality and disability at last follow-up. The patients diagnosed by angiograms more frequently had at presentation hemiparesis or a persistent neurologic deficit or stroke, more frequent infarcts on MRI and an increased mortality. These differences were mainly related to the different size of the vessels involved in the 2 groups. Although most patients responded to therapy with glucocorticoids alone or in conjunction with cyclophosphamide and tended to improve during the follow-up period, an overall increased mortality rate was observed. Relapses occurred in one-quarter of the patients and were less frequent in patients treated with prednisone and cyclophosphamide compared with those treated with prednisone alone. The mortality rate and degree of disability at last follow-up were greater in those with increasing age, cerebral infarctions on MRI, angiographic large vessel involvement, and diagnosis made by angiography alone, but were lower in those with gadolinium-enhanced lesions on MRI and in those with cerebral amyloid angiopathy. The annual incidence rate of PCNSV was estimated at 2.4 cases per 1,000,000 person-years. PCNSV appears to consist of several subsets defined by the size of the vessels involved, the clinical characteristics at presentation, MRI findings, and histopathological patterns on biopsy. Early recognition and treatment may reduce poor outcomes

Vasculitis of the gastrointestinal tract in chronic periaortitis

The term "chronic periaortitis" (CP), proposed by Mitchinson in 1984, comprises 3 main entities: idiopathic retroperitoneal fibrosis (IRF), inflammatory abdominal aortic aneurysms (IAAAs), and perianeurysmal retroperitoneal fibrosis (PRF).The presence of constitutional symptoms, high acute-phase reactants, positive autoantibodies, and associated autoimmune diseases suggests a systemic inflammatory process. Histopathologic findings show vasculitis with fibrinoid necrosis involving the aortic vasa vasorum as well as the small and medium retroperitoneal vessels.We reviewed the medical records of 608 patients with a diagnosis of vasculitis involving the gastrointestinal (GI) tract at the Mayo Clinic between January 1996 and December 2007. Only patients with biopsy-proven or typical angiographic findings of vasculitis localized to the GI tract were included.Five patients were identified with evidence of CP (1 patient with PRF, 1 with IRF, and 3 with IAAAs). Three patients were men, and the median age at diagnosis was 49 years. The diagnosis of GI vasculitis and CP was made simultaneously in 4 patients. At the time of onset, all patients had abdominal pain and constitutional manifestations; the median erythrocyte sedimentation rate was 62.5 mm/1 h (range, 20-86 mm/1 h). All patients had evidence of mesenteric vasculitis at angiography. Three patients also had associated renal artery stenoses. Abdominal computed tomography showed spleen infarcts in 2 patients, bowel wall thickening in 1, and liver infarction in 1. Two patients underwent surgical intervention for acute abdomen; there was histologic evidence of small bowel infarcts and infarction of the spleen and liver in 1. Oral prednisone was administered to all 5 patients (median starting dose, 60 mg/d; range, 25-80 mg/d). Three patients also received immunosuppressive agents, 1 tamoxifen, and 1 anti-tumor necrosis factor therapy. All patients had at least 1 relapse or recurrence of vasculitis, but at last visit, GI vasculitis and CP were in remission in all 5 patients.This study provides evidence that GI manifestations due to mesenteric vasculitis may be associated with CP. Vasculitic involvement of the renal arteries is also frequently present in these patients. Aggressive immunosuppressive treatment should be promptly initiated to forestall abdominal complications. These findings reinforce the hypothesis that a vasculitic process plays an important role in the pathogenesis of CP

Online questionnaire, clinical and biomechanical measurements for outcome prediction of plantar heel pain: feasibility for a cohort study

BACKGROUND: Plantar heel pain (PHP) accounts for 11-15% of foot symptoms requiring professional care in adults. Recovery is variable, with no robust prognostic guides for sufferers, clinicians or researchers. Therefore, we aimed to determine the validity, reliability and feasibility of questionnaire, clinical and biomechanical measures selected to generate a prognostic model in a subsequent cohort study. METHODS: Thirty-six people (19 females & 17 males; 20-63 years) were recruited with equal numbers in each of three groups: people with PHP (PwPHP), other foot pain (PwOP) and healthy (H) controls. Eighteen people performed a questionnaire battery twice in a randomised order to determine online and face-to-face agreement. The remaining 18 completed the online questionnaire once, plus clinical measurements including strength and range of motion, mid-foot mobility, palpation and ultrasound assessment of plantar fascia. Nine of the same people underwent biomechanical assessment in the form of a graded loaded challenge augmenting walking with added external weight and amended step length on two occasions. Outcome measures were (1) feasibility of the data collection procedure, measurement time and other feedback; (2) establishing equivalence to usual procedures for the questionnaire battery; known-group validity for clinical and imaging measures; and initial validation and reliability of biomechanical measures. RESULTS: There were no systematic differences between online and face-to-face administration of questionnaires (p-values all > .05) nor an administration order effect (d = - 0.31-0.25). Questionnaire reliability was good or excellent (ICC2,1_absolute)(ICC 0.86-0.99), except for two subscales. Full completion of the survey took 29 ± 14 min. Clinically, PwPHP had significantly less ankle-dorsiflexion and hip internal-rotation compared to healthy controls [mean (±SD) for PwPHP-PwOP-H = 14°(±6)-18°(±8)-28°(±10); 43°(±4)- 45°(±9)-57°(±12) respectively; p < .02 for both]. Plantar fascia thickness was significantly higher in PwPHP (3.6(0.4) mm vs 2.9(0.4) mm, p = .01) than the other groups. The graded loading challenge demonstrated progressively increasing ground reaction forces. CONCLUSION: Online questionnaire administration was valid therefore facilitating large cohort recruitment and being relevant to remote service evaluation and research. The physical and ultrasound examination revealed the expected differences between groups, while the graded loaded challenge progressively increases load and warrants future research. Clinician and researchers can be confident about these methodological approaches and the cohort study, from which useful clinical tools should result, is feasible. LEVEL OF EVIDENCE: IV

Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels

Primary central nervous system vasculitis (PCNSV) is a rare and poorly understood syndrome. We describe the clinical findings in 8 patients who appear to have a distinct subset of PCNSV. We identified 101 consecutive patients with PCNSV who were seen between January 1, 1983, and December 31, 2003. The diagnosis was based on conventional angiography in 70 patients and on central nervous system biopsy in 31 patients. Six of the 31 patients also had angiograms showing changes of vasculitis. Thus, 76 patients of the cohort had abnormal angiograms. Eight of the 101 patients had normal angiograms ("angiography-negative") but had brain biopsies that showed vasculitis. We compared the clinical and laboratory findings and outcomes of the 8 patients with angiography-negative PCNSV with those of the 76 patients with PCNSV whose angiograms showed evidence of vasculitis ("angiography-positive"). In comparison with the 76 patients with angiography-positive PCNSV, the 8 patients with angiography-negative PCNSV more commonly had 1) a cognitive disorder (87.5% vs. 43.4%; p =.024); 2) cerebrospinal fluid abnormalities (a protein level &gt;or=700 mg/L or a white blood cell count &gt;or=10 x 10(6)/L) (100% vs. 35.5%; p =.034); and 3) meningeal or parenchymal enhancing lesions on magnetic resonance imaging (75.0% vs. 23.9%; p =.007). Other differences between the 2 groups were observed but were not significantly different. All patients with angiography-negative PCNSV responded to treatment and none died. Angiography-negative PCNSV appears to be a distinct subtype of cerebral vasculitis with small vessel involvement beyond the resolution of conventional angiography and is associated with a favorable outcome

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Performance Measures Based on How Adults With Cancer Feel and Function: Stakeholder Recommendations and Feasibility Testing in Six Cancer Centers

PURPOSE Patient-reported outcome measures (PROMs) that assess how patients feel and function have potential for evaluating quality of care. Stakeholder recommendations for PRO-based performance measures (PMs) were elicited, and feasibility testing was conducted at six cancer centers. METHODS Interviews were conducted with 124 stakeholders to determine priority symptoms and risk adjustment variables for PRO-PMs and perceived acceptability. Stakeholders included patients and advocates, caregivers, clinicians, administrators, and thought leaders. Feasibility testing was conducted in six cancer centers. Patients completed PROMs at home 5-15 days into a chemotherapy cycle. Feasibility was operationalized as $75$ 75% patient acceptability. RESULTS Stakeholder priority PRO-PMs for systemic therapy were GI symptoms (diarrhea, constipation, nausea, vomiting), depression/anxiety, pain, insomnia, fatigue, dyspnea, physical function, and neuropathy. Recommended risk adjusters included demographics, insurance type, cancer type, comorbidities, emetic risk, and difficulty paying bills. In feasibility testing, 653 patients enrolled (approximately 110 per site), and 607 (93%) completed PROMs, which indicated high feasibility for home collection. The majority of patients (470 of 607; 77%) completed PROMs without a reminder call, and 137 (23%) of 607 completed them after a reminder call. Most patients (72%) completed PROMs through web, 17% paper, or 2% interactive voice response (automated call that verbally asked patient questions). For acceptability, . 95% of patients found PROM items to be easy to understand and complete. CONCLUSION Clinicians, patients, and other stakeholders agree that PMs that are based on how patients feel and function would be an important addition to quality measurement. This study also shows that PRO-PMs can be feasibly captured at home during systemic therapy and are acceptable to patients. PRO-PMs may add value to the portfolio of PMs as oncology transitions from fee-for-service payment models to performance-based care that emphasizes outcome measures

Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p &lt;.05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3–9; median total sample = 1,279.5, range = 276–3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Δr =.002 or.014, depending on analytic approach). The median effect size for the revised protocols (r =.05) was similar to that of the RP:P protocols (r =.04) and the original RP:P replications (r =.11), and smaller than that of the original studies (r =.37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r =.07, range =.00–.15) were 78% smaller, on average, than the original effect sizes (median r =.37, range =.19–.50)