Low Rates of Both Lipid-Lowering Therapy Use and Achievement of Low-Density Lipoprotein Cholesterol Targets in Individuals at High-Risk for Cardiovascular Disease across Europe

Aims To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. Methods and Results Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients’ 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE 5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE 10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels ( 2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as 1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD-related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72%and 1.61% among high-risk and very-high-risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin 40 mg/day or rosuvastatin 20 mg/day). Among veryhigh- risk patients, this figure was 8.4%. Conclusions There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in EuropeWriting support was provided by Oxford PharmaGenesis Ltd, Oxford, UK, and was funded by AstraZenec

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in <i>RUNX1</i>, <i>GATA2</i>, and <i>DDX41</i>

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation

BEAM allogeneic transplantation for patients with Hodgkin\u27s disease who relapse after autologous transplantation is safe and effective.

Because few patients failing autologous transplantation for Hodgkin\u27s disease survive long-term, we explored reduced-intensity allografts using BEAM conditioning and early withdrawal of immunosuppression as an alternative to palliative chemotherapy. Ten patients with Hodgkin\u27s disease underwent an allograft, receiving either matched sibling peripheral blood stem cells (5), partially matched sibling bone marrow (1), or matched unrelated bone marrow (4). Graft-versus-host disease (GVHD) prophylaxis was mini-methotrexate and FK-506 with weaning at day 60. The median age of patients was 35 years (range: 21 to 49 years). The median time from initial diagnosis was 73 months (range: 12 to 172 months) and from autograft was 49 months (range: 5 to 143 months). One patient was in CR, 5 patients were in partial remission, 3 were in relapse, and 1 patient had primary refractory disease. All patients\u27 transplants engrafted rapidly, and the 100-day mortality was 0. Two patients developed acute GVHD. Five of the 9 patients beyond 100 days have developed mild chronic GVHD, of which 1 case was progressive and required systemic therapy. All 10 responded: 8 complete responses and 2 partial remissions. Three patients have relapsed (at 2, 6, and 8 months, respectively), 1 has died at 4 months. At a mean of 12 months (range: 1 to 21 months) after allograft, 9 of 10 patients are alive, with 7 in continuous remission. BEAM allogeneic transplantation with early reduction in immunosuppression is safe (no treatment-related deaths) and effective in advanced Hodgkin\u27s disease where autografts have failed. A graft versus lymphoma effect appears to be a significant contributing factor in responding patients

Primary localized cutaneous nodular amyloidosis successfully treated with cyclophosphamide

Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare subtype of localized cutaneous amyloidosis and can be associated with various connective tissue disorders. It can be difficult to treat and past therapies include surgical excision, dermabrasion, electrodessication and curettage, cryotherapy and laser therapy. We present a case of a middle-aged woman with PLCNA associated with CREST (calcinosis, Raynaud phenomenon, oesophageal motility disorders, sclerodactyly and telangiectasia) syndrome and Sjögren\u27s syndrome responding to cyclophosphamide with no new amyloid deposits and resolution of skin ulceration after many years of resistance to drug therapy. It is important to monitor these patients for progression into systemic amyloidosis

Going home? An ethnographic study of assessment of capacity and best interests in people with dementia being discharged from hospital

Objective: To understand how, on medical wards, judgements about capacity and best interests with respect to going home are made – in line with the Mental Capacity Act 2005 – for people with dementia and how decision-making around hospital discharge for people with dementia and their families might be improved. Design: Ward-based ethnography. Observational data were captured through: detailed fieldnotes, in-depth interviews, medical-record review and focus groups. Themes and key issues identified using constant comparative analysis of 29 cases. Participants: Theoretical sampling of key stakeholders, including patients with dementia (with and without residence capacity), their relatives and a range of practitioners from the multi-disciplinary teams providing health and social care. Setting: Three hospital wards (acute and rehabilitation) in two hospitals within two NHS healthcare trusts in the North of England over a period of nine months between 2008 and 2009. Results: Analysis highlights the complexity of judgements about capacity and best interests, along with the workings of the MCA, in relation to decisions about place of residence for people with dementia facing discharge from hospital. Five key themes emerged from data: the complexity of borderline decisions; the requirement for better understanding of assessment approaches in relation to residence capacity; the need for better documentation; the importance of narrative; and the crucial relevance of time and timing in making these decisions. Conclusions: We need: more support and training for practitioners, as well as support for patients and families; clarity about the information to be imparted to the person with dementia; more advocacy for people with dementia; appropriate assessments embedded in routine clinical practice; the patient with dementia to be centre-stage in this decision-making; and properly resourced step-down or rehabilitation units to facilitate timely and good decision-making about place of residence

Expanding the biotechnology potential of lactobacilli through comparative genomics of 213 strains and associated genera

Lactobacilli are a diverse group of species that occupy diverse nutrient-rich niches associated with humans, animals, plants and food. They are used widely in biotechnology and food preservation, and are being explored as therapeutics. Exploiting lactobacilli has been complicated by metabolic diversity, unclear species identity and uncertain relationships between them and other commercially important lactic acid bacteria. The capacity for biotransformations catalysed by lactobacilli is an untapped biotechnology resource. Here we report the genome sequences of 213 Lactobacillus strains and associated genera, and their encoded genetic catalogue for modifying carbohydrates and proteins. In addition, we describe broad and diverse presence of novel CRISPR-Cas immune systems in lactobacilli that may be exploited for genome editing. We rationalize the phylogenomic distribution of host interaction factors and bacteriocins that affect their natural and industrial environments, and mechanisms to withstand stress during technological processes. We present a robust phylogenomic framework of existing species and for classifying new species.PUBLISHEDpeer-reviewe