Topographic and electronic contrast of the graphene moir\'e on Ir(111) probed by scanning tunneling microscopy and non-contact atomic force microscopy

Epitaxial graphene grown on transition metal surfaces typically exhibits a moir\'e pattern due to the lattice mismatch between graphene and the underlying metal surface. We use both scanning tunneling microscopy (STM) and atomic force microscopy (AFM) experiments to probe the electronic and topographic contrast of the graphene moir\'e on the Ir(111) surface. While STM topography is influenced by the local density of states close to the Fermi energy and the local tunneling barrier height, AFM is capable of yielding the 'true' surface topography once the background force arising from the van der Waals (vdW) interaction between the tip and the substrate is taken into account. We observe a moir\'e corrugation of 35$\pm$10 pm, where the graphene-Ir(111) distance is the smallest in the areas where the graphene honeycomb is atop the underlying iridium atoms and larger on the fcc or hcp threefold hollow sites.Comment: revised versio

Functional Roles of the IgM Fc Receptor in the Immune System

It is now evident from studies of mice unable to secrete IgM that both non-immune “natural” and antigen-induced “immune” IgM are important for protection against pathogens and for regulation of immune responses to self-antigens. Since identification of its Fc receptor (FcμR) by a functional cloning strategy in 2009, the roles of FcμR in these IgM effector functions have begun to be explored. Unlike Fc receptors for switched Ig isotypes (e.g., FcγRs, FcεRs, FcαR, Fcα/μR, pIgR, FcRn), FcμR is selectively expressed by lymphocytes: B, T, and NK cells in humans and only B cells in mice. FcμR may have dual signaling ability: one through a potential as yet unidentified adaptor protein non-covalently associating with the FcμR ligand-binding chain via a His in transmembrane segment and the other through its own Tyr and Ser residues in the cytoplasmic tail. FcμR binds pentameric and hexameric IgM with a high avidity of ~10 nM in solution, but more efficiently binds IgM when it is attached to a membrane component via its Fab region on the same cell surface (cis engagement). Four different laboratories have generated Fcmr-ablated mice and eight different groups of investigators have examined the resultant phenotypes. There have been some clear discrepancies reported that appear to be due to factors including differences in the exons of Fcmr that were targeted to generate the knockouts. One common feature among these different mutant mice, however, is their propensity to produce autoantibodies of both IgM and IgG isotypes. In this review, we briefly describe recent findings concerning the functions of FcμR in both mice and humans and propose a model for how FcμR plays a regulatory role in B cell tolerance

Longitudinal regional brain volume loss in schizophrenia: Relationship to antipsychotic medication and change in social function.

BACKGROUND: Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators. METHOD: Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age=34.7, SD=0.77) and at follow-up (mean age=43.4, SD=0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA. RESULTS: Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction. CONCLUSION: Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.Academy of Finland, Medical Research Council, Sigrid Jusélius Foundation and the Signe and Ane Gyllenberg Foundation, Finland, Stanley Foundation, Brain & Behavior Research Foundation. The work was partially completed within the University of Cambridge Behavioural and Clinical Neuroscience Institute, supported by a joint award from the Medical Research Council and Wellcome Trust.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.schres.2015.06.01

Assessing risks of polypharmacy involving medications with anticholinergic properties

PURPOSE Anticholinergic burden (ACB), the cumulative effect of anticholinergic medications, is associated with adverse outcomes in older people but is less studied in middle-aged populations. Numerous scales exist to quantify ACB. The aims of this study were to quantify ACB in a large cohort using the 10 most common anticholinergic scales, to assess the association of each scale with adverse outcomes, and to assess overlap in populations identified by each scale. METHODS We performed a longitudinal analysis of the UK Biobank community cohort (502,538 participants, baseline age: 37-73 years, median years of follow-up: 6.2). The ACB was calculated at baseline using 10 scales. Baseline data were linked to national mortality register records and hospital episode statistics. The primary outcome was a composite of all-cause mortality and major adverse cardiovascular event (MACE). Secondary outcomes were all-cause mortality, MACE, hospital admission for fall/fracture, and hospital admission with dementia/delirium. Cox proportional hazards models (hazard ratio [HR], 95% CI) quantified associations between ACB scales and outcomes adjusted for age, sex, socioeconomic status, body mass index, smoking status, alcohol use, physical activity, and morbidity count. RESULTS Anticholinergic medication use varied from 8% to 17.6% depending on the scale used. For the primary outcome, ACB was significantly associated with all-cause mortality/MACE for each scale. The Anticholinergic Drug Scale was most strongly associated with mortality/MACE (HR = 1.12; 95% CI, 1.11-1.14 per 1-point increase in score). The ACB was significantly associated with all secondary outcomes. The Anticholinergic Effect on Cognition scale was most strongly associated with dementia/delirium (HR = 1.45; 95% CI, 1.3-1.61 per 1-point increase). CONCLUSIONS The ACB was associated with adverse outcomes in a middle- to older-aged population. Populations identified and effect size differed between scales. Scale choice influenced the population identified as potentially requiring reduction in ACB in clinical practice or intervention trials

Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth cohort

This naturalistic study analysed the association between cumulative lifetime antipsychotic dose and cognition in schizophrenia after an average of 16.5 years of illness. Sixty participants with schizophrenia and 191 controls from the Northern Finland Birth Cohort 1966 were assessed at age 43 years with a neurocognitive test battery. Cumulative lifetime antipsychotic dose-years were collected from medical records and interviews. The association between antipsychotic dose-years and a cognitive composite score based on principal component analysis was analysed using linear regression. Higher lifetime antipsychotic dose-years were significantly associated with poorer cognitive composite score, when adjusted for gender, onset age and lifetime hospital treatment days. The effects of typical and atypical antipsychotics did not differ. This is the first report of an association between cumulative lifetime antipsychotic dose and global cognition in midlife schizophrenia. Based on these data, higher lifetime antipsychotic dose-years may be associated with poorer cognitive performance at age 43 years. Potential biases related to the naturalistic design may partly explain the results; nonetheless, it is possible that large antipsychotic doses harm cognition in schizophrenia in the long-term.Peer reviewe

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

<b>Background</b> Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.<p></p> <b>Methods and findings</b> The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.<p></p> <b>Conclusions</b> Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems

Personalised lung cancer risk stratification and lung cancer screening: do general practice electronic medical records have a role?

Background: In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility. Methods: The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination. Results: Age 55–75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots). Discussion: A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact

Sex differences in the diagnosis of advanced cancer and subsequent outcome in people with chronic kidney disease: an analysis of a national population cohort

Background: In the general population, advanced cancer stage at presentation is associated with poorer health outcomes. People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We sought to determine whether people with CKD were more likely to present with advanced stage cancer, whether this was associated with survival, and whether these associations varied by sex. Methods: Data were from Secure Anonymised Information Linkage Databank (SAIL), a Welsh primary care database with linkage to cancer and death registries. We included patients with a de- novo cancer diagnosis (2011-2017), and at least two kidney function tests in the two years prior to diagnosis. Estimated glomerular filtration rate based on serum creatinine (eGFRcr) was calculated using the CKD-EPI 2009 equation (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer (stage 3 or 4 at diagnosis) by different values of eGFRcr at baseline. Cox proportional hazards models tested associations between eGFRcr at baseline and all-cause mortality risk (reference eGFR 75 to <90). Findings: There were 66,128 patients: 30,857 (46.7%) were female, mean age was 69.1 (standard deviation [SD] 13.8) years in females and 70.6 (SD 11.1) years in males; median eGFRcr at baseline was 78 (interquartile range [IQR] 63 – 90) mL/min/1.73m2 in both females and males. Over a median follow-up time of 3.1 (IQR 0.5 – 5.7) years in females and 2.9 (IQR 0.5-5.5) years in males, there were 17,303 deaths in females and 20,855 in males. An eGFRcr <30 was associated with higher odds of presenting with advanced cancer in males (OR 1.33 95% CI 1.09-1.62), but not in females (OR 1.17 95% CI 0.92-1.50); positive associations were primarily driven by prostate and breast cancers. With lower eGFRcr, hazards of cancer death increased in both sexes, but lower eGFRcr was associated with greater hazards of cancer death in females (eGFRcr <30: HR 1.71, 95% CI 1.56-1.88, p<0.001; male versus female comparison HR 0.88, 95% CI 0.78-0.90; p=0.037). Interpretation: CKD was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites (except prostate and breast), but was associated with reduced survival. Despite an initial survival advantage compared to males, females with CKD had disproportionately higher hazards of death. Though potential explanations for reduced survival after a cancer diagnosis are manifold, scrutiny of access to, efficacy, and safety of cancer treatments in people with CKD – particularly females with CKD – are warranted

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Background Rare variants ingenecodingregions likely have agreater impactondisease-relatedphenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-basedexome array analyses of15,449genes infivelarge incidence cohortsof individualswith type 1diabetes andproteinuriawere analyzedfor survival time toESKD, testing the top gene in a sixth cohort (n52372/1115 events all cohorts) and replicating in two retrospective case-control studies (n51072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17- b dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n54196; P value53.331027). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions HSD17B14 gene ismechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.Peer reviewe