A Field Study of Consociationalism in the Northern Ireland Assembly: A Moderating Influence or Threat to Democracy?

This paper is the outcome of a month-long exploratory study on whether consociationalism has a moderating influence on politics in Northern Ireland. I analyzed the impact of consociationalism on policymaking, party platforms and voter choice to determine if it strengthens and enlarges the middle ground or bifurcates the political community into two extreme and conflicting political agendas. Data was obtained through a literature study and eight interviews with academics as well as political representatives and advisors. This research tested two competing theories of consociationalism: David Horowitz’s theory of consociationalism as a centrifugal force and John McGarry’s and Brendand O’Leary’s theory that consociationalism encourages cooperation and unifying politics. It is concluded that consociationalism has had a dramatic moderating influence on policies and political platforms, but voter choice is still controlled by ethnic allegiances. The disconnect between voter choice and actual governance within Stormont allows parties to grandstand on loose, undefined and shifting platforms which stifles the democratic process. This paper recommends a shift in electoral systems or minor changes to the current consociational structure

HIDDen: Hospice Inpatient Deep vein thrombosis Detection prospective longitudinal observational study to explore the prevalence, symptom burden and natural history of venous thromboembolism in people with advanced cancer

BACKGROUND: The prevalence of deep venous thrombosis in patients with advanced cancer is unconfirmed and it is unknown whether current international thromboprophylaxis guidance is applicable to this population. We aimed to determine prevalence and predictors of femoral deep vein thrombosis in patients admitted to specialist palliative care units (SPCUs). METHODS: We did this prospective longitudinal observational study in five SPCUs in England, Wales, and Northern Ireland (four hospices and one palliative care unit). Consecutive adults with cancer underwent bilateral femoral vein ultrasonography on admission and weekly until death or discharge for a maximum of 3 weeks. Data were collected on performance status, attributable symptoms, and variables known to be associated with venous thromboembolism. Patients with a short estimated prognosis (<5 days) were ineligible. The primary endpoint of the study was the prevalence of femoral deep vein thrombosis within 48 h of SPCU admission, analysed by intention to treat. This study is registered with the ISRCTN registry, number ISRCTN97567719. FINDINGS: Between June 20, 2016, and Oct 16, 2017, 343 participants were enrolled (mean age 68·2 years [SD 12·8; range 25-102]; 179 [52%] male; mean Australian-modified Karnofsky performance status 49 [SD 16·6; range 20-90]). Of 273 patients with evaluable scans, 92 (34%, 95% CI 28-40) had femoral deep vein thrombosis. Four participants with a scan showing no deep vein thrombosis on admission developed a deep vein thrombosis on repeat scanning over 21 days. Previous venous thromboembolism (p=0·014), being bedbound in the past 12 weeks for any reason (p=0·003), and lower limb oedema (p=0·009) independently predicted deep vein thrombosis. Serum albumin concentration (p=0·43), thromboprophylaxis (p=0·17), and survival (p=0·45) were unrelated to deep vein thrombosis. INTERPRETATION: About a third of patients with advanced cancer admitted to SPCUs had a femoral deep vein thrombosis. Deep vein thrombosis was not associated with thromboprophylaxis, survival, or symptoms other than leg oedema. These findings are consistent with venous thromboembolism being a manifestation of advanced disease rather than a cause of premature death. Thromboprophylaxis for SPCU inpatients with poor performance status seems to be of little benefit. FUNDING: National Institute for Health Research (Research for Patient Benefit programme)

Predictors of severe relapse in pregnant women with psychotic or bipolar disorders

Pregnancy in women with severe mental illness is associated with adverse outcomes for mother and infant. There are limited data on prevalence and predictors of relapse in pregnancy. A historical cohort study using anonymised comprehensive electronic health records from secondary mental health care linked with national maternity data was carried out. Women with a history of serious mental illness who were pregnant (2007–2011), and in remission at the start of pregnancy, were studied; severe relapse was defined as admission to acute care or self-harm. Predictors of relapse were analysed using random effects logistic regression to account for repeated measures in women with more than one pregnancy in the study period. In 454 pregnancies (389 women) there were 58 (24%) relapses in women with non-affective psychoses and 25 (12%) in women with affective psychotic or bipolar disorders. Independent predictors of relapse included non-affective psychosis (adjusted OR = 2.03; 95% CI = 1.16–3.54), number of recent admissions (1.37; 1.03–1.84), recent self-harm (2.24; 1.15–4.34), substance use (2.15; 1.13–4.08), smoking (2.52; 1.26–5.02) and non-white ethnicity (black ethnicity: 2.37; 1.23,4.57, mixed/other ethnicity: 2.94; 1.32,6.56). Women on no regular medication throughout first trimester were also at greater risk of relapse in pregnancy (1.99; 1.05–3.75). There was no interaction between severity of illness and medication status as relapse predictors. Therefore, women with non-affective psychosis and higher number of recent acute admissions are at significant risk of severe relapse in pregnancy. Continuation of medication in women with severe mental illness who become pregnant may be protective

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

miRNA-Seq identifies a serum miRNA panel, which combined with APRI can detect and monitor liver disease in paediatric Cystic Fibrosis

Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on non-specific assessments, while liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical and imaging assessments as follows: CFLD (n=44), CF patients with no evidence of liver disease (CFnoLD, n=40) and healthy controls (n=40). Serum miRNAs were analysed using miRNA-sequencing. Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, while miR-142-3p and let-7g-5p were downregulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an AUROC=0.91 (sensitivity=83%, specificity=92%;

Red-flag sepsis and SOFA identifies different patient population at risk of sepsis-related deaths on the general ward

Controversy exists regarding the best diagnostic and screening tool for sepsis outside the intensive care unit (ICU). Sequential organ failure assessment (SOFA) score has been shown to be superior to systemic inflammatory response syndrome (SIRS) criteria, however, the performance of “Red Flag sepsis criteria” has not been tested formally. The aim of the study was to investigate the ability of Red Flag sepsis criteria to identify the patients at high risk of sepsis-related death in comparison to SOFA based sepsis criteria. We also investigated the comparison of Red Flag sepsis to quick SOFA (qSOFA), SIRS, and national early warning score (NEWS) scores and factors influencing patient mortality. Patients were recruited into a 24-hour point-prevalence study on the general wards and emergency departments across all Welsh acute hospitals. Inclusion criteria were: clinical suspicion of infection and NEWS 3 or above in-line with established escalation criteria in Wales. Data on Red Flag sepsis and SOFA criteria was collected together with qSOFA and SIRS scores and 90-day mortality. 459 patients were recruited over a 24-hour period. 246 were positive for Red Flag sepsis, mortality 33.7% (83/246); 241 for SOFA based sepsis criteria, mortality 39.4% (95/241); 54 for qSOFA, mortality 57.4% (31/54), and 268 for SIRS, mortality 33.6% (90/268). 55 patients were not picked up by any criteria. We found that older age was associated with death with OR (95% CI) of 1.03 (1.02–1.04); higher frailty score 1.24 (1.11–1.40); DNA-CPR order 1.74 (1.14–2.65); ceiling of care 1.55 (1.02–2.33); and SOFA score of 2 and above 1.69 (1.16–2.47). The different clinical tools captured different subsets of the at-risk population, with similar sensitivity. SOFA score 2 or above was independently associated with increased risk of death at 90 days. The sequalae of infection-related organ dysfunction cannot be reliably captured based on routine clinical and physiological parameters alone

Tau‐mediated synaptic dysfunction is coupled with HCN channelopathy

INTRODUCTION: In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels contribute to disease‐associated abnormalities in multiple neurodegenerative diseases. METHODS: To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age‐matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons. RESULTS: Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization‐induced membrane voltage “sag” and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents. DISCUSSION: Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network‐wide structural and functional synaptic deficits. Highlights: - Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are functionally linked to the development of tauopathy. - Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy. - Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization‐induced membrane voltage “sag” demonstrating a detrimental effect of tau abnormalities on HCN channel function. - Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice

Sepsis-related deaths in the at-risk population on the wards: attributable fraction of mortality in a large point-prevalence study

Objective Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. Results 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%)

Regulation of mammalian gastrin/CCK receptor (CCK2R) expression in vitro and in vivo

The gastrin/CCK receptor (CCK2R) mediates the physiological functions of gastrin in the stomach, including stimulation of acid secretion and cellular proliferation and migration, but little is known about the factors that regulate its expression. We identified endogenous CCK2R expression in several cell lines and used luciferase promoter–reporter constructs to define the minimal promoter required for transcription in human gastric adenocarcinoma, AGS, and rat gastric mucosa, RGM1, cells. Consensus binding sites for SP1, C/EBP and GATA were essential for activity. Following serum withdrawal from RGM1 and AR42J cells, endogenous CCK2R mRNA abundance and the activity of a CCK2R promoter–reporter construct were significantly elevated. Transcription of CCK2R was also increased in AGS-GR and RGM1 cells by gastrin through mechanisms partly dependent upon protein kinase C (PKC) and mitogen/extracellular signal-regulated kinase (MEK). Gastrin significantly increased endogenous CCK2R expression in RGM1 cells, and CCK2R protein expression was elevated in the stomach of hypergastrinaemic animals. In mice with cryoulcers in the acid-secreting mucosa, CCK2R expression increased progressively in the regenerating mucosa adjacent to the ulcer repair margin, evident at 6 days postinjury and maximal at 13 days. De novo expression of CCK2R was observed in the submucosa beneath the repairing ulcer crater 6–9 days postinjury. Many of the cells in mucosa and submucosa that expressed CCK2R in response to cryoinjury were identified as myofibroblasts, since they coexpressed vimentin and smooth muscle α-actin but not desmin. The data suggest that increased CCK2R expression might influence the outcome of epithelial inflammation or injury and that the response may be mediated in part by myofibroblasts