We examined the relationship between retinal nerve fiber layer (RNFL) thickness and cognitive function in a population of older British adults.
Participants of the European Prospective Investigation ...of Cancer (EPIC) Norfolk cohort study underwent ophthalmic and cognitive assessment. Measurements of RNFL thickness were made using the Heidelberg Retina Tomograph (HRT). Cognitive testing included a short form of the Mini-Mental State Examination (SF-MMSE), an animal naming task, a letter cancellation task, the Hopkins Verbal Learning Test (HVLT), the National Adult Reading Test (NART), and the Paired Associates Learning Test. Multivariable linear regression models were used to assess associations of RNFL thickness with cognitive test scores, adjusted for age, sex, education level, social class, visual acuity, axial length, and history of cataract surgery.
Data were available from 5563 participants with a mean age of 67 years. A thicker HRT-derived RNFL thickness was associated with better scores for the SF-MMSE (0.06; 95% confidence interval CI, 0.02, 0.10, P = 0.005), HVLT (0.16, 95% CI 0.03, 0.29; P = 0.014), and NART (-0.24, 95% CI -0.46, -0.02, P = 0.035). The associations of RNFL thickness with SF-MMSE and HVLT remained significant following further adjustment for NART.
We found a significant association between HRT-derived RNFL thickness and scores from cognitive tests assessing global function, recognition, learning, episodic memory, and premorbid intelligence. However, the associations were weak and not currently of predictive value. Further research is required to confirm and clarify the nature of these associations, and identify biological mechanisms.
Systematic searches are integral to identifying the evidence that is used in National Institute for Health and Care Excellence (NICE) public health guidelines (PHGs). This study analyses the sources, ...including bibliographic databases and other techniques, required for PHGs. The aims were to analyse the sources used to identify the publications included in NICE PHGs; and to assess whether fewer sources could have been searched to retrieve these publications. Data showing how the included publications had been identified was collated using search summary tables. Three scenarios were created to test various combinations of sources to determine whether fewer sources could have been used. The sample included 29 evidence reviews, compiled using 13 searches, to support 10 PHG topics. Across the PHGs, 23 databases and six other techniques retrieved included publications. A mean reduction in total results of 6.5% could have been made if the minimum set of sources plus Cochrane Library, Embase, and MEDLINE were searched. On average, Cochrane Library, Embase, and MEDLINE contributed 76.8% of the included publications, with other databases adding 11% and other techniques 12.2%. None of the searches had a minimum set that was comprised entirely of databases. There was not a core set of sources for PHGs. A range of databases and techniques, covering a multi‐disciplinary evidence base, was required to identify all included publications. It would be possible to reduce the number of sources searched and make some gains in productivity. It is important to create a tailored set of sources to do an efficient search.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)‐based therapy to direct‐acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac ...toxicity. In this study, we sought to better understand the potential off‐target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS‐986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty‐four patients received IFN‐free BMS‐986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%‐50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T‐wave inversions were the most sensitive predictor of LVEF dysfunction. B‐type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS‐986094 toxicity. Conclusion: A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease. (Hepatology 2015;62:409–416
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To evaluate whether a simple health and wellness coaching (HWC) program embedded within routine clinical practice resulted in improved opioid weaning and discontinuation.
Retrospective double cohort ...study comparing longitudinal opioid use data and numeric pain scale ratings for patients in each group.
Single noninstitutional subspecialty pain management practice.
Twenty (daily opioid using) patients undergoing a multifo-cal HWC program with integrated pain neuroscience education (PNE) compared to 20 age- and gender-matched (daily opioid using) patients undergoing usual care.
A systematized series of interactive self-management topics/lessons on basic health topics pertinent to chronic pain, eg, posture, mobility, nutrition, sleep, stress management, and PNE.
Daily morphine milligram equivalents (MMEs) trajectory and discontinuation success (hypothesis and outcome measure formulated before data collection); numeric pain scale rating trajectory (hypothesis and outcome measure formulated after data collection).
MME decrease was significantly greater among cases (93.5 percent) than controls (50 percent; p = 0.004) as was discontinuation of opioids (30 percent vs 0). Cases reported decreased longitudinal 10-digit pain scale rating (-0.8) compared to controls (+0.1) without statistical significance.
Providing simple and salient HWC including PNE within pain management can significantly improve opioid weaning and discontinuation while mitigating pain.
Natural Killer T (NKT) cells and Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells that express semi-invariant αβ T cell receptors (TCRs) through which they recognise CD1d and MR1 ...molecules, respectively, in complex with specific ligands. These cells play important roles in health and disease in many organs, but their precise intra-organ location is not well established. Here, using CD1d and MR1 tetramer staining techniques, we describe the precise location of NKT and MAIT cells in lymphoid and peripheral organs. Within the thymus, NKT cells were concentrated in the medullary side of the corticomedullary junction. In spleen and lymph nodes, NKT cells were mainly localised within T cell zones, although following in vivo activation with the potent NKT-cell ligand α-GalCer, they expanded throughout the spleen. MAIT cells were clearly detectable in Vα19 TCR transgenic mice and were rare but detectable in lymphoid tissue of non-transgenic mice. In contrast to NKT cells, MAIT cells were more closely associated with the B cell zone and red pulp of the spleen. Accordingly, we have provided an extensive analysis of the in situ localisation of NKT and MAIT cells and suggest differences between the intra-organ location of these two cell types.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•IL-36γ induces MMP9 and NGAL expression by gingival epithelial cells.•p38 MAP kinase signaling enables differential induction of MMP9 and NGAL by IL-36γ.•Epithelial differentiation potentiates ...IL-36γ-inducible MMP9 and NGAL expression.•Porphyromonas gingivalis gingipain proteinases antagonise MMP9 and NGAL expression.
IL-36 cytokines are critical regulators of mucosal inflammation and homeostasis. IL-36γ regulates the expression of inflammatory cytokines and antimicrobial proteins by gingival epithelial cells (e.g. TIGK cells). Here, we show that IL-36γ also regulates the expression of matrix metalloproteinase 9 (MMP9) and neutrophil gelatinase-associated lipocalin (NGAL), important mediators of antimicrobial immunity and tissue homeostasis in mucosal epithelia. MMP9 and NGAL were not similarly induced by IL-17 or IL-22, thus indicating the importance of IL-36γ in the regulation of MMP9 and NGAL. Mechanistically, MMP9 and NGAL expression was demonstrated to be induced in an IRAK1- and NF-κB-dependent manner. Furthermore, signaling by p38 MAP kinase may enable their expression to be independently regulated by IL-36γ. The stronger IL-36γ-inducible expression of MMP9 and NGAL in terminally differentiating TIGK cells suggests that control of their expression is associated with the maturation of the gingival epithelium. Although MMP9 and NGAL expression in epithelial cells can also be induced by bacteria, their expression in TIGK cells was not induced by the periodontal pathogen Porphyromonas gingivalis, most likely due to antagonism by the gingipain proteinase virulence factors. This study advances our understanding of how IL-36γ may promote oral mucosal immunity and tissue homeostasis, and how this may be dysregulated by bacterial pathogens.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In mid-June 2009 the State of Victoria in Australia appeared to have the highest notification rate of pandemic (H1N1) 2009 influenza in the world. We hypothesise that this was because community ...transmission of pandemic influenza was already well established in Victoria at the time testing for the novel virus commenced. In contrast, this was not true for the pandemic in other parts of Australia, including Western Australia (WA).
We used data from detailed case follow-up of patients with confirmed infection in Victoria and WA to demonstrate the difference in the pandemic curve in two Australian states on opposite sides of the continent. We modelled the pandemic in both states, using a susceptible-infected-removed model with Bayesian inference accounting for imported cases.
Epidemic transmission occurred earlier in Victoria and later in WA. Only 5% of the first 100 Victorian cases were not locally acquired and three of these were brothers in one family. By contrast, 53% of the first 102 cases in WA were associated with importation from Victoria. Using plausible model input data, estimation of the effective reproductive number for the Victorian epidemic required us to invoke an earlier date for commencement of transmission to explain the observed data. This was not required in modelling the epidemic in WA.
Strong circumstantial evidence, supported by modelling, suggests community transmission of pandemic influenza was well established in Victoria, but not in WA, at the time testing for the novel virus commenced in Australia. The virus is likely to have entered Victoria and already become established around the time it was first identified in the US and Mexico.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease, characterised by progressive failure of the neuromuscular system. A (G4C2)n repeat expansion in C9ORF72 ...is the most common genetic cause of ALS and frontotemporal dementia (FTD). To date, the balance of evidence indicates that the (G4C2)n repeat causes toxicity and neurodegeneration via a gain-of-toxic function mechanism; either through direct RNA toxicity or through the production of toxic aggregating dipeptide repeat proteins. Here, we have generated a stable and isogenic motor neuronal NSC34 cell model with inducible expression of a (G4C2)102 repeat, to investigate the gain-of-toxic function mechanisms. The expression of the (G4C2)102 repeat produces RNA foci and also undergoes RAN translation. In addition, the expression of the (G4C2)102 repeat shows cellular toxicity. Through comparison of transcriptomic data from the cellular model with laser-captured spinal motor neurons from C9ORF72-ALS cases, we also demonstrate that the PI3K/Akt cell survival signalling pathway is dysregulated in both systems. Furthermore, partial knockdown of Pten rescues the toxicity observed in the NSC34 (G4C2)102 cellular gain-of-toxic function model of C9ORF72-ALS. Our data indicate that PTEN may provide a potential therapeutic target to ameliorate toxic effects of the (G4C2)n repeat.
BackgroundNeonatal herpes simplex virus infection is a rare but dangerous condition with a high mortality and morbidity unless recognised and treated early. A recent study1 suggests that the UK ...incidence may have increased since the last national surveillance studies were undertaken 15 and 30 years ago.2,3 There is currently no national guidance on when to initiate treatment for suspected neonatal HSV. Rising numbers of HSV cases may support the wider use of empirical treatment.ObjectivesTo define the: (1) current burden of HSV disease and virus types, in UK and Irish infants less than 90 days, over a two-year period, (2) types of HSV disease ie disseminated, meningoencephalitis or skin/eye/mouth disease, (3) presentations and management, (4) source of transmission, (5) antenatal risk factors.MethodsProspective surveillance of HSV infection in infants < 90 days of age in UK and Ireland commenced in July 2019 through the British Paediatric Surveillance Unit (BPSU). Paediatricians reporting cases were requested to complete a detailed semi-anonymised questionnaire. Case notifications & data from completed questionnaires during the first 18 months, July 2019 - Jan 2021, are reported here.Results137 cases reported to BPSU: 8 were errors, 80 clinicians completed questionnaires, 21 confirmed duplicates, leaving 59 cases for analysis. Estimated incidence is 6.9 cases per 100 000 live births based on 2019 UK & Ireland birth rates. 31 (53%) male, 17 (29%) born <37 weeks. 21 (36%) had disseminated (blood pcr positive), 18 (30%) encephalitis and 20 (34%) skin/eye/mouth (SEM) disease. HSV1: 29 (49%), HSV 2: 25 (42%), unknown:5 (9%). More of those with disseminated and CNS disease had HSV2 infections and more with SEM disease had HSV1. Presenting features of disseminated disease were non specific and only 3/21 (14%) presented with a fever. 10/21 (47.6%) had a CRP of less than 20 at presentation, 11/21 (52.3%) had a transaminitis. Disseminated disease was present in 4/5 (80%) babies born at <28 weeks and 11/39 (28%) >37 weeks gestation.Aciclovir was commenced in 54/59 but in only 23/59 (39.0%) on the day of presentation. Overall mortality was 22% but 57% in those with disseminated disease. Mortality by gestation was 60% <28 weeks, 25% 28–36+6 weeks and 18% >37 weeks.ConclusionsIncidence of neontatal HSV has doubled since the last national surveillance study. Mortality remains high and presenting features of disseminated disease are non-specific. Absence of fever in 86% of cases demonstrates that HSV should not only be considered in the assessment of the febrile infant. Awareness of this disease needs to be raised to enable early recognition and treatment.ReferencesBatra D, Davies P, Manktelow BN, et al. The incidence and presentation of neonatal herpes in a single UK tertiary centre, 2006–2013. Archives of Disease in Childhood 2014;99:916–921.Tookey P, et al. Surveillance of neonatal herpes in the British Isles 2004–2006. Submitted for publication.Tookey P1, Peckham CS. Neonatal herpes simplex virus infection in the British Isles. Paediatr Perinat Epidemiol 1996 Oct;10(4):432–42.
PDF
![[Ru(η6-p-cymene)Cl2(pta)] (...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1359-7345/small "[Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells")
