Enhancing epidemiological surveillance of the emergence of the SARS-CoV-2 Omicron variant using spike gene target failure data,England, 15 November to 31 December 2021

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS.     

Prevalence and prognostic role of anaemia in patients with acute heart failure and preserved or depressed ventricular function

Observations available for patients with acute heart failure (HF) show conflicting results, and the prognostic role of anaemia ascertained on hospital admission is not well defined. We investigated the database of the Italian Survey on Acute Heart Failure (IS-AHF) to analyze prevalence, factors associated with and the prognostic role of anaemia (defined as haemoglobin < 12 g/dl) in patients hospitalized for acute HF with either depressed or preserved (>40%) ejection fraction (EF). The median haemoglobin level of the 2,318 patients considered in this analysis was 13 g/dl (inter-quartile range 11.5–14.3). The prevalence of anaemia was 31%. Patients who had anaemia were older, more frequently female gender, hospitalized for a chronic destabilized HF, had higher prevalence of preserved EF, hyponatremia, elevated troponin and other comorbidities (including diabetes, peripheral artery disease, chronic renal failure) than those who did not have anaemia. During the hospital stay, they were treated with higher doses of diuretics, and more frequently required mechanical ventilation and ultrafiltration, and less frequently received ACEi/ARB, aldosterone blockers and beta-blockers at hospital discharge. In-hospital mortality was 12.1 and 5.3% in patients with and without anaemia, respectively (p < 0.0001). In the multivariable analysis, anaemia was a significant independent predictor of in-hospital mortality apart from age, low systolic blood pressure, impaired renal function, elevated troponin assay, the non use of beta-blocker and the requirement of inotropic drug. In conclusion, anaemia diagnosed at hospital admission for acute HF is a frequent comorbidity with meaningful implications on the clinical management and prognosis both in patients with reduced and preserved EF.     

Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology

Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep‐like state of cortical slow‐wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures.     

Achieving euvolemia in peritoneal dialysis patients: a surprisingly difficult proposition

Preservation of residual renal function and reduced early mortality rates are likely to reflect the relative ease with which euvolemia can be achieved in peritoneal dialysis (PD) patients. Yet, there is concern that these patients are frequently fluid loaded, fuelled by the problems of ultrafiltration failure and worse survival observed in anuric patients with low fluid removal. In reality, the proportion of PD patients that are overhydrated is not dissimilar to hemodialysis but the challenges in achieving euvolemia might be different. These include (i) the undesirability of driving down the dry weight, in part to avoid excess glucose exposure, in part because there is a trade off in preserving residual renal function, (ii) limitations in our knowledge of how best to measure and apply measurements of fluid status in clinical practice, (iii) limitations imposed by the therapy itself (e.g., membrane function, sodium sieving), and (iv) the influence of hypoalbuminemia on fluid distribution. Treatment options that enable improved fluid management are available (e.g., automated peritoneal dialysis and icodextrin for rapid transporters, dietary salt restriction) or on the horizon (e.g., low sodium dialysates). We now need studies that aid clinicians in their decision making to enable best fluid management in their patients.     

Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.     

Otolith signals contribute to inter-individual differences in the perception of gravity-centered space

The aim of the present study was to investigate (1) the relative contribution of the egocentric reference as well as body orientation perception to visual horizon percept during tilt or during increased gravito-inertial acceleration (GiA, hypergravity environment) conditions and (2) the role of vestibular signals in the inter-individual differences observed in these perceptual modalities. Perceptual estimates analysis showed that backward tilt induced (1) an elevation of the visual horizon, (2) an elevation of the egocentric estimation (visual straight ahead) and (3) an overestimation of body tilt. The increase in the magnitude of GiA induced (1) a lowering of the apparent horizon, (2) a lowering of the straight ahead and (3) a perception of backward tilt. Overall, visual horizon percept can be expressed as the combination of body orientation perception and egocentric estimation. When assessing otolith reactivity using off-vertical axis rotation (OVAR), only visual egocentric estimation was significantly correlated with horizontal OVAR performance. On the one hand, we found a correlation between a low modulation amplitude of the otolith responses and straight ahead accuracy when the head axis was tilted relative to gravity. On the other hand, the bias of otolith responses was significantly correlated with straight ahead accuracy when subjects were submitted to an increase in the GiA. Thus, straight ahead sense would be dependent to some extent to otolith function. These results are discussed in terms of the contribution of otolith inputs in the overall multimodal integration subtending spatial constancy.     

Modulation of Ki67 and myogenic regulatory factor expression by tocotrienol-rich fraction ameliorates myogenic program of senescent human myoblasts

IntroductionReplicative senescence results in dysregulation of cell proliferation and differentiation, which plays a role in the regenerative defects observed during age-related muscle atrophy. Vitamin E is a well-known antioxidant, which potentially ameliorates a wide range of age-related manifestations. The aim of this study was to determine the effects of tocotrienol-rich fraction (TRF) in modulating the expression of proliferation- and differentiation-associated proteins in senescent human myoblasts during the differentiation phase.Material and methodsHuman skeletal muscle myoblasts were cultured until senescence. Young and senescent cells were treated with TRF for 24 h before and after differentiation induction, followed by evaluation of cellular morphology and efficiency of differentiation. Expression of cell proliferation marker Ki67 protein and myogenic regulatory factors MyoD and myogenin were determined.ResultsOur findings showed that treatment with TRF significantly improved the morphology of senescent myoblasts. Promotion of differentiation was observed in young and senescent myoblasts with TRF treatment as shown by the increased fusion index and larger size of myotubes. Increased Ki67 and myogenin expression with TRF treatment was also observed in senescent myoblasts, suggesting amelioration of the myogenic program by TRF during replicative senescence.ConclusionsTRF modulates the expression of regulatory factors related to proliferation and differentiation in senescent human myoblasts and could be beneficial for ameliorating the regenerative defects during aging.     

Critical and systematic evaluation of data for estimating human exposures to 2,4-dichlorophenoxyacetic acid (2,4-D) – quality and generalizability

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) has been commercially available since the 1940’s. Despite decades of data on 2,4-D in food, air, soil, and water, as well as in humans, the quality the quality of these data has not been comprehensively evaluated. Using selected elements of the Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument (temporal variability, avoidance of sample contamination, analyte stability, and urinary methods of matrix adjustment), the quality of 156 publications of environmental- and biomonitoring-based 2,4-D data was examined. Few publications documented steps were taken to avoid sample contamination. Similarly, most studies did not demonstrate the stability of the analyte from sample collection to analysis. Less than half of the biomonitoring publications reported both creatinine-adjusted and unadjusted urine concentrations. The scope and detail of data needed to assess temporal variability and sources of 2,4-D varied widely across the reviewed studies. Exposures to short-lived chemicals such as 2,4-D are impacted by numerous and changing external factors including application practices and formulations. At a minimum, greater transparency in reporting of quality control measures is needed. Perhaps the greatest challenge for the exposure community is the ability to reach consensus on how to address problems specific to short-lived chemical exposures in observational epidemiology investigations. More extensive conversations are needed to advance our understanding of human exposures and enable interpretation of these data to catch up to analytical capabilities. The problems defined in this review remain exquisitely difficult to address for chemicals like 2,4-D, with short and variable environmental and physiological half-lives and with exposures impacted by numerous and changing external factors.