Using high-resolution climate change information in water management: a decision-makers' perspective.

The UK Climate Change Act requires the Environment Agency to report the risks it faces from climate change and actions taken to address these. Derived information from projections is critical to understanding likely impacts in water management. In 2019, the UK published an ensemble of high-resolution model simulations. The UKCP Local (2.2 km) projections can resolve smaller scale physical processes that determine rainfall and other variables at subdaily time-scales with the potential to provide new insights into extreme events, storm runoff and drainage management. However, simulations also need to inform adaptation. The challenge ahead is to identify and provide derived products without the need for further analysis by decision-makers. These include a wider evaluation of uncertainty, narratives about rainfall change across the projections and bias-corrected datasets. Future flood maps, peak rainfall estimates, uplift factors and future design storm profiles also need detailed guidance to support their use. Central government support is justified in the provision of up-to-date impacts information to inform flood risk management, given the large risks and exposure of all sectors. The further development of projections would benefit from greater focus and earlier scoping with industry representatives, operational tool developers and end users. This article is part of a discussion meeting issue 'Intensification of short-duration rainfall extremes and implications for flash flood risks'.

Chronic breathlessness associated with poorer physical and mental health-related quality of life (SF-12) across all adult age groups.

Little is known about the impact of chronic breathlessness (modified Medical Research Council (mMRC) score ≥2 for most days, at least three of the last six months) on health-related quality of life (Short Form-12 (SF-12)). 3005 adults from randomly selected households were interviewed face-to-face in South Australia. mMRC ≥2 community prevalence was 2.9%. Adjusted analyses showed clinically meaningful and statistically significant decrements of physical and mental components of SF-12 (mean SF-12 summary scores in physical (-13.0 (-16.0 to -10.2)) and mental (-10.7 (-13.7 to -7.8)) components compared with people with mMRC=0) as chronic breathlessness severity increased, across five age groupings.

Who experiences higher and increasing breathlessness in advanced cancer? The longitudinal EPCCS Study.

PURPOSE: Breathlessness is a major cause of suffering in advanced cancer. We aimed to determine the symptom trajectory in people with advanced cancer and to identify those at increased risk of experiencing higher or increasing breathlessness over time in advanced cancer. PATIENTS AND METHODS: This was an analysis of the multinational, prospective, longitudinal European Palliative Care Cancer Symptom (EPCCS) study. We included adults with confirmed incurable cancer enrolled in palliative care, with prospective monthly assessments for up to 6 months, withdrawal or death, whichever came first. Symptom severity (0-10 numerical rating scales) was analyzed using multivariate random coefficients regression. RESULTS: A total of 1689 patients (50 % women; mean age 65.7 ± [standard deviation; SD] 12.4 years) were included. Main diagnoses were digestive (31 %), lung (20 %), and breast (17 %) cancers. During a median follow-up of 62 (interquartile range, 0 to 133) days, 65 % were breathless at some point and 36 % of all patients reported moderate/severe breathlessness. The group mean (1.6 points; SD, 2.4) was unchanged over time, but the severity varied markedly between patients and over time. Independent predictors for worse breathlessness were COPD, lung cancer, living alone, lung metastases, anxiety, pain, depression, and lower performance status. Predictors of worsening breathlessness over time were low performance status (p = 0.039) and moderate to severe pain (p = 0.012). CONCLUSION: In the largest longitudinal clinical study to date in advanced cancer alone, breathlessness was frequent and associated with factors including respiratory disease, other concurrent unpleasant symptoms, and impaired performance status. Increase in severity over time was predicted by performance status and pain.

Relationship between iron deficiency and expression of genes involved in iron metabolism in human myocardium and skeletal muscle.

BACKGROUND: Iron deficiency (ID) is associated with adverse prognosis in patients with heart failure. This study aims to investigate the relationship between ID and expression of genes involved in iron metabolism in human myocardium and skeletal muscle, focusing on Transferrin 1 receptor (TfR1), the main pathway of cellular iron uptake. METHODS: Patients undergoing elective CABG were assessed prior to surgery with echocardiography and serum iron parameters. Core needle biopsies were collected from the left and right ventricle (LV, RV), the right atrium and intercostal skeletal muscle (SM). Gene expression analyses were done by mRNA sequencing. RESULTS: Of 69 patients (median age 69 years, 91% men), 28% had ID. 26% had HFrEF, 25% had HFpEF physiology according to echocardiographic findings and NT-proBNP levels, and 49% had normal LV function. The expression of TfR1 was increased in patients with ID compared to patients without ID in ventricular tissue (p = 0.04) and in intercostal SM (p = 0.01). The increase in TfR1 expression in LV and RV was more pronounced when analysing patients with absolute ID (S-Ferritin<100 µg/L). Analysing the correlation between various iron parameters, S-Ferritin levels showed the strongest correlation with TfR1 expression. There was no correlation with NT-proBNP levels and no difference in TfR1 expression between different HF phenotypes. CONCLUSIONS: In patients undergoing elective CABG we found an association between ID and increased TfR1 expression in myocardium regardless of LV function, indicating physiologically upregulated TfR1 expression in the presence of ID to restore intracellular iron needs. CLINICAL TRIAL REGISTRATION: Clinicaltrials.govNCT03671122.

Global climate-driven trade-offs between the water retention and cooling benefits of urban greening.

Urban greening can potentially help mitigate heat-related mortality and flooding facing the >4 billion urban population worldwide. However, the geographical variation of the relative combined hydrological and thermal performance benefits of such interventions are unknown. Here we quantify globally, using a hydrological model, how climate-driven trade-offs exist between hydrological retention and cooling potential of urban greening such as green roofs and parks. Using a Budyko framework, we show that water retention generally increases with aridity in water-limited environments, while cooling potential favors energy-limited climates. Our models suggest that common urban greening strategies cannot yield high performance simultaneously for addressing both urban heat-island and urban flooding problems in most cities globally. Irrigation, if sustainable, may enhance cooling while maintaining retention performance in more arid locations. Increased precipitation variability with climate change may reduce performance of thinner green-infrastructure more quickly compared to greened areas with thicker soils and root systems. Our results provide a conceptual framework and first-order quantitative guide for urban development, renewal and policymaking.

A method for generating obstructive thrombi in the coronary arteries of the conscious dog.

A technique for staging the generation of obstructive thrombi in the coronary arteries of conscious dogs is described. At thoracotomy, electrodes are placed in the lumina of coronary artery branches. When thrombus generation in proximity to the intraluminal electrode tip is desired, anodal current is applied to the exteriorised end of the electrode. In each of nine anaesthetised adult mongrel dogs two to seven intracoronary electrodes were implanted for a total of 35. One to 75 days later, 50 to 800 microA anodal current was applied to 16 electrodes for 30 min to 48 h. Upon autopsy, thrombi in various stages of organisation were found in proximity to the intracoronary portion of 15 electrodes. Six electrodes were found to be damaged or broken. In contrast, only four of the 13 control electrodes were sites of thrombus formation. In seven dogs tissue sections indicated either myocardial ischaemia or infarct in regions whose perfusion was blocked by thrombi. This method may provide for discretionary generation of intracoronary thrombi in the desired quantity, at the preferred site(s), at selected times of onset. Consequently, it offers the possibility of adjusting the onset, severity, and time course of myocardial ischaemia.

Organotellurium compounds as efficient retarders of lipid peroxidation in methanol.

Diaryl tellurides were found efficiently to retard azo-initiated lipid peroxidation of linoleic acid in methanol. The most efficient compounds, 31 and 39, contained one and two hydroxyl groups, respectively, in the para positions and methyl groups in all four positions ortho to tellurium. As determined by the values of n.kinh, these materials were as effective retarders of lipid peroxidation as vitamin E. Contrary to the conventional antioxidants examined, diaryl tellurides were found to inhibit peroxidation for long times, seemingly with an autocatalytic mechanism. Diaryl tellurides were found to be partially oxidized during the peroxidation. The reduction of tellurium (IV) compounds to the divalent state during the conditions of the experiment is discussed. The reactivity of some diaryl chalcogenides toward 2,2-diphenyl-1-picrylhydrazyl (DPPH) in methanol was studied. All compounds investigated were less reactive than vitamin E. One of the most active organotellurium compounds, bis(4-aminophenyl) telluride, reacted considerably faster with DPPH than the corresponding selenide or sulfide. It was concluded that mechanisms involving both hydrogen atom transfer and electron transfer were operative in the reaction of organotellurides with DPPH.

Quantification of human plasma phospholipid transfer protein (PLTP): relationship between PLTP mass and phospholipid transfer activity.

A sensitive sandwich-type enzyme-linked immunosorbent assay (ELISA) for human plasma phospholipid transfer protein (PLTP) has been developed using a monoclonal capture antibody and a polyclonal detection antibody. The ELISA allows for the accurate quantification of PLTP in the range of 25-250 ng PLTP/assay. Using the ELISA, the mean plasma PLTP concentration in a Finnish population sample (n = 159) was determined to be 15.6 +/- 5.1 mg/l, the values ranging from 2.30 to 33.4 mg/l. PLTP mass correlated positively with HDL-cholesterol (r = 0.36, P < 0.001), apoA-I (r = 0.37, P < 0.001), apoA-II (r = 0.20, P < 0.05), Lp(A-I) (r=0.26, P=0.001) and Lp(A-I/A-II) particles (r=0.34, P<0.001), and negatively with body mass index (BMI) (r = -0.28, P < 0.001) and serum triacylglycerol (TG) concentration (r = -0.34, P < 0.001). PLTP mass did not correlate with phospholipid transfer activity as measured with a radiometric assay. The specific activity of PLTP, i.e. phospholipid transfer activity divided by PLTP mass, correlated positively with plasma TG concentration (r=0.568, P<0.001), BMI (r=0.45, P<0.001), apoB (r = 0.45, P < 0.001). total cholesterol (r=0.42, P < 0.001), LDL-cholesterol (r = 0.34, P < 0.001) and age (r = 0.36, P < 0.001), and negatively with HDL-cholesterol (r= -0.33, P < 0.001), Lp(A-I) (r= -0.21, P < 0.01) as well as Lp(A-I/A-II) particles (r = -0.32, P < 0.001). When both PLTP mass and phospholipid transfer activity were adjusted for plasma TG concentration, a significant positive correlation was revealed (partial correlation, r = 0.31, P < 0.001). The results suggest that PLTP mass and phospholipid transfer activity are strongly modulated by plasma lipoprotein composition: PLTP mass correlates positively with parameters reflecting plasma high density lipoprotein (HDL) levels, but the protein appears to be most active in subjects displaying high TG concentration.

Critical review of non-invasive respiratory monitoring in medical care.

Respiratory failure can be difficult to predict. It can develop into a life-threatening condition in just a few minutes, or it can build up more slowly. Thus continuous monitoring of respiratory activity should be mandatory in clinical, high-risk situations, and appropriate monitoring equipment could be life-saving. The review considers non-invasive methods and devices claimed to provide information about respiratory rate or depth, or gas exchange. Methods are categorised into those responding to movement, volume and tissue composition detection; air flow; and blood gas concentration. The merits and limitations of the methods and devices are analysed, considering information content and their ability to minimise the rate of false alarms and false non-alarms. It is concluded that the field of non-invasive respiratory monitoring is still in an exploratory phase, with numerous reports on specific device solutions but less work on evaluation and adaptation to clinical requirements. Convincing evidence of the clinical usefulness of respiratory monitors is still lacking. Devices responding only to respiratory rate, and lacking information about actual gas exchange, will have limited clinical value. Furthermore, enhancement in specificity and sensitivity to avoid false alarms and non-alarms will be necessary to meet clinical requirements. Miniature CO2 sensors are identified as one route towards substantial improvement.

Psychophysiological stress responses, muscle tension, and neck and shoulder pain among supermarket cashiers.

This study examined psychological and physiological stress, as well as muscle tension and musculoskeletal symptoms, among 72 female supermarket cashiers. Stress levels were found to be significantly elevated at work, as reflected in the catecholamines, blood pressure, heart rate, electromyographic (EMG) activity, and self-reports. Fifty cashiers (70%) suffering from neck-shoulder pain (trapezius myalgia) were found to have higher EMG activity at work and reported more tension after work. Women who kept a diary for 1 week and reported more musculoskeletal pain (above the median) were older, had higher blood pressure, and reported more work stress and psychosomatic symptoms. The elevated stress levels at work are consistent with data from workers involved in other types of repetitive tasks and can be important for the high prevalence of neck and shoulder symptoms among the cashiers.

Coronary artery bypass graft surgery up-regulates genes involved in platelet aggregation.

BACKGROUND: During and shortly after coronary artery bypass graft (CABG) surgery, there is an increase in thromboembolic events. CABG, a strong inflammatory stimulus, is associated with a hypercoaguable state. Platelets might contribute to this hypercoaguable state because they have a pivotal role in thrombosis. In the days following surgery there is augmented platelet regeneration in response to the inflammatory stimulus. OBJECTIVES: The aim of this study was to investigate any changes in platelet mRNA profiles to test the hypothesis that post-CABG surgery platelets are associated with a prothrombotic state. METHODS: Blood was sampled and platelets purified from 11 patients before and 3-6 days after CABG. Gene expression profiling was performed using low density array (LDA) plates for seven of the patients. RESULTS: Forty-five genes were examined and those significantly up-regulated were glycoprotein (GP)IIb, GPIIIa and cyclooxygenase-1 (COX-1). These findings were confirmed in four more patients, including flow cytometry analysis of the GPIIb/IIIa receptor. CONCLUSIONS: CABG surgery up-regulates mRNA and protein levels of proteins that are key players in platelet aggregation. Marked elevation of GPIIb/IIIa mRNA levels results in significantly increased GPIIb/IIIa expression in platelets post-CABG surgery, which may be a reason for increased thrombus formation and myocardial infarction after CABG.

An outbreak of Providencia stuartii urinary tract infections. Patients with condom catheters are a reservoir of the bacteria.

We investigated an outbreak of multiple antibiotic-resistant Providencia stuartii urinary tract infections that occurred on a neurology ward. Only patients who had been catheterized became infected. However, approximately 10% of patients with condom catheter urinary drainage systems were colonized, ie, P stuartii was present on their skin and in the urine drainage bags but not in fresh-voided urine. Patient urinals were also contaminated. The outbreak was terminated by segregating infected and colonized patients from other patients who required either external or indwelling urinary catheters and by stopping the practice of exchanging urinals among patients.

Membrane protein lateral interactions control Semliki Forest virus budding.

Semliki Forest virus, SFV, directs the synthesis of two membrane proteins, p62 and E1, which form a p62E1 heterodimer in the endoplasmic reticulum. After being transported to the plasma membrane (PM), they are incorporated into the virus membrane during the process of virus budding. Electronmicroscopic analyses of the envelope in matured virus show that the heterodimers are clustered into trimeric structures (spikes) which further form a regular surface lattice with T = 4. In this work we have used a genetic approach to study the importance of the trimerization event for virus budding. We have coexpressed a budding competent form of the virus heterodimer with another one which cannot be used for particle formation because of a defect in nucleocapsid (NC) binding. We show that the NC binding-deficient heterodimer is able to inhibit the budding of the competent one in a concentration-dependent manner and that the NC binding-competent heterodimers can rescue the incompetent ones into virus particles. This suggests that the heterodimers are complexed together, probably into the trimeric structures (spikes), at the PM to expose a multivalent binding site for the NC and thereby drive efficient virus budding.

Information needs and information seeking behaviour in primary health care.

A questionnaire survey of 186 general practitioners in Sweden showed that 67% saw the overall supply of medical information as less satisfactory or unsatisfactory, and that 80% experienced major hindrances in seeking relevant information. The most frequent need for information concerned general medicine, with respect to both diagnosis and choice of therapy. Of situations which required additional information, only every second was completely resolved. These results imply a need for a reorganization of the supply of information to general practitioners. As they cannot depend on conventional medical libraries for day-to-day information, personal libraries should be improved and updated regularly, and be readily to hand. Computer technology should be considered for communication between health care providers, and as support for differential diagnosis in general medicine.

The M1 and NP proteins of influenza A virus form homo- but not heterooligomeric complexes when coexpressed in BHK-21 cells.

The nucleoprotein (NP) and matrix protein (M1) are the most abundant structural proteins of influenza A virus. M1 forms a protein layer beneath the viral envelope and NP constitutes the protein backbone of the ribonucleoproteins (RNPs). In order to elucidate the functions of these proteins in virus assembly we have expressed NP and M1 in BHK-21 cells using Semliki Forest virus replicons and analysed their molecular interactions. We found that both M1 and NP engaged in extensive homooligomerization reactions soon after synthesis. However, there was no detectable heterooligomerization taking place between the two viral proteins, nor between these and host proteins. One interpretation of these results is that homooligomers, and not monomers, of NP and M1 are used as building blocks during RNP assembly and formation of the submembranous M1 layer, respectively. The complete absence of M1-NP heterooligomers suggests, on the other hand, that these two major viral proteins do not interact directly with each other during virus assembly. We also found that a fraction of M1 associated with cellular membranes. This did not, however, result in membrane budding or vesicularization as was the case with the matrix protein of vesicular stomatitis virus when expressed separately (P. A. Justice and others, Journal of Virology 69, 3156-3160, 1995).

Characterization of the nuclear translocation of acidic fibroblast growth factor.

The subcellular localization of human acidic FGF (aFGF; FGF-1) expressed to high levels by using a bacteriophage T7 RNA polymerase-driven vaccinia virus expression system was studied in BHK21 and HeLa cells. Acidic FGF was detected by immunoblotting or immunofluorescence using an affinity-purified rabbit polyclonal antibody. The nuclei of most transfected cells, but not nuclei of control cells, were strongly immunoreactive. The nuclear accumulation of aFGF was confirmed by subcellular fractionation and immunoblotting, indicating that about 50% of the expressed protein was located in the nuclei at 12 h after transfection. It has previously been reported that a putative N-terminal nuclear localization sequence (NLS) in aFGF is required for full mitogenic activity (Imamura et al., Science 249, 1567-1570, 1990). We found that deletion of the first 27 residues including the putative NLS did not prevent the nuclear translocation of aFGF in either cell type. This observation suggests that the putative NLS sequence is not essential for targeting aFGF to the cell nucleus. To analyze further the mechanism of nuclear import, purified aFGF was microinjected into the cytoplasm of growing BHK21 cells under various conditions. In chilled (4 degrees C) or ATP-depleted cells, the injected aFGF entered the nucleus with similar efficiency to that in control cells at 37 degrees C. This suggests that aFGF, which has a molecular mass of only 16,500, enters the cell nucleus by free diffusion, and possibly becomes trapped by binding to some nuclear structures. When added exogenously to growing BHK21 cells, aFGF was not localized to the nucleus. Instead, a punctate staining pattern in the cytosol was observed, reminiscent of that in the endosomal-lysosomal compartments. In addition, a diffuse extracellular surface-staining was evident. This result demonstrates that receptor-mediated endocytosis of aFGF does not result in its translocation to the nucleus, as has been reported for basic FGF.

Specific interactions between retrovirus Env and Gag proteins in rat neurons.

In this work we have studied the intracellular localization properties of the Gag and Env proteins of Moloney murine leukemia virus (MLV) and human immunodeficiency virus (HIV) in dorsal root ganglion (DRG) neurons of rat. These neurons form thick bundles of axons, which facilitates protein localization studies by immunofluorescence analyses. When such neuron cultures were infected with recombinant Semliki Forest virus particles carrying the gag genes of either retrovirus, the expressed Gag proteins were localized to both the somatic and the axonal regions of the DRG neurons. In contrast, the Env proteins were confined only to the somatic region. When the Gag and Env proteins were coexpressed, the Gag proteins were also excluded from the axons. This effect of the Env proteins was shown to be dependent on the concentration of the Gag proteins in the neuron and also to be specific for homologous pairs of retrovirus proteins. Therefore, the results suggest that there are specific interactions between the Env and the Gag proteins of MLV and HIV in the DRG neurons.

Oligomerization-dependent folding of the membrane fusion protein of Semliki Forest virus.

The spikes of alphaviruses are composed of three copies of an E2-E1 heterodimer. The E1 protein possesses membrane fusion activity, and the E2 protein, or its precursor form, p62 (sometimes called PE2), controls this function. Both proteins are, together with the viral capsid protein, translated from a common C-p62-E1 coding unit. In an earlier study, we showed that the p62 protein of Semliki Forest virus (SFV) dimerizes rapidly and efficiently in the endoplasmic reticulum (ER) with the E1 protein originating from the same translation product (so-called heterodimerization in cis) (B.-U. Barth, J. M. Wahlberg, and H. Garoff, J. Cell Biol. 128:283-291, 1995). In the present work, we analyzed the ER translocation and folding efficiencies of the p62 and E1 proteins of SFV expressed from separate coding units versus a common one. We found that the separately expressed p62 protein translocated and folded almost as efficiently as when it was expressed from a common coding unit, whereas the independently expressed E1 protein was inefficient in both processes. In particular, we found that the majority of the translocated E1 chains were engaged in disulfide-linked aggregates. This result suggests that the E1 protein needs to form a complex with p62 to avoid aggregation. Further analyses of the E1 aggregation showed that it occurred very rapidly after E1 synthesis and could not be avoided significantly by the coexpression of an excess of p62 from a separate coding unit. These latter results suggest that the p62-E1 heterodimerization has to occur very soon after E1 synthesis and that this is possible only in a cis-directed reaction which follows the synthesis of p62 and E1 from a common coding unit. We propose that the p62 protein, whose synthesis precedes that of the E1 protein, remains in the translocon of the ER and awaits the completion of E1. This strategy enables the p62 protein to complex with the E1 protein immediately after the latter has been made and thereby to control (suppress) its fusion activity.