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Objectives: The aim of this study was to analyze whether subgroups of immunosuppressive (IS) medications conferred different outcomes in COVID-19. Methods: The study involved a multicenter retrospective cohort of consecutive immunosuppressed patients (ISPs) hospitalized with COVID-19 from March to July, 2020. The primary outcome was in-hospital mortality. A propensity score-matched (PSM) model comparing ISP and non-ISP was planned, as well as specific PSM models comparing individual IS medications associated with mortality. Results: Out of 16 647 patients, 868 (5.2%) were on chronic IS therapy prior to admission and were considered ISPs. In the PSM model, ISPs had greater in-hospital mortality (OR 1.25, 95% CI 0.99-1.62), which was related to a worse outcome associated with chronic corticoids (OR 1.89, 95% CI 1.43-2.49). Other IS drugs had no repercussions with regard to mortality risk (including calcineurin inhibitors (CNI); OR 1.19, 95% CI 0.65-2.20). In the pre-planned specific PSM model involving patients on chronic IS treatment before admission, corticosteroids were associated with an increased risk of mortality (OR 2.34, 95% CI 1.43-3.82). Conclusions: Chronic IS therapies comprise a heterogeneous group of drugs with different risk profiles for severe COVID-19 and death. Chronic systemic corticosteroid therapy is associated with increased mor-tality. On the contrary, CNI and other IS treatments prior to admission do not seem to convey different outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

Artículo con numerosos autores sólo se mencionan el primero, los de la UAM y el grupo colectivo, Objectives: A decrease in blood cell counts, especially lymphocytes and eosinophils, has been described in patients with serious Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2), but there is no knowledge of their potential role of the recovery in these patients’ prognosis This article aims to analyse the effect of blood cell depletion and blood cell recovery on mortality due to COVID-19. Design: This work was a retrospective, multicentre cohort study of 9644 hospitalised patients with confirmed COVID-19 from the Spanish Society of Internal Medicine’s SEMI-COVID-19 Registry. Setting: This study examined patients hospitalised in 147 hospitals throughout Spain. Participants: This work analysed 9644 patients (57.12% male) out of a cohort of 12,826 patients 18 years of age hospitalised with COVID-19 in Spain included in the SEMI-COVID-19 Registry as of 29 May 2020. Main outcome measures: The main outcome measure of this work is the effect of blood cell depletion and blood cell recovery on mortality due to COVID-19. Univariate analysis was performed to determine possible predictors of death, and then multivariate analysis was carried out to control for potential confounders. Results: An increase in the eosinophil count on the seventh day of hospitalisation was associated with a better prognosis, including lower mortality rates (5.2% vs. 22.6% in non-recoverers, OR 0.234; 95% CI, 0.154 to 0.354) and lower complication rates, especially regarding the development of acute respiratory distress syndrome (8% vs. 20.1%, p = 0.000) and ICU admission (5.4% vs. 10.8%, p = 0.000). Lymphocyte recovery was found to have no effect on prognosis. Treatment with inhaled or systemic glucocorticoids was not found to be a confounding factor. Conclusion: Eosinophil recovery in patients with COVID-19 who required hospitalisation had an independent prognostic value for all-cause mortality and a milder course

Does oxygen concentration during 3-day embryo culture affect obstetric and neonatal outcomes?

Aida Sefidani Forough,1 Esther TL Lau,1 Kathryn J Steadman,1,2 Julie AY Cichero,1,2 Greg J Kyle,1 Jose Manuel Serrano Santos,1 Lisa M Nissen1 1School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia; 2School of Pharmacy, University of Queensland, Brisbane, QLD, Australia Abstract: Solid oral dosage forms such as tablets and capsules are generally the preferred method of drug delivery due to their convenience, cost, and acceptability. However, for many people, it can be a challenge to swallow solid oral medications, even those with healthy swallowing function. This review describes current strategies available to facilitate medication administration to otherwise healthy people with pill-swallowing difficulties. In general, restoring and maintaining the ability to swallow pills whole should ideally be the first choice in managing people with pill-swallowing difficulties. A number of strategies can potentially make it easier to swallow pills whole. These include postural adjustments, using pill-swallowing aids, and teaching pill-swallowing techniques. Where these are not successful or appropriate, then other approaches have to be considered using alternative formulations/routes of administration or deprescribing. If there is no other option, and it is not directly contraindicated for each specific medication dosage form, pills may be modified and mixed in foods and drinks to aid swallowing. In conclusion, people with pill-swallowing difficulties can benefit from a number of strategies designed to facilitate swallowing medications. However, these strategies should be further evaluated with regard to the evidence relating to both their efficacy and safety. Keywords: swallowing difficulties, pill swallowing, medication administration, oral dosage forms, tablets, capsules

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

Endometriosis affects up to 50% of women with infertility [1]. It is a costly disease with an estimated annual economic burden in the United States of $78.05 billion in 2013 [2].

Apicomplexan parasites invade host cells and immediately initiate cell division. The extracellular parasite discharges transmembrane proteins onto its surface to mediate motility and invasion. These are shed by intramembrane cleavage a process associated with invasion but otherwise poorly understood. Functional analysis of Toxoplasma rhomboid 4 a surface intramembrane protease by conditional overexpression of a catalytically inactive form produced a profound block in replication. This was completely rescued by expression of the cleaved cytoplasmic tail of Toxoplasma or Plasmodium apical membrane antigen 1 (AMA1). These results reveal an unexpected function for AMA1 in parasite replication and suggest that invasion proteins help to promote parasite switch from an invasive to a replicative mode.

Host cell invasion by the Apicomplexa critically relies on regulated secretion of transmembrane micronemal proteins (TM MICs). Toxoplasma gondii possesses functionally non redundant MIC complexes that participate in gliding motility host cell attachment moving junction formation rhoptry secretion and invasion. The TM MICs are released onto the parasite's surface as complexes capable of interacting with host cell receptors. Additionally TgMIC2 simultaneously connects to the actomyosin system via binding to aldolase. During invasion these adhesive complexes are shed from the surface notably via intramembrane cleavage of the TM MICs by a rhomboid protease. Some TM MICs act as escorters and assure trafficking of the complexes to the micronemes. We have investigated the properties of TgMIC6 TgMIC8 TgMIC8.2 TgAMA1 and the new micronemal protein TgMIC16 with respect to interaction with aldolase susceptibility to rhomboid cleavage and presence of trafficking signals. We conclude that several TM MICs lack targeting information within their C terminal domains indicating that trafficking depends on yet unidentified proteins interacting with their ectodomains. Most TM MICs serve as substrates for a rhomboid protease and some of them are able to bind to aldolase. We also show that the residues responsible for binding to aldolase are essential for TgAMA1 but dispensable for TgMIC6 function during invasion.

Despite efforts made to improve the in vitro embryo culture conditions used during assisted reproduction procedures, human embryos must adapt to different in vitro oxygen concentrations and the new metabolic milieu provided by the diverse culture media used for such protocols. It has been shown that the embryo culture environment can affect not only cellular metabolism, but also gene expression in different species of mammalian embryos. Therefore we wanted to compare the metabolic footprint left by human cleavage-stage embryos under two types of oxygen atmospheric culture conditions (6% and 20% O-2). The spent culture media from 39 transferred and implanted embryos from a total of 22 patients undergoing egg donation treatment was analyzed; 23 embryos came from 13 patients in the 6% oxygen concentration group, and 16 embryos from 9 patients were used in the 20% oxygen concentration group. The multivariate statistics we used in our analysis showed that human cleavage-stage embryos grown under both types of oxygen concentration left a similar metabolic fingerprint. We failed to observe any change in the net depletion or release of relevant analytes, such as glucose and especially fatty acids, by human cleavage-stage embryos under either type of culture condition. Therefore it seems that low oxygen tension during embryo culture does not alter the global metabolism of human cleavage-stage embryos.

Our objective was to determine the frequency and time of day when we detect the greatest number of hyperglycaemic and hypoglycaemic episodes in patients with type 2 diabetes mellitus (DM) on insulin. We also studied whether any clinical feature could be associated with more frequent hypoglycaemia or hyperglycaemia. We conducted an observational study of 51 patients with type 2 diabetes mellitus who were on insulin and metabolically stable. We followed the patients for 8 weeks, performing two daily capillary blood glucose measurements before and 2 hours after each of the three main meals in turn. A profile was also prepared from 6 capillary blood glucose measurements performed before and after meals every 4 days. The likelihood of observing hyperglycaemia increased 48% before dinner (taking pre-breakfast capillary blood glucose as a reference). The likelihood of observing hypoglycaemia was 3.4 times greater in pre-lunch capillary blood glucose measurements and was more frequent in patients with lower BMI. In patients with type 2 DM stabilised by insulin, performing pre-dinner capillary blood glucose measurements identifies hyperglycaemia more often than at other times of the day, while pre-lunch measurement identifies hypoglycaemia more often, the latter being more common in patients with lower BMI.

Contraction and insulin increase glucose uptake in skeletal muscle. While the insulin pathway, better characterized, requires activation of phosphoinositide 3-kinase (PI3K) and atypical protein kinase (aPKC), muscle contraction seems to share insulin-activated components to increase glucose uptake. This study aimed to investigate the interrelation between the pathway involved in glucose uptake evoked by insulin and muscle contraction. Isolated muscle of rats was treated with solvent (control), insulin, wortmannin (PI3K inhibitor) and the combination of insulin plus wortmannin. After treatment, muscles were electrically stimulated (contracted) or remained at rest. Glucose transporter 4 (GLUT4) localization, glucose uptake and phospho-aPKC (aPKC activated form) were assessed. Muscle contraction and insulin increased glucose uptake in all conditions when compared with controls not stimulating an effect that was accompanied by an increase in GLUT4 and of phospho-aPKC at the muscle membrane. Contracted muscles treated with insulin did not show additive effects on glucose uptake or aPKC activity compared with the response when these stimuli were applied alone. Inhibition of PI3K blocked insulin effect on glucose uptake and aPKC but not in the contractile response. Thus, muscle contraction seems to stimulate aPKC and glucose uptake independently of PI3K. Therefore, aPKC may be a convergence point and a rate limit step in the pathway by which, insulin and contraction, increase glucose uptake in skeletal muscle. Copyright (c) 2014 John Wiley & Sons, Ltd.

During the life span, phenotypic and structural modifications on skeletal muscle contribute to a reduction on glucose uptake either in basal state or triggered by insulin, but the underlying mechanisms for this decline are not entirely identified. A reduction in the expression of skeletal muscle glucose transporters (GLUTs), glucose transporter type 1 (GLUT1) and glucose transporter type 4 (GLUT4), has been associated to such phenomena, but unlike the case of insulin, only few studies have addressed the effect of age on muscle-contraction-induced glucose uptake. The aim of the study was to investigate the influence of age on GLUT1 and GLUT4 expression in skeletal muscle and its relation to the glucose uptake induced by muscle contraction. For this purpose, soleus muscle from Wistar rats aged 4, 10, 22 and 42?weeks were isolated and electrically stimulated (30?min, 10?Hz, 20?V, 0.2?ms). After stimulation, glucose uptake and GLUT1 and GLUT4 expression and localisation were evaluated. Muscle contraction caused an increase in glucose uptake in all studied groups. In addition, the absolute rates of glucose uptake were negatively correlated with age. The expression of GLUT4 was lower in older animals, whereas no relation between age and GLUT1 expression was found. Immunohistochemistry confirmed the ontogenic effect on GLUT4 expression and suggested an age-related modification on GLUT1 distribution within the muscle fibres; for instance, this protein seems to be present mainly out of the sarcoplasm. The present findings demonstrate that the ability of muscle contraction to increase glucose uptake is not influenced by age, whereas glucose uptake under basal conditions decreases with age. Copyright (C) 2011 John Wiley & Sons, Ltd.

University of Technology, Sydney. Faculty of Science. Bacterial cell division involves the invagination of the membrane and the cell wall to form a septum at midcell, between two replicated chromosomes. From a molecular perspective, the main event in cell division is the formation of a circumferential structure, the Z ring, formed by polymerisation of the tubulin-like FtsZ protein. The Z ring recruits a multi-protein complex to the division site, forming a division apparatus that eventually constricts as the septum forms. FtsA, a eukaryotic actin homologue, is another division protein, known to interact directly with FtsZ. It has been proposed that FtsA promotes Z ring formation; however its exact role has remained unknown. This thesis investigateshow FtsA affects the Z ring and cytokinesis in the Gram-positive model organism, Bacillus subtilis. Interestingly, FtsA is essential in Escherichia coli, the Gram-negative model organism, but not in Bacillus subtilis. Rather, deletion of the ftsA gene in vegetatively-growing B. subtilis cells causes a significant reduction in Z ring formation and cell division is severely diminished while cell growth is maintained, resulting in cell filamentation (long cells without septa). To confirm that this phenotype is due to the inability of FtsZ to efficiently form rings, Z ring formationwas examined in the absence of FtsA, during the first round of cell division following B. subtilis spore germination. Surprisingly the Z rings formed with wild-type efficiency. However, unlike wild-type cells that showed subsequent constriction of these Z rings leading to septum formation, Z rings did not constrict immediately in the ftsA mutant and persisted into the second cycle of division. These results reveal for the first time that, unlike E. coli, FtsA is not required for Z ring formation in B. subtilis. To understand the delay in Z ring constriction, further experiments were conducted to determine if the recruitment of downstream division proteins to the Z ring is affectedin the absence of FtsA. The live-cell microscopy data confirmed that the recruitment of DivIB, and presumably other downstream division proteins that are co-recruited with DivIB, is delayed in ftsA-mutant cells, but occurs with wild-type efficiency. However, after recruitment of DivIB, Z ring constriction and septation are still inefficient in the absence of FtsA. These observations indicate a primary role for FtsA in B. subtilis in the later stages of division, that is, after the division apparatus has assembled. This work reveals a novel perspective on the function of this protein. In an attempt to further explore how Z ring constriction is affected by FtsA, microscopy studies were designed to analyse this cell process. Different Z ring constriction defects were observed in ftsA-mutant cells. Importantly, it was shown that, in the absence of FtsA, constriction is either significantly delayed or never occurs, resulting in destabilisation of the Z ring, indicating that FtsA is required for efficient Z ring constriction in B. subtilis. This finding raised the possibility that FtsA may be affecting the dynamics of the Z ring during cytokinesis. To verify this, the rate of FtsZ turnover in Z rings of ftsA-mutant cells was investigated. The results demonstrated a decrease in the rate of the FtsZ turnover in the Z ring in the absence of FtsA, possibly enough to cause an effect on Z ring constriction.

An unusual but effective way to determine at threshold the dpi -> NN transition strength is to exploit the hadronic ground-state broadening in pionic deuterium, accessible by x-ray spectroscopy. The broadening is dominated by the true absorption channel dpi- -> nn, which is related to s-wave pion production pp -> dpi+ by charge symmetry and detailed balance. Using the exotic atom circumvents the problem of Coulomb corrections to the cross section as necessary in the production experiments. Our dedicated measurement finds (1171+23/-49) meV for the broadening yielding (252+5/-11) \mub., Comment: 4 pages, 2 figures, 1 table