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OBJECTIVES: The aim of the study is to provide an overview of Drug-drug Interactions (DDIs) and adverse effects caused by drugs used in SARS-CoV-2 infection during the first epidemic wave. METHODS: We retrospectively analyzed patients treated by drugs used in SARS-CoV-2 infection (Azithromycin, Hydroxychloroquine and/or Lopinavir/ritonavir) between 15th March 2020 to 17th April 2020. A review of adverse events and DDI-risky drug association on medical record was conducted for each patient. Each adverse events was analyzed by the Centre régional de pharmacovigilance (CRPV) to assess causality of drugs used in SARS-CoV-2 infection. RESULTS: A total of 312 precriptions were analyzed during the period, of which 110 prescriptions had 157 drug association at risk of DDIs; 26 adverse events were reported. Causality assessment by CRPV concluded that 10 (35,7 %) adverse effects were possibly related to SARS-CoV-2 drugs with only 2 (7,1 %) related to DDIs. CONCLUSIONS: Despite risk of adverse drug reactions and DDIs related to drugs used in SARS-CoV-2 infection, few iatrogenics diseases were found.

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The first systematic study of opacity dependence on atomic number at stellar interior temperatures is used to evaluate discrepancies between measured and modeled iron opacity [J. E. Bailey et al., Nature (London) 517, 56 (2015)NATUAS0028-083610.1038/nature14048]. High-temperature (>180 eV) chromium and nickel opacities are measured with ±6%-10% uncertainty, using the same methods employed in the previous iron experiments. The 10%-20% experiment reproducibility demonstrates experiment reliability. The overall model-data disagreements are smaller than for iron. However, the systematic study reveals shortcomings in models for density effects, excited states, and open L-shell configurations. The 30%-45% underestimate in the modeled quasicontinuum opacity at short wavelengths was observed only from iron and only at temperature above 180 eV. Thus, either opacity theories are missing physics that has nonmonotonic dependence on the number of bound electrons or there is an experimental flaw unique to the iron measurement at temperatures above 180 eV.

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We describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of pregnancy, the ARV was tenofovir-emtricitabine, atazanavir-ritonavir, and DTG (50 mg once daily). From the interaction between atazanavir and DTG via CYP3A4 and UGT1A1 and placental efflux transporter inhibition and considering the infant's probable enzymatic immaturity, the DTG elimination half-life was estimated to be 4-fold longer in neonates than in adults.

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Nearly a century ago it was recognized that radiation absorption by stellar matter controls the internal temperature profiles within stars. Laboratory opacity measurements, however, have never been performed at stellar interior conditions, introducing uncertainties in stellar models. A particular problem arose when refined photosphere spectral analysis led to reductions of 30-50 per cent in the inferred amounts of carbon, nitrogen and oxygen in the Sun. Standard solar models using the revised element abundances disagree with helioseismic observations that determine the internal solar structure using acoustic oscillations. This could be resolved if the true mean opacity for the solar interior matter were roughly 15 per cent higher than predicted, because increased opacity compensates for the decreased element abundances. Iron accounts for a quarter of the total opacity at the solar radiation/convection zone boundary. Here we report measurements of wavelength-resolved iron opacity at electron temperatures of 1.9-2.3 million kelvin and electron densities of (0.7-4.0) × 10(22) per cubic centimetre, conditions very similar to those in the solar region that affects the discrepancy the most: the radiation/convection zone boundary. The measured wavelength-dependent opacity is 30-400 per cent higher than predicted. This represents roughly half the change in the mean opacity needed to resolve the solar discrepancy, even though iron is only one of many elements that contribute to opacity.

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An x-ray grating spectrometer was built in order to measure opacities in the 50 eV to 250 eV spectral range with an average spectral resolution ∼ 50. It has been used at the LULI-2000 laser facility at École Polytechnique (France) to measure the Δn = 0, n = 3 transitions of several elements with neighboring atomic number: Cr, Fe, Ni, and Cu in the same experimental conditions. Hence a spectrometer with a wide spectral range is required. This spectrometer features one line of sight looking through a heated sample at backlighter emission. It is outfitted with one toroidal condensing mirror and several flat mirrors cutting off higher energy photons. The spectral dispersion is obtained with a flatfield grating. Detection consists of a streak camera sensitive to soft x-ray radiation. Some experimental results showing the performance of this spectrometer are presented.

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This paper deals with theoretical studies on the 2p-3d absorption in iron, nickel, and copper plasmas related to LULI2000 (Laboratoire pour l'Utilisation des Lasers Intenses, 2000J facility) measurements in which target temperatures were of the order of 20 eV and plasma densities were in the range 0.004-0.01 g/cm(3). The radiatively heated targets were close to local thermodynamic equilibrium (LTE). The structure of 2p-3d transitions has been studied with the help of the statistical superconfiguration opacity code SCO and with the fine-structure atomic physics codes HULLAC and FAC. A new mixed version of the sco code allowing one to treat part of the configurations by detailed calculation based on the Cowan's code RCG has been also used in these comparisons. Special attention was paid to comparisons between theory and experiment concerning the term features which cannot be reproduced by SCO. The differences in the spin-orbit splitting and the statistical (thermal) broadening of the 2p-3d transitions have been investigated as a function of the atomic number Z. It appears that at the conditions of the experiment the role of the term and configuration broadening was different in the three analyzed elements, this broadening being sensitive to the atomic number. Some effects of the temperature gradients and possible non-LTE effects have been studied with the help of the radiative-collisional code SCRIC. The sensitivity of the 2p-3d structures with respect to temperature and density in medium-Z plasmas may be helpful for diagnostics of LTE plasmas especially in future experiments on the Δn=0 absorption in medium-Z plasmas for astrophysical applications.

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The recent discovery of the presence of variable amounts of the carcinogenic compound acrylamide in a wide range of severely heat-treated food products, such as fried potatoes, biscuits, bread and coffee or malt, as a result of the heat process, has induced an important research in the area of the Maillard reaction in food. The interaction between a specific food composition and the heat process applied results in the development of complex oxidation and glycation reactions, which give rise to a mixture of flavoured compounds and possible neoformed contaminants (NFC). Recommendations by the European Commission aim at monitoring the content of major NFC, such as acrylamide and furan, in a list of food products commercialized in Europe. On the other hand, the Commission for European Normalization (CEN) has created recently a new workgroup (WG13) responsible for normalization of analytical method for NFC assessment. The European collective research ICARE was carried out to identify the possible health consequences of the ingestion of heat-treated products, characterize the reaction kinetics leading to NFC and evaluate some mitigation procedures proposed by the CIAA toolbox, and finally develop a simple, rapid and non destructive control method based on fluorescence acquisition on the crushed food products and chemometric analysis of the spectral information. This paper summarizes the objectives and essential results obtained in the scope of the project, highlighting the need for evaluating the distribution of NFC in food products commercialized in Europe, as well as the impact of the food formula/recipe and process on Maillard derived NFC food levels. The potential of the Fluoralys sensor regarding its ability to control food contamination with NFC is presented. A decrease in NFC concentration of heat processed food should allow significantly limiting the exposure of populations to NFC and consequently the potential related health risk.

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Understanding stellar interiors, inertial confinement fusion, and Z pinches depends on opacity models for mid-Z plasmas in the 100-300 eV temperature range. These models are complex and experimental validation is crucial. In this paper we describe the diagnosis of the first experiments to measure iron plasma opacity at a temperature high enough to produce the charge states and electron configurations that exist in the solar interior. The dynamic Hohlraum x-ray source at Sandia National Laboratories' Z facility was used to both heat and backlight Mg/Fe CH tamped foils. The backlighter equivalent brightness temperature was estimated to be T(r) approximately 314 eV+/-8% using time-resolved x-ray power and imaging diagnostics. This high brightness is significant because it overwhelms the sample self-emission. The sample transmission in the 7-15.5 A range was measured using two convex potassium acid phthalate crystal spectrometers that view the backlighter through the sample. The average spectral resolution over this range was estimated to be lambda/deltalambda approximately 700 by comparing theoretical crystal resolution calculations with measurements at 7.126, 8.340, and 12.254 A. The electron density was determined to be n(e)=6.9+/-1.7 x 10(21) cm(-3) using the Stark-broadened Mg Hebeta, Hegamma, and Hedelta lines. The temperature inferred from the H-like to He-like Mg line ratios was T(e)=156+/-6 eV. Comparisons with three different spectral synthesis models all have normalized chi(2) that is close to unity, indicating quantitative consistency in the inferred plasma conditions. This supports the reliability of the results and implies the experiments are suitable for testing iron opacity models.

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BACKGROUND: Pancreatic fistula following pancreaticoduodenectomy is relatively common, and remains a major cause of morbidity and mortality. The aim of this study was to evaluate the results of two-layered duct-to-mucosa pancreaticogastrostomy as a method for restoring pancreaticoenteric continuity. METHODS: Prospectively collected data from 100 consecutive patients who underwent Whipple's pancreaticoduodenectomy for tumour were evaluated. All operations were performed by the same surgeon. RESULTS: The perioperative 60-day mortality rate was 1.0 per cent. There were no pancreatic fistulas or anastomotic leaks. Sixteen patients had significant complications that delayed discharge from hospital. Twenty-one patients subsequently required empirical pancreatic exocrine supplements. CONCLUSION: Two-layered duct-to-mucosa pancreaticogastrostomy for restoration of pancreaticoenteric continuity after pancreaticoduodenectomy is associated with a low incidence of complications.

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BACKGROUND: Endoscopic retrograde cholangio pancreatography (ERCP) is a technically challenging procedure. Glyceryl trinitrate (GTN) has been shown to reduce tone in the sphincter of Oddi (SO), cannulation of which is a rate-limiting factor. A double-blind randomized control trial was performed to assess whether topical GTN on the SO would facilitate cholangiography and/or bile duct cannulation. METHODS: 104 patients requiring ERCP for biliary symptoms were randomized into two groups, 52 controls pretreated with 5 ml 0.9% normal saline (NS) and 52 pretreated with 5 ml GTN (concentration 1 mg/ml). RESULTS: There was no significant between the control group and the GTN group in primary cannulation rate (p = 0.76), time taken to cholangiography (p = 0.58), or time to cannulation (p = 0.43). CONCLUSION: Topically administered GTN to the SO does not aid in obtaining a cholangiogram or cannulation during an ERCP.

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A prospective study was carried out on 143 consecutive patients with palpable lumps larger than 2 cm in size which were clinically suspicious of carcinoma. One hundred and five lumps proved to be malignant and 38 were benign. Of the 105 patients with malignancy, confirmation was made in 95 by fine-needle aspiration cytology (FNAC) with a sensitivity of 90.4% and 100 by core biopsy with a sensitivity of 95.2%. The sensitivity of core biopsies increased with the number of cores taken (one core, 76.2%; two cores, 80.9%, three cores, 89.2%; four cores, 95.2%). The combined sensitivity of FNAC and core biopsies was 100%, and so are complementary in the accurate diagnosis of breast cancer. Patients presenting to the breast clinic with a solid suspicious breast lump larger than 2 cm can benefit from FNAC and a minimum of four core biopsies to improve diagnosis.

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AIMS: Seroma formation is a recognised complication of breast surgery causing wound pain and discomfort. It was hypothesised that daily aspiration of symptomatic seromas that formed after breast surgery would encourage flap adherence to the chest wall, thereby allowing swifter resolution of seroma. METHODS: Thirty-six patients undergoing mastectomy and/or axillary clearance who formed seroma post operatively, were randomised into two groups either having daily aspiration of seroma or aspiration as required by patient symptoms. RESULTS: The daily aspiration required significantly more attendances for aspiration (P<0.005) and the time from surgery to final aspiration was not reduced. CONCLUSION: Daily aspiration of symptomatic seroma did not result in swifter resolution.

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BACKGROUND: There is uncertainty as to whether preservation or elective division of the ilioinguinal nerve influences pain and sensory loss following inguinal hernia repair. METHODS: In 20 men with primary bilateral inguinal hernias undergoing open tension-free mesh repair, the sides (right or left) were randomized for preservation or division of the ilioinguinal nerve. Patients were reviewed on day 1, 4 weeks and 6 months after operation. Any pain or numbness, as well as any loss of sensation in the area supplied by the nerve, was recorded. RESULTS: No significant difference was seen in pain or numbness between the divided and preserved sides. Sensory loss detected by clinical examination was more common following the division of the nerve compared with preservation. CONCLUSION: Within the limitations of a small sample size, elective division of the ilioinguinal nerve during inguinal hernia repair does not appear to be associated with a significant increase in postoperative symptoms.

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In seminatural environments, prepartum sows leave the herd and construct a maternal nest (a dug out hollow lined with vegetation) prior to the birth of their piglets. The endocrine drives motivating this behavior are not understood, but may involve prostaglandin (PG) F2alpha. This study examined the effect of PGF2alpha treatment on the behavior of pseudopregnant gifts housed in a large enclosure. Pseudopregnancy was induced using 5 mg/ml estradiol valerate/day im from days 11 to 15 of the estrous cycle (first day of estrus = day 0). The gifts' behavior was recorded on a control day, during which no treatment was given, and a test day (= 45.9 +/- 0.42 days of pseudopregnancy) when gilts received either 15 mg PGF2alpha (dinoprost: Lutalyse, Upjohn, Crawley, UK, n = 11) or 0.9% saline (n = 10) im at 11.00 h. PGF2alpha-treated gilts traveled further and were more frequently >10 m from the nearest pig than saline-treated animals. In the hour following injection, PGF2alpha-treated animals also showed increased frequencies of rooting and pawing the ground and stood for longer than saline-treated animals. However, gathering and carrying nest materials were not increased. These results suggest that PGF2alpha, given as a single dose to extensively housed gilts, initiated many, but not all, of the behaviors characteristic of prepartum nest building. The dose and duration of PGF2alpha treatment may have limited the observed behaviors. In addition, environmental feedback is likely to affect the degree to which some nest building behaviors are expressed.

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Previously we created two strains of factor VIII-deficient mice by insertion of a neo gene into (1) the 3' end of exon 16 and (2) exon 17 of the factor VIII gene. Affected mice of both strains have no plasma factor VIII activity, yet are healthy with no spontaneous bleeding. Factor VIII-deficient females bred with affected males survive pregnancy and delivery. We used reverse transcriptase-polymerase chain reaction of liver RNA to characterize factor VIII mRNA processing. Factor VIII mRNA of the exon 16 knockout strain contains neo sequences plus 17 bp of intron 16 due to use of a cryptic donor site in intron 16. All factor VIII mRNA of the exon 17 knockout strain lacks exon 17 and neo sequences. In skipping exon 17, the intron 16 donor site or a cryptic donor site 46 bp 3' to the intron 16 donor site are used. Thus, factor VIII deficiency in exon 16 knockout mice is due to truncated protein, while in exon 17 knockout mice it is due to either truncated or partially deleted protein. After immunizing exon 16 knockout mice with human recombinant factor VIII, two monoclonal antibodies were obtained that recognize < 100 pg of mouse factor VIII light chain. Assay of cryoprecipitate from the plasma of affected mice failed to show factor VIII light chain.

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Almost complete purification (> 95%) of the 46-kDa murine, one-carbon, reduced folate transporter (RFT) at a recovery of 20% was obtained by ligand-directed immunoaffinity fractionation from transporter overproducing L1210/R83 cells. These cells were labeled with the N-hydroxysuccinimide ester of [3H]aminopterin (AMT), the isolated plasma membrane alkaline washed to remove nonintegral membrane proteins, detergent-solubilized, and RFT-separated on an anti-AMT antibody-protein G-Sepharose column followed by preparative SDS-polyacrylamide gel electrophoresis. Anti-RFT antibody, subsequently derived, differentially blotted (L1210/R83 >> L1210/0) a 46-kDa protein during SDS-polyacrylamide gel electrophoresis of plasma membrane from L1210/R83 and L1210 cells and in L1210/R83 cells after trichloroacetic acid precipitation. In contrast to that reported for human tumor cells, glycosidase treatment of RFT revealed no common N- or O-linked core oligosaccharides associated with this protein. The same 46-kDa protein at different relative levels was revealed in a Western blot of plasma membrane from other murine tumors. Blotting of plasma membrane from methotrexate resistant, transport defective L1210 cell variants exhibited wild-type levels of a less electrophoretically mobile RFT or greater levels of the same 46-kDa RFT which could not be affinity labeled with N-hydroxysuccinimide-[3H]AMT. The same antibody differentially blotted a 83-kDa plasma membrane protein from human HL-60 and CCRF-CEM cells with different levels of reduced folate transport and affinity labeling of RFT, verifying the conserved nature of this protein consistent with earlier functional studies.

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Studies are described examining further the decline in folate analogue influx mediated by the one-carbon reduced-folate transport system in HL-60 cells following induction of maturation by cytodifferentiation agents. To facilitate the investigation of the underlying basis of this phenomenon, we derived a variant (HL-60/LCV) with 4-5-fold elevated influx capacity (Vmax) for folate analogues. A commensurate increase in the putative transporter for this system was documented by affinity labeling of these cells with N-hydroxysuccinimide-[3H]aminopterin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the affinity labeled plasma membrane in HL-60/LCV cells delineated a protein peak at Mr = 75,000-80,000. This was substantially greater than the analogous transporter (Mr = 45,000-47,000) we had delineated (Yang, C.-H., Sirotnak, F.M., and Mines, L.S. (1988) J. Biol. Chem. 263, 9703-9709) with the same methodology in the L1210 cell plasma membrane. In addition, the rate of translocation of the Mr = 75,000-80,000 transporter in HL-60 and HL-60/LCV cells was 2-fold lower than the rate of translocation determined for the Mr = 45,000-47,000 transporter in L1210 cells. During induced maturation of HL-60/LCV cells toward the granulocyte pathway, [3H]methotrexate (MTX) influx capacity and the amount of the affinity labeled transporter decreased rapidly in a parallel fashion. The decrease in [3H]MTX influx and in affinity labeling and in the amount of the Mr = 75,000-80,000 transporter was 5-fold following exposure to 210 mM dimethyl sulfoxide (Me2SO) for 5 days during growth in culture. Moreover, during cycloheximide treatment, the decay in [3H]MTX influx at 37 degrees C and in amount of affinity labeled transporter was the same (t1/2 = 144-155 min) for both control and Me2SO-treated HL-60/LCV cells. These results, which reveal no difference in metabolic turnover for control and Me2SO-treated cells, suggest that the decline in folate analogue influx in HL-60/LCV influx cells is a very early event in the program of differentiation and probably occurs by down-regulation of synthesis of the transporter for the one-carbon reduced-folate transport system.

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Two hundred women presenting with primary breast carcinoma were studied to find the most accurate single or combination of methods to assess breast tumour size. Correlations of the maximum clinical, mammographic and ultrasound tumour diameter were made with maximum histological diameter. Tumour size could be assessed clinically in all 200 patients, and overestimated the size of small tumours and underestimated large tumours (P less than 0.001). Mammographic measurement, which was possible in 145 (72.5%), underestimated the size of large tumours (P less than 0.01). Only 100 women underwent ultrasound examination (size assessed in 86%) and this modality tended to underestimate the size of all tumours (P less than 0.05). All methods of measurement showed similar correlations with histological size. Stepwise linear regression showed that the most accurate and practical estimation could be made using the formula: Histological size = 0.5 x mammographic size + 0.5 x clinical size. We conclude that clinical measurement of breast cancer size is as accurate as that from mammography or ultrasound. Accuracy can be improved by the use of a simple formula of both clinical and mammographic measurements.

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