Assessment of the effects of sulfate and nitrate on the temporal evolution of Klebsiella oxytoca and Staphylococcus aureus abundance under shaking conditions, in aquatic microcosm

Most chemicals in natural aquatic media can be assimilated by bacteria. The impact of various environmental conditions on this microbial process is not always clear. This study aimed at investigating changes in the abundance of Klebsiella oxytoca and Staphylococcus aureus under different shaking conditions, in aquatic microcosms containing nitrate and sulfate. Sodium chloride solution (8.5 g NaCl•L-1), and nitrate and sulfate solutions (0.005, 0.05, 0.5 and 5 g•L-1) containing bacteria were supplemented with tryptic peptone at a final concentration of 10 g•L-1. The solutions were incubated under shaking conditions (300, 350 and 400 rev•min-1). Bacteriological analyses were performed hourly over a 6-h period. During the first 3 h of incubation, results showed that the highest values of the apparent cell growth rates (CAGRs) with K2SO4 in pure cultures, at a shaking speed 400 rev•min-1, were 0.656 h-1 for S. aureus, and 0.364 h-1 for K. oxytoca. In mixed culture, the CAGR was 0.235 h-1 for S. aureus, and 0.388 h-1 for K. oxytoca, both recorded at 300 rev•min-1. With KNO3 in pure culture solutions, the CAGR was 0.353 h-1 for S. aureus at 300 rev•min-1, and 0.367 h-1 for K. oxytoca at 350 rev•min-1. In mixed culture it was 0.454 h-1 for S. aureus and 0.393 h-1 for K. oxytoca, both recorded at 350 rev•min-1. The highest value of the apparent cell inhibition rate (CAIR) for S. aureus was 0.520 h-1 in K2SO4 (5 g•L-1, 400 rev•min-1), and 0.115 h-1 in KNO3 (5 g•L-1, 300 rev•min-1). For K. oxytoca, it was 0.07 h-1 in K2SO4 in pure culture (0.05 g•L-1, 300 rev•min-1), and 0.044 h-1 in mixed culture (0.05 g•L-1, 350 rev•min-1). In KNO3 it was 0.239 h-1 in mixed culture (5 g•L-1, 300 rev•min-1). The growth and inhibition potentials of different microbial species were impacted by the chemical concentrations and the movement speeds.L’impact de diverses conditions environnementales sur l’assimilation bactérienne dans l’eau, des composés chimiques est peu connu. La présente étude a visé l’évaluation de la dynamique d’abondance de Klebsiella oxytoca et Staphylococcus aureus sous diverses conditions, en milieu aquatique microcosme contenant du sulfate ou nitrate. Des solutions du NaCl (8,5 g•L-1), sulfate et nitrate (0,005, 0,05, 0,5 et 5 g•L-1) contenant des cellules ont été enrichies à la peptone trypsique (concentration finale 10 g•L-1), puis incubées sous conditions dynamiques (300, 350 et 400 tr•min-1). Les analyses bactériologiques ont été effectuées pendant 6 h. Il ressort qu’au cours des trois premières heures d'incubation, le taux de croissance cellulaire apparent (TCCA) le plus élevé en culture pure, contenant du K2SO4, est de 0,656 h-1 pour S. aureus, et 0,364 h-1 pour K. oxytoca, enregistrés à 400 tr•min-1. En culture mixte, il est de 0,235 h-1 pour S. aureus, et 0,388 h-1 pour K. oxytoca, enregistrés à 300 tr•min-1. Avec du KNO3, en culture pure, le TCCA est de 0,353 h-1 pour S. aureus à 300 tr•min-1, et 0,367 h-1 à 350 tr•min-1 pour K. oxytoka. En culture mixte, il est de 0,454 h-1 pour S. aureus et 0,393 h-1 pour K. oxytoca, enregistrés à 350 tr•min-1. Le taux d’inhibition cellulaire apparent (TICA) le plus élevé de S. aureus est de 0,520 h-1 en présence du K2SO4 (5 g•L-1, 400 tr•min-1), et 0,115 h-1 en présence de KNO3 (5 g•L-1, 300 tr•min-1). Pour K. oxytoca, il est de 0,07 h-1 avec du K2SO4 en culture pure (0,05 g•L-1, 300 tr•min-1), et 0,044 h-1 en culture mixte (0,05 g•L-1, 350 tr•min-1). Avec du KNO3, il est de 0,239 h-1 en culture mixte (5 g•L-1, 300 tr•min-1). La croissance et l’inhibition des microorganismes sont affectées par les concentrations en sels et la vitesse de mouvements du milieu

Acceleration and Deceleration in the Internationalization Process of the Firm

By adopting a processual and dynamic view on internationalization, we develop the concepts of acceleration and deceleration, providing analytical tools to enhance our understanding of the non-linearity and multidimensionality of internationalization. We argue that acceleration and deceleration are embedded in the internationalization process and are a consequence of the firm’s capability to absorb and integrate acquired knowledge, and to find and exploit opportunities. In addition, we advance the idea that changes in speed are further influenced by how the firm integrates and coordinates the resources it has deployed within and across various internationalization dimensions. Thus, it emerges that the overall evolution of commitment to internationalization is more complex than received theories tend to present; therefore, empirical studies should aim to include a wide set of international activities and processes embedded in time

Observed and simulated time evolution of HCl, ClONO2, and HF total column abundances

Time series of total column abundances of hydrogen chloride (HCl), chlorine nitrate (ClONO2), and hydrogen fluoride (HF) were determined from ground-based Fourier transform infrared (FTIR) spectra recorded at 17 sites belonging to the Network for the Detection of Atmospheric Composition Change (NDACC) and located between 80.05°N and 77.82°S. By providing such a near-global overview on ground-based measurements of the two major stratospheric chlorine reservoir species, HCl and ClONO2, the present study is able to confirm the decrease of the atmospheric inorganic chlorine abundance during the last few years. This decrease is expected following the 1987 Montreal Protocol and its amendments and adjustments, where restrictions and a subsequent phase-out of the prominent anthropogenic chlorine source gases (solvents, chlorofluorocarbons) were agreed upon to enable a stabilisation and recovery of the stratospheric ozone layer. The atmospheric fluorine content is expected to be influenced by the Montreal Protocol, too, because most of the banned anthropogenic gases also represent important fluorine sources. But many of the substitutes to the banned gases also contain fluorine so that the HF total column abundance is expected to have continued to increase during the last few years. The measurements are compared with calculations from five different models: the two-dimensional Bremen model, the two chemistry-transport models KASIMA and SLIMCAT, and the two chemistry-climate models EMAC and SOCOL. Thereby, the ability of the models to reproduce the absolute total column amounts, the seasonal cycles, and the temporal evolution found in the FTIR measurements is investigated and inter-compared. This is especially interesting because the models have different architectures. The overall agreement between the measurements and models for the total column abundances and the seasonal cycles is good. Linear trends of HCl, ClONO2, and HF are calculated from both measurement and model time series data, with a focus on the time range 2000–2009. This period is chosen because from most of the measurement sites taking part in this study, data are available during these years. The precision of the trends is estimated with the bootstrap resampling method. The sensitivity of the trend results with respect to the fitting function, the time of year chosen and time series length is investigated, as well as a bias due to the irregular sampling of the measurements. The measurements and model results investigated here agree qualitatively on a decrease of the chlorine species by around 1%yr-1. The models simulate an increase of HF of around 1%yr-1. This also agrees well with most of the measurements, but some of the FTIR series in the Northern Hemisphere show a stabilisation or even a decrease in the last few years. In general, for all three gases, the measured trends vary more strongly with latitude and hemisphere than the modelled trends. Relative to the FTIR measurements, the models tend to underestimate the decreasing chlorine trends and to overestimate the fluorine increase in the Northern Hemisphere. At most sites, the models simulate a stronger decrease of ClONO2 than of HCl. In the FTIR measurements, this difference between the trends of HCl and ClONO2 depends strongly on latitude, especially in the Northern Hemisphere.Peer reviewe

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6-48 months with Duchenne muscular dystrophy amenable to exon 51 skipping

Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skip-amenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6–48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24–48 months, n = 9; Cohort 2: aged 6 to 4 years of age. These data support the safety and tolerability of eteplirsen at the approved 30-mg/kg dose in boys as young as 6 months old

Colonial palynomorphs from the Upper Ordovician of north-eastern Iran : ‘thalli’, coenobial Chlorophyceae (Hydrodictyaceae) or cyanobacteria?

This study documents ‘colonial’ palynomorphs from the Upper Ordovician Ghelli Formation of north-eastern Iran. The aggregates of organic-walled microfossils come from the Katian Armoricochitina nigerica–Ancyrochitina merga chitinozoan biozones of this formation. The ‘colonial’ microfossils can be classified as acritarchs and/or cryptospores, but they cannot be attributed to a particular biological group. Some specimens resemble ‘thalli’ of putative spores, such as Grododowon orthogonalis Strother 2017. Other clusters may suggest an affinity to green algal groups, in particular to colonial chlorophyceaen algae, most probably belonging to Hydrodictyaceae. Some specimens also show morphological similarities with cyanobacterial groups. There is so far no evidence to relate these ‘colonial’ palynomorphs to primitive land plants, but we hypothesise that they were possibly produced by ancient green algal lineages with some kind of subaerial existence

Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones

Risdiplam in Type 1 Spinal Muscular Atrophy

BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.)

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients to untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: Over 1,600 patient-years of follow-up (>700 patients) were studied from six real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-meter walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for non-genotypic prognostic factors. DISCUSSION: These findings suggest viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study