Measurements of morphodynamics of a sheltered beach along the Dutch Wadden Sea

A field campaign was carried out at a sheltered sandy beach with the aim of gaining new insights into the driving processes behind sheltered beach morphodynamics. Detailed measurements of the local hydrodynamics, bed-level changes and sediment composition were collected at a man-made beach on the leeside of the barrier island Texel, bordering the Marsdiep basin that is part of the Dutch Wadden Sea. The dataset consists of (1) current, wave and turbidity measurements from a dense cross-shore array and a 3ĝ€¯km alongshore array; (2) sediment composition data from beach surface samples; (3) high-Temporal-resolution RTK-GNSS beach profile measurements; (4) a pre-campaign spatially covering topobathy map; and (5) meteorological data. This paper outlines how these measurements were set up and how the data have been processed, stored and can be accessed. The novelty of this dataset lies in the detailed approach to resolve forcing conditions on a sheltered beach, where morphological evolution is governed by a subtle interplay between tidal and wind-driven currents, waves and bed composition, primarily due to the low-energy (near-Threshold) forcing. The data are publicly available at 4TU Centre for Research Data at: 10.4121/19c5676c-9cea-49d0-b7a3-7c627e436541

Measurements of morphodynamics of a sheltered beach along the Dutch Wadden Sea

A field campaign was carried out at a sheltered sandy beach with the aim of gaining new insights into the driving processes behind sheltered beach morphodynamics. Detailed measurements of the local hydrodynamics, bed-level changes and sediment composition were collected at a man-made beach on the leeside of the barrier island Texel, bordering the Marsdiep basin that is part of the Dutch Wadden Sea. The dataset consists of (1) current, wave and turbidity measurements from a dense cross-shore array and a 3 km alongshore array; (2) sediment composition data from beach surface samples; (3) high-temporal-resolution RTK-GNSS beach profile measurements; (4) a pre-campaign spatially covering topobathy map; and (5) meteorological data. This paper outlines how these measurements were set up and how the data have been processed, stored and can be accessed. The novelty of this dataset lies in the detailed approach to resolve forcing conditions on a sheltered beach, where morphological evolution is governed by a subtle interplay between tidal and wind-driven currents, waves and bed composition, primarily due to the low-energy (near-threshold) forcing. The data are publicly available at 4TU Centre for Research Data at: https://doi.org/10.4121/19c5676c-9cea-49d0-b7a3-7c627e436541 (Van der Lugt et al., 2023).</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Turning the tide: comparison of tidal flow by periodic sea level fluctuation and by periodic bed tilting in scaled landscape experiments of estuaries

Analogue models or scale experiments of estuaries and short tidal basins are notoriously difficult to create in the laboratory because of the difficulty to obtain currents strong enough to transport sand. Our recently discovered method to drive tidal currents by periodically tilting the entire flume leads to intense sediment transport in both the ebb and flood phase, causing dynamic channel and shoal patterns. However, it remains unclear whether tilting produces periodic flows with characteristic tidal properties that are sufficiently similar to those in nature for the purpose of landscape experiments. Moreover, it is not well understood why the flows driven by periodic sea level fluctuation, as in nature, are not sufficient for morphodynamic experiments. Here we compare for the first time the tidal currents driven by sea level fluctuations and by tilting. Experiments were run in a 20  ×  3 m straight flume, the Metronome, for a range of tilting periods and with one or two boundaries open at constant head with free inflow and outflow. Also, experiments were run with flow driven by periodic sea level fluctuations. We recorded surface flow velocity along the flume with particle imaging velocimetry and measured water levels along the flume. We compared the results to a one-dimensional model with shallow flow equations for a rough bed, which was tested on the experiments and applied to a range of length scales bridging small experiments and large estuaries. We found that the Reynolds method results in negligible flows along the flume except for the first few metres, whereas flume tilting results in nearly uniform reversing flow velocities along the entire flume that are strong enough to move sand. Furthermore, tidal excursion length relative to basin length and the dominance of friction over inertia is similar in tidal experiments and reality. The sediment mobility converges between the Reynolds method and tilting for flumes hundreds of metres long, which is impractical. Smaller flumes of a few metres in length, on the other hand, are much more dominated by friction than natural systems, meaning that sediment suspension would be impossible in the resulting laminar flow on tidal flats. Where the Reynolds method is limited by small sediment mobility and high tidal range relative to water depth, the tilting method allows for independent control over the variables flow depth, velocity, sediment mobility, tidal period and excursion length, and tidal asymmetry. A periodically tilting flume thus opens up the possibility of systematic biogeomorphological experimentation with self-formed estuaries

Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The "Twisted" Case of QWFGLM b(6)

While recent studies have shown that for some peptides, such as oligoglycines and Leu-enkephalin, mid-sized b fragment ions exist as a mixture of oxazolone and macrocycle structures, other primary structure motifs, such as QWFGLM, are shown to exclusively give rise to macrocycle structures. The aim of this study was to determine if certain amino acid residues are capable of suppressing macrocycle formation in the corresponding b fragment. The residues proline and 4-amino-methylbenzoic acid (4AMBz) were chosen because of their intrinsic rigidity, in the expectation that limited torsional flexibility may impede "head-to-tail" macrocycle formation. The presence of oxazolone versus macrocycle b(6) fragment structures was validated by infrared multiple photon dissociation (IRMPD) spectroscopy, using the free electron laser FELIX. It is confirmed that proline disfavors macrocycle formation in the cases of Q (P) under bar WFGLM b(7) and in Q (P) under bar FGLM b(6). The 4AMBz substitution experiments show that merely QWFG(4AMBz) M b(6), with 4AMBz in the fifth position, exhibits a weak oxazolone band. This effect is likely ascribed to a stabilization of the oxazolone structure, due to an extended oxazolone ring-phenyl p-electron system, not due to the rigidity of the 4AMBz residue. These results show that some primary structures have an intrinsic propensity to form macrocycle structures, which is difficult to disrupt, even using residues with limited torsional flexibility

Pharmacokinetics and safety of tobramycin nebulization with the I-neb® and PARI-LC Plus® in children with cystic fibrosis: a randomized, crossover study

AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC® Plus nebulizer in children with cystic fibrosis (CF). METHODS: A randomized, open-label, crossover study was performed. In two separate study visits blood samples from 22 children were collected following TIS nebulization with the I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by one month, in which one of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian pharmacokinetic modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard eGFR values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and eGFR revealed no abnormalities. Increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest, however, TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with CF resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury

Influence of allopurinol on thiopurine associated toxicity: A retrospective population-based cohort study

Aims: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. Methods: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. Results: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30–0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89–1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01–8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). Conclusion: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis : A randomized, crossover study

AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. METHODS: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury