We determined optimal vancomycin starting dose regimens in infants ≤180 days of age to achieve the highest probability of target attainment with an area under the concentration-time curve for 24 h ...(AUC
) of ≥400 using population pharmacokinetic (PK) modeling. Secondarily, determination of the relationship between serum creatinine (SCR) and vancomycin clearance in neonates was done. A retrospective population PK study was designed and included pediatric patients ≤180 days old who had received vancomycin and had a serum vancomycin concentration sampled. A population PK model was developed using Pumas (v1.0.5). Simulation was performed with various dosing regimens to evaluate the probability of AUC
target attainment and probability of trough of ≤20 mg/liter, and comparison to published models was performed. Individual clearance estimates, obtained from the final model, were plotted against SCR and faceted by age quartiles to assess the relationship between SCR and vancomycin clearance. A total of 934 patients were included in the study (58.6% male; median age, 43.6 days range of 0 to 184; median number of concentration samples, 1 range of 1 to 29). A one-compartment model was developed with body weight (WT), SCR, and postmenstrual age (PMA) identified as significant covariates on clearance. Plotting vancomycin clearance versus SCR demonstrated no clear relationship between the two at <10 days postnatal age (PNA). Dosing regimens to attain AUC
and trough targets were stratified according to SCR for ≥10 days PNA and PMA for <10 days PNA. A vancomycin population PK model was developed for pediatric patients <180 days of age incorporating WT, SCR, and PMA. The relationship between vancomycin clearance and serum creatinine is not clear at <10 days PNA.
Linezolid standard dosing is fixed at 600 mg every 12 h (q12h) for adults. Literature suggests critically ill, obese patients require higher doses. The study aim is 2-fold: (i) to describe linezolid ...pharmacokinetics (PK), and (ii) to evaluate if PK/pharmacodynamic (PD) target attainment is achieved with standard dosing in critically ill, obese patients with severe skin and soft tissue infections (SSTIs). Adult patients with a body mass index (BMI) of ≥30 kg/m
and receiving intravenous (i.v.) linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 h postinfusion and as a trough. Target attainment was defined as achieving area under the concentration-time curve from 0 to 24 h to MIC (AUC
/MIC) of ≥100 h*mg/liter. Monte Carlo simulations were used to determine the probability of target attainment (PTA). Eleven patients were included in the study. The median BMI was 45.7 kg/m
, and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses, and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC
/MIC targets, for noncirrhotic patients at 140 kg, the PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs of 0.5, 1, 2, and 4 mg/liter, respectively. In conclusion, target attainment of ≥90% is not achieved with standard linezolid doses for noncirrhotic patients ≥140 kg with MICs of ≥2 mg/liter. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.
Infectious cDNA clones were developed for Grapevine leafroll-associated virus 3 (GLRaV-3, genus Ampelovirus, family Closteroviridae). In vitro RNA transcripts generated from cDNA clones showed ...replication via the production of 3′-coterminal subgenomic (sg) mRNAs in Nicotiana benthamiana protoplasts. The detection of sgRNAs and the recovery of progeny recombinant virions from N. benthamiana leaves agroinfiltrated with full-length cDNA clones confirmed RNA replication and virion formation. The 5′ non-translated region (5′ NTR) of GLRaV-3 was exchangeable between genetic variants and complement the corresponding cognate RNA functions in trans. Mutational analysis of the 5′ NTR in minireplicon cDNA clones showed that the conserved 40 nucleotides at the 5′-terminus were indispensable for replication, compared to downstream variable portion of the 5′ NTR. Some of the functional mutations in the 5′ NTR were tolerated in full-length cDNA clones and produced sgRNAs and virions in N. benthamiana leaves, whereas other mutations affected replication and virion formation.
Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin ...system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide frusemide), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2-4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication. Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.
A series of novel N-((1H-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-substituted-4, 5-dihydro-1-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-substituted-4, 5-dihydro-1H-pyrazol-3-yl) benzenamine were ...synthesized by treating various 1-(4-((1H-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one with phenyl hydrazine in the presence of sodium acetate through a simple ring closure reaction. The starting material, 1-(4-((1H-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one,-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one, was synthesized from o-phenylenediamine by a multistep synthesis. All the synthesized compounds were characterized by spectroscopic means and elemental analyses. The title compounds were investigated for in vitro antibacterial and antifungal properties against some human pathogenic microorganisms by employing the agar streak dilution method using Ciprofloxacin and Ketoconazole as standard drugs. All title compounds showed activity against the entire strains of microorganism. Structural activity relationship studies reveal that compounds possessing an electron-withdrawing group display better activity than the compounds containing electron-donating groups, whereas the unsubstituted derivatives display moderate activity. Based on the results obtained, N-((1H-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-(4-(trifluoromethyl) phenyl)-4,5-dihydro-1H-pyrazol-3-yl) benzenamine 5i was found to be very active compared with the rest of the compounds and standard drugs that were subjected to antimicrobial assay.
•Deep learning can accurately identify pain in patients presenting to the ED.•AI approaches allow for population-level insights and patterns.•Pain presentations to the ED changed with the Covid-19 ...pandemic.
To determine the incidence of patients presenting in pain to a large Australian inner-city emergency department (ED) using a clinical text deep learning algorithm.
A fine-tuned, domain-specific, transformer-based clinical text deep learning model was used to interpret free-text nursing assessments in the electronic medical records of 235,789 adult presentations to the ED over a three-year period. The model classified presentations according to whether the patient had pain on arrival at the ED. Interrupted time series analysis was used to determine the incidence of pain in patients on arrival over time. We described the changes in the population characteristics and incidence of patients with pain on arrival occurring with the start of the Covid-19 pandemic.
55.16% (95%CI 54.95%–55.36%) of all patients presenting to this ED had pain on arrival. There were differences in demographics and arrival and departure patterns between patients with and without pain. The Covid-19 pandemic initially precipitated a decrease followed by a sharp, sustained rise in pain on arrival, with concurrent changes to the population arriving in pain and their treatment.
Applying a clinical text deep learning model has successfully identified the incidence of pain on arrival. It represents an automated, reproducible mechanism to identify pain from routinely collected medical records. The description of this population and their treatment forms the basis of intervention to improve care for patients with pain. The combination of the clinical text deep learning models and interrupted time series analysis has reported on the effects of the Covid-19 pandemic on pain care in the ED, outlining a methodology to assess the impact of significant events or interventions on pain care in the ED.
Applying a novel deep learning approach to identifying pain guides methodological approaches to evaluating pain care interventions in the ED, giving previously unavailable population-level insights.
The Bay of Bengal (BoB) is characterized by a shallow (∼10–20 m deep) fresh layer associated with 40–60 m deep warm near‐surface layer during the post‐monsoon season (October–November). We use hourly ...observations from a moored buoy at 15°N, 90°E along with satellite and ocean analysis data sets to understand the evolution of the near‐surface layer during the passage of two category‐3 cyclonic storms: Cyclone Titli (7–11 October 2018) and cyclone Gaja (10–15 November 2018). The mooring was ∼200 km away to the right of the two cyclone tracks. A 15 day (22 September–7 October) break in the Indian summer monsoon resulted in clear skies, calm winds, and sea surface temperature warming (SST) by 2.8°C before Titli. During Titli, near‐surface thermal stratification restricted vertical mixing to 20 m depth and limited SST cooling at the mooring. During passage of cyclone Gaja, fresh Irrawaddy River water associated with a subsurface warm layer was advected to the mooring by mesoscale eddy flow. Cyclone winds could not break through the near‐surface density stratification associated with this river water. Shear associated with near‐inertial currents led to delayed mixed layer deepening after the cyclone's passage but there was no cold wake along the track of Gaja due to mixing of subsurface warm water to the surface. We illustrate the relevant processes at work for the two cyclones based on mixed layer salt and heat balance at 15°N, 90°E. This study demonstrates the importance of ocean preconditioning and thermohaline stratification on SST evolution under the influence of post‐monsoon cyclones in BoB.
Plain Language Summary
The Bay of Bengal (BoB) is an active zone for genesis of tropical cyclones. During the post‐monsoon season, the near‐surface ocean in the Bay is stable due to presence of a thin, fresh layer of river water and the subsurface waters are generally warm. In this study, we use in‐situ mooring, satellite, and ocean analysis data sets to understand how the preexisting temperature and the salinity structure of the ocean can influences the ocean's response to two severe tropical cyclones, Titli and Gaja, that occurred in the Bay during October–November 2018. In the case of Titli, we observe that warming of the sea surface prior to arrival of cyclone resulted in strong thermal stratification, which restricted vertical mixing to a depth of 20 m under strong cyclone winds. During the passage of Gaja, river water with a subsurface warm layer advected to the mooring location resulted in stable stratification, which did not allow cyclone‐induced mixing. We observe a delayed deepening of the mixed layer to 40 m depth due to shear induced by inertial currents and near‐surface warming after the passage of cyclone Gaja. This study demonstrates the importance of preexisting upper ocean temperature and salinity stratification for mixed layer evolution under post‐monsoon tropical cyclones in the BoB.
Key Points
Strong thermal stratification due to warming during a monsoon break period restricted vertical mixing depth during the passage of cyclone Titli
No cold wake along the track of cyclone Gaja due to cyclone‐induced mixing of subsurface warm water associated with the river water
Ocean preconditioning and thermohaline stratification are important for sea surface temperature evolution under post‐monsoon cyclones in the Bay of Bengal
We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of high-J CO lines (Jup = 6, 7, 8) and associated dust continuum toward five strongly lensed, dusty, star-forming galaxies ...at redshift z = 2.7-5.7. These galaxies, discovered in the South Pole Telescope survey, are observed at 0 2-0 4 resolution with ALMA. Our high-resolution imaging coupled with the lensing magnification provides a measurement of the structure and kinematics of molecular gas in the background galaxies with spatial resolutions down to kiloparsec scales. We derive visibility-based lens models for each galaxy, accurately reproducing observations of four of the galaxies. Of these four targets, three show clear velocity gradients, of which two are likely rotating disks. We find that the reconstructed region of CO emission is less concentrated than the region emitting dust continuum even for the moderate-excitation CO lines, similar to what has been seen in the literature for lower-excitation transitions. We find that the lensing magnification of a given source can vary by 20%-50% across the line profile, between the continuum and line, and between different CO transitions. We apply Large Velocity Gradient modeling using apparent and intrinsic line ratios between lower-J and high-J CO lines. Ignoring these magnification variations can bias the estimate of physical properties of interstellar medium of the galaxies. The magnitude of the bias varies from galaxy to galaxy and is not necessarily predictable without high-resolution observations.
Purpose
To conduct a mechanistic investigation of the interaction between aliskiren and grapefruit juice in healthy subjects.
Methods
Twenty-eight subjects received an oral dose of aliskiren 300 mg ...(highest recommended clinical dose) with 300 mL of either water or grapefruit juice in a two-way crossover design. Safety and pharmacokinetic analyses were performed. In vitro studies were performed in HEK293 cells to investigate the role of organic anion transporting polypeptide (OATP) transporter-mediated uptake of aliskiren.
Results
Co-administration of a single dose of aliskiren with grapefruit juice decreased the plasma concentration of aliskiren, with mean decreases in the AUC
inf
, AUC
last
, and C
max
of 38, 37, and 61%, respectively. The uptake of
14
Caliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination atorvastatin and rifamycin had no effect on
14
Caliskiren accumulation in either cell type. The uptake of
14
Caliskiren and
3
Hfexofenadine was linear in OATP1A2-expressing cells and was reduced by naringin, with IC
50
values of 75.5 ± 11.6 and 24.2 ± 2.0 μM, respectively.
Conclusions
Grapefruit juice decreases exposure of aliskiren partially via inhibition of intestinal OATP1A2.
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