Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age

AIMS Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. METHODS A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function. RESULTS A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. CONCLUSIONS Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation

Statistical analysis of magnetic divertor configuration influence on H-mode transitions

DIII-D plasmas are compared for two upper divertor configurations: with the outer strike point on the small angle slot (SAS) divertor target and with the outer strike point on the horizontal divertor target (HT). Scanning the vertical distance between the magnetic null point and the divertor target over a range 0.10–0.16 m is shown to increase the threshold power, Pth , and edge plasma power, PLoss , for the low-to-high confinement (L–H) and H–L transitions respectively, by up to a factor of 1.4. The X-point height scans were performed at three L-mode core plasma line average electron densities, n¯e= 1.2, 2.2 and 3.6 ×1019m−3 , to investigate the density dependence of divertor magnetic configuration influence on Pth . The X-point height, Zx-pt , was further extended across the range 0.16–0.22 m with the more open HT divertor configuration, for which a clear decrease in Pth with increasing Zx-pt is observed. The dependence of Pth on divertor magnetic geometry is further investigated using a time-dependent probability density function (PDF) model and information geometry to elucidate the roles played by pedestal plasma turbulence and perpendicular velocity flows. The degree of stochasticity of the plasma turbulence is observed to be sensitive to the plasma heating rate. The calculated square of the information rate shows changes in the relative density fluctuations and perpendicular velocity PDFs begin 2–5 ms prior to the L–H transition for three plasmas; providing a crucial measurement of the dynamic timescale of external transport barrier formation. Additionally, both information length and rate provide potential predictors of the L–H transition for these plasmas

Fine Structure in the Circumstellar Environment of a Young, Solar-like Star: the Unique Eclipses of KH 15D

Results of an international campaign to photometrically monitor the unique pre-main sequence eclipsing object KH 15D are reported. An updated ephemeris for the eclipse is derived that incorporates a slightly revised period of 48.36 d. There is some evidence that the orbital period is actually twice that value, with two eclipses occurring per cycle. The extraordinary depth (~3.5 mag) and duration (~18 days) of the eclipse indicate that it is caused by circumstellar matter, presumably the inner portion of a disk. The eclipse has continued to lengthen with time and the central brightness reversals are not as extreme as they once were. V-R and V-I colors indicate that the system is slightly bluer near minimum light. Ingress and egress are remarkably well modeled by the passage of a knife-edge across a limb-darkened star. Possible models for the system are briefly discussed.Comment: 19 pages, 5 figure

TESS Discovery of an ultra-short-period planet around the nearby M dwarf LHS 3844

Data from the newly-commissioned \textit{Transiting Exoplanet Survey Satellite} (TESS) has revealed a "hot Earth" around LHS 3844, an M dwarf located 15 pc away. The planet has a radius of $1.32\pm 0.02$ $R_\oplus$ and orbits the star every 11 hours. Although the existence of an atmosphere around such a strongly irradiated planet is questionable, the star is bright enough ($I=11.9$, $K=9.1$) for this possibility to be investigated with transit and occultation spectroscopy. The star's brightness and the planet's short period will also facilitate the measurement of the planet's mass through Doppler spectroscopy.Comment: 10 pages, 4 figures. Submitted to ApJ Letters. This letter makes use of the TESS Alert data, which is currently in a beta test phase, using data from the pipelines at the TESS Science Office and at the TESS Science Processing Operations Cente

Informing the design of a national screening and treatment programme for chronic viral hepatitis in primary care: qualitative study of at-risk immigrant communities and healthcare professionals

n Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedThis paper presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP-PG-1209-10038).

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding.

To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems

Precise Measurements of Self-absorbed Rising Reverse Shock Emission from Gamma-ray Burst 221009A

The deaths of massive stars are sometimes accompanied by the launch of highly relativistic and collimated jets. If the jet is pointed towards Earth, we observe a "prompt" gamma-ray burst due to internal shocks or magnetic reconnection events within the jet, followed by a long-lived broadband synchrotron afterglow as the jet interacts with the circum-burst material. While there is solid observational evidence that emission from multiple shocks contributes to the afterglow signature, detailed studies of the reverse shock, which travels back into the explosion ejecta, are hampered by a lack of early-time observations, particularly in the radio band. We present rapid follow-up radio observations of the exceptionally bright gamma-ray burst GRB 221009A which reveal an optically thick rising component from the reverse shock in unprecedented detail both temporally and in frequency space. From this, we are able to constrain the size, Lorentz factor, and internal energy of the outflow while providing accurate predictions for the location of the peak frequency of the reverse shock in the first few hours after the burst.Comment: 11 figures, 4 table