Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transporter-mediated monoamine efflux with weak to no activity at pre- or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS

Adjacent level discitis after anterior cervical discectomy and fusion (ACDF): a case report

This report describes a case of spondylodiscitis occurring adjacent to levels at which anterior cervical discectomy and fusion was performed. The objective is to describe a rare cause of spondylodiscitis and discuss its successful management. Post-operative discitis involving the same level is a known occurrence. We report an interesting case of spondylodiscitis occurring at the adjacent level of fusion, and to our knowledge this is the first such case reported in literature. A two-level decompression and fusion was performed at C5–6 and C6–7 levels with PEEK cages and anterior cervical plating in a middle-aged gentleman for persistent axial neck pain and left-sided radiculopathy involving C6 and C7 distribution. After 6 weeks, the patient presented to us with complaints of mild paresthesia in the abdomen and extremities. Radiological investigations including plain radiographs and MRI revealed a surprising finding of discitis at C4–5 level with an associated epidural abscess. In view of the patient’s myelopathic symptoms, surgical debridement and decompression of the spinal cord was performed. The plate and screws were removed, the cages were left intact, and the C4–5 disc level was reconstructed with tricortical iliac crest autograft. No further instrumentation was performed. The biopsy specimen from the disc at C4–5 level grew Serratia marcescens. It was contemplated that C4–5 discitis was initiated by inoculation of bacteria at the superior endplate of C5 by contaminated vertebral pins/drill-bit or screws. Adjacent level discitis is a rare but potentially serious complication of anterior cervical fusion. A high index of suspicion of infection is necessary if the patient complains of new symptoms after anterior cervical fusion. Thorough assessment and aggressive treatment is necessary for successful management

Acquired immunologic tolerance: with particular reference to transplantation

The first unequivocally successful bone marrow cell transplantation in humans was recorded in 1968 by the University of Minnesota team of Robert A. Good (Gatti et al. Lancet 2: 1366–1369, 1968). This achievement was a direct extension of mouse models of acquired immunologic tolerance that were established 15 years earlier. In contrast, organ (i.e. kidney) transplantation was accomplished precociously in humans (in 1959) before demonstrating its feasibility in any experimental model and in the absence of a defensible immunologic rationale. Due to the striking differences between the outcomes with the two kinds of procedure, the mechanisms of organ engraftment were long thought to differ from the leukocyte chimerism-associated ones of bone marrow transplantation. This and other concepts of alloengraftment and acquired tolerance have changed over time. Current concepts and their clinical implications can be understood and discussed best from the perspective provided by the life and times of Bob Good

Study of hadronic event-shape variables in multijet final states in pp collisions at √s=7 TeV

Peer reviewe

Surgeon volume and 30 day mortality for brain tumours in England.

BACKGROUND: There is evidence that surgeons who perform more operations have better outcomes. However, in patients with brain tumours, all of the evidence comes from the USA. METHODS: We examined all English patients with an intracranial neoplasm who had an intracranial resection in 2008-2010. We included surgeons who performed at least six operations over 3 years, and at least one operation in the first and last 6 months of the period. RESULTS: The analysis data set comprised 9194 operations, 163 consultant neurosurgeons and 30 centres. Individual surgeon volumes varied widely (7-272; median=46). 72% of operations were on the brain, and 30 day mortality was 3%. A doubling of surgeon load was associated with a 20% relative reduction in mortality. Thirty day mortality varied between centres (0·95-8·62%) but was not related to centre workload. CONCLUSIONS: Individual surgeon volumes correlated with patient 30 day mortality. Centres and surgeons in England are busier than surgeons and centres in the USA. There is no relationship between centre volume and 30 day mortality in England. Services in the UK appear to be adequately arranged at a centre level, but would benefit from further surgeon sub-specialisation

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta