Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (<i>CES1</i>) Variants

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure

Effects of Renal Denervation on Insulin Sensitivity and Inflammatory Markers in Nondiabetic Patients with Treatment-Resistant Hypertension

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p=0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p=0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies

Use of high intensity X-ray analysis as tool to create new, fundamental models for phase transformations and residual stress in ductile cast iron

Recent advances in high resolution X-Ray methods that involve use of synchrotron facilities have made it possible to do high resolution, in-situ experimental studies of phase transformations in engineering materials thus providing detailed and accurate information on the processes that take place during such phase transformations. This paper describes how such facilities can be applied to study solidification of cast iron and formation of residual stress after eutectoid transformation by resolving the processes in 3D and time

Propranolol in the treatment of infantile haemangiomas:lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey

Oral propranolol is widely prescribed as first line treatment for infantile haemangiomas (IHs) and anecdotally prescribing practice differs widely between centres

Recent warming trends of the Greenland ice sheet documented by historical firn and ice temperature observations and machine learning

Surface melt on the Greenland ice sheet has been increasing in intensity and extent over the last decades due to Arctic atmospheric warming. Surface melt depends on the surface energy balance, which includes the atmospheric forcing but also the thermal budget of the snow, firn and ice near the ice sheet surface. The temperature of the ice sheet subsurface has been used as an indicator of the thermal state of the ice sheet's surface. Here, we present a compilation of 4612 measurements of firn and ice temperature at 10 m below the surface (T10 m) across the ice sheet, spanning from 1912 to 2022. The measurements are either instantaneous or monthly averages. We train an artificial neural network model (ANN) on 4597 of these point observations, weighted by their relative representativity, and use it to reconstruct T10 m over the entire Greenland ice sheet for the period 1950–2022 at a monthly timescale. We use 10-year averages and mean annual values of air temperature and snowfall from the ERA5 reanalysis dataset as model input. The ANN indicates a Greenland-wide positive trend of T10 m at 0.2 ∘C per decade during the 1950–2022 period, with a cooling during 1950–1985 (−0.4 ∘C per decade) followed by a warming during 1985–2022 (+0.7 ∘ per decade). Regional climate models HIRHAM5, RACMO2.3p2 and MARv3.12 show mixed results compared to the observational T10 m dataset, with mean differences ranging from −0.4 ∘C (HIRHAM) to 1.2 ∘C (MAR) and root mean squared differences ranging from 2.8 ∘C (HIRHAM) to 4.7 ∘C (MAR). The observation-based ANN also reveals an underestimation of the subsurface warming trends in climate models for the bare-ice and dry-snow areas. The subsurface warming brings the Greenland ice sheet surface closer to the melting point, reducing the amount of energy input required for melting. Our compilation documents the response of the ice sheet subsurface to atmospheric warming and will enable further improvements of models used for ice sheet mass loss assessment and reduce the uncertainty in projections.</p

Naturally Occurring Lipid A Mutants in Neisseria meningitidis from Patients with Invasive Meningococcal Disease Are Associated with Reduced Coagulopathy

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease

Management of nystagmus in children : a review of the literature and current practice in UK specialist services

Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillations of one or both eyes, initiated by a slow phase. It is not uncommon in the UK and regularly seen in paediatric ophthalmology and adult general/strabismus clinics. In some cases, it occurs in isolation, and in others, it occurs as part of a multisystem disorder, severe visual impairment or neurological disorder. Similarly, in some cases, visual acuity can be normal and in others can be severely degraded. Furthermore, the impact on vision goes well beyond static acuity alone, is rarely measured and may vary on a minute-to-minute, day-to-day or month-to-month basis. For these reasons, management of children with nystagmus in the UK is varied, and patients report hugely different experiences and investigations. In this review, we hope to shine a light on the current management of children with nystagmus across five specialist centres in the UK in order to present, for the first time, a consensus on investigation and clinical management