Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes

AIM: To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS: This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION: Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.     

Identifying the emergence of the superficial peroneal nerve through deep fascia on ultrasound and by dissection: Implications for regional anesthesia in foot and ankle surgery

Regional anesthesia relies on a sound understanding of anatomy and the utility of ultrasound in identifying relevant structures. We assessed the ability to identify the point at which the superficial peroneal nerve (SPN) emerges through the deep fascia by ultrasound on 26 volunteers (mean age 27.85 years ± 13.186; equal male: female). This point was identified, characterized in relation to surrounding bony landmarks (lateral malleolus and head of the fibula), and compared to data from 16 formalin‐fixed human cadavers (mean age 82.88 years ± 6.964; equal male: female). The SPN was identified bilaterally in all subjects. On ultrasound it was found to pierce the deep fascia of the leg at a point 0.31 (±0.066) of the way along a straight line from the lateral malleolus to the head of the fibula (LM‐HF line). This occurred on or anterior to the line in all cases. Dissection of cadavers found this point to be 0.30 (±0.062) along the LM‐HF line, with no statistically significant difference between the two groups (U = 764.000; exact two‐tailed P = 0.534). It was always on or anterior to the LM‐HF line, anterior by 0.74 cm (±0.624) on ultrasound and by 1.51 cm (±0.509) during dissection. This point was significantly further anterior to the LM‐HF line in cadavers (U = 257.700, exact two‐tailed P < 0.001). Dissection revealed the nerve to divide prior to emergence in 46.88% (n = 15) limbs, which was not identified on ultrasound (although not specifically assessed). Such information can guide clinicians when patient factors (e.g., obesity and peripheral edema) make ultrasound‐guided nerve localization more technically challenging. Clin. Anat. 32:390–395, 2019. © 2019 Wiley Periodicals, Inc.     

Global silicate weathering flux overestimated because of sediment–water cation exchange

Rivers carry the dissolved and solid products of silicate mineral weathering, a process that removes CO2 from the atmosphere and provides a key negative climate feedback over geological timescales. Here we show that, in some river systems, a reactive exchange pool on river suspended particulate matter, bonded weakly to mineral surfaces, increases the mobile cation flux by 50%. The chemistry of both river waters and the exchange pool demonstrates exchange equilibrium, confirmed by Sr isotopes. Global silicate weathering fluxes are calculated based on riverine dissolved sodium (Na⁺) from silicate minerals. The large exchange pool supplies Na⁺ of nonsilicate origin to the dissolved load, especially in catchments with widespread marine sediments, or where rocks have equilibrated with saline basement fluids. We quantify this by comparing the riverine sediment exchange pool and river water chemistry. In some basins, cation exchange could account for the majority of sodium in the river water, significantly reducing estimates of silicate weathering. At a global scale, we demonstrate that silicate weathering fluxes are overestimated by 12 to 28%. This overestimation is greatest in regions of high erosion and high sediment loads where the negative climate feedback has a maximum sensitivity to chemical weathering reactions. In the context of other recent findings that reduce the net CO2 consumption through chemical weathering, the magnitude of the continental silicate weathering fluxes and its implications for solid Earth CO2 degassing fluxes need to be further investigated.

For decades, silicate weathering has been postulated to provide the negative climate feedback on Earth that prevents a runaway greenhouse climate like on Venus (1). Silicate mineral dissolution with carbonic acid converts atmospheric CO2 into carbonate, and releases essential nutrients to the terrestrial and marine biosphere (2). There have been many attempts to quantify the silicate weathering flux (3), mostly assuming that riverine dissolved sodium (Na+) is derived only from silicate minerals and rock salt. Here we show that there is a major addition of nonsilicate Na+ to the critical zone from ancient seawater, weakly bonded to sedimentary rocks and supplied to waters via the cation exchange process. The implication is not only that the silicate weathering flux is overestimated at a global scale, but that this nonsilicate Na+ is most important in regions previously thought to have the highest silicate weathering fluxes (so called weathering-limited regions) and greatest climate sensitivity.Cation exchange is a rapid chemical reaction between cations in the dissolved phase and mineral surfaces, particularly clays (4). Major and trace cations such as calcium (Ca2+), magnesium (Mg2+), sodium (Na+), potassium (K+), and strontium (Sr2+) form the cation exchange pool, which balances negative charges on river-borne clay particle surfaces. This exchange takes place on interlayer sites, between the tetrahedral and octahedral layers, or on exposed surfaces (4). The importance of the cation exchange pool is well recognized in soils and aquifers (4, 5), has significant implications for enhanced weathering (6), and has been proposed as an important mechanism for buffering the composition of river waters (7–9). However, data on the riverine exchange pool are only available for two large river systems [Amazon and Ganges-Brahmaputra (10, 11)], despite its significance in providing a source of elements that are immediately bioavailable (12), and their potential for biasing the quantification of silicate weathering (9).It is increasingly recognized that rapidly reactive phases have a strong influence on the chemistry of river waters (13, 14). Cation exchange is a rapid reaction occurring continuously in soils, as riverine freshwaters evolve downstream interacting with particulate matter, and when they mix with seawater (15, 16). Important examples of cation exchange are the “swapping” of divalent cations Ca2+ and Mg2+ with Na+, in particular when there is a major change in water composition such as when fluvial clays reach the ocean,Caclay2++2Nawater+⇋2Naclay++Cawater2+.[1]As a result, marine sediments have an exchange pool that is dominated by Na+ (17). Subsequently, these marine sediments are uplifted and emplaced on the continents where Na+ in the exchange pool is released by cation exchange with Ca-rich fresh waters (9). This has major implications for estimates of silicate weathering fluxes and associated CO2 consumption, because they are calculated using the Na+ content of rivers (3). Cerling et al. (9) proposed that the Na+-rich exchange pool exerts an important control on natural waters, based on charge balance arguments from river water chemistry, but this hypothesis has never been rigorously tested (18) by determining the flux and composition of the exchange pool of rivers around the world.In this contribution, we present a large dataset of fluvial sediment cation exchange capacity (CEC) and composition in several of the world’s largest river basins. By comparing with the concomitant dissolved load chemistry, we demonstrate that 1) the exchange pool in river sediments is in equilibrium with the river water; 2) the fraction of mobile elements in the exchange pool relative to the dissolved pool can be significant, particularly in rapidly eroding, weathering-limited catchments; and 3) given reasonable inferences on the composition of old marine sedimentary rocks, modern-day silicate weathering has been overestimated and carbonate weathering has been underestimated. The results reduce the estimated magnitude of the silicate weathering flux, but increase the supply of base cations (e.g., Ca2+, which can be a limiting nutrient) to the biosphere, suggesting a greater role of organic carbon burial compared with silicate weathering for the long-term atmospheric CO2 sink.     

Adaptive learning can result in a failure to profit from good conditions: implications for understanding depression

Background and objectives: Depression is a major medical problem diagnosed in an increasing proportion of people and for which commonly prescribed psychoactive drugs are frequently ineffective. Development of treatment options may be facilitated by an evolutionary perspective; several adaptive reasons for proneness to depression have been proposed. A common feature of many explanations is that depressive behaviour is a way to avoid costly effort where benefits are small and/or unlikely. However, this viewpoint fails to explain why low mood persists when the situation improves. We investigate whether a behavioural rule that is adapted to a stochastically changing world can cause inactivity which appears similar to the effect of depression, in that it persists after the situation has improved.Methodology: We develop an adaptive learning model in which an individual has repeated choices of whether to invest costly effort that may result in a net benefit. Investing effort also provides information about the current conditions and rates of change of the conditions.Results: An individual following the optimal behavioural strategy may sometimes remain inactive when conditions are favourable (i.e. when it would be better to invest effort) when it is poorly informed about the current environmental state. Initially benign conditions can predispose an individual to inactivity after a relatively brief period of negative experiences.Conclusions and implications: Our approach suggests that the antecedent factors causing depressed behaviour could go much further back in an individual s history than is currently appreciated. The insights from our approach have implications for the ongoing debate about best treatment options for patients with depressive symptoms.     

Mid- to long-term survivorship of oxidised zirconium total knee replacements performed in patients under 50 years of age

Background

Oxidised zirconium has the wear properties of ceramic with the breakage resistance of metal. This results in less wear and is of benefit to younger, higher demand patients. We report the short- to mid-term survival of 103 Profix zirconium total knee replacements performed in patients under 50 years of age at time of surgery.

Activities of moxifloxacin against,and emergence of resistance in,Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model

The pharmacodynamics of moxifloxacin against Streptococcus pneumoniae and Pseudomonas aeruginosa were investigated in a pharmacokinetic infection model. Three strains of S. pneumoniae, moxifloxacin, and two strains of P. aeruginosa were used. Antibacterial effect and emergence of resistance were measured for both species over a 72-h period using an initial inoculum of about 10(8) CFU/ml. At equivalent area under the curve (AUC)/MIC ratios, S. pneumoniae was cleared from the model while P. aeruginosa was not. For S. pneumoniae, the area under the bacterial kill curve up to 72 h could be related to AUC/MIC ratio using an inhibitory maximum effect (E(max)) model (concentration required for 50% E(max) [EC(50)], 45 +/- 22; r(2), 0.97). For P. aeruginosa even at the highest AUC/MIC ratio (427), bacterial clearance was insufficient for the EC(50) to be calculated. Emergence of resistance occurred with P. aeruginosa but not to any significant extent with S. pneumoniae. Emergence of resistance in P. aeruginosa as measured by population analysis profile (PAP-AUC) was dependent on drug exposure and time of exposure. In weighted least-squares regression analysis AUC/MIC ratio was predictive of PAP-AUC. When emergence of resistance was measured by the time for the colony counts on media containing antibiotic to increase by 2 logs, again AUC/MIC was the best predictor of emergence of resistance. However, for both experiments using S. pneumoniae and P. aeruginosa the correlation between all the pharmacodynamic parameters was high. These data indicate that for a given fluoroquinolone the magnitude of the AUC/MIC ratio for antibacterial effect is dependent on the bacterial species. Emergence of resistance is dependent on (i) species, (ii) duration of drug exposure, and (iii) drug exposure. A single AUC/MIC ratio magnitude is not adequate to predict antibacterial effect or emergence of resistance for all bacterial species.     

Pharmacodynamics of minocycline against Staphylococcus aureus in an in vitro pharmacokinetic model

Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log₁₀-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P < 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r² of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and −1-log-unit, −2-log-unit, and −3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.     

Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder

A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD–Combined Type and 22 controls) aged 10–18 years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.     

Outcomes of Donation After Circulatory Death Heart Transplantation in Australia

Background

Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice.