Antibody-drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin.

INTRODUCTION: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. AREAS COVERED: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. EXPERT OPINION: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

Controlling Near-Surface Ni Composition in Octahedral PtNi(Mo) Nanoparticles by Mo Doping for a Highly Active Oxygen Reduction Reaction Catalyst.

We report and study the translation of exceptionally high catalytic oxygen electroreduction activities of molybdenum-doped octahedrally shaped PtNi(Mo) nanoparticles from conventional thin-film rotating disk electrode screenings (3.43 ± 0.35 A mgPt-1 at 0.9 VRHE) to membrane electrode assembly (MEA)-based single fuel cell tests with sustained Pt mass activities of 0.45 A mgPt-1 at 0.9 Vcell, one of the highest ever reported performances for advanced shaped Pt alloys in real devices. Scanning transmission electron microscopy with energy dispersive X-ray analysis (STEM-EDX) reveals that Mo preferentially occupies the Pt-rich edges and vertices of the element-anisotropic octahedral PtNi particles. Furthermore, by combining in situ wide-angle X-ray spectroscopy, X-ray fluorescence, and STEM-EDX elemental mapping with electrochemical measurements, we finally succeeded to realize high Ni retention in activated PtNiMo nanoparticles even after prolonged potential-cycling stability tests. Stability losses at the anodic potential limits were mainly attributed to the loss of the octahedral particle shape. Extending the anodic potential limits of the tests to the Pt oxidation region induced detectable Ni losses and structural changes. Our study shows on an atomic level how Mo adatoms on the surface impact the Ni surface composition, which, in turn, gives rise to the exceptionally high experimental catalytic ORR reactivity and calls for strategies on how to preserve this particular surface composition to arrive at performance stabilities comparable with state-of-the-art spherical dealloyed Pt core-shell catalysts.

Direct observations of dynamic PtCo interactions in fuel cell catalyst precursors at the atomic level using E(S)TEM.

Reduction reactions in practical bimetallic platinum-cobalt electrode catalyst precursors containing platinum, cobalt and cobalt oxides in hydrogen at 200, 450 and 700 °C for 6 h have been studied in situ using an aberration corrected environmental (scanning) transmission electron microscope (AC E(S)TEM). Little difference was observed in reduction at 200 °C but during and after reduction at 450 °C, small nanoparticles less than 3 nm in diameter with tetragonal PtCo structures were observed and limited Pt3 Co ordering could be seen on the surfaces of larger nanoparticles. During and after reduction at 700 °C, fully ordered Pt3 Co and PtCo nanoparticles larger than 4 nm were produced and the average nanoparticle size almost trebled relative to the fresh precursor. After reduction at 450 and 700 °C, most nanoparticles were disordered platinum/cobalt alloys with fcc structure. After reduction at 700 °C many of the smallest nanoparticles disappeared suggesting Ostwald ripening had occurred. Mechanisms concerning the thermal transformation of mixed cobalt and platinum species are discussed, offering new insights into the creation of bimetallic platinum-cobalt nanoparticles in fuel cell catalysts.

Mesoscale simulations of confined Nafion thin films.

The morphology and transport properties of thin films of the ionomer Nafion, with thicknesses on the order of the bulk cluster size, have been investigated as a model system to explain the anomalous behaviour of catalyst/electrode-polymer interfaces in membrane electrode assemblies. We have employed dissipative particle dynamics (DPD) to investigate the interaction of water and fluorocarbon chains, with carbon and quartz as confining materials, for a wide range of operational water contents and film thicknesses. We found confinement-induced clustering of water perpendicular to the thin film. Hydrophobic carbon forms a water depletion zone near the film interface, whereas hydrophilic quartz results in a zone with excess water. There are, on average, oscillating water-rich and fluorocarbon-rich regions, in agreement with experimental results from neutron reflectometry. Water diffusivity shows increasing directional anisotropy of up to 30% with decreasing film thickness, depending on the hydrophilicity of the confining material. A percolation analysis revealed significant differences in water clustering and connectivity with the confining material. These findings indicate the fundamentally different nature of ionomer thin films, compared to membranes, and suggest explanations for increased ionic resistances observed in the catalyst layer.

An observational cohort study of 3 units versus 5 units slow intravenous bolus oxytocin in women undergoing elective caesarean delivery.

This study sought to compare postpartum blood loss and maternal outcomes after 3IU and 5IU oxytocin at elective caesarean delivery. In a prospective observational study, 73 women undergoing elective caesarean delivery under spinal anaesthetic received a slow I.V. injection of either 3IU (n = 35) or 5IU (n = 38) oxytocin after delivery. The main outcome was gravimetrically measured 24-hour postpartum blood loss with a non-inferiority margin of 300 mL. Uterine tone, phenylephrine dose, emesis and hypotension after oxytocin administration were secondary outcomes. Gravimetric postpartum blood loss was lower in the 3IU group (-58.8 mL [95% CI: -212.1, 94.3]) after adjusting for BMI, pre-delivery vasopressor dose, parity, and risk of uterine atony, with the upper confidence limit below the 300 mL margin in support of non-inferiority. Patients receiving 3IU had a higher (non-significant) rate of having post-delivery phenylephrine to treat hypotension (RR = 1.59 [95% CI: 0.97, 2.63]), but of those treated, the 3IU group required significantly less (-427 mcg [95% CI: -740, -114]). The 3IU group had a lower prevalence of vomiting compared to those receiving 5IU (6% versus 24%; P = 0.047). Administration of 3IU oxytocin was non-inferior compared to standard 5IU with respect to blood loss in women undergoing elective caesarean delivery.

Feasibility of a multi-modal exercise program on cognition in older adults with Type 2 diabetes - a pilot randomised controlled trial.

BACKGROUND: Type 2 Diabetes (T2D) is associated with increased risk of dementia. We aimed to determine the feasibility of a randomised controlled trial (RCT) examining the efficacy of exercise on cognition and brain structure in people with T2D. METHODS: A 6-month pilot parallel RCT of a progressive aerobic- and resistance-training program versus a gentle movement control group in people with T2D aged 50-75 years (n = 50) at the University of Tasmania, Australia. Assessors were blinded to group allocation. Brain volume (total, white matter, hippocampus), cortical thickness and white matter microstructure (fractional anisotrophy and mean diffusivity) were measured using magnetic resonance imaging, and cognition using a battery of neuropsychological tests. Study design was assessed by any changes (during the pilot or recommended) to the protocol, recruitment by numbers screened and time to enrol 50 participants; randomisation by similarity of characteristics in groups at baseline, adherence by exercise class attendance; safety by number and description of adverse events and retention by numbers withdrawn. RESULTS: The mean age of participants was 66.2 (SD 4.9) years and 48% were women. There were no changes to the design during the study. A total of 114 people were screened for eligibility, with 50 participants with T2D enrolled over 8 months. Forty-seven participants (94%) completed the study (23 of 24 controls; 24 of 26 in the intervention group). Baseline characteristics were reasonably balanced between groups. Exercise class attendance was 79% for the intervention and 75% for the control group. There were 6 serious adverse events assessed as not or unlikely to be due to the intervention. Effect sizes for each outcome variable are provided. CONCLUSION: This study supports the feasibility of a large scale RCT to test the benefits of multi-modal exercise to prevent cognitive decline in people with T2D. Design changes to the future trial are provided. TRIAL REGISTRATION: ANZCTR 12614000222640 ; Registered 3/3/2014; First participant enrolled 26/6/2014, study screening commenced 1/9/2014; Australian and New Zealand Clinical Trial Registry.

Brachial-to-radial systolic blood pressure amplification in patients with type 2 diabetes mellitus.

Brachial-to-radial-systolic blood pressure amplification (Bra-Rad-SBPAmp) can affect central SBP estimated by radial tonometry. Patients with type 2 diabetes mellitus (T2DM) have vascular irregularities that may alter Bra-Rad-SBPAmp. By comparing T2DM with non-diabetic controls, we aimed to determine the (1) magnitude of Bra-Rad-SBPAmp; (2) haemodynamic factors related to Bra-Rad-SBPAmp; and (3) effect of Bra-Rad-SBPAmp on estimated central SBP. Twenty T2DM (64±8 years) and 20 non-diabetic controls (60±8 years; 50% male both) underwent simultaneous cuff deflation and two-dimensional ultrasound imaging of the brachial and radial arteries. The first Korotkoff sound (denoting SBP) was identified from the first inflection point of Doppler flow during cuff deflation. Bra-Rad-SBPAmp was calculated by radial minus brachial SBP. Upper limb and systemic haemodynamics were recorded by tonometry and ultrasound. Radial SBP was higher than brachial SBP for T2DM (136±19 vs 127±17 mm Hg; P<0.001) and non-diabetic controls (135±12 vs 121±11 mm Hg; P<0.001), but Bra-Rad-SBPAmp was significantly lower in T2DM (9±8 vs 14±7 mm Hg; P=0.042). The product of brachial mean flow velocity × brachial diameter was inversely and independently correlated with Bra-Rad-SBPAmp in T2DM (ß=-0.033 95% confidence interval -0.063 to -0.004, P=0.030). When radial waveforms were calibrated using radial, compared with brachial SBP, central SBP was significantly higher in both groups (T2DM, 116±13 vs 125±15 mm Hg; and controls, 112±10 vs 124±11 mm Hg; P<0.001 both) and there was a significant increase in the number of participants classified with 'central hypertension' (SBP⩾130 mm Hg; P=0.004). Compared with non-diabetic controls, Bra-Rad-SBPAmp is significantly lower in T2DM. Regardless of disease status, radial SBP is higher than brachial SBP and this results in underestimation of central SBP using brachial-BP-calibrated radial tonometry.

BJP is linking its articles to the IUPHAR/BPS Guide to PHARMACOLOGY.

LINKED EDITORIALS: This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/abstract and http://onlinelibrary.wiley.com/doi/10.1111/bph.12856/abstract. VIDEO: To view the video on the IUPHAR/BPS Guide to PHARMACOLOGY, visit: https://www.youtube.com/watch?v=Qhy3q33VtRI.

Exercise blood pressure: clinical relevance and correct measurement.

Blood pressure (BP) is a mandatory safety measure during graded intensity clinical exercise stress testing. While it is generally accepted that exercise hypotension is a poor prognostic sign linked to severe cardiac dysfunction, recent meta-analysis data also implicate excessive rises in submaximal exercise BP with adverse cardiovascular events and mortality, irrespective of resting BP. Although more data is needed to derive submaximal normative BP thresholds, the association of a hypertensive response to exercise with increased cardiovascular risk may be due to underlying hypertension that has gone unnoticed by conventional resting BP screening methods. Delayed BP decline during recovery is also associated with adverse clinical outcomes. Thus, above and beyond being used as a routine safety measure during stress testing, exercise (and recovery) BP may be useful for identifying high-risk individuals and also as an aid to optimise care through appropriate follow-up after exercise stress testing. Accordingly, careful attention should be paid to correct measurement of exercise stress test BP (before, during and after exercise) using a standardised approach with trained operators and validated BP monitoring equipment (manual or automated). Recommendations for exercise BP measurement based on consolidated international guidelines and expert consensus are presented in this review.

Cardiovascular effects of methacholine-induced airway obstruction in man.

Cardiovascular disease is the most frequent cause of death in people with chronic respiratory disease. The cause of this association has been attributed to airway obstruction leading to cardiovascular dysfunction (increased central blood pressure (BP) and aortic stiffness). However, this has never been experimentally tested. Methacholine is routinely used to stimulate airway function changes that mimic airway pathology. This study aimed to determine the cardiovascular effects of methacholine-induced airway obstruction. Fifteen healthy young adults (aged 22.9±2.5 years; 4 male; mean±S.D.) underwent a bronchial challenge test (randomized, blinded, cross-over design) in which they received nebulized methacholine inhalation in serially increasing concentrations (from 0.39 to 25 mg/ml) or saline (0.9%; control) on two separate days. Bronchoconstriction was assessed by forced expiratory volume at one second (FEV1) and cardiovascular effects by augmentation index, brachial BP, central BP, heart rate and aortic stiffness. Methacholine significantly decreased FEV1 from baseline to peak inhaled concentration compared with saline (-0.48±0.34 vs. -0.07±0.16 L; p<0.001), but there was no between-group change in augmentation index (1.6±7.0 vs. 3.7±10.2% p=0.49), brachial systolic BP (-3.3±7.6 vs. -4.7±5.7 mmHg; p=0.59), central systolic BP (-1.1±5.2 vs. -0.3±5.5 mmHg; p=0.73), heart rate (0.4±7.1 vs. -0.8±6.6 bpm; p=0.45) or aortic stiffness (0.2±1.3 vs. 0.8±1.8 m/s; p=0.20; n=12). Thus, methacholine induced airway obstruction does not acutely change brachial BP or central haemodynamics. This finding refutes the notion that airway obstruction per se leads to cardiovascular dysfunction, at least in healthy individuals in the acute setting.

Ambulatory and central haemodynamics during progressive ascent to high-altitude and associated hypoxia.

High-altitude hypoxia causes major cardiovascular changes, which may result in raised resting brachial blood pressure (BP). However, the effect of high-altitude hypoxia on more sensitive measures of BP control (such as 24 h ambulatory BP and resting central BP) is largely unknown. This study aimed to assess this and compare high-altitude responses to resting brachial BP, as well as determine the haemodynamic correlates of acute mountain sickness (AMS) during a progressive trekking ascent to high-altitude. Measures of oxygen saturation (pulse oximetry), 24 h ambulatory BP, resting brachial and central BP (Pulsecor) were recorded in 10 adults (aged 27±4, 30% male) during a 9-day trek to Mount Everest base camp, Nepal. Data were recorded at sea level (stage 1; <450 m above sea level (ASL)) and at progressive ascension to 3440 m ASL (stage 2), 4350 m ASL (stage 3) and 5164 m ASL (stage 4). The Lake Louise score (LLS) was used to quantify AMS symptoms. Total LLS increased stepwise from sea level to stage 4 (0.3±0.7 vs 4.4±2.0, P=0.012), whereas oxygen saturation decreased to 77±9% (P=0.001). The highest recordings of 24 h ambulatory, daytime, night time, brachial and central systolic BP and diastolic BP were achieved at stage 3, which were significantly greater than at sea level (P<0.005 for all). Twenty-four-hour ambulatory heart rate (HR) and night HR correlated with oxygen saturation (r=-0.741 and -0.608, both P<0.001) and total LLS (r=0.648 and r=0.493, both P<0.001). We conclude that 24 h ambulatory BP, central BP and HR are elevated during high-altitude hypoxia, but AMS symptoms are only related to tachycardia.

Waiting a few extra minutes before measuring blood pressure has potentially important clinical and research ramifications.

Office blood pressure (BP) is recommended to be measured after 5 min of seated rest, but it may decrease for 10 min of seated rest. This study aimed to determine the change (and its clinical relevance) in brachial and central BP from 5 to 10 min of seated rest. Office brachial and central BP (measured after 5 and 10 min), left ventricular (LV) mass index, 7-day home and ambulatory BP were measured in 250 participants with treated hypertension. Office brachial and central BP were significantly lower at 10-min compared with 5-min BP (P<0.001). Seven-day home systolic BP (SBP) was significantly lower than office SBP measured at 5 min (P<0.001), but was similar to office SBP at 10 min (P=0.511). From 5 to 10 min, the percentage of participants with controlled BP increased and the percentage of participants with high central pulse pressure (PP) decreased (P<0.001). Moreover, brachial and central PP were significantly correlated with LV mass index measured at 10 min (r=0.171, P=0.006 and r=0.139, P=0.027, respectively), but not at 5 min (r=0.115, P=0.068 and r=0.084, P=0.185, respectively). BP recorded after 10 min is more representative of true BP control. These findings have relevance to appropriate diagnosis of hypertension and design of clinical trials.

Osteoarthritis bone marrow lesions at the knee and large artery characteristics.

OBJECTIVE: There is evidence to suggest vascular involvement in the initiation and progression of osteoarthritis (OA). The relationship between large artery characteristics and pathogenesis of OA has not been investigated and was the aim of this study. DESIGN: Large artery characteristics (i.e., aortic stiffness, brachial and central blood pressure (BP) variables) and bone marrow lesions (BMLs; measured by magnetic resonance imaging as a surrogate index of OA) were recorded in 208 participants (aged 63 ± 7 years; mean ± SD) with symptomatic knee OA. Relationships between large artery characteristics and BML were assessed by multiple regression adjusting for age, sex and body mass index. RESULTS: There was a high prevalence of BML presence in the study population (70%), but no significant difference between participants with and without BML for all large artery and BP variables (P > 0.05 all). Furthermore, there were no significant relationships between BML size and aortic stiffness (r = -0.033, P = 0.71), central pulse pressure (r = 0.028, P = 0.74), augmentation index (r = 0.125, P = 0.14), brachial pulse pressure (r = 0.005, P = 0.95) or brachial systolic BP (r = -0.066, P = 0.44). When participants were stratified according to high or low aortic stiffness, there was no significant difference between groups regarding the proportion of those with a BML (64% vs. 70% respectively; P = 0.69). CONCLUSIONS: Variables indicative of large artery characteristics are not significantly correlated with BML size or presence in people with symptomatic knee OA. Thus, large artery characteristics may not have a causative influence in the development of OA, but this needs to be confirmed in prospective studies.

Central blood pressure in the management of hypertension: soon reaching the goal?

Blood pressure (BP) is conventionally measured by cuff at the brachial artery as an indication of pressure experienced by the organs. However, individual variation in pulse pressure amplification means that brachial cuff BP may be a poor representation of true central BP. Estimation of central BP is now possible using non-invasive methods that are amenable for widespread use. This paper reviews the evidence regarding the potential value of central BP in hypertension management. The major lines of evidence that support the use of central BP as a clinical tool include the: (1) major discrepancies in central BP among people with similar brachial BP; (2) independent relationship of central BP with end-organ damage; (3) independent relationship of central BP with cardiovascular (CV) events and mortality; (4) differential central and brachial BP responses to antihypertensive medications and; (5) improvements in end-organ damage after therapy more strongly relate to central than brachial BP. Despite all this, important evidence gaps relating to clinical use of central BP need fulfilling. These include the lack of central BP reference values and randomized, controlled studies to determine if: (1) central BP can help with diagnostic/therapeutic decisions and; (2) CV outcome is improved by targeting therapy towards lowering central BP levels. Additional challenges such as standardization of central BP methods, and understanding which patients are most likely to benefit from central BP monitoring also need to be determined. Overall, the future for central BP as a worthwhile clinical instrument appears positive, but there is much to be done.

Exercise aortic stiffness: reproducibility and relation to end-organ damage in men.

Resting aortic stiffness (pulse wave velocity; aortic PWV (aPWV)) independently predicts end-organ damage and mortality. Exercise haemodynamics have been shown to unmask cardiovascular abnormalities, otherwise undetectable at rest, but the response of aPWV to exercise has never been examined. This study aimed to develop a technique to measure exercise aPWV, determine reproducibility and relation to subclinical end-organ damage with aging. Healthy younger (n=17, 30±8 years) and older (n=18, 54±8 years) untreated men underwent cardiovascular assessment at rest and during low intensity semirecumbent cycling. Tonometry was used to assess aPWV and central blood pressure (BP). All participants underwent 24 h ambulatory BP (ABP) monitoring. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Fifteen participants had testing repeated within 28±18 days. Exercise aPWV had good reproducibility (mean difference=-0.35±0.61 m s(-1), intraclass correlations=0.874, P<0.001) and was increased 26% above resting values in younger men (5.8±0.9 vs 7.3±1.6 m s(-1), P<0.001) and 19% above resting values in older men (6.3±1.0 vs 7.4±0.9 m s(-1), P<0.001). Exercise, but not resting, aPWV was significantly correlated with eGFR in older men (r=-0.633, P=0.005), and this was maintained after correction for age, body mass index and daytime systolic ABP (r=-0.656, P=0.008). Conversely, in younger men there was no significant association between eGFR and aPWV either at rest (r=-0.031, P=0.906) or during exercise (r=-0.117, P=0.655). Exercise aPWV is reproducible and significantly associated with kidney function in healthy older men. Further studies to determine the physiology and clinical relevance of raised exercise aPWV are warranted.

Building HIA approaches into strategies for green space use: an example from Plymouth's (UK) Stepping Stones to Nature project.

The health and well-being benefits of access to green space are well documented. Research suggests positive findings regardless of social group, however barriers exist that limit access to green space, including proximity, geography and differing social conditions. Current public health policy aims to broaden the range of environmental public health interventions through effective partnership working, providing opportunities to work across agencies to promote the use of green space. Health Impact Assessment (HIA) is a combination of methods and procedures to assess the potential health and well-being impacts of policies, developments and projects. It provides a means by which negative impacts can be mitigated and positive impacts can be enhanced, and has potential application for assessing green space use. This paper describes the application of a HIA approach to a multi-agency project (Stepping Stones to Nature--SS2N) in the UK designed to improve local green spaces and facilitate green space use in areas classified as having high levels of deprivation. The findings suggest that the SS2N project had the potential to provide significant positive benefits in the areas of physical activity, mental and social well-being. Specific findings for one locality identified a range of actions that could be taken to enhance benefits, and mitigate negative factors such as anti-social behaviour. The HIA approach proved to be a valuable process through which impacts of a community development/public health project could be enhanced and negative impacts prevented at an early stage; it illustrates how a HIA approach could enhance multi-agency working to promote health and well-being in communities.