The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Advances in retinopathy of prematurity imaging.

Retinopathy of prematurity (ROP) remains the leading cause of childhood blindness worldwide. Recent advances in ROP imaging have significantly improved our understanding of the pathogenesis and pathophysiological course of ROP including the acute phase, regression, reactivation, and late complications, known as adult ROP. Recent progress includes various contact and noncontact wide-field imaging devices for fundus imaging, smartphone-based fundus photography, wide-field fluorescein angiography, handheld optical coherence tomography (OCT) devices for wide-field en face OCT images, and OCT angiography. Images taken by those devices were incorporated in the recently updated guidelines of ROP, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3). ROP imaging has also allowed the real-world adoption of telemedicine- and artificial intelligence (AI)-based screening. Recent study demonstrated proof of concept that AI has a high diagnostic performance for the detection of ROP in a real-world screening. Here, we summarize the recent advances in ROP imaging and their application for screening, diagnosis, and management of ROP.

Exercise-induced amplification of mitogen-stimulated oxidative burst in whole blood is strongly influenced by neutrophil counts during and following exercise.

This study characterized the effect of moderate- or vigorous-intensity exercise on leukocyte counts, using fingertip sampling, and mitogen-stimulated oxidative burst, measured in whole blood with a point-of-care test. In a randomized crossover design, 13 healthy adults (mean ± SD age: 22 ± 2 years; seven male, six female) cycled for 30-min, once at 52 ± 5% V˙ O2peak and on another occasion at 74 ± 9% V˙ O2peak . Blood was sampled at baseline, immediately post-exercise, and 15- and 60-min post-exercise. The leukocyte differential and mitogen-stimulated Reactive Oxygen Species (ROS) production were assessed. Lymphocytes increased immediately post-exercise and decreased below pre-exercise levels 15- and 60-min later. Lymphocyte mobilization immediately post-exercise was 59 ± 36% greater with vigorous- compared to moderate-intensity exercise (p < 0.01). Neutrophils increased immediately after exercise (38 ± 19%, p < 0.01) remaining elevated 60-min later (50 ± 34%, p < 0.01; averaged across intensities) and did not differ between intensities (p = 0.259). Mitogen-stimulated ROS production was amplified immediately (+32 ± 37%, p < 0.01) and 60-min post-exercise (+56 ± 57%, p < 0.01; averaged across intensities) compared to rest and did not differ with intensity (p = 0.739). Exercise-induced amplification of ROS production was abolished when correcting for neutrophil, monocyte and platelet counts and correlated most strongly with neutrophil mobilization immediately (r = 0.709, p < 0.01) and 60-min after vigorous exercise (r = 0.687, p < 0.01). Leukocyte kinetics can be assessed using fingertip blood sampling in exercise settings. Exercise-induced amplification of oxidative burst is detectable with a point-of-care test, but results are strongly influenced by neutrophil counts, which may not be routinely quantified.

The mobilisation of early mature CD56dim-CD16bright NK cells is blunted following a single bout of vigorous intensity exercise in Type 1 Diabetes.

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Although T cell mediated, a number of other immune cells are also critically involved in coordinating the events leading to T1D. Specifically, innate subsets play an important role in the pathogenesis of T1D. NK cells are one of the first cell types to infiltrate the pancreas, causing damage and release of beta cell antigens. Previous work in our group has shown differential mobilisation of highly differentiated CD8+ T cells during vigorous intensity exercise in T1D compared to a control cohort. Here, we aimed to explore exercise-induced mobilisation of other cell types involved in T1D pathogenesis. In this study, we investigated the effects of a single bout of vigorous (80% predicted VO2max) intensity exercise on innate cell mobilisation in T1D and control participants. T1D (N=12, mean age 33.2yrs, predicted VO2max 32.2 ml.kg.min⁻¹, BMI 25.3 kg.m⁻²) and control (N=12, mean age 29.4yrs, predicted VO2 max 38.5 ml.kg.min⁻¹, BMI 23.7 kg.m⁻² male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. NK cell subsets mobilised during vigorous intensity exercise in both control and T1D participants. However, mature NK cells, defined as the CD56dimCD16bright subset, displayed a lower percentage increase following vigorous intensity exercise in T1D participants (Control: 185.12%, T1D: 97.06%). This blunted mobilisation was specific to early mature NK cells (KIR+) but not later differentiated NK cells (KIR+CD57+). Myeloid lineage subsets mobilised to a similar extent in both control and T1D participants. In conclusion, vigorous exercise mobilises innate immune cells in people with T1D albeit to a different extent to those without T1D. This mobilisation of innate immune cells provides a mechanistic argument to support exercise in people with T1D where it has the potential to improve surveillance for infection and to modulate the autoimmune response to the beta cell.

Imaging in Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness worldwide. Barriers to ROP screening and difficulties with subsequent evaluation and management include poor access to care, lack of physicians trained in ROP, and issues with objective documentation. Digital retinal imaging can help address these barriers and improve our knowledge of the pathophysiology of the disease. Advancements in technology have led to new, non-mydriatic and mydriatic cameras with wider fields of view as well as devices that can simultaneously incorporate fluorescein angiography, optical coherence tomography (OCT), and OCT angiography. Image analysis in ROP is also being employed through smartphones and computer-based software. Telemedicine programs in the United States and worldwide have utilized imaging to extend ROP screening to infants in remote areas and have shown that digital retinal imaging can be reliable, accurate, and cost-effective. In addition, tele-education programs are also using digital retinal images to increase the number of healthcare providers trained in ROP. Although indirect ophthalmoscopy is still an important skill for screening, digital retinal imaging holds promise for more widespread screening and management of ROP.

Total Ionizing Dose Effects on TiN/Ti/HfO2/TiN Resistive Random-Access Memory Studied via Electrically Detected Magnetic Resonance.

We observe a gamma-irradiation induced change in electrically detected magnetic resonance (EDMR) in TiN/Ti/HfO2/TiN resistive random access memory (RRAM). EDMR measurements exclusively detect electrically active defects which are directly involved in the transport mechanisms within these devices. The EDMR response has an isotropic g-value of 2.001 ± 0.0003. The response increases dramatically with increased gamma-irradiation. We tentatively associate this EDMR response with spin dependent trap assisted tunneling (SDTAT) events at O 2 - centers coupled to hafnium ions. Although our study cannot fully identify the role of these defects in electronic transport, the study does unambiguously identify changes in transport defects caused by the ionizing radiation on defects involved in electronic transport in RRAM devices. This work also contributes more broadly to the RRAM field by providing direct, though incomplete, information about atomic scale defects involved in electronic transport in leading RRAM systems.

Parasitic engineering for RRAM control.

The inevitable current overshoot which follows forming in filamentary RRAM devices is often perceived as a source of variability that should be minimized. This sentiment has led to efforts to curtail the overshoot by decreasing the parasitic capacitance using highly integrated 1T-1R or 1R-1R device structures. While this is readily achievable in single device test structures, it poses an intricate design constraint for memory array designs. Several papers (Degraeve et al., 2010, 2014; Fantini et al., 2013; Raghavan et al., 2013; Padovani et al., 2015) suggest that there is insufficient current to form stable filaments for small parasitic capacitances and/or low current compliance levels. Thus, the relationship between minimizing overshoot current and improved filament stability is tenuous. In this study, we utilize the forming energy-based understanding of filamentary forming to reveal that the parasitic capacitance should be optimized, rather than minimized for better filament control.

Detailed Vascular Anatomy of the Human Retina by Projection-Resolved Optical Coherence Tomography Angiography.

Optical coherence tomography angiography (OCTA) is a noninvasive method of 3D imaging of the retinal and choroidal circulations. However, vascular depth discrimination is limited by superficial vessels projecting flow signal artifact onto deeper layers. The projection-resolved (PR) OCTA algorithm improves depth resolution by removing projection artifact while retaining in-situ flow signal from real blood vessels in deeper layers. This novel technology allowed us to study the normal retinal vasculature in vivo with better depth resolution than previously possible. Our investigation in normal human volunteers revealed the presence of 2 to 4 distinct vascular plexuses in the retina, depending on location relative to the optic disc and fovea. The vascular pattern in these retinal plexuses and interconnecting layers are consistent with previous histologic studies. Based on these data, we propose an improved system of nomenclature and segmentation boundaries for detailed 3-dimensional retinal vascular anatomy by OCTA. This could serve as a basis for future investigation of both normal retinal anatomy, as well as vascular malformations, nonperfusion, and neovascularization.

Exercise-induced B cell mobilisation: Preliminary evidence for an influx of immature cells into the bloodstream.

The number of peripheral blood B lymphocytes doubles during acute exercise, but the phenotypic composition of this response remains unknown. In two independent exercise studies, using complimentary phenotyping strategies, we investigated the mobilisation patterns of distinct B cell subsets. In study one, nine healthy males (mean±SD age: 22.1±3.4years) completed a continuous cycling bout at 80% V̇O2MAX for 20min. In study two, seven healthy experienced cyclists (mean±SD age: 29.9±4.7years) completed a 30min cycling trial at a workload corresponding to +5% of the individual blood lactate threshold. In study one, CD3-CD19+ B cell subsets were classified into immature (CD27-CD10+), naïve (CD27-CD10-), memory (CD27+CD38-), plasma cells/plasmablasts (CD27+CD38+) and finally, recently purported 'B1' cells (CD27+ CD43+ CD69-). In study two, CD20+ B cells were classified into immature (CD27-IgD-), naïve (CD27-IgD+), and IgM+/IgG+/IgA+ memory cells (CD27+IgD-). Total B cells exhibited a mean increase of 88% (study one) and 60% (study two) during exercise. In both studies, immature cells displayed the greatest increase, followed by memory cells, then naïve cells (study one: immature 130%>mature 105%>naïve 84%; study two: immature 110%>mature 56%>naïve 38%). Our findings show that, unlike T cells and NK cells, B cell mobilisation is not driven by effector status, and, for the first time, that B cell mobilisation during exercise is comprised of immature CD27- IgD-/CD10+ cells.

The value of surveys in obstetric anaesthesia.

BACKGROUND: The Obstetric Anaesthetists' Association (OAA) has facilitated national surveys in obstetric anaesthesia since 1998. We wanted to examine trends in OAA-approved surveys since this time. METHODS: OAA-approved surveys performed between January 1998 and December 2012 were examined for the year they were carried out, the format (postal or electronic), the target group and the response rate. We determined whether each survey was presented or published. For each survey published as a substantive paper, we identified the number of times the publication had been cited. We also surveyed lead obstetric anaesthetists and expert witnesses practising in obstetric anaesthesia on the perceived usefulness of OAA-approved surveys. RESULTS: One hundred and thirty-five surveys approved by the OAA were carried out between 1998 and 2012. Response rates have fallen over the years, reaching a current plateau of 65%. Response rates varied with the target group. Seventy-eight percent of surveys were presented and 83% were published in some form. For surveys published as substantive papers (n=34, 25%), the median [IQR (range)] number of citations was 6 [3-11 (0-36)] per publication. Our survey of lead obstetric anaesthetists had a response rate of 62%. Those who replied rated OAA surveys a median [IQR (range)] of 6 [5-7 (1-9)] on a 0-10 scale of usefulness to their clinical practice. CONCLUSIONS: Response rates to OAA-approved surveys have declined but remain acceptable despite an increase in the number of surveys performed. Most surveys were presented or published in some form.

Identification of the midline by obese and non-obese women during late pregnancy.

During central neuraxial blockade, identifying the midline in parturients can be difficult, particularly if they are obese. We assessed the ability of women in late pregnancy, both obese and non-obese, to identify the midline of their own back by pointing and by pinprick discrimination with reference to the true midline identified by ultrasound. Thirteen out of 25 (52%) obese women were accurate to within 5 mm in identifying the midline of their back by pointing with their fingertip, compared with 21/25 (84%) non-obese women (p = 0.03). The median (IQR [range]) fingertip-midline distance was greater in obese women (5 (5-10 [0-10]) mm compared with non-obese women (2 (0-5 [0-12]) mm; p = 0.007). Identification of the midline using pinprick was poorer by obese women (median (IQR [range]) 33 (25-45 [3-85]) mm) than by non-obese women (18 (13-25 [8-40]) mm; p < 0.0001). However, women in both groups were correct > 99% of the time in identifying that a stimulus was either to the left or to the right side.

Safety guideline: skin antisepsis for central neuraxial blockade.

Concise guidelines are presented that recommend the method of choice for skin antisepsis before central neuraxial blockade. The Working Party specifically considered the concentration of antiseptic agent to use and its method of application. The advice presented is based on previously published guidelines, laboratory and clinical studies, case reports, and on the known properties of antiseptic agents.

The antioxidant enzyme peroxiredoxin-2 is depleted in lymphocytes seven days after ultra-endurance exercise.

PURPOSE: Peroxiredoxin-2 (PRDX-2) is an antioxidant and chaperone-like protein critical for cell function. This study examined whether the levels of lymphocyte PRDX-2 are altered over 1 month following ultra-endurance exercise. METHODS: Nine middle-aged men undertook a single-stage, multi-day 233 km (145 mile) ultra-endurance running race. Blood was collected immediately before (Pre), upon completion/retirement (Post), and following the race at Day 1, Day 7 and Day 28. Lymphocyte lysates were examined for PRDX-2 by reducing and non-reducing SDS-PAGE with western blotting. In a sub-group of men who completed the race (n = 4), PRDX-2 oligomeric state (indicative of redox status) was investigated. RESULTS: Ultra-endurance exercise caused significant changes in lymphocyte PRDX-2 (F(4,32) 3.409, p = 0.020, η(2) = 0.299): 7 days after the race, PRDX-2 levels in lymphocytes had fallen to 30% of pre-race values (p = 0.013) and returned to near-normal levels at Day 28. Non-reducing gels demonstrated that dimeric PRDX-2 (intracellular reduced PRDX-2 monomers) was increased in three of four race completers immediately post-race, indicative of an 'antioxidant response'. Moreover, monomeric PRDX-2 was also increased immediately post-race in two of four race-completing subjects, indicative of oxidative damage, which was not detectable by Day 7. CONCLUSIONS: Lymphocyte PRDX-2 was decreased below normal levels 7 days after ultra-endurance exercise. Excessive accumulation of reactive oxygen species induced by ultra-endurance exercise may underlie depletion of lymphocyte PRDX-2 by triggering its turnover after oxidation. Low levels of lymphocyte PRDX-2 could influence cell function and might, in part, explain reports of dysregulated immunity following ultra-endurance exercise.

Cardiopulmonary resuscitation in the pregnant patient: a manikin-based evaluation of methods for producing lateral tilt.

The importance of minimising aortocaval compression during cardiopulmonary resuscitation in late pregnancy is widely accepted. Current European guidelines suggest employing manual displacement of the uterus with left lateral tilt to achieve this. Several methods for producing lateral tilt have been described; however, the optimum method is unknown. By performing simulated cardiopulmonary resuscitation on a manikin, we compared four of these methods: a folded labour ward pillow; a pre-formed foam wedge; a custom-made hard wooden wedge; and the 'human wedge'. Primary outcome measures were maintenance of adequate tilt, stability and effectiveness of chest compressions (rate, depth and adequate release). Overall, the foam and wooden wedges were significantly more stable and reliable at maintaining tilt than the pillow (p<0.0001); the wooden wedge was more stable and effective than the foam wedge (p<0.0001). Chest compressions were least effective with the human wedge (p=0.02). Effectiveness of chest compressions with lateral tilt was comparable to that reported previously in supine manikin studies. We recommend the use of dedicated foam or hard wedges rather than pillows or the human wedge for producing lateral tilt during cardiopulmonary resuscitation.

An evaluation of the ability of leucocyte depletion filters to remove components of amniotic fluid.

Haemorrhage remains an important cause of maternal mortality worldwide. Cell salvage carries a theoretical risk of amniotic fluid embolus syndrome and is too expensive for use in many parts of the world. To explore cheaper options, we investigated whether a leucocyte depletion filter alone removes components of pure amniotic fluid. Amniotic fluid was collected from 10 women during elective caesarean section and passed through a LeukoGuard® RS filter. Pre- and post-filtration samples were compared in the laboratory. Lamellar bodies and fetal squames were almost completely removed (filtration efficacy 96.6% and 99.9%, respectively; p<0.0001 and <0.0004), and hair was completely removed (p=0.002). Filtration had no effect on concentrations of α-fetoprotein, tissue factor or endothelin-1, or on the presence of meconium or vernix. Additional work is required to evaluate whether cell salvage using filtration alone may be useful in maternal haemorrhage in the developing world.