Laser pulse control of a Q-switched Nd:YVO₄ bounce geometry laser using a secondary cavity

Pulsed laser operation is desirable for a wide range of applications such as laser micromachining in industrial manufacturing and laser marking for product identification. In these cases it is beneficial to have flexibility in the parameters of the laser pulse to suit the specific application. This can include the ability to achieve a wide range of pulse repetition rates, with some applications requiring variation of laser pulse rate from high rate (multi-kHz) to low rate or even an off-state in a fast timescale. To generate ultrahigh pulse rates requires Q-switched lasers with ultrahigh gain, but problems can arise if the modulation element is insufficient to prevent laser action or hold-off lasing at low repetition rates. In these cases, lasing output can occur when it is not desired. In this work we present a novel method for pulse control in a high gain bounce amplifier Q-switched system by using a secondary cavity to clamp the gain and allow for clean single pulse operation from very high (800kHz) to very low (e.g.1kHz) repetition rates

Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations

Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al3+ in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain

From Stock Bottle to Vaccine: Elucidating the Particle Size Distributions of Aluminum Adjuvants Using Dynamic Light Scattering.

The physicochemical properties of aluminum salts are key determinants of their resultant adjuvanticity in vivo when administered as part of a vaccine. While there are links between particle size and the efficacy of the immune response, the limited literature directly characterizing the PSD of aluminum adjuvants has stymied the elucidation of such a relationship for these materials. Hence, this comparative study was undertaken to monitor the PSD of aluminum adjuvants throughout the process of vaccine formulation using DLS. A significant proportion of the stock suspensions was highly agglomerated (>9 μm) and Alhydrogel® exhibited the smallest median size (2677 ± 120 nm) in comparison to Adju-Phos® or Imject alum® (7152 ± 308 and 7294 ± 146 nm respectively) despite its large polydispersity index (PDI). Dilution of these materials induced some degree of disaggregation within all samples with Adju-Phos® being the most significantly affected. The presence of BSA caused the median size of Alhydrogel® to increase but these trends were not evident when model vaccines were formulated with either Adju-Phos® or Imject alum®. Nevertheless, Alhydrogel® and Adju-Phos® exhibited comparable median sizes in the presence of this protein (4194 ± 466 and 4850 ± 501 nm respectively) with Imject alum® being considerably smaller (2155 ± 485 nm). These results suggest that the PSD of aluminum adjuvants is greatly influenced by dilution and the degree of protein adsorption experienced within the vaccine itself. The size of the resultant antigen-adjuvant complex may be important for its immunological recognition and subsequent clearance from the injection site

The size of micro-crystalline tyrosine (MCT®) influences its recognition and uptake by THP-1 macrophages in vitro

The physicochemical hallmarks of particulate immunopotentiators play a pivotal role with regards to their adjuvanticity in vivo. These properties have not been fully characterised in the case of MCT®, an amino acid-based adjuvant used as an alternative to aluminium salts in subcutaneous allergy immunotherapy (SCIT). This study presents a full characterisation of MCT® and in a preliminary capacity reveals how parameters, specifically particle size, might influence the recognition of MCT® by antigen presenting cells (APCs) in vitro. Light microscopic analysis demonstrated that MCT® was composed of highly crystalline needles, the majority of which exceeded 10 μm in length under physiological conditions (median size – 20.8 μm). While the substantial length of crystals presented a significant barrier to cellular recognition and uptake, isolated incidences of perpendicular recognition were observed owing to the smaller comparative width of crystallites (median size – 2.8 μm). This appeared to allow a small proportion of material to be ingested both fully and partially by THP-1 macrophages, although further studies are required to unequivocally confirm this observation. Preferential recognition of needle tips also favoured the direct presentation of antigen to immune cells as proteinaceous adsorption appeared to be isolated to these regions. Furthermore, the data herein provide valuable insights into the mechanisms surrounding how this adjuvant potentiates an immunological response following administration

Pathwise Accuracy and Ergodicity of Metropolized Integrators for SDEs

Metropolized integrators for ergodic stochastic differential equations (SDE) are proposed which (i) are ergodic with respect to the (known) equilibrium distribution of the SDE and (ii) approximate pathwise the solutions of the SDE on finite time intervals. Both these properties are demonstrated in the paper and precise strong error estimates are obtained. It is also shown that the Metropolized integrator retains these properties even in situations where the drift in the SDE is nonglobally Lipschitz, and vanilla explicit integrators for SDEs typically become unstable and fail to be ergodic.Comment: 46 pages, 5 figure

Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study

Objectives: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care.Design: Cross-sectional analysis at 5-year follow-up in a prospective cohort study.Setting: Thirty-two general practitioner surgeries in England.Participants: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5?years and had complete follow-up data for HRQoL and functional status (FS).Primary and secondary outcome measures HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ?70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result.Results: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p < 0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p< 0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p< 0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p< 0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p< 0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend < 0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend < 0.001)), and for obese (body mass index (BMI) ?30?kg/m2) versus BMI < 25?kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend < 0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend < 0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p< 0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (?30?mg/mmol vs < 3?mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p< 0.001), 2.18 (95% CI 0.80 to 5.96, p for trend < 0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend < 0.001) and 4.23 (95% CI 2.48 to 7.20), respectively).Conclusions: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment

Developing effective practice learning for tomorrow's social workers

This paper considers some of the changes in social work education in the UK, particularly focusing on practice learning in England. The changes and developments are briefly identified and examined in the context of what we know about practice learning. The paper presents some findings from a small scale qualitative study of key stakeholders involved in practice learning and education in social work and their perceptions of these anticipated changes, which are revisited at implementation. The implications for practice learning are discussed