High Dynamic Range Imaging at the Quantum Limit with SPAD-based Image Sensors

This paper examines methods to best exploit the High Dynamic Range (HDR) of the single photon avalanche diode (SPAD) in a high fill-factor HDR photon counting pixel that is scalable to megapixel arrays. The proposed method combines multi-exposure HDR with temporal oversampling in-pixel. We present a silicon demonstration IC with 96 × 40 array of 8.25 µm pitch 66% fill-factor SPAD-based pixels achieving >100 dB dynamic range with 3 back-to-back exposures (short, mid, long). Each pixel sums 15 bit-planes or binary field images internally to constitute one frame providing 3.75× data compression, hence the 1k frames per second (FPS) output off-chip represents 45,000 individual field images per second on chip. Two future projections of this work are described: scaling SPAD-based image sensors to HDR 1 MPixel formats and shrinking the pixel pitch to 1–3 µm

Development and Validation of a LC-MS/MS Assay for Quantification of Parathyroid Hormone (PTH 1-34) in human Plasma

Background: Teriparatide [recombinant human PTH (1-34)] is an osteoanabolic agent for treatment of osteoporosis. The effect on bone decreases the risk of vertebral and non-vertebral fractures and increases bone mineral density (BMD) in post-menopausal women with osteoporosis. Measurement of PTH (1-34) is valuable in assessing treatment response and concordance with therapy.Aim: To develop and validate a method for quantification of PTH (1-34) using Liquid chromatography tandem mass spectrometry (LC-MS/MS) and to perform comparison with a commercial immunoassay.  Method: Sample extraction was developed using a Waters (Milford, MA, USA) Oasis® HLB µElution solid phase extraction. Quantification m/z transition 589>656 was used on Waters/Micromass® Quattro Ultima™ Pt mass spectrometer to measure PTH (1-34) in human plasma using rat PTH (1-34) as internal standard. Validation criteria were carried out against industry standards. PTH (1-34) results obtained from human subjects given Teriparatide (Fortsteo, Eli Lilly, IN, USA) (n=390) were compared against results obtained from an immunoassay (IDS; Boldon Tyne and Wear. UK).  Results and Discussion: LC-MS/MS produced a linear calibration curve from 10 to 2000 pg/mL (r2 >0.990). The LLoQ and LLoD for PTH (1-34) were 10 pg/mL and 2.1 pg/mL respectively. The inter- /intra-assay precision (CV%) of the method were 98.3% for four QCs (20, 100, 200, and 800 pg/mL). The mean recovery of PTH (1-34) was 107.2%. Method comparison between the LC-MS/MS and immunoassay using human EDTA plasma samples showed a high correlation (r2 = 0.950). A concentration-dependent, negative bias of 35.5% was observed across the range of 0 – 800 pg/mL. The immunoassay showed a 7% cross reactivity to human PTH (1-84) and 44% to rat PTH (1-34), no interference was observed in the LC-MS/MS method. Matrix effect and cross reactivity to human PTH (1-84) in the immunoassay were the likely contributing factors to the bias between the methods. The oxidised form of PTH (1-34) does not interfere with our LC-MS/MS method.  Conclusion: Our LC-MS/MS method demonstrated linearity over the calibration range, good precision and accuracy, excellent analyte recovery, and negligible matrix effects. The method was successfully used for measurements of PTH (1-34) in rat and human plasma

A business model perspective for ICTs in public engagement

This is the post-print version of the Article. The official published article can be accessed from the link below - Copyright @ 2012 ElsevierPublic institutions, in their efforts to promote meaningful citizen engagement, are increasingly looking at the democratic potential of Information and Communication Technologies (ICTs). Previous studies suggest that such initiatives seem to be impeded by socio-technical integration barriers such as low sustainability, poor citizen acceptance, coordination difficulties, lack of understanding and failure to assess their impact. Motivated by these shortcomings, the paper develops and applies a business model perspective as an interceding framework for analysis and evaluation. The underlying principle behind this approach is that it is not technology per se which determines success, but rather the way in which the businessmodel of the technological artifact is configured and employed to achieve the strategic goals. The business model perspective is empirically demonstrated with the case of an online petitioning system implemented by a UK local authority. The case illustrates the importance of considering ICTs in public engagement from a holistic view to make them more manageable and assessable

A LC-MS/MS method for the diagnostic measurement of cAMP in plasma and urine

Background: Parathyroid hormone (PTH) plays a key role in calcium and phosphate homeostasis. Upon binding to its receptor, it signals via a second messenger, cyclic adenosine 3, 5’ monophosphate (cAMP). Lack of increase in plasma and urinary cAMP concentrations in response to PTH are used as diagnostic markers for pseudohypoparathyroidism (PHP), a condition primarily associated with resistance to PTH (Ellsworth-Howard Test).  Aims: 1) Develop and validate a LC-MS/MS method for the quantification of cAMP in plasma and urine. 2) Investigate assay performance in a rat pharmacokinetic study investigating the response to an oral dose of PTH (1-34) and the response to subcutaneous (sc) PTH administration in a patient with suspected PHP.  Method: cAMP and 13C5-cAMP internal standard were extracted from EDTA plasma using a weak anion exchange solid phase extraction. Chromatography was performed in positive electrospray ionisation mode, using a pentafluorophenyl column with a 10 mins 2% formic acid water:acetonitrile gradient. Transitions were m/z 330/136 for cAMP and 335/136 for 13C5-cAMP. Over concentrations ranging from 4.6 (lower limit of quantification) to 293.5 nmol/L, the calibration curve was linear (mean curve fits of >0.95, 5 repeats) and intra- and inter-assay precisions were <12% and <8%, respectively. Spiked recovery was 98±5%.  Application: A single oral dose of 5 mg/kg PTH (1–34) or placebo was administered to Sprague-Dawley rats after an overnight fast. cAMP was analysed in EDTA samples obtained at baseline, prior to dosing and every 15 min for 1h and then hourly for another 3h after dosing. In the suspected PHP patient, urinary cAMP was measured after a standard 20µg sc injection of teriparatide (Forsteo).  Results: In rats, plasma PTH (1-34) and cAMP increased significantly within 15min of dosing, reaching peak values between 15 and 30 mins. PTH (1–34) concentration increased significantly by up to 6770-fold, although response to PTH (1-34) varied between animals. Plasma cAMP typically tripled, from 36.5±3.7 nmol/L at baseline to 108.9±26.3 nmol/L. Placebo had no effect.Urine cAMP from the suspected PHP patient did not change significantly reflecting a lack of biological response to sc PTH (1-34) despite a significant increase in plasma PTH (1-34) (27.8 to 101.1 pmol/L).  Conclusion: The present method was robust and selective. It also showed utility in determining cAMP in biological systems and the ability to study the effect of drugs such as Forsteo

ARCII: A Phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer

Background and purpose Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). Materials and methods Radiotherapy (50.4 Gy/28 fractions; boost to 59.4 Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3–10 days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n = 6) evaluated hypoxia (18F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. Results The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5–85.5%) and median OS was 17.4 months (90% CI: 12.8–18.8). The 1-year PFS was 21.8% (90% CI: 8.9–38.3%) and median PFS was 5.5 months (90% CI: 4.1–8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. Conclusions CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer

Constitutivism

A brief explanation and overview of constitutivism

Long-term efficacy of botulinum toxin A for treatment of blepharospasm,hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes

PURPOSE: To investigate the long-term effectiveness and safety of botulinum neurotoxin A (BoNT-A) treatment in patients with blepharospasm (BEB), hemifacial spasm (HFS), and entropion (EN) and to use for the first time two modified indexes, 'botulin toxin escalation index-U' (BEI-U) and 'botulin toxin escalation index percentage' (BEI-%), in the dose-escalation evaluation. METHODS: All patients in this multicentre study were followed for at least 10 years and main outcomes were clinical efficacy, duration of relief, BEI-U and BEI-%, and frequency of adverse events. RESULTS: BEB, HFS, and EN patients received a mean BoNT-A dose with a significant inter-group difference (P<0.0005, respectively). The mean (+/-SD) effect duration was statistically different (P=0.009) among three patient groups. Regarding the BoNT-A escalation indexes, the mean (+/-SD) values of BEI-U and BEI-% were statistically different (P=0.035 and 0.047, respectively) among the three groups. In BEB patients, the BEI-% was significantly increased in younger compared with older patients (P=0.008). The most frequent adverse events were upper lid ptosis, diplopia, ecchymosis, and localized bruising. CONCLUSIONS: This long-term multicentre study supports a high efficacy and good safety profile of BoNT-A for treatment of BEB, HFS, and EN. The BEI indexes indicate a significantly greater BoNT-A-dose escalation for BEB patients compared with HFS or EN patients and a significantly greater BEI-% in younger vsolder BEB patients. These results confirm a greater efficacy in the elderly and provide a framework for long-term studies with a more flexible and reliable evaluation of drug-dose escalation