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Introduction: Although associated with respiratory morbidity, elective endotracheal intubation (ETI) for laser photocoagulation for retinopathy of prematurity (ROP) is the standard practice at our institution, with 100% of patients undergoing preoperation ETI. To mitigate this risk, we strove to reduce the percentage of infants intubated for laser photocoagulation by 30% by June 2022., Methods: We assembled a multidisciplinary team and implemented a deep sedation guideline utilizing dexmedetomidine, fentanyl, and midazolam with noninvasive ventilation support for laser photocoagulation in January 2020. Outcome, process, and balancing measures tracked the efficacy and safety of the quality improvement project., Results: We reduced the percentage of infants requiring intubation for laser photocoagulation from 100% (8/8) to 10% (1/10). We reduced the average time to return to baseline respiratory status from 224.1 to 33.8 hours (9.3d to1.4 d). Cardiorespiratory index scores slightly increased (1 to 1.2), and pain scores remained unchanged after interventions., Conclusions: A multidisciplinary team approach using a deep sedation guideline and noninvasive ventilation can safely reduce the requirement for intubation during laser photocoagulation with a faster return to baseline respiratory status., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

We experimentally investigated a pilot-aided digital signal processing (DSP) chain in combination with high-order geometric constellation shaping to increase the achievable information rates (AIRs) in standard intradyne coherent transmission systems. We show that the AIR of our system at 15 GBd was maximised using geometrically-shaped (GS) 2048 quadrature amplitude modulation (QAM), reaching 18.0 b/4D-symbol in back-to-back transmission and 16.9 b/4D-symbol after transmission through 100 km of a single-mode fibre after subtracting the pilot overhead (OH). This represents the highest-order GS format demonstrated to date, supporting the highest AIR of any standard intradyne system using conventional optics and 8-bit electronics. Detailed characterisation of the DSP, transceiver performance, and transmission modelling has also been carried out to provide insight into sources of impairments and directions for further improvement.

The management of wavelength routed optical mesh networks is complex with many potential light path routes and numerous physical layer impairments to transmission performance. This complexity can be reduced by applying the ideas of abstraction from computer science where different equipment is described in the same basic terms. The noise-to-signal ratio can be used as a metric to describe the quality of transmission performance of a signal propagated through a network element and accumulates additively through a sequence of such elements allowing the estimation of end-to-end performance. This study aims to explore the robustness of the noise-to-signal ratio metric in an installed fibre infrastructure. We show that the abstracted noise-to-signal ratio is independent of the observers and their location. We confirm that the abstracted noise-to-signal ratio can reasonably predict the performance of light-paths subsequently set in our network. Having a robust network element abstraction that can be incorporated into routeing engines allows the network management controller to make decisions on the most effective way to use the network resources in terms of the routeing and data coding format.

Wavelength routed optical switching promises low power and latency networking for data centres, but requires a wideband wavelength tuneable source (WTS) capable of sub-nanosecond switching at every node. We propose a hybrid WTS that uses time-interleaved tuneable lasers, each gated by a semiconductor optical amplifier, where the performance of each device is optimised using artificial intelligence. Through simulation and experiment we demonstrate record wavelength switch times below 900 ps across 6.05 THz (122×50 GHz) of continuously tuneable optical bandwidth. A method for further bandwidth scaling is evaluated and compared to alternative designs.

A frequency-domain multiple-input multiple-output (FD-MIMO) equalizer employing a momentum-based gradient descent update algorithm is proposed for polarization multiplexing coherent receivers. Its performance in operation with dynamically varying optical channels is investigated and the impact of filter update delays, arising from the latency of the fast Fourier transforms (FFTs) and other digital signal processing (DSP) operations in the feedback loop, is assessed. We show that the proposed momentum-based gradient descent algorithm used to control the equalizer response has significantly greater tolerance to feedback delay than the conventional gradient descent algorithm. We considered a 92 Gbaud dual-polarization 64 QAM receiver, with DSP operating at two samples per symbol, and with the equalizer operating on blocks of 512 and 1024 samples (i.e., 512/1024-point FFT). We found that at an optical signal-to-noise power ratio (OSNR) of 35 dB, the momentum-based gradient descent algorithm can successfully track state-of-polarization (SOP) rotation at frequencies of up to 50 kHz and with filter update delays of up to 14 blocks (39 ns). In comparison, using the conventional gradient descent algorithm in an otherwise identical receiver, the equalizer performance starts to deteriorate at SOP rotation frequencies above 20 kHz.

Seizure prediction is feasible, but greater accuracy is needed to make seizure prediction clinically viable across a large group of patients. Recent work crowdsourced state-of-the-art prediction algorithms in a worldwide competition, yielding improvements in seizure prediction performance for patients whose seizures were previously found hard to anticipate. The aim of the current analysis was to explore potential performance improvements using an ensemble of the top competition algorithms. The results suggest that minor increments in performance may be possible; however, the outcomes of statistical testing limit the confidence in these increments. Our results suggest that for the specific algorithms, evaluation framework, and data considered here, incremental improvements are achievable but there may be upper bounds on machine learning-based seizure prediction performance for some patients whose seizures are challenging to predict. Other more tailored approaches that, for example, take into account a deeper understanding of preictal mechanisms, patient-specific sleep-wake rhythms, or novel measurement approaches, may still offer further gains for these types of patients., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder that prominently affects the basal ganglia, leading to affective, cognitive, behavioral, and motor decline. The primary site of neuron loss in HD is the striatal part of the basal ganglia, with GABAergic medium size spiny neurons (MSNs) being nearly completely lost in advanced HD., Objective: Based on the hypothesis that mutant huntingtin (mHTT) protein injures neurons via transcriptional dysregulation, we set out to establish a transcriptional profile of HD disease progression in the well characterized transgenic mouse model, R6/2, and two Knock-in models (KI); zQ175KI (expressing mutant mouse/human chimeric Htt protein) and HdhQ200 HET KI (carrying one allele of expanded mouse CAG repeats)., Methods: In this study, we used quantitative PCR (qPCR) to evaluate striatal mRNA levels of markers of neurotransmission, neuroinflammation, and energy metabolism., Results: After analyzing and comparing transcripts from pre-symptomatic and symptomatic stages, markers expressed in the basal ganglia MSNs, which are typically involved in maintaining normal neurotransmission, showed a genotype-specific decrease in mRNA expression in a pattern consistent with human studies. In contrast, transcripts associated with neuroinflammation and energy metabolism were mostly unaffected in these animal models of HD., Conclusion: Our results show that transcripts linked to neurotransmission are significantly reduced and are consistent with disease progression in both zQ175KI and R6/2 transgenic mouse models.

We propose an autoencoding sequence-based transceiver for communication over dispersive channels with intensity modulation and direct detection (IM/DD), designed as a bidirectional deep recurrent neural network (BRNN). The receiver uses a sliding window technique to allow for efficient data stream estimation. We find that this sliding window BRNN (SBRNN), based on end-to-end deep learning of the communication system, achieves a significant bit-error-rate reduction at all examined distances in comparison to previous block-based autoencoders implemented as feed-forward neural networks (FFNNs), leading to an increase of the transmission distance. We also compare the end-to-end SBRNN with a state-of-the-art IM/DD solution based on two level pulse amplitude modulation with an FFNN receiver, simultaneously processing multiple received symbols and approximating nonlinear Volterra equalization. Our results show that the SBRNN outperforms such systems at both 42 and 84 Gb/s, while training fewer parameters. Our novel SBRNN design aims at tailoring the end-to-end deep learning-based systems for communication over nonlinear channels with memory, such as the optical IM/DD fiber channel.

Accurate seizure prediction will transform epilepsy management by offering warnings to patients or triggering interventions. However, state-of-the-art algorithm design relies on accessing adequate long-term data. Crowd-sourcing ecosystems leverage quality data to enable cost-effective, rapid development of predictive algorithms. A crowd-sourcing ecosystem for seizure prediction is presented involving an international competition, a follow-up held-out data evaluation, and an online platform, Epilepsyecosystem.org, for yielding further improvements in prediction performance. Crowd-sourced algorithms were obtained via the 'Melbourne-University AES-MathWorks-NIH Seizure Prediction Challenge' conducted at kaggle.com. Long-term continuous intracranial electroencephalography (iEEG) data (442 days of recordings and 211 lead seizures per patient) from prediction-resistant patients who had the lowest seizure prediction performances from the NeuroVista Seizure Advisory System clinical trial were analysed. Contestants (646 individuals in 478 teams) from around the world developed algorithms to distinguish between 10-min inter-seizure versus pre-seizure data clips. Over 10 000 algorithms were submitted. The top algorithms as determined by using the contest data were evaluated on a much larger held-out dataset. The data and top algorithms are available online for further investigation and development. The top performing contest entry scored 0.81 area under the classification curve. The performance reduced by only 6.7% on held-out data. Many other teams also showed high prediction reproducibility. Pseudo-prospective evaluation demonstrated that many algorithms, when used alone or weighted by circadian information, performed better than the benchmarks, including an average increase in sensitivity of 1.9 times the original clinical trial sensitivity for matched time in warning. These results indicate that clinically-relevant seizure prediction is possible in a wider range of patients than previously thought possible. Moreover, different algorithms performed best for different patients, supporting the use of patient-specific algorithms and long-term monitoring. The crowd-sourcing ecosystem for seizure prediction will enable further worldwide community study of the data to yield greater improvements in prediction performance by way of competition, collaboration and synergism.10.1093/brain/awy210_video1awy210media15817489051001.

Biocompatible antibody-nanoparticle conjugates have attracted interest as anticancer agents due to their potential to selectively target therapeutic agents at disease sites. However, new formulation and conjugation approaches are urgently needed to improve their uniformity for clinical applications. Here, a pH-responsive benzaldehyde-functionalized poly[oligo(ethylene glycol) methacrylate- st - para- formyl phenyl methacrylate]- b -poly[2-(diisopropyl)aminoethyl methacrylate] [P(OEGMA- st -pFPMA)- b -PDPA] block copolymer, prepared by reversible addition-fragmentation chain transfer polymerization, produced PEGylated nanoparticles (pH ∼ 7.4) by a single emulsion-solvent evaporation formulation approach. Efficient site-specific attachment of an aminooxy-functionalized anti-EGFR single-domain antibody (sdAb) on these benzaldehyde-decorated nanoparticles is achieved by oxime bond formation. These nanoconjugates can specifically bind EGFR (modified ELISA) and have enhanced uptake over nonfunctionalized controls in EGFR-positive HeLa cells. Encapsulation of rhodamine 6G dye and its dispersion upon cellular uptake, consistent with nanoparticle stability loss at pH < 5.7, prove their ability to facilitate triggered release in endosomal compartments and highlight their potential for use as next-generation antibody-drug nanoconjugates for therapeutic drug delivery.

We demonstrate a method for experimentally characterizing the second order statistics of nonlinear interference noise (NLIN) as an intersymbol interference (ISI) process. The method enables measurement of the properties of high-order ISI coefficients, which have been largely overlooked in the past. The ability of measuring these statistics is imperative for designing effective NLIN mitigation schemes. The variance, temporal correlation times, and cross correlations of the various ISI coefficients are evaluated in several system implementations.

High-speed broadband services require optical fibres in access networks, in which multiple subscribers are connected to service providers, to satisfy the continuously growing bandwidth demand. The primitive signaling scheme used in access networks enables the use of low-cost equipment but diminishes the bandwidth available to end-users. Thus, current technology will be unable to support future broadband demands. Coherent communication systems offer significantly improved power- and bandwidth-efficiency, but require fundamental simplifications to become economically viable for access networks. Here, we demonstrate a promising simplified coherent receiver exhibiting a robust performance against polarisation fluctuations over an installed fibre network. It enables the realisation of high-order modulation formats and offers high sensitivities, achieving a four-fold increase in the supported number of subscribers and approximately doubling the transmission distance compared to the recently standardized access technology. The proposed solution indicates that digital coherent technology can be feasible and transform the access networks, enabling ubiquitous new services and applications with uncontended, multi-gigabits/user broadband connections.

The optimisation of span length when designing optical communication systems is important from both performance and cost perspectives. In this paper, the optimisation of inter-amplifier spacing and the potential increase of span length at fixed information rates in optical communication systems with practically feasible nonlinearity compensation schemes have been investigated. It is found that in DP-16QAM, DP-64QAM and DP-256QAM systems with practical transceiver noise limitations, single-channel digital backpropagation can allow a 50% reduction in the number of amplifiers without sacrificing information rates compared to systems with optimal span lengths and linear compensation.

Nyquist-spaced transmission and digital signal processing have proved effective in maximising the spectral efficiency and reach of optical communication systems. In these systems, Kerr nonlinearity determines the performance limits, and leads to spectral broadening of the signals propagating in the fibre. Although digital nonlinearity compensation was validated to be promising for mitigating Kerr nonlinearities, the impact of spectral broadening on nonlinearity compensation has never been quantified. In this paper, the performance of multi-channel digital back-propagation (MC-DBP) for compensating fibre nonlinearities in Nyquist-spaced optical communication systems is investigated, when the effect of signal spectral broadening is considered. It is found that accounting for the spectral broadening effect is crucial for achieving the best performance of DBP in both single-channel and multi-channel communication systems, independent of modulation formats used. For multi-channel systems, the degradation of DBP performance due to neglecting the spectral broadening effect in the compensation is more significant for outer channels. Our work also quantified the minimum bandwidths of optical receivers and signal processing devices to ensure the optimal compensation of deterministic nonlinear distortions.

An analytical model considering modulation-dependent nonlinear effects and second-order interactions between signal and optical amplifier noise is presented for Nyquist-spaced wavelength-division-multiplexing optical communication systems. System performance of dual-polarization modulation formats, such as DP-QPSK, DP-16QAM, and DP-64QAM, is investigated using both the analytical model and numerical simulations. A good agreement between analytical and numerical results shows that, in the case of full-field nonlinearity compensation, accounting for second-order interactions becomes essential to predict system performance of both single- and multi-channel systems at optimum launched powers and beyond. This effect is validated via numerical simulations for signal bandwidths up to ∼1  THz.

This paper investigates the impact of transceiver noise on the performance of digital back-propagation (DBP). A generalized expression to estimate the signal-to-noise ratio (SNR) obtained using DBP in the presence of transceiver noise is described. This new expression correctly accounts for the nonlinear beating between the transceiver noise and the signal in the optical fiber transmission link. The transceiver noise-signal nonlinear beating has been identified as the main reason for the discrepancy between predicted and practical performance of DBP; which has not been previously suggested. This nonlinear beating has been included in the GN model, allowing DBP gains in practical systems to be predicted analytically. Experiments and split-step simulations with and without polarization-mode dispersion (PMD) in the transmission link have been performed. The results show that the impact of transceiver noise greatly outweighs that of PMD, and the analytical expressions are confirmed by the numerical simulations.

The relationship between modulation format and the performance of multi-channel digital back-propagation (MC-DBP) in ideal Nyquist-spaced optical communication systems is investigated. It is found that the nonlinear distortions behave independent of modulation format in the case of full-field DBP, in contrast to the cases of electronic dispersion compensation and partial-bandwidth DBP. It is shown that the minimum number of steps per span required for MC-DBP depends on the chosen modulation format. For any given target information rate, there exists a possible trade-off between modulation format and back-propagated bandwidth, which could be used to reduce the computational complexity requirement of MC-DBP.

The Gaussian noise model is used to estimate the performance of three digital nonlinearity compensation (NLC) algorithms in C-band, long-haul, optical fiber transmission, when the span length and NLC bandwidth are independently varied. The algorithms are receiver-side digital backpropagation (DBP), transmitter-side DBP (digital precompensation), and Split NLC (an equal division of DBP between transmitter and receiver). For transmission over 100×100 km spans, the model predicts a 0.2 dB increase in SNR when applying Split NLC (versus DBP) to a single 32 GBd channel (from 0.4 dB to 0.6 dB), monotonically increasing with NLC bandwidth up to 1.6 dB for full-field NLC. The underlying assumptions of this model and the practical considerations for implementation of Split NLC are discussed. This work demonstrates, theoretically, that, regardless of the transmission scenario, it is always beneficial to divide NLC between transmitter and receiver, and identifies the transmission regimes where Split NLC is particularly advantageous.

Digital backpropagation (DBP) is a promising digital-domain technique to mitigate Kerr-induced nonlinear interference. While it successfully removes deterministic signal-signal interactions, the performance of ideal DBP is limited by stochastic effects, such as polarization-mode dispersion (PMD). In this paper, we consider an ideal full-field DBP implementation and modify it to additionally account for PMD; reversing the PMD effects in the backward propagation by passing the reverse propagated signal also through PMD sections, which concatenated equal the inverse of the PMD in the forward propagation. These PMD sections are calculated analytically at the receiver based on the total accumulated PMD of the link estimated from channel equalizers. Numerical simulations show that, accounting for nonlinear polarization-related interactions in the modified DBP algorithm, additional signal-to-noise ratio gains of 1.1 dB are obtained for transmission over 1000 km.

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Current treatment guidelines for biologic therapies in psoriasis differ in their recommendation for the monitoring of adverse events., Objective: The aim of this paper was to draw together evidence from the currently available guidelines as a summary of how biologics licensed for the treatment of psoriasis should be monitored for adverse events., Methods: The MEDLINE database was searched to identity the current literature on the safety and screening guidance associated with infliximab, etanercept, adalimumab, ustekinumab, and secukinumab., Limitations: This study was limited by the lack of data evaluating monitoring in patients with psoriasis undergoing treatment with a biologic therapy., Results: This review of the current literature highlights that there are areas of routine screening, which are recommended in current practice, which require further evidence to investigate its true utility., Conclusion: Most screening and monitoring tests performed routinely in clinical practice are supported by minimal clinical evidence, highlighting the need for more studies to evaluate the role and value of the different modalities of screening and monitoring for adverse events in those with psoriasis receiving treatment with biologic therapies., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Most of the digital data transmitted are carried by optical fibres, forming the great part of the national and international communication infrastructure. The information-carrying capacity of these networks has increased vastly over the past decades through the introduction of wavelength division multiplexing, advanced modulation formats, digital signal processing and improved optical fibre and amplifier technology. These developments sparked the communication revolution and the growth of the Internet, and have created an illusion of infinite capacity being available. But as the volume of data continues to increase, is there a limit to the capacity of an optical fibre communication channel? The optical fibre channel is nonlinear, and the intensity-dependent Kerr nonlinearity limit has been suggested as a fundamental limit to optical fibre capacity. Current research is focused on whether this is the case, and on linear and nonlinear techniques, both optical and electronic, to understand, unlock and maximize the capacity of optical communications in the nonlinear regime. This paper describes some of them and discusses future prospects for success in the quest for capacity., (© 2016 The Authors.)

Optical fibre underpins the global communications infrastructure and has experienced an astonishing evolution over the past four decades, with current commercial systems transmitting data rates in excess of 10 Tb/s over a single fibre core. The continuation of this dramatic growth in throughput has become constrained due to a power dependent nonlinear distortion arising from a phenomenon known as the Kerr effect. The mitigation of fibre nonlinearities is an area of intense research. However, even in the absence of nonlinear distortion, the practical limit on the transmission throughput of a single fibre core is dominated by the finite signal-to-noise ratio (SNR) afforded by current state-of-the-art coherent optical transceivers. Therefore, the key to maximising the number of information bits that can be reliably transmitted over a fibre channel hinges on the simultaneous optimisation of the modulation format and code rate, based on the SNR achieved at the receiver. In this work, we use an information theoretic approach based on the mutual information and the generalised mutual information to characterise a state-of-the-art dual polarisation m-ary quadrature amplitude modulation transceiver and subsequently apply this methodology to a 15-carrier super-channel to achieve the highest throughput (1.125 Tb/s) ever recorded using a single coherent receiver.

Contextual research on time and place requires a consistent measurement instrument for neighborhood conditions in order to make unbiased inferences about neighborhood change. We develop such a time-invariant measure of neighborhood socio-economic status (NSES) using exploratory and confirmatory factor analyses fit to census data at the tract level from the 1990 and 2000 U.S. Censuses and the 2008-2012 American Community Survey. A single factor model fit the data well at all three time periods, and factor loadings--but not indicator intercepts--could be constrained to equality over time without decrement to fit. After addressing remaining longitudinal measurement bias, we found that NSES increased from 1990 to 2000, and then--consistent with the timing of the "Great Recession"--declined in 2008-2012 to a level approaching that of 1990. Our approach for evaluating and adjusting for time-invariance is not only instructive for studies of NSES but also more generally for longitudinal studies in which the variable of interest is a latent construct.

Superchannel transmission spaced at the symbol rate, known as Nyquist spacing, has been demonstrated for effectively maximizing the optical communication channel capacity and spectral efficiency. However, the achievable capacity and reach of transmission systems using advanced modulation formats are affected by fibre nonlinearities and equalization enhanced phase noise (EEPN). Fibre nonlinearities can be effectively compensated using digital back-propagation (DBP). However EEPN which arises from the interaction between laser phase noise and dispersion cannot be efficiently mitigated, and can significantly degrade the performance of transmission systems. Here we report the first investigation of the origin and the impact of EEPN in Nyquist-spaced superchannel system, employing electronic dispersion compensation (EDC) and multi-channel DBP (MC-DBP). Analysis was carried out in a Nyquist-spaced 9-channel 32-Gbaud DP-64QAM transmission system. Results confirm that EEPN significantly degrades the performance of all sub-channels of the superchannel system and that the distortions are more severe for the outer sub-channels, both using EDC and MC-DBP. It is also found that the origin of EEPN depends on the relative position between the carrier phase recovery module and the EDC (or MC-DBP) module. Considering EEPN, diverse coding techniques and modulation formats have to be applied for optimizing different sub-channels in superchannel systems.

Transmission of a net 467-Gb/s PDM-16QAM Nyquist-spaced superchannel is reported with an intra-superchannel net spectral efficiency (SE) of 6.6 (b/s)/Hz, over 364-km SMF-28 ULL ultra-low loss optical fiber, enabled by bi-directional second-order Raman amplification and digital nonlinearity compensation. Multi-channel digital back-propagation (MC-DBP) was applied to compensate for nonlinear interference; an improvement of 2 dB in Q(2) factor was achieved when 70-GHz DBP bandwidth was applied, allowing an increase in span length of 37 km.

Barrett oesophagus develops when the lower oesophageal squamous epithelium is replaced with columnar epithelium, which shows both intestinal and gastric differentiation. No consensus has been reached on the origin of Barrett oesophagus. Theories include a direct origin from the oesophageal-stratified squamous epithelium, or by proximal migration of the gastric cardiac epithelium with subsequent intestinalization. Variations of this theory suggest the origin is a distinctive cell at the squamocolumnar junction, the oesophageal gland ducts, or circulating bone-marrow-derived cells. Much of the supporting evidence comes from experimental models and not from studies of Barrett mucosa. In this Perspectives article, we look at the Barrett lesion itself: at its phenotype, its complexity, its clonal architecture and its stem cell organization. We conclude that Barrett glands are unique structures, but share many similarities with gastric glands undergoing the process of intestinal metaplasia. We conclude that current evidence most strongly supports an origin from stem cells in the cardia.

The authors report on the downlink performance of a 10 Gb/s long-reach and ultra-dense wavelength-division multiplexed passive optical network, based on a multicarrier transmitter realized by using an externally injected gain-switched distributed-feedback laser diode. Each of the comb channels, spaced by 10 GHz, is modulated with a 3 Gbaud dual polarization quadrature phase shift keying signal that included a 20% overhead for forward error correction. Frequency selectivity and enhanced receiver sensitivity is achieved by employing a digital coherent receiver to receive the signal. Experimental results achieved in a back-to-back and 100 km transmission scenarios show an excellent worst case receiver sensitivity of -44 dBm.

We investigated ultra-long-haul transmission of polarization-switched QPSK (PS-QPSK) and polarization-division-multiplexed BPSK (PDM-BPSK) at 42.9 Gbit/s experimentally as well as by means of computer simulations. PDM-BPSK allowed transmission distances in excess of 14,040 km to be achieved, compared to 13,640 km for PS-QPSK. However, PS-QPSK offers a significant reduction in receiver complexity due to the lower symbol-rate., (© 2011 Optical Society of America)

The sensitivity of the four-dimensional modulation format, polarization-switched quadrature phase shift keying (PS-QPSK), is compared with polarization division multiplexed QPSK (PDM-QPSK), binary phase shift keying (PDM-BPSK) and 8-ary quadrature amplitude modulation (PDM-8QAM) at a constant bitrate (12.5 Gbit/s) using a preamplified signal to improve receiver sensitivity. The sensitivity without preamplification is also obtained. PS-QPSK is found to maintain a sensitivity advantage over the reference formats in line with theory with an absolute sensitivity of -52.7 dBm (4.2 photons/bit), assuming hard decision FEC., (© 2011 Optical Society of America)

iASPP, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is an evolutionarily conserved inhibitor of p53 which is frequently upregulated in human cancers. However, little is known about the role of iASPP under physiological conditions. Here, we report that iASPP is a critical regulator of epithelial development. We demonstrate a novel autoregulatory feedback loop which controls crucial physiological activities by linking iASPP to p63, via two previously unreported microRNAs, miR-574-3p and miR-720. By investigating its function in stratified epithelia, we show that iASPP participates in the p63-mediated epithelial integrity program by regulating the expression of genes essential for cell adhesion. Silencing of iASPP in keratinocytes by RNA interference promotes and accelerates a differentiation pathway, which also affects and slowdown cellular proliferation. Taken together, these data reveal iASPP as a key regulator of epithelial homeostasis.

We demonstrate, for the first time, the generation and transmission of polarization-switched QPSK (PS-QPSK) signals at 42.9 Gb/s. Long-haul transmission of PS-QPSK is experimentally investigated in a recirculating loop and compared with transmission of dual-polarization QPSK (DP-QPSK) at 42.9 Gb/s per channel. A reduction in the required OSNR of 0.7 dB was found at a BER of 3.8 x 10(-3), resulting in an increase in maximum reach of more than 30% for a WDM system operating on a 50 GHz frequency grid. The maximum reach of 13640 km for WDM PS-QPSK is, to the best of our knowledge, the longest distance reported for 40 Gb/s WDM transmission, over an uncompensated link, with standard fiber and amplification., (© 2011 Optical Society of America)

We investigate the impact of channel spacing and nonlinear transmission over 120 km of standard single mode fiber for a 10 Gbit/s long-reach wavelength division multiplexed passive optical network (WDM-PON). We employed polarization division multiplexed quadrature phase shift keying (PDM-QPSK), which allowed data transmission at 3.125 GBaud, including a 25% overhead for forward error correction. To receive this spectrally efficient modulation format, a digital coherent receiver was employed, allowing for both frequency selectivity and an increased sensitivity of -45 dBm (25 photons/bit).We investigated a channel spacing as low as 5 GHz, for which the loss budget was 48.6 dB, increasing to 54.0 dB for a 50 GHz grid.

Background: There are few reports of the practical use of adalimumab outside of a clinical trial setting and, to our knowledge, none from the U.K., Objectives: We assessed the efficacy and safety of adalimumab in a cohort of patients with severe psoriasis attending a tertiary dermatology referral centre in the U.K., Methods: A retrospective case-note review was used to identify all patients initiated on adalimumab for psoriasis. RESI;TS: Baseline Psoriasis Area and Severity Index (PASI) was 24+/-11 (range 9-54; n=46). After 4 months' treatment with adalimumab 64% (29/45), of patients had achieved PASI 75 (75% decrease from baseline) whilst 80% (36/45) of patients met NICE criteria for continuation of treatment. Therapy was well-tolerated. Importantly, 68% (21/31) of patients who had previously received another tumour necrosis factor alpha inhibitor met NICE criteria for continuation of treatment at 16 weeks., Conclusions: In a cohort of U.K. patients with severe psoriasis, adalimumab has proved to be a significant addition to the expanding armamentarium of biologics for psoriasis. Pharmacovigilance, in the form of registries, is essential to assess the long-term safety of such drugs.

In this paper long-haul, single channel, polarization multiplexed 16-state quadrature amplitude modulation (PDM-QAM-16) transmission at 112 Gbit/s is investigated. Novel digital signal processing techniques are used to perform carrier phase estimation and symbol estimation, in combination with nonlinear digital backpropagation. The results obtained demonstrate that the use of digital nonlinear backpropagation increases the optimum launch power from -4 dBm to -1 dBm with a consequent increase in maximum reach from 1440 km to 2400 km, which is a record transmission distance for QAM-16 reported to date for an SMF link with EDFAs only. Furthermore, experimental measurements are supported by simulations, based on the link used in the experiment.

The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes.

Background: Large-scale clinical trials provide clear evidence of the efficacy and short-term toxicity of biologic therapies for psoriasis. However, to date, there are few reports of the practical use of these therapies outside of the trial setting and, to our knowledge, none from a U.K. cohort of patients with psoriasis., Objectives: (i) To assess efficacy and safety of efalizumab, etanercept and infliximab in a U.K. cohort of patients with psoriasis, with mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index 21.8 and 21.7, respectively, outside of the clinical trial setting. (ii) To examine our approach to the processes involved in the initiation of biologic therapies in the era of National Institute for Health and Clinical Excellence guidance., Methods: A retrospective case-note review to identify all patients initiated on biologic therapies for psoriasis in a U.K. tertiary referral centre., Results: At 3 months of treatment the efficacy of efalizumab (n = 28), etanercept (n = 70) and infliximab (n = 20), as assessed by PASI 75 (75% decrease from baseline score), was 24%, 35% and 85%, respectively. All three biologics used were well tolerated. Combination therapy with traditional systemic agents was required either at transition to, or to counter relapse while established on, a biologic therapy in 30% of cases. Streamlined approaches to screening and funding significantly (P

Steroid hormones are a diverse class of structurally related molecules, derived from cholesterol, that include androgens, estrogens, progesterone and corticosteroids. They represent an important group of physiologically active signalling molecules that bind intracellular receptor proteins and regulate genes involved in developmental, reproductive and metabolic processes. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains, but possess distinct N-terminal domains (NTD) of unique length and amino acids sequence. The NTD contains sequences important for gene regulation, exhibit structure plasticity and are likely to contribute to the specificity of the steroid hormone/receptor response.

The AR (androgen receptor) is a ligand-activated transcription factor and member of the steroid receptor superfamily. The AR responds to the ligands testosterone and dihydrotestosterone and activates multiple downstream genes required in development and reproduction. During the events of transactivation, the AR makes specific protein-protein interactions with several basal transcription factors such as TBP (TATA-box-binding protein) and TFIIF (transcription factor IIF). These interactions occur predominantly within a defined region termed AF1 (activation function-1) located within the highly disordered N-terminal domain of the receptor. Our focus is on the structural aspects of AF1 and how this flexible and disordered domain generates functional interactions with regulators of transcription. Our working hypothesis is that AR-AF1 domain exhibits induced folding when contacted by transcription regulators (such as TFIIF) into a more compact and 'active' conformation, enabling further co-regulator recruitment and ultimately transcription. Structural flexibility and intrinsic disorder of AR-AF1 were studied using predictive algorithms and fluorescence spectroscopy under different experimental conditions and the results revealed this domain retains characteristics indicative of molten-globule or pre-molten-globule-like structures. We hypothesize that this partially folded intermediate state is important for, and enables the AF1 domain to make, multiple protein-protein interactions. The structural aspects of AR-AF1 and interactions with TFIIF are discussed.

The N-type voltage-gated calcium channel (Ca(v)2.2) functions in neurons to regulate neurotransmitter release. It comprises a clinically relevant target for chronic pain. We have validated a calcium mobilization approach to assessing Ca(v)2.2 pharmacology in two stable Ca(v)2.2 cell lines: alpha1(B), alpha2delta, beta(3)-HEK-293 and alpha1(B), beta(3)-HEK-293. Ca(v)2.2 channels were opened by addition of KCl and Ca(2+) mobilization was measured by Fluo-4 fluorescence on a fluorescence imaging plate reader (FLIPR(96)). Ca(v)2.2 expression and biophysics were confirmed by patch-clamp electrophysiology (EP). Both cell lines responded to KCl with adequate signal-to-background. Signals from both cell lines were inhibited by omega-conotoxin (ctx)-MVIIa and omega-conotoxin (ctx)-GVIa with IC(50) values of 1.8 and 1nM, respectively, for the three-subunit stable, and 0.9 and 0.6nM, respectively, for the two-subunit stable. Other known Ca(v)2.2 blockers were characterized including cadmium, flunarizine, fluspirilene, and mibefradil. IC(50) values correlated with literature EP-derived values. Novel Ca(v)2.2 pharmacology was identified in classes of compounds with other primary pharmacological activities, including Na(+) channel inhibitors and antidepressants. Novel Na(+) channel compounds with high potency at Ca(v)2.2 were identified in the phenoxyphenyl pyridine, phenoxyphenyl pyrazole, and other classes. The highest potency at Ca(v)2.2 tricyclic antidepressant identified was desipramine.

A fluorescent imaging plate reader (FLIPR) membrane potential (V(m)) assay was evaluated for pharmacological characterization and high-throughput screening (HTS) of rat glycine transporter type 2 (rGlyT(2)) in a stable rGlyT(2)-HEK cell line. Data show that glycine activation of rGlyT(2) consistently results in a concentration-dependent V(m) response on the FLIPR that is blocked by the potent and selective GlyT(2) antagonist 4-benzyloxy-3,5-dimethoxy-N-[1-dimethylamino-cyclopentyl)methyl]-benz-amide (Org-25543). Agonist and antagonist pharmacologies match those reported using conventional [(3)H]glycine uptake assays and electrophysiology. The glycine response is dependent on buffer ionic composition consistent with GlyT(2) physiology. Assay signal-to-background and coefficient of variation meets sufficient statistical criteria to conduct HTS. The results of a screen of the chemical inventory demonstrate that the assay is able to successfully identify and confirm GlyT(2) inhibitors. The advantages of this assay are its homogeneity, compatibility with both 96- and 384-well formats, and lack of radioactivity usage. Thus, the authors conclude that a fluorescence-based V(m) assay on FLIPR is a viable approach for identification and pharmacological profiling of small molecule modulators of the electrogenic transporter rGlyT(2).

A number of organizations have advised against the use of placebo substitution, including the American Pain Society, Agency for Healthcare Policy and Research, World Health Organization, Healthcare Facilities Accreditation Program, Joint Commission on Accreditation of Healthcare Organizations, Education for Physicians on End-of-Life Care Project (cosponsored by the American Medical Association and The Robert Wood Johnson Foundation), American Nursing Association, and the American Society of Pain Management Nurses. This white paper describes the literature and rationale in support of the American Osteopathic Association's (AOA's) position on the controversial subject of the use of placebos for pain management in terminally ill patients.

Molecular analysis of development frequently implies the isolation and characterization of genes with specific spatial and temporal expression patterns. Several methods have been developed to identify such DNA sequences. The most comprehensive technique involves the genomewide probing of DNA sequence microarrays with mRNA sequences. However, at present this technology is limited to the few organisms for which the entire genome has been sequenced. Here, we describe a subtractive hybridization technique, called selective amplification via biotin and restriction-mediated enrichment (SABRE), which allows the selective amplification of cDNA fragments representing differentially expressed mRNA species. The method involves the competitive hybridization of an excess of driver cDNA fragments (D) to a trace of tester cDNA fragments (T), and the subsequent purification of tester homohybrids (in which both strands are contributed by the tester cDNA). After competitive hybridization, cDNA fragments that are more abundant in the tester than in the driver are enriched in the tester homohybrids. However, as the fraction of tester homohybrids is very small [T(2)/(D + T)(2)], their purification requires highly efficient procedures. In SABRE, the isolation of tester homohybrids is afforded by a combination of three successive steps: removal of biotinylated terminal sequences from most of the heterohybrids by S1 nuclease digestion, capture of biotinylated hybrids with streptavidin-coated paramagnetic beads, and specific release of homohybrids from the beads by restriction nuclease digestion. If several rounds of SABRE selection are performed in series, even relatively rare differentially expressed mRNA sequences may result in the production of predominant cDNA fragments in the final tester homohybrid population., (Copyright 2001 Academic Press.)

To study the molecular mechanisms of circadian gene expression, we have sought to identify genes whose expression in mouse liver is regulated by the transcription factor DBP (albumin D-site-binding protein). This PAR basic leucine zipper protein accumulates according to a robust circadian rhythm in nuclei of hepatocytes and other cell types. Here, we report that the Cyp2a4 gene, encoding the cytochrome P450 steroid 15alpha-hydroxylase, is a novel circadian expression gene. This enzyme catalyzes one of the hydroxylation reactions leading to further metabolism of the sex hormones testosterone and estradiol in the liver. Accumulation of CYP2A4 mRNA in mouse liver displays circadian kinetics indistinguishable from those of the highly related CYP2A5 gene. Proteins encoded by both the Cyp2a4 and Cyp2a5 genes also display daily variation in accumulation, though this is more dramatic for CYP2A4 than for CYP2A5. Biochemical evidence, including in vitro DNase I footprinting on the Cyp2a4 and Cyp2a5 promoters and cotransfection experiments with the human hepatoma cell line HepG2, suggests that the Cyp2a4 and Cyp2a5 genes are indeed regulated by DBP. These conclusions are corroborated by genetic studies, in which the circadian amplitude of CYP2A4 and CYP2A5 mRNAs and protein expression in the liver was significantly impaired in a mutant mouse strain homozygous for a dbp null allele. These experiments strongly suggest that DBP is a major factor controlling circadian expression of the Cyp2a4 and Cyp2a5 genes in the mouse liver.

The objective of this study was to identify the direct cost and length of hospitalization of diabetes-related lower extremity amputations among Hispanics, African Americans, non-Hispanic whites, and Asians. The authors used a database from the office of Statewide Planning and Development in California that identified all hospitalizations for lower extremity amputations in the state in 1991. Amputation level was defined by the ICD-9-CM codes 84.11-84.18. The total hospital charges for diabetes-related lower extremity amputations for the state of California in 1991 was $141 million. The mean hospital charge (HC) per patient with all ethnic groups combined was $27,930; and the mean length of stay (LOS) was 15.9 days. African Americans had significantly higher mean charges ($32,383) and longer stays (17.3 days) compared to all other ethnic groups (p < .05). Toe-level amputations had lower HC (p < .05) and LOS (p < .01) than other amputation levels for all race groups. One-quarter of the population received multiple amputations during their hospital stay. These patients incurred significantly higher hospital charges ($44,731) and stayed in the hospital longer (23.4 days) than those receiving only a single amputation. There was a considerable variation in the HC and LOS among ethnic groups by level of amputation. The direct charges reported in this study suggest considerably higher overall direct costs than have been previously reported in the medical literature. The greater burden of disease experienced by African Americans is probably related to their higher amputation cost and longer hospitalization.

Pressure reduction is of pivotal importance in any treatment plan designed to heal diabetic foot ulcers. However, to our knowledge, no work has evaluated the effect of ambulatory pressure reducing devices on postural stability (PS) in high risk diabetics. Therefore, the purpose of this study was to compare PS associated with 5 off-loading strategies: total contact casts with cast boot, total contact casts with heel, removable cast walker, half-shoes, and canvas shoes using a repeat measure design. Twenty-six diabetic patients with foot ulcers were enrolled in the study. Using a digital pressure platform, the degree of sway was measured as total deviation of center of force. Three 30 second trials were evaluated using Turkey's studentized range test for multiple comparisons (alpha = 0.05). Sway was significantly greater with total contact casts with heel compared to other devices. While total contact casting remains the gold standard with which to treat neuropathic ulcers, care should be taken when placing patients in any devices that may exacerbate postural instability. The results suggest that total contact casts with an incorporated rubber heel may indeed accentuate sway. It is therefore recommended that the rubber heel be eliminated in lieu of a protective cast boot when using this modality.

Objective: To compare the effectiveness of therapeutic, comfort, and athletic shoes with and without viscoelastic insoles., Research Design and Methods: We compared pressure reduction at ulcer sites under the hallux (n = 10), first metatarsal (n = 10), and lesser metatarsals (n = 12), using extra-depth, athletic, and comfort shoes with and without viscoelastic insoles. A rubber-soled canvas oxford was used to establish baseline pressure values., Results: When used in conjunction with a viscoelastic insole, all shoe types reduced mean peak plantar pressure better than their non-insoled counterparts (P < 0.05). Consistently, comfort shoes reduced pressure significantly better than both the cross trainers and extra-depth shoes for ulcers under the first and lesser metatarsals (P < 0.05). For each shoe type, the addition of the viscoelastic insole provided a significant reduction in mean peak pressure (P < 0.05). Compared with stock insoles, viscoelastic insoles reduced pressures an additional 5.4-20.1% at ulcer sites. The same trend was also observed at regions of the foot not associated with an ulceration., Conclusions: When used in conjunction with a viscoelastic insole, both the comfort and athletic cross-trainer shoes studied were as, if not more, effective than commonly prescribed therapeutic shoes in reducing mean peak first and lesser metatarsal pressures. Furthermore, comfort shoes were as effective as therapeutic shoes in reducing pressure under the great toe. Both of these shoe types may be viable options to prevent the development or recurrence of foot ulcers.