Robustness and stability of doubly periodic patterns of the focusing nonlinear Schrödinger equation.

The nonlinear Schrödinger equation possesses doubly periodic solutions expressible in terms of the Jacobi elliptic functions. Such solutions can be realized through doubly periodic patterns observed in experiments in fluid mechanics and optics. Stability and robustness of these doubly periodic wave profiles in the focusing regime are studied computationally by using two approaches. First, linear stability is considered by Floquet theory. Growth will occur if the eigenvalues of the monodromy matrix are of a modulus larger than unity. This is verified by numerical simulations with input patterns of different periods. Initial patterns associated with larger eigenvalues will disintegrate faster due to instability. Second, formation of these doubly periodic patterns from a tranquil background is scrutinized. Doubly periodic profiles are generated by perturbing a continuous wave with one Fourier mode, with or without the additional presence of random noise. Effects of varying phase difference, perturbation amplitude, and randomness are studied. Varying the phase angle has a dramatic influence. Periodic patterns will only emerge if the perturbation amplitude is not too weak. The growth of higher-order harmonics, as well as the formation of breathers and repeating patterns, serve as a manifestation of the classical problem of Fermi-Pasta-Ulam-Tsingou recurrence.

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes.

Cytotoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C terminus of these CTL epitopes is considered to be produced by the proteasome. Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus protein EBNA3C, and a clinically important epitope from the melanoma protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing, and nardilysin contributed to both the C-terminal and N-terminal generation of CTL epitopes. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

Single-cell RNA sequencing identifies molecular targets associated with poor in vitro maturation performance of oocytes collected from ovarian stimulation.

STUDY QUESTION: What is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them? SUMMARY ANSWER: The GATA-1/CREB1/WNT signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes. WHAT IS KNOWN ALREADY: rIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM. STUDY DESIGN, SIZE, DURATION: We applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human oocytes were collected from donors aged 28-41 years with a body mass index of <30. RNA extraction, cDNA generation, library construction and sequencing were performed in one preparation. scRNA-seq data were then processed and analysed. Selected genes in the rIVM versus IVO comparison were validated by quantitative real-time PCR. For the gallic acid study, we collected immature oocytes from 5-month-old mice and studied the effect of 10-µM gallic acid on their maturation rate. MAIN RESULTS AND THE ROLE OF CHANCE: The transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P < 0.05) were found to be enriched in metabolic processes, biosynthesis and oxidative phosphorylation. Among these DEGs, we identified a repression of WNT/ß-catenin signalling in rIVM when compared with IVO oocytes. We found that oestradiol levels exhibited a significant age-independent correlation with the IVO mature oocyte ratio (MII ratio) for each donor. rIVM oocytes from women with a high MII ratio were found to have over-represented cellular processes such as anti-apoptosis. To further identify targets that contribute to the poor clinical outcomes of rIVM, we compared oocytes collected from young donors with a high MII ratio with oocytes from donors of advanced maternal age and lower MII ratio, and revealed that CREB1 is an important regulator. Thus, our study identified that GATA-1/CREB1/WNT signalling was repressed in both rIVM oocytes versus IVO oocytes and in rIVM oocytes of lower versus higher quality. Consequently we investigated gallic acid, as a potential antioxidant substrate in human rIVM medium, and found that it increased the mouse oocyte maturation rate by 31.1%. LARGE SCALE DATA: Raw data from this study can be accessed through GSE158539. LIMITATIONS, REASONS FOR CAUTION: In the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator. WIDER IMPLICATIONS OF THE FINDINGS: This study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare.

Four-wave mixing and coherently coupled Schrödinger equations: Cascading processes and Fermi-Pasta-Ulam-Tsingou recurrence.

Modulation instability, breather formation, and the Fermi-Pasta-Ulam-Tsingou recurrence (FPUT) phenomena are studied in this article. Physically, such nonlinear systems arise when the medium is slightly anisotropic, e.g., optical fibers with weak birefringence where the slowly varying pulse envelopes are governed by these coherently coupled Schrödinger equations. The Darboux transformation is used to calculate a class of breathers where the carrier envelope depends on the transverse coordinate of the Schrödinger equations. A "cascading mechanism" is utilized to elucidate the initial stages of FPUT. More precisely, higher order nonlinear terms that are exponentially small initially can grow rapidly. A breather is formed when the linear mode and higher order ones attain roughly the same magnitude. The conditions for generating various breathers and connections with modulation instability are elucidated. The growth phase then subsides and the cycle is repeated, leading to FPUT. Unequal initial conditions for the two waveguides produce symmetry breaking, with "eye-shaped" breathers in one waveguide and "four-petal" modes in the other. An analytical formula for the time or distance of breather formation for a two-waveguide system is proposed, based on the disturbance amplitude and instability growth rate. Excellent agreement with numerical simulations is achieved. Furthermore, the roles of modulation instability for FPUT are elucidated with illustrative case studies. In particular, depending on whether the second harmonic falls within the unstable band, FPUT patterns with one single or two distinct wavelength(s) are observed. For applications to temporal optical waveguides, the present formulation can predict the distance along a weakly birefringent fiber needed to observe FPUT.

A systematic review of the effects of advance care planning facilitators training programs.

BACKGROUND: Advance care planning (ACP) is the process of ongoing communication among patients, family and health care professionals regarding what plans for future care are preferred in the event that patients become unable to make their own decisions. Clinicians play an important role in ACP as both initiators and decision coaches. However, lack of training for clinicians has frequently been reported as the reason for low involvement in ACP discussions - hence the present review evaluates the effectiveness of ACP training programs for healthcare professionals to guide the development of novel training programs for them in the future. METHODS: A literature search for intervention studies was conducted independently by two reviewers in July 2018. Participants included all healthcare professionals working with adult patients suffering from terminal illness. The primary outcomes were the professionals' knowledge of and attitudes towards ACP, and self-perceived competence in ACP conversations. The Effective Public Health Practice Project appraisal tool was used to examine the quality of the studies included. RESULTS: A total of 4025 articles were identified, and ten eligible articles, covering 1081 participants, were included in the review. However, there is a lack of high quality randomized controlled trials of providing ACP training for nurses working in non-palliative care hospital settings. The overall quality of the intervention studies was moderate. All the studies included used instructional sessions in their interventions, while some contained group discussion, role-play and the use of advanced technology. The training programs increased the knowledge, attitudes towards shared decision-making, perceived communication skills, confidence, comfort and experiences concerned with discussing end-of-life (EOL) issues. Patient advocacy, job satisfaction and perceived level of adequate training for EOL care were improved. The use of 'decision aids' was rated as acceptable and clinically useful. CONCLUSIONS: Training for healthcare professionals in ACP has positive effects on their knowledge, attitude and skills. The use of decision aids and advanced technology, instructional sessions with role play, training content focused on ACP communication skills and the needs and experience of patient in the ACP process, and a values-based ACP process are all those factors that made the ACP training programs effective.

Non-percolating small metallic clusters and sharp suppression of metallicity in RE0.55Sr0.45Mn1-xRuxO3 manganites.

The origin of the anomalous sharp phase transition from a ferromagnetic metal into a ferromagnetic insulator has been investigated in ruthenium (Ru)-doped RE0.55Sr0.45Mn1-xRuxO3 (0 ≤ x ≤ 0.25) manganites (RESRMO) with RE(A-site) = Sm, Eu and Gd. The transition is independent of RE and occurs at a Ru doping level x of around 0.16-0.18. The analysis of the temperature derivative of the resistivity and the magneto-resistance at high temperatures as a function of x suggests that the suppression of metallicity originates from the doping driven magnetic/spin disorder that coexist within the ferromagnetic metallic/insulating matrix in these compounds.

Meteorological factors to fall: a systematic review.

There existed systematic review on studies investigating the association between hip fractures and external risk factors including meteorological factors. Albeit the fact that most serious common fall injury is a hip fracture, it cannot account for all injuries forms of fall. There was a lack of systematic review covering all fall-related injury or deaths to thoroughly summarise meteorological aspects of fall. This study aimed to systematically review epidemiological studies of fall and fall-related circumstances without restriction to hip fracture. A systematic search in three databases, namely PubMed, CINAHL Plus and EMBASE, was performed. Searches in two Chinese databases named the Wanfang Med Online and the China Journal Net were done in addition. A total of 29 studies were identified. The study site, fall cases identification, meteorological factors and findings of all the selected studies were being extracted. The quality of the studies was critically appraised. We identified some of the environmental risk factors to fall among those studies. Ranging from the lower ambient temperature, the presence of snow cover, seasonal factors, and time of the day to location of fall, these factors have different levels of impact related to higher incidence or mortality of fall. To conclude, a better understanding of injury mechanisms is a prerequisite for preventive interventions.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Haemodynamic Variations of Flow to Renal Arteries in Custom-Made and Pivot Branch Fenestrated Endografting.

OBJECTIVE: This study aimed to investigate variation of blood flow to renal arteries in custom-made and pivot branch (p-branch) fenestrated endografting, using a computational fluid dynamics (CFD) technique. METHODS: Idealised models of custom-made and p-branch fenestrated grafting were constructed on a basis of a 26 mm stent graft. The custom-made fenestration was designed with a 6 mm diameter, while the 5 mm depth renal p-branch was created with a 6 mm inner and 15 mm outer fenestration. Two configurations (option A and option B) were constructed with different locations of p-branches. Option A had both renal p-branches at the same level, whereas option B contained two staggered p-branches at lower positions. The longitudinal stent orientation in both custom-made and p-branch models was represented by a takeoff angle (ToA) between the renal stent and distal stent graft centreline, varying from 55° to 125°. Computational simulations were performed with realistic boundary conditions governing the blood flow. RESULTS: In both custom-made and p-branch fenestrated models, the flow rate and wall shear stress (WSS) were generally higher and recirculation zones were smaller when the renal stent faced caudally. In custom-made models, the highest flow rate (0.390 L/min) was detected at 70° ToA and maximum WSS on vessel segment (16.8 Pa) was attained at 55° ToA. In p-branch models, option A and option B displayed no haemodynamic differences when having the same ToA. The highest flow rate (0.378 L/min) and maximum WSS on vessel segment (16.7 Pa) were both calculated at 55° ToA. The largest and smallest recirculation zones occurred at 90° and 55° ToA respectively in both custom-made and p-branch models. Custom-made fenestrated models exhibited consistently higher flow rate and shear stress and smaller recirculation zones in renal arteries than p-branch models at the same ToA. CONCLUSIONS: Navigating the renal stents towards caudal orientation can achieve better haemodynamic outcomes in both fenestrated devices. Custom-made fenestrated stent grafts are the preferred choice for elective patients. Further clinical evidence is required to validate the computational simulations.

A connection between the maximum displacements of rogue waves and the dynamics of poles in the complex plane.

Rogue waves of evolution systems are displacements which are localized in both space and time. The locations of the points of maximum displacements of the wave profiles may correlate with the trajectories of the poles of the exact solutions from the perspective of complex variables through analytic continuation. More precisely, the location of the maximum height of the rogue wave in laboratory coordinates (real space and time) is conjectured to be equal to the real part of the pole of the exact solution, if the spatial coordinate is allowed to be complex. This feature can be verified readily for the Peregrine breather (lowest order rogue wave) of the nonlinear Schrödinger equation. This connection is further demonstrated numerically here for more complicated scenarios, namely the second order rogue wave of the Boussinesq equation (for bidirectional long waves in shallow water), an asymmetric second order rogue wave for the nonlinear Schrödinger equation (as evolution system for slowly varying wave packets), and a symmetric second order rogue wave of coupled Schrödinger systems. Furthermore, the maximum displacements in physical space occur at a time instant where the trajectories of the poles in the complex plane reverse directions. This property is conjectured to hold for many other systems, and will help to determine the maximum amplitudes of rogue waves.

Characterization of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae from a healthcare region in Hong Kong.

Carbapenem-resistant Enterobacteriaceae represents a major public health issue. This study investigated the clonality and resistance mechanisms of 92 carbapenem-resistant E. coli (n = 21) and K. pneumoniae (n = 71) isolates collected consecutively from clinical specimens and patients at high risk of carriage between 2010 and 2012 in a healthcare region in Hong Kong. Combined disk tests (CDTs) and the Carba NP test were used for phenotypic detection of carbapenemases. PCR assays were used to detect carbapenemase genes. All isolates were intermediate or resistant to at least one carbapenem. Nine (9.8 %) isolates were genotypic carbapenemase producers and included six K. pneumoniae (one ST1306/bla IMP-4, one ST889/bla IMP-4, two ST11/bla KPC-2, one ST258/bla KPC-2, one ST483/bla NDM-1) and three E. coli (one ST131/bla IMP-4, two ST744/ bla NDM-1) isolates. All nine isolates carrying carbapenemase genes could be detected by the CDTs and the Carba NP test. PCR identified bla CTX-M and bla AmpC alone or in combination in 77.8 % (7/9) and 96.4 % (80/83) of the carbapenemase-producers and non-producers, respectively. Porin loss was detected in 22.2 % (2/9) and 59.0 % (49/83) of the carbapenemase-producers and non-producers, respectively. Overall, the E. coli clones were diverse (14 different STs), but 36.6 % (26/71) of the K. pneumoniae isolates belonged to ST11. In conclusion, the prevalence of carbapenemases among carbapenem-nonsusceptible E. coli and K. pneumoniae remained low in Hong Kong. Porin loss combined with AmpC and/or CTX-M type ESBL was the major mechanism of carbapenem resistance in the study population.

Graphene-deposited photonic crystal fibers for continuous refractive index sensing applications.

We present a pilot demonstration of an optical fiber based refractive index (RI) sensor involving the deposition of graphene onto the surface of a segment of a photonic crystal fiber (PCF) in a fiber-based Mach-Zehnder Interferometer (MZI). The fabrication process is relatively simple and only involves the fusion splicing of a PCF between two single mode fibers. The deposition process relies only on the cold transfer of graphene onto the PCF segment, without the need for further physical or chemical treatment. The graphene overlay modified the sensing scheme of the MZI RI sensor, allowing the sensor to overcome limitations to its detectable RI range due to free spectral range issues. This modification also allows for continuous measurements to be obtained without the need for reference values for the range of RIs studied and brings to light the potential for simultaneous dual parameter sensing. The sensor was able to achieve a RI sensitivity of 9.4 dB/RIU for the RIs of 1.33-1.38 and a sensitivity of 17.5 dB/RIU for the RIs of 1.38-1.43. It also displayed good repeatability and the results obtained were consistent with the modeling.

Experimental demonstration of a soft x-ray self-seeded free-electron laser.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

Reduction of amyloid-beta levels in mouse eye tissues by intra-vitreally delivered neprilysin.

Amyloid-beta (Aß) is a group of aggregation-prone, 38- to 43-amino acid peptides generated in the eye and other organs. Numerous studies suggest that the excessive build-up of low-molecular-weight soluble oligomers of Aß plays a role in the progression of Alzheimer's disease and other brain degenerative diseases. Recent studies raise the hypothesis that excessive Aß levels may contribute also to certain retinal degenerative diseases. These findings, together with evidence that a major portion of Aß is released as monomer into the extracellular space, raise the possibility that a technology enabling the enzymatic break-down of monomeric Aß in the living eye under physiological conditions could prove useful for research on ocular Aß physiology and, perhaps ultimately, for therapeutic applications. Neprilysin (NEP), an endopeptidase known to cleave Aß monomer into inactive products, is a membrane-associated protein. However, sNEP, a recombinant form of the NEP catalytic domain, is soluble in aqueous medium. With the aim of determining the Aß-cleaving activity of exogenous sNEP in the microenvironment of the intact eye, we analyzed the effect of intra-vitreally delivered sNEP on ocular Aß levels in mice that exhibit readily measurable, aqueous buffer-extractable Aß40 and Aß42, two principal forms of Aß. Anesthetized 10-month wild-type (C57BL/6J) and 2-3-month 5XFAD transgenic mice received intra-vitreal injections of sNEP (0.004-10 µg) in one eye and were sacrificed at defined post-treatment times (30 min - 12 weeks). Eye tissues (combined lens, vitreous, retina, RPE and choroid) were homogenized in phosphate-buffered saline, and analyzed for Aß40 and Aß42 (ELISA) and for total protein (Bradford assay). The fellow, untreated eye of each mouse served as control, and concentrations of Aß (pmol/g protein) in the treated eye were normalized to that of the untreated control eye. In C57BL/6J mice, as measured at 2 h after sNEP treatment, increasing amounts of injected sNEP yielded progressively greater reductions of Aß40, ranging from 12% ± 3% (mean ± SEM; n = 3) with 4 ng sNEP to 85% ± 13% (n = 5) with 10 µg sNEP. At 4 ng sNEP the average Aß40 reduction reached >70% by 24 h following treatment and remained near this level for about 8 weeks. In 5XFAD mice, 10 µg sNEP produced an Aß40 decrease of 99% ± 1% (n = 4) and a substantial although smaller decrease in Aß42 (42% ± 36%; n = 4) within 24 h. Electroretinograms (ERGs) were recorded from eyes of C57BL/6J and 5XFAD mice at 9 days following treatment with 4 ng or 10 µg sNEP, conditions that on average led, respectively, to an 82% and 91% Aß40 reduction in C57BL/6J eyes, an 87% and 92% Aß40 reduction in 5XFAD eyes, and a 23% and 52% Aß42 reduction in 5XFAD eyes. In all cases, sNEP-treated eyes exhibited robust ERG responses, consistent with a general tolerance of the posterior eye tissues to the investigated conditions of sNEP treatment. The sNEP-mediated decrease of ocular Aß levels reported here represents a possible approach for determining effects of Aß reduction in normally functioning eyes and in models of retinal degenerative disease.

Evaluation of polybrominated diphenyl ethers (PBDEs) in matched cat sera and house dust samples: investigation of a potential link between PBDEs and spontaneous feline hyperthyroidism.

The cause of feline hyperthyroidism (FH), a common endocrinopathy of domestic cats, is unknown. A potential association between exposure to environmental contaminants polybrominated diphenyl ethers (PBDEs) and FH was investigated. The median serum level for the sum of congeners BDE-47, BDE-99, BDE-153, BDE-154 and BDE-183 (Σ5) in hyperthyroid and euthyroid cats was 82 and 174 ng g(-1)lw respectively with no significant difference in PBDE levels or profiles between groups. Overall, the median (min to max) concentration of PBDEs in cat serum (n=65) was 118 ng g(-1)lw (5-5260 ng g(-1)lw), which is approximately 10 times higher than that observed in the Australian human population. Furthermore, congener composition in feline serum samples was dominated by congener BDE-99, followed by BDE-47 then BDE-153 which differs from results of human biomonitoring. There was no correlation between PBDE levels in feline serum samples and matched house dust samples (n=25). However the similarity of BDE-47/99 ratio in each matrix suggests dust is likely the dominant exposure. Calculation of the daily exposure dose via dust ingestion for cats equated to a mean of 33 ng kg(-1) bw d(-1) (0.2-150 ng kg(-1) bw d(-1)). Differences in exposure estimates for Australian and US cats, based on dust ingestion alone, are consistent with the observed differences in body burdens. Our results do not support a role for PBDE exposure in the aetiopathogenesis of FH.

A coupled "AB" system: Rogue waves and modulation instabilities.

Rogue waves are unexpectedly large and localized displacements from an equilibrium position or an otherwise calm background. For the nonlinear Schrödinger (NLS) model widely used in fluid mechanics and optics, these waves can occur only when dispersion and nonlinearity are of the same sign, a regime of modulation instability. For coupled NLS equations, rogue waves will arise even if dispersion and nonlinearity are of opposite signs in each component as new regimes of modulation instability will appear in the coupled system. The same phenomenon will be demonstrated here for a coupled "AB" system, a wave-current interaction model describing baroclinic instability processes in geophysical flows. Indeed, the onset of modulation instability correlates precisely with the existence criterion for rogue waves for this system. Transitions from "elevation" rogue waves to "depression" rogue waves are elucidated analytically. The dispersion relation as a polynomial of the fourth order may possess double pairs of complex roots, leading to multiple configurations of rogue waves for a given set of input parameters. For special parameter regimes, the dispersion relation reduces to a cubic polynomial, allowing the existence criterion for rogue waves to be computed explicitly. Numerical tests correlating modulation instability and evolution of rogue waves were conducted.