Spatio-temporal breather dynamics in microcomb soliton crystals.

Solitons, the distinct balance between nonlinearity and dispersion, provide a route toward ultrafast electromagnetic pulse shaping, high-harmonic generation, real-time image processing, and RF photonic communications. Here we uniquely explore and observe the spatio-temporal breather dynamics of optical soliton crystals in frequency microcombs, examining spatial breathers, chaos transitions, and dynamical deterministic switching - in nonlinear measurements and theory. To understand the breather solitons, we describe their dynamical routes and two example transitional maps of the ensemble spatial breathers, with and without chaos initiation. We elucidate the physical mechanisms of the breather dynamics in the soliton crystal microcombs, in the interaction plane limit cycles and in the domain-wall understanding with parity symmetry breaking from third-order dispersion. We present maps of the accessible nonlinear regions, the breather frequency dependences on third-order dispersion and avoided-mode crossing strengths, and the transition between the collective breather spatio-temporal states. Our range of measurements matches well with our first-principles theory and nonlinear modeling. To image these soliton ensembles and their breathers, we further constructed panoramic temporal imaging for simultaneous fast- and slow-axis two-dimensional mapping of the breathers. In the phase-differential sampling, we present two-dimensional evolution maps of soliton crystal breathers, including with defects, in both stable breathers and breathers with drift. Our fundamental studies contribute to the understanding of nonlinear dynamics in soliton crystal complexes, their spatio-temporal dependences, and their stability-existence zones.

Intraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.

Targeting greater pump flow and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) could potentially alleviate renal hypoxia and reduce the risk of postoperative acute kidney injury (AKI). Therefore, in an observational study of 93 patients undergoing on-pump cardiac surgery, we tested whether intraoperative hemodynamic management differed between patients who did and did not develop AKI. Then, in 20 patients, we assessed the feasibility of a larger-scale trial in which patients would be randomized to greater than normal target pump flow and MAP, or usual care, during CPB. In the observational cohort, MAP during hypothermic CPB averaged 68.8 ± 8.0 mmHg (mean ± SD) in the 36 patients who developed AKI and 68.9 ± 6.3 mmHg in the 57 patients who did not (p = 0.98). Pump flow averaged 2.4 ± 0.2 L/min/m2 in both groups. In the feasibility clinical trial, compared with usual care, those randomized to increased target pump flow and MAP had greater mean pump flow (2.70 ± 0.23 vs. 2.42 ± 0.09 L/min/m2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m2 ). Target MAP ≥80 mmHg was achieved in 66.6% of patients in the intervention group but in only 27.3% of patients in the usual care group. Nevertheless, MAP during CPB did not differ significantly between the two groups. We conclude that little insight was gained from our observational study regarding the impact of variations in pump flow and MAP on the risk of AKI. However, a clinical trial to assess the effects of greater target pump flow and MAP on the risk of AKI appears feasible.

Coherent terahertz radiation with 2.8-octave tunability through chip-scale photomixed microresonator optical parametric oscillation.

High-spectral-purity frequency-agile room-temperature sources in the terahertz spectrum are foundational elements for imaging, sensing, metrology, and communications. Here we present a chip-scale optical parametric oscillator based on an integrated nonlinear microresonator that provides broadly tunable single-frequency and multi-frequency oscillators in the terahertz regime. Through optical-to-terahertz down-conversion using a plasmonic nanoantenna array, coherent terahertz radiation spanning 2.8-octaves is achieved from 330 GHz to 2.3 THz, with ≈20 GHz cavity-mode-limited frequency tuning step and ≈10 MHz intracavity-mode continuous frequency tuning range at each step. By controlling the microresonator intracavity power and pump-resonance detuning, tunable multi-frequency terahertz oscillators are also realized. Furthermore, by stabilizing the microresonator pump power and wavelength, sub-100 Hz linewidth of the terahertz radiation with 10-15 residual frequency instability is demonstrated. The room-temperature generation of both single-frequency, frequency-agile terahertz radiation and multi-frequency terahertz oscillators in the chip-scale platform offers unique capabilities in metrology, sensing, imaging and communications.

Phase I/II open-label trial of intravenous allogeneic mesenchymal stromal cell therapy in adults with recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder due to a lack of type VII collagen. At present, treatment is mainly supportive. OBJECTIVES: To determine whether intravenous allogeneic bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) are safe in RDEB adults and if the cells improve wound healing and quality of life. METHODS: We conducted a prospective, phase I/II, open-label study recruiting 10 RDEB adults to receive 2 intravenous infusions of BM-MSCs (on day 0 and day 14; each dose 2-4 × 106 cells/kg). RESULTS: BM-MSCs were well tolerated with no serious adverse events to 12 months. Regarding efficacy, there was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch. One individual showed a transient increase in type VII collagen. LIMITATIONS: Open-label trial with no placebo. CONCLUSIONS: MSC infusion is safe in RDEB adults and can have clinical benefits for at least 2 months.

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin.RESULTSGene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected.CONCLUSIONTo our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation.TRIAL REGISTRATIONClincalTrials.gov NCT02493816.FUNDINGCure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, and Fondation René Touraine Short-Exchange Award.

Spectrum of Darkness, Agent of Light: Myopia, Keratoconus, Ocular Surface Disease, and Evidence for a Profoundly Vitamin D-dependent Eye.

Serial observations obtained over more than eight years and 10,000 patient encounters in a general ophthalmology practice serving a population highly prone to chronic vitamin D (D3) deficiency, facilitated by the Oculus Pentacam Scheimpflug imaging system (Oculus Optikgeräte GmbH, Wetzlar, Germany), resulted in the recognition of consistent, predictable, and highly reproducible patterns of mechanical, optical, and physiologic change in the cornea and other ocular structures correlated to adequate vs. inadequate vitamin D availability. These patterns were identified from an analysis of more than 20,000 topographical and digital imaging studies, manifest refraction results, and other clinical ophthalmic exam findings recorded during patient visits. The main outcome measures included improved corneal and global optical quality and function, decreased ametropia, improved stability, and decreased subjective symptoms of compromised acuity and comfort. Adequate D3 replacement consistently yielded some degree of objective structural improvement in all subjects observed. The rate of improvement varied and synergistic interaction with cofactors was also suggested in particular topical steroids. A plausible explanation for the cause and mechanism of most myopia emerged and keratoconus, in particular, appears to be the extreme presentation of otherwise common corneal disturbances associated with inadequate vitamin D availability. Emmetropization mechanisms appear to awaken and reactivate with adequate D3. Intraocular pressure control likewise shows evidence of being vitamin D regulated and may play a significant interactive role in emmetropization and relief from ametropia. Ocular surface disease and inflammatory activity can be markedly alleviated in addition. As the findings are most readily appreciated via topographical map changes, a series of case reports are presented, selected from the mass of similar data, to illustrate specific aspects of these findings in the hope of inspiring controlled trials to better delineate their significance. Taken as a whole, these observations suggest the human eye may be profoundly dependent upon adequate vitamin D availability for many critical optical, structural, and physiologic properties. Myopia may represent the end result of adverse emmetropization feedback generated by low vitamin D-related irregular corneal astigmatism.

Pressure and Flow Characteristics of a Novel Bidirectional Cannula for Cardiopulmonary Bypass.

OBJECTIVE: Femoral arterial cannulation is associated with a significant risk of lower limb ischemia. The aim of the study was to assess the pressure and flow in the femoral artery using a novel bidirectional femoral cannula in a sheep model of peripheral cardiopulmonary bypass. METHODS: Peripheral cardiopulmonary bypass was established using a multistage venous cannula inserted into the internal jugular vein and the bidirectional or a conventional arterial cannula into the femoral artery in seven adult ewes. Systemic and distal perfusion pressures and flow rates were measured during cardiopulmonary bypass with flow rates of 1, 2, 3, and 4 L/min. Lower limb venous oxygen saturation and lactate levels were also measured. RESULTS: A significantly higher blood flow in the lower limb using the bidirectional cannula was observed and compared with a conventional cannula at all flow rates (mean flow 115 mL/min vs 10 mL/min, P < 0.05). The mean distal perfusion pressure was also significantly higher in the bidirectional cannula group (86 mm Hg vs 45 mm Hg at 4 L/min of flow, P < 0.05). The bidirectional cannula was associated with higher venous oxygen saturations in the lower limb than in the conventional cannula group; however, lower limb lactate production was similar in the two groups. CONCLUSIONS: This in vivo data demonstrates superior distal flow and pressure characteristics of a novel bidirectional cannula compared with a conventional femoral cannula during peripheral cardiopulmonary bypass.

Effects of dilute-acid pretreatment conditions on filtration performance of corn stover hydrolyzate.

The reaction conditions used during dilute-acid pretreatment of lignocellulosic biomass control the carbohydrate digestion yield and also hydrolyzate properties. Depending on the conversion route of interest, solid-liquid separation (SLS) may be required to split the hemicellulose-rich liquor from the cellulose-rich insoluble solids, and slurry properties are important for SLS. Corn stover was pretreated at different reaction conditions and the slurries were assessed for conversion yield and filtration performance. Increasing pretreatment temperature reduced the solids mean particle size and resulted in slower slurry filtration rates when vacuum filtered or pressure filtered. Corn stover pretreated at 165°C for 10min and with 1% H2SO4 exhibited the highest xylose yield and best filtration performance with a no-wash filtration rate of 80kg/hm2 and cake permeability of 15x10-15.

Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.

Real-time dynamics and cross-correlation gating spectroscopy of free-carrier Drude slow-light solitons.

Optical solitons-stable waves balancing delicately between nonlinearities and dispersive effects-have advanced the field of ultrafast optics and dynamics, with contributions spanning from supercontinuum generation to soliton fission, optical event horizons, Hawking radiation and optical rogue waves, among others. Here, we investigate picojoule soliton dynamics in silicon slow-light, photonic-bandgap waveguides under the influence of Drude-modeled, free-carrier-induced nonlinear effects. Using real-time and single-shot amplified dispersive Fourier transform spectroscopy simultaneously with high-fidelity cross-correlation frequency resolved optical gating at femtojoule sensitivity and femtosecond resolution, we examine the soliton stability limits, the soliton dynamics including free-carrier quartic slow-light scaling and acceleration, and the Drude electron-hole plasma-induced perturbations in the Cherenkov radiation and modulation instability. Our real-time single-shot and time-averaged cross-correlation measurements are matched with our detailed theoretical modeling, examining the reduced group velocity free-carrier kinetics on solitons at the picojoule scale.

Assessing pretreatment reactor scaling through empirical analysis.

BACKGROUND: Pretreatment is a critical step in the biochemical conversion of lignocellulosic biomass to fuels and chemicals. Due to the complexity of the physicochemical transformations involved, predictively scaling up technology from bench- to pilot-scale is difficult. This study examines how pretreatment effectiveness under nominally similar reaction conditions is influenced by pretreatment reactor design and scale using four different pretreatment reaction systems ranging from a 3 g batch reactor to a 10 dry-ton/days continuous reactor. The reactor systems examined were an automated solvent extractor (ASE), steam explosion reactor (SER), ZipperClave®Reactor (ZCR), and large continuous horizontal screw reactor (LHR). To our knowledge, this is the first such study performed on pretreatment reactors across a range of reaction conditions and at different reactor scales. RESULTS: The comparative pretreatment performance results obtained for each reactor system were used to develop response surface models for total xylose yield after pretreatment and total sugar yield after pretreatment followed by enzymatic hydrolysis. Near- and very-near-optimal regions were defined as the set of conditions that the model identified as producing yields within one and two standard deviations of the optimum yield. Optimal conditions identified in the smallest scale system (the ASE) were within the near-optimal region of the largest scale reactor system evaluated. The maximum total sugar yields for the ASE and LHR were [Formula: see text], while [Formula: see text] was the optimum observed in the ZipperClave. CONCLUSIONS: The optimum condition identified using the automated and less costly to operate ASE system was within the very-near-optimal space for the total xylose yield of both the ZCR and the LHR, and was within the near-optimal space for total sugar yield for the LHR. This indicates that the ASE is a good tool for cost effectively finding near-optimal conditions for operating pilot-scale systems. Additionally, using a severity factor approach to optimization was found to be inadequate compared to a multivariate optimization method. Finally, the ASE and the LHR were able to enable significantly higher total sugar yields after enzymatic hydrolysis relative to the ZCR, despite having similar optimal conditions and total xylose yields. This underscores the importance of mechanical disruption during pretreatment to improvement of enzymatic digestibility.

Lentiviral Engineered Fibroblasts Expressing Codon-Optimized COL7A1 Restore Anchoring Fibrils in RDEB.

Cells therapies, engineered to secrete replacement proteins, are being developed to ameliorate otherwise debilitating diseases. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by defects of type VII collagen, a protein essential for anchoring fibril formation at the dermal-epidermal junction. Whereas allogeneic fibroblasts injected directly into the dermis can mediate transient disease modulation, autologous gene-modified fibroblasts should evade immunological rejection and support sustained delivery of type VII collagen at the dermal-epidermal junction. We demonstrate the feasibility of such an approach using a therapeutic grade, self-inactivating-lentiviral vector, encoding codon-optimized COL7A1, to transduce RDEB fibroblasts under conditions suitable for clinical application. Expression and secretion of type VII collagen was confirmed with transduced cells exhibiting supranormal levels of protein expression, and ex vivo migration of fibroblasts was restored in functional assays. Gene-modified RDEB fibroblasts also deposited type VII collagen at the dermal-epidermal junction of human RDEB skin xenografts placed on NOD-scid IL2Rgamma(null) recipients, with reconstruction of human epidermal structure and regeneration of anchoring fibrils at the dermal-epidermal junction. Fibroblast-mediated restoration of protein and structural defects in this RDEB model strongly supports proposed therapeutic applications in man.

English professional football players concussion knowledge and attitude.

BACKGROUND: Concussions are a common pathology in football and multiple misconceptions exist amongst the players and managers. To address these misconceptions, and potentially reduce concussion associated sequela, effective educational interventions need to be developed. However, the current knowledge and attitude status must be ascertained to appropriately develop these interventions. The purpose of this study was to assess the concussion knowledge and attitude of English professional footballers. METHODS: Twenty-six participants from one English Football League Championship club completed the study. A mixed methods approach included the Rosenbaum Concussion Knowledge and Attitudes Survey (RoCKAS) and a semi-structured interview. The RoCKAS contains separate knowledge (0-25) and attitude (15-75) scores and was followed by a semi-structured interview consisting of concussion knowledge, attitude, and behavior related questions. RESULTS: The mean score on the RoCKAS knowledge was 16.4 ± 2.9 (range 11-22) and the attitude score was 59.6 ± 8.5 (range 41-71). The interview responses identified inconsistencies between the RoCKAS and the intended behaviors, endorsing multiple concussion misconceptions, and revealed barriers to concussion reporting. CONCLUSION: The results of this study suggest that Championship Level English footballers have moderate concussion knowledge, safe attitudes, and good concussion symptom recognition when assessed with pen and paper questionnaires. However, within the semi-structured interview many respondents reported unsafe concussion behaviors despite accurately identifying the potential risks. Further, multiple barriers to concussion reporting were identified which included perceived severity of the injury, game situations, and the substitution rule. These findings can help form the foundation of educational interventions to potentially improve concussion reporting behaviors amongst professional footballers.

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes.

The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet the contribution of specific components of the cytoskeleton to nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between the cytolinker plectin and F-actin controls keratin network organisation and the 3D nuclear morphology of keratinocytes. Using micro-patterned surfaces to precisely manipulate cell shape, we find that cell adhesion and spreading regulate the size and shape of the nucleus. Disruption of the keratin cytoskeleton through loss of plectin facilitated greater nuclear deformation, which depended on acto-myosin contractility. Nuclear morphology did not depend on direct linkage of the keratin cytoskeleton with the nuclear membrane, rather loss of plectin reduced keratin filament density around the nucleus. We further demonstrate that keratinocytes have abnormal nuclear morphologies in the epidermis of plectin-deficient, epidermolysis bullosa simplex patients. Taken together, our data demonstrate that plectin is an essential regulator of nuclear morphology in vitro and in vivo and protects the nucleus from mechanical deformation.

Lysyl Hydroxylase 3 Localizes to Epidermal Basement Membrane and Is Reduced in Patients with Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention.

Transesophageal Echocardiography Guidance of Antegrade Cardioplegia Delivery for Cardiac Surgery.

OBJECTIVES: The initial volume of antegrade cardioplegia used to induce asystole during aortic cross-clamp still is based on empiric methods and may be excessive, potentially leading to hyperkalemia, myocardial edema, and acute left ventricular distention from aortic regurgitation. The objectives were to determine whether the volume of cardioplegia required to induce asystole is proportional to left ventricular mass, and whether the degree of left ventricular distention is proportional to the severity of aortic regurgitation. DESIGN: Prospective observational study. SETTING: Two tertiary university hospitals. INTERVENTIONS: Transesophageal echocardiography was used to estimate left ventricular mass (prolate ellipse revolution formula), quantify aortic regurgitation, and monitor for distention during initial antegrade cardioplegia delivery. The volume of cardioplegia required for asystole was recorded. PARTICIPANTS: Fifty-eight patients aged over 18 years scheduled for cardiac surgery requiring aortic cross-clamping. MEASUREMENTS AND MAIN RESULTS: There was a weak correlation of left ventricular mass and antegrade cardioplegia volume required for asystole (r = 0.35, p = 0.047). The degree of left ventricular distention correlated moderately with the severity of aortic regurgitation (r = 0.55, p = 0.007) and was excessive and stopped early (aborted) in 24% of all patients, including 18% of 39 patients without aortic regurgitation. An aortic regurgitation vena contracta of 0.3 cm predicted aborted cardioplegia with modest accuracy (AUC 0.81, 0.66-0.99, p = 0.02, sensitivity 71%, specifity 81%). CONCLUSIONS: Estimated left ventricular mass is not a useful predictor of the initial volume of antegrade cardioplegia required to induce asystole. However transesophageal echocardiography can predict and monitor for left ventricular distention, which is common.