Cutting Edge: Systemic Autoimmunity in Murine STAT3 Gain-of-Function Syndrome Is Characterized by Effector T Cell Expansion in the Absence of Overt Regulatory T Cell Dysfunction.

Germline gain-of-function mutations in the transcriptional factor STAT3 promote early-onset multisystemic autoimmunity. To investigate how increased STAT3 promotes systemic inflammation, we generated a transgenic knock-in strain expressing a pathogenic human mutation STAT3K392R within the endogenous murine locus. As predicted, STAT3K392R mice develop progressive lymphoid hyperplasia and systemic inflammation, mirroring the human disease. However, whereas the prevailing model holds that increased STAT3 activity drives human autoimmunity by dysregulating the balance between regulatory T cells and Th17 cell differentiation, we observed increased Th17 cells in the absence of major defects in regulatory T cell differentiation or function. In addition, STAT3K392R animals exhibited a prominent accumulation of IFN-γ-producing CD4+ and CD8+ T cells. Together, these data provide new insights into this complex human genetic syndrome and highlight the diverse cellular mechanisms by which dysregulated STAT3 activity promotes breaks in immune tolerance.

Cutting Edge: A Threshold of B Cell Costimulatory Signals Is Required for Spontaneous Germinal Center Formation in Autoimmunity.

Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.

TACI haploinsufficiency protects against BAFF-driven humoral autoimmunity in mice.

Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.

Coherent waveguide laser arrays in semiconductor quantum well membranes.

Coherent laser arrays compatible with silicon photonics are demonstrated in a waveguide geometry in epitaxially grown semiconductor membrane quantum well lasers transferred on substrates of silicon carbide and oxidised silicon; we record lasing thresholds as low as 60 mW of pump power. We study the emission of single lasers and arrays of lasers in the sub-mm range. We are able to create waveguide laser arrays with modal widths of approximately 5 - 10 µm separated by 10 - 20 µm, using real and reciprocal space imaging we study their emission characteristics and find that they maintain their mutual coherence while operating on either single or multiple longitudinal modes per lasing cavity.

High power 739 nm VECSELs for future Yb+ ion cooling.

We present an operational characterization of a vertical-external-cavity surface-emitting laser emitting around 739 nm with over 150 mW in a single fundamental spatial mode. Results show that the laser is capable of oscillating on a single cavity axial mode at 740 nm for up to 22 mW. Tuning of the optical emission is shown to reach 737.3 nm. Furthermore, at best performance, the laser exhibits a slope efficiency of 8.3% and a threshold power of 1.27 W for an output coupler reflectivity of 98%.

Supercontinuum generation in tantalum pentoxide waveguides for pump wavelengths in the 900 nm to 1500 nm spectral region.

We characterize the spectral broadening performance in silica clad and unclad Tantalum pentoxide (Ta2O5) waveguides as a function of the input pulse central wavelength and polarization, sweeping over a wavelength range from 900 nm to 1500 nm, with an average incident power of 110 mW. The waveguides are 0.7 µm high and between 2.2 and 3.2 µm wide, and the SiO2 top cladding layer is 2 µm thick. We model the dispersion of the higher order spatial modes, and use numerical simulations based on the generalized nonlinear Schrödinger equation to analyze the nonlinear behaviour of the spatial modes within the waveguides as well as the dispersive effects observed in the experiments. We achieve octave spanning supercontinuum with an average power of 175 mW incident on the waveguide at 1000 nm pump wavelength.

Zinc-indiffused MgO:PPLN waveguides for blue/UV generation via VECSEL pumping.

We present the design and characterization of a zinc-indiffused periodically poled lithium-niobate ridge waveguide for second-harmonic generation of ∼390nm light from 780 nm. We use a newly developed, broadband near-infrared vertical external-cavity surface-emitting laser (VECSEL) to investigate the potential for lower-footprint nonlinear optical pump sources as an alternative to larger commercial laser systems. We demonstrate a VECSEL with an output power of 500 mW, containing an intracavity birefringent filter for spectral narrowing and wavelength selection. In this first demonstration of using a VECSEL to pump a nonlinear waveguide, we present the ability to generate 1 mW of ∼390nm light with further potential for increased efficiency and size reduction.

Semiconductor disk laser in bi-frequency operation by laser ablation micromachining of a laser mirror.

We present bi-frequency continuous wave oscillation in a semiconductor disk laser through direct writing of loss-inducing patterns onto an intra-cavity high reflector mirror. The laser is a Vertical External Cavity Surface Emitting Laser which is optically pumped by up to 1.1 W of 808 nm light from a fibre coupled multi-mode diode laser, and oscillates on two Hermite-Gaussian spatial modes simultaneously, achieving wavelength separations between 0.2 nm and 5 nm around 995 nm. We use a Digital Micromirror Device (DMD) enabled laser ablation system to define spatially specific loss regions on a laser mirror by machining away the Bragg layers from the mirror surface. The ablated pattern is comprised of two orthogonal lines with the centermost region undamaged, and is positioned in the laser cavity so as to interact with the lasing mode, thereby promoting the simultaneous oscillation of the fundamental and a higher order spatial mode. We demonstrate bi-frequency oscillation over a range of mask gap sizes and pump powers.

Carrier frequency modulation of an acousto-optic modulator for laser stabilization.

The stabilization of lasers to absolute frequency references is a fundamental requirement in several areas of atomic, molecular and optical physics. A range of techniques are available to produce a suitable reference onto which one can 'lock' the laser, many of which depend on the specific internal structure of the reference or are sensitive to laser intensity noise. We present a novel method using the frequency modulation of an acousto-optic modulator's carrier (drive) signal to generate two spatially separated beams, with a frequency difference of only a few MHz. These beams are used to probe a narrow absorption feature and the difference in their detected signals leads to a dispersion-like feature suitable for wavelength stabilization of a diode laser. This simple and versatile method only requires a narrow absorption line and is therefore suitable for both atomic and cavity based stabilization schemes. To demonstrate the suitability of this method we lock an external cavity diode laser near the 85Rb 5S1/2 → 5P3/2, F = 3 → F' = 4 using sub-Doppler pump probe spectroscopy and also demonstrate excellent agreement between the measured signal and a theoretical model.

Stabilized fiber-optic Mach-Zehnder interferometer for carrier-frequency rejection.

We have demonstrated stabilization of a fiber-optic Mach-Zehnder interferometer, with a centimeter-scale path difference, to the transmission minimum for the carrier wave of a frequency-modulated laser beam. A time-averaged extinction of 32 dB, limited by the bandwidth of the feedback, was maintained over several hours. The interferometer was used to remove the carrier wave from a 780 nm laser beam that had been phase modulated at 2.7 GHz.

Retinopathy of prematurity: from oxygen management to molecular manipulation.

INTRODUCTION: Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the premature retina with the potential to progress to extraretinal neovascularisation. This review serves as an introduction to retinopathy of prematurity (ROP), outlining key parts of ROP pathophysiology, diagnosis and treatment. ROP is traditionally diagnosed by indirect ophthalmoscopy and classified using anatomical zones, stages of disease, and the presence or absence of "plus disease" (dilation and tortuosity of the major retinal arterioles and venules). ROP has a bi-phasic pathophysiology: initial hyperoxia causes reduced retinal vascularisation, followed by pathological vaso-proliferation resulting from subsequent hypoxia and driven by vascular endothelial growth factor (VEGF). ADVANCEMENTS IN MANAGEMENT: This review summarises previous trials to establish optimum oxygen exposure levels in newborns and more recently the development of anti-VEGF agents locally delivered to block pathological neovascularisation, which is technically easier to administer and less destructive than laser treatment. FUTURE DIRECTIONS: There remains an ongoing concern regarding the potential unwanted systemic effects of intravitreally administered anti-VEGF on the overall development of the premature baby. Ongoing dosing studies may lessen these fears by identifying the minimally effective dose required to block extraretinal neovascularisation.

Solution-focused approaches in adult mental health research: A conceptual literature review and narrative synthesis.

Solution-focused approaches are one approach to treatment used in a wide variety of settings in modern mental healthcare services. As yet, there has been no overall synthesis of how this approach is understood in the adult mental health literature. This conceptual review aimed to synthesize the ways that solution-focused approaches have been conceptualized and understood, within the adult mental health literature, in the five decades since their conception. A systematic search followed by multiple techniques from the narrative synthesis approach were used to develop a conceptual framework of the extracted data. Fifty-six papers published between 1993 and 2019 were included in the review. These papers spanned a variety of clinical contexts and countries, but despite this the underlying key principles and concepts of solution-focused approaches were remarkably similar over time and setting. Thematic analysis of extracted data outlined five key themes relevant to the conceptualization of this approach. This conceptual framework will help support clinicians using solution-focused techniques or therapies by giving them a coherent understanding of such approaches, by what mechanisms they work, and how key principles of this approach can be utilized in adult mental health settings.

Bi-frequency operation in a membrane external-cavity surface-emitting laser.

We report on the achievement of continuous wave bi-frequency operation in a membrane external-cavity surface-emitting laser (MECSEL), which is optically pumped with up to 4 W of 808 nm pump light. The presence of spatially specific loss of the intra-cavity high reflectivity mirror allows loss to be controlled on certain transverse cavity modes. The regions of spatially specific loss are defined through the removal of Bragg layers from the surface of the cavity high reflectivity mirror in the form of crosshair patterns with undamaged central regions, which are created using a laser ablation system incorporating a digital micromirror device (DMD). By aligning the laser cavity mode with the geometric centre of the loss patterns, the laser simultaneously operated on two Hermite-Gaussian spatial modes: the fundamental HG00 and the higher order HG11 mode. We demonstrate bi-frequency operation over a range of pump powers and sizes of spatial loss features, with a wavelength separation of approximately 5 nm centred at 1005 nm.

The effect of short-term resistance training on hip and knee kinematics during vertical drop jumps.

The purpose of this study was to determine the effect of a weight-bearing free weight resistance training program alone on knee flexion, hip flexion, and knee valgus during unilateral and bilateral drop jump tasks. Twenty-nine young adult females with previous athletic experience were randomly divided into a control (n = 16) and a resistance training (n = 13) groups. The resistance training group completed 8 weeks of lower extremity, weight-bearing exercises using free weights, whereas the control group did not train. A pre- and posttest was conducted to measure knee valgus, knee flexion, and hip flexion during unilateral (30 cm) and bilateral (60 cm) vertical drop jumps for maximum height. Joint angles were determined using 3-dimensional electromagnetic tracking sensors (MotionMonitor; Innovative Sports Training, Inc., Chicago, IL, USA). Initial training intensity for the bilateral squat was 50% of the subject's 1 repetition maximum (RM), which increased 5% each week to 85% during the final week. Sets and repetitions ranged from 2 to 4 and from 4 to 12, respectively. The training loads for all other exercises (lunge, step-up, unilateral squat, and Romanian deadlift) increased from 15RM to 6RM from the initial to the final week. A repeated measures analysis of variance was used to determine differences in the hip and knee joint angles. No significant differences for knee valgus and hip flexion measures were found between the groups after training; however, knee flexion angle significantly increased in the training group from the pretest (77.2 ± 4.1°) to posttest (83.2 ± 3.7°) during the bilateral drop jump. No significant changes occurred during the unilateral drop jump. Bilateral measures for knee flexion, hip flexion, and knee valgus were significantly (p < 0.05) greater than the unilateral measures during the drop jump task, which indicate an increased risk for anterior cruciate ligament (ACL) injury during unilateral drop jumps. The data support that the strength and conditioning specialist can implement resistance training alone during a short-term training period to reduce the risk of ACL injury by increasing knee flexion during a bilateral drop jump task. Increased knee flexion angles after resistance training may indicate a reduced risk for knee injury from improved neuromuscular control, resulting in a softer landing.

Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner.

Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell-specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell-specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell-specific Hem-1-deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) - alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.

The impact of drug samples on prescribing to the uninsured.

OBJECTIVE: To determine whether drug samples are associated with physicians prescribing fewer generic, less costly medications. METHODS: We conducted a retrospective study at a large university-affiliated internal medicine practice containing over 70 physicians. Using a pharmacy database, we identified all prescriptions written to uninsured or Medicaid patients that belonged to one of four classes of chronic medications. For the 9 months before and after the clinic closed its drug sample closet, we calculated the percentage of medications prescribed as generics and the mean cost of a 30-day supply of a prescription. RESULTS: Of 8911 prescriptions, 1973 met inclusion criteria. For uninsured patients, the percentage of medications prescribed as generics rose from 12% to 30% after the clinic closed its drug sample closet (P = 0.004). By consecutive three month periods, the percentage of prescribed generic medications rose steadily to a maximum of 40% (P < 0.001). For Medicaid patients, there was no significant change in generic prescribing (63% generic with samples versus 65% generic without samples, P = 0.42). Two factors were associated with generic prescribing in logistic regression: the absence of drug samples (OR 4.54, 95% CI 1.37-15.0) and the prescriber being an attending physician (OR 5.26, 95% CI 2.24-12.4). There was no statistically significant change in cost for either group. CONCLUSIONS: Physicians were three times more likely to prescribe generic medications to uninsured patients after drug samples were removed from the office. Drug samples may paradoxically lead to higher costs if physicians with access to samples prescribe more brand-name only drugs.

Rightsizing Projects for Non-Research-Intensive Schools of Nursing via Academic-Clinical Partnerships.

Most academic-clinical partnerships are described as formal agreements between schools of nursing at research-intensive universities and large teaching hospitals. This article demonstrates less formal versions of academic-clinical partnerships established between a small, private liberal arts university school of nursing and 2 regional clinical agencies. In both exemplars, students, faculty, and staff contributed to evidence-based practice projects. Schools of nursing in non-research-intensive environments can develop right-size academic-clinical partnerships that are beneficial for all parties involved.

Alcohol Consumption and the Physical Availability of Take-Away Alcohol: Systematic Reviews and Meta-Analyses of the Days and Hours of Sale and Outlet Density.

OBJECTIVE: Systematic reviews and meta-analyses were completed studying the effect of changes in the physical availability of take-away alcohol on per capita alcohol consumption. Previous reviews examining this topic have not focused on off-premise outlets where take-away alcohol is sold and have not completed meta-analyses. METHOD: Systematic reviews were conducted separately for policies affecting the temporal availability (days and hours of sale) and spatial availability (outlet density) of take-away alcohol. Studies were included up to December 2015. Quality criteria were used to select articles that studied the effect of changes in these policies on alcohol consumption with a focus on natural experiments. Random-effects meta-analyses were applied to produce the estimated effect of an additional day of sale on total and beverage-specific consumption. RESULTS: Separate systematic reviews identified seven studies regarding days and hours of sale and four studies regarding density. The majority of articles included in these systematic reviews, for days/hours of sale (7/7) and outlet density (3/4), concluded that restricting the physical availability of take-away alcohol reduces per capita alcohol consumption. Meta-analyses studying the effect of adding one additional day of sale found that this was associated with per capita consumption increases of 3.4% (95% CI [2.7, 4.1]) for total alcohol, 5.3% (95% CI [3.2, 7.4]) for beer, 2.6% (95% CI [1.8, 3.5]) for wine, and 2.6% (95% CI [2.1, 3.2]) for spirits. The small number of included studies regarding hours of sale and density precluded meta-analysis. CONCLUSIONS: The results of this study suggest that decreasing the physical availability of take-away alcohol will decrease per capita consumption. As decreasing per capita consumption has been shown to reduce alcohol-related harm, restricting the physical availability of take-away alcohol would be expected to result in improvements to public health.

Genetic determinants of the metabolic syndrome.

Complex interactions between inherited factors and the environment determine an individual's susceptibility to type 2 diabetes mellitus and related syndromes. Insulin resistance, obesity, hypertension, and hyperlipidemia frequently precede the development of frank diabetes and aggregate in families. Several genome-wide scans have recently been performed in families with this constellation of findings, called the "metabolic syndrome." These analyses strongly support an inherited component to the syndrome. In this review, we provide an overview of the evidence in support of an inherited contribution to the metabolic syndrome and the search for causative genomic regions. When multiple genome scans involving different patient cohorts implicate a common genomic region as susceptible to the metabolic syndrome, it is highly likely that causative genes reside in that area. Identification of these genes will dramatically improve our understanding of the mechanisms that underlie the metabolic syndrome, and could lead to novel treatment strategies. It is hoped that these therapies will also prevent the future development of type 2 diabetes mellitus and atherosclerotic complications, both common among individuals affected by the metabolic syndrome.