Cellular Origin of Spontaneous Ganglion Cell Spike Activity in Animal Models of Retinitis Pigmentosa

Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36–210 d old) rd1 mouse show that the ongoing oscillatory spike activity in both cell types is driven by strong rhythmic synaptic input from presynaptic neurons that is blocked by CNQX. The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input

Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat by Pyrrole-Imidazole Polyamides

The host factor LSF represses the human immunodeficiency virus type 1 long terminal repeat (LTR) by mediating recruitment of histone deacetylase. We show that pyrrole-imidazole polyamides targeted to the LTR can specifically block LSF binding both in vitro and within cells via direct access to chromatin, resulting in increased LTR expression

Embedding in a Finite 2-Generator Semigroup

We augment the body of existing results on embedding finite semigroups of a certain type into 2-generator finite semigroups of the same type. The approach adopted applies to finite semigroups the idempotents of which form a band and also to finite orthodox semigroups

Typology of Teacher Leadership Programs

Education leaders are perennially seeking new ways to build the capacity of teachers to enhance learning experiences for all students. Teacher leadership, which we define as teachers’ support of the improvement of teaching and learning beyond their own classroom, has long been a source of interest and experimentation (Wenner & Campbell, 2017; York-Barr & Duke, 2004). Teacher leadership recognizes teachers’ instructional expertise as an asset for educational improvement, capitalizes upon teachers’ relationships with their colleagues to support change, and may provide career advancement opportunities to improve job satisfaction and the professionalization of teaching. For these and other reasons, states, districts, funders and teachers themselves have become increasingly interested in the promise of teacher leadership. In this study, we map the landscape of teacher leadership programs across the U.S. and identify commonalities and distinctions amongst the range of programs. Using a variety of search approaches to capture publicly-available information, we document 285 state, local, university, and foundation-sponsored programs that use a variety of techniques to support teachers as leaders. We then categorize the forms of support, attending to program models, objectives, sponsorship, and audience. We identify three major forms of support provided by teacher leadership programs: (1) preparation of teachers with knowledge and skills that can help them to lead; (2) positioning of teachers in leadership roles to capitalize upon their expertise; and (3) recognition of teachers as leaders through awards and other forms of appreciation or acknowledgement. While some programs focus only on one of these approaches, most employed a combination of these forms of support. Based on this, we define seven types of teacher leadership programs and provide an interactive depiction of this typology, with examples, to illustrate the variation within each of the seven types. While there are undoubtedly programs that escaped our view, as well as homegrown and informal initiatives that we could not document, this systematic search is the broadest scan of the teacher leadership program landscape conducted in the Unites States to date

Theoretical Calculations of Supersonic Wave Drag at Zero Lift for a Particular Store Arrangement

An analysis, based on the linearized thin-airfoil theory for supersonic speeds, of the wave drag at zero lift has been carried out for a simple two-body arrangement consisting of two wedgelike surfaces, each with a rhombic lateral cross section and emanating from a common apex. Such an arrangement could be used as two stores, either embedded within or mounted below a wing, or as auxiliary bodies wherein the upper halves could be used as stores and the lower halves for bomb or missile purposes. The complete range of supersonic Mach numbers has been considered and it was found that by orienting the axes of the bodies relative to each other a given volume may be redistributed in a manner which enables the wave drag to be reduced within the lower supersonic speed range (where the leading edge is substantially subsonic). At the higher Mach numbers, the wave drag is always increased. If, in addition to a constant volume, a given maximum thickness-chord ratio is imposed, then canting the two surfaces results in higher wave drag at all Mach numbers. For purposes of comparison, analogous drag calculations for the case of two parallel winglike bodies with the same cross-sectional shapes as the canted configuration have been included. Consideration is also given to the favorable (dragwise) interference pressures acting on the blunt bases of both arrangements

A prospective adaptive utility trial to validate performance of a novel urine exosome gene expression assay to predict high-grade prostate cancer in patients with prostate-specific antigen 2-10ng/ml at initial biopsy

BACKGROUND: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. OBJECTIVE: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. DESIGN, SETTING, AND PARTICIPANTS: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2-10ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. RESULTS AND LIMITATIONS: In a total of 503 patients, with median age of 64 yr, median PSA 5.4ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n=519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. CONCLUSIONS: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. PATIENT SUMMARY: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2-10ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator\u27s and standard clinical data

Cost-Effective Use of Silver Dressings for the Treatment of Hard-to-Heal Chronic Venous Leg Ulcers

Aim To estimate the cost-effectiveness of silver dressings using a health economic model based on time-to-wound-healing in hard-to-heal chronic venous leg ulcers (VLUs). Background Chronic venous ulceration affects 1–3% of the adult population and typically has a protracted course of healing, resulting in considerable costs to the healthcare system. The pathogenesis of VLUs includes excessive and prolonged inflammation which is often related to critical colonisation and early infection. The use of silver dressings to control this bioburden and improve wound healing rates remains controversial. Methods A decision tree was constructed to evaluate the cost-effectiveness of treatment with silver compared with non-silver dressings for four weeks in a primary care setting. The outcomes: ‘Healed ulcer’, ‘Healing ulcer’ or ‘No improvement’ were developed, reflecting the relative reduction in ulcer area from baseline to four weeks of treatment. A data set from a recent meta-analysis, based on four RCTs, was applied to the model. Results Treatment with silver dressings for an initial four weeks was found to give a total cost saving (£141.57) compared with treatment with non-silver dressings. In addition, patients treated with silver dressings had a faster wound closure compared with those who had been treated with non-silver dressings. Conclusion The use of silver dressings improves healing time and can lead to overall cost savings. These results can be used to guide healthcare decision makers in evaluating the economic aspects of treatment with silver dressings in hard-to-heal chronic VLUs

A Cure for HIV Infection: "Not in My Lifetime" or "Just Around the Corner"?

With the advent and stunning success of combination antiretroviral therapy (ART) to prolong and improve quality of life for persons with HIV infection, HIV research has been afforded the opportunity to pivot towards studies aimed at finding "a cure." The mere idea that cure of HIV might be possible has energized researchers and the community towards achieving this goal. Funding agencies, both governmental and private, have targeted HIV cure as a high priority; many in the field have responded to these initiatives and the cure research agenda is robust. In this "salon" two editors of Pathogens and Immunity, Michael Lederman and Daniel Douek ask whether curing HIV is a realistic, scalable objective. We start with an overview perspective and have asked a number of prominent HIV researchers to add to the discussion