Broadly Neutralizing Antibodies as Treatment: Effects on Virus and Immune System

Purpose of Review The purpose of this study is to summarize recent advances in the use of broadly neutralizing antibodies (bNAbs) as therapeutics in human clinical trials and in non-human primate (NHP) models. We seek to highlight lessons from these studies with an emphasis on consequences to the virus and immune system. Recent Findings In the past 10 years, advances in HIV-1 trimer structure and B cell isolation methods have precipitated the identification of “new-generation” anti-HIV antibodies with broad and potent neutralization. In the past 2 years, the concept of using these bNAbs as therapeutic tools has moved from NHP models into human clinical trials. These trials have investigated the effects of bNAb infusions into patients chronically infected with HIV-1, while the NHP model has investigated treatment during acute infection. Summary Through this work, the relationship between in vitro breadth and potency and in vivo clinical effect, although unresolved, is gradually being elucidated. These results emphasize the need for combination antibody therapy

Jizz and the joy of pattern recognition:virtuosity, discipline and the agency of insight in UK naturalists’ arts of seeing

Approaches to visual skilling from anthropology and STS have tended to highlight the forces of discipline and control in understanding how shared visual accounts of the world are created in the face of potential differences brought about by multi-sensorial perception. Drawing upon a range of observational and interview material from an immersion in naturalist training and biological recording activities between 2003 and 2009, I focus upon jizz, a distinct form of gestalt perception much coveted by naturalist communities in the UK. Jizz is described as a tacit and embodied way of seeing that instantaneously reveals the identity of a species, relying upon but simultaneously suspending the arduous and meticulous study of an organism’s diagnostic characteristics. I explore the potential and limitations of jizz to allow for both visual precision and an enchanted and varied form of encounter with nature. In so doing, I explore how the specific characteristics of wild, intangible and irreverent virtuoso performance work closely together with disciplining taxonomic standards. As such, discipline and irreverence work together, are mutually enabling, and allow for an accommodation rather than a segregation of potential difference brought about by perceptual variety

A Phase I Trial of Aminolevulinic Acid-Photodynamic Therapy for Treatment of Oral Leukoplakia

Background Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia. Methods Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585 nm). Clinical, histologic, and biologic markers were assessed. Results Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4 J/cm2. One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3 months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study. Conclusions ALA PDT could be safely administered with a light dose up to 4 J/cm2 and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT

The Lavic Lake Fault: A Long-Term Cumulative Slip Analysis via Combined Field Work and Thermal Infrared Hyperspectral Airborne Remote Sensing

The 1999 Hector Mine earthquake ruptured to the surface in eastern California, with >5 m peak right-lateral slip on the Lavic Lake fault. The cumulative offset and geologic slip rate of this fault are not well defined, which inhibits tectonic reconstructions and risk assessment of the Eastern California Shear Zone (ECSZ). With thermal infrared hyperspectral airborne imagery, field data, and auxiliary information from legacy geologic maps, we created lithologic maps of the area using supervised and unsupervised classifications of the remote sensing imagery. We optimized a data processing sequence for supervised classifications, resulting in lithologic maps over a test area with an overall accuracy of 71 ± 1% with respect to ground-truth geologic mapping. Using all of the data and maps, we identified offset bedrock features that yield piercing points along the main Lavic Lake fault and indicate a 1036 +27/−26 m net slip, with 1008 +14/−17 m horizontal and 241 +51/−47 m vertical components. For the contribution from distributed shear, modern off-fault deformation values from another study imply a larger horizontal slip component of 1276 +18/−22 m. Within the constraints, we estimate a geologic slip rate of <4 mm/yr, which does not increase the sum geologic Mojave ECSZ rate to current geodetic values. Our result supports previous suggestions that transient tectonic activity in this area may be responsible for the discrepancy between long-term geologic and present-day geodetic rates

Implementation in rehabilitation: a roadmap for practitioners and researchers

PURPOSE: Despite growth in rehabilitation research, implementing research findings into rehabilitation practice has been slow. This creates inequities for patients and is an ethical issue. However, methods to investigate and facilitate evidence implementation are being developed. This paper aims to make these methods relevant and accessible for rehabilitation researchers and practitioners.\ud METHODS: Rehabilitation practice is varied and complex and occurs within multilevel healthcare systems. Using a "road map" analogy, we describe how implementation concepts and theories can inform implementation strategies in rehabilitation. The roadmap involves a staged journey that considers: the nature of evidence; context for implementation; navigation tools for implementation; strategies to facilitate implementation; evaluation of implementation outcomes; and sustainability of implementation. We have developed a model to illustrate the journey, and four case studies exemplify implementation stages in rehabilitation settings. RESULTS AND CONCLUSIONS: Effective implementation strategies for the complex world of rehabilitation are urgently required. The journey we describe unpacks that complexity to provide a template for effective implementation, to facilitate translation of the growing evidence base in rehabilitation into improved patient outcomes. It emphasizes the importance of understanding context and application of relevant theory, and highlights areas which should be targeted in new implementation research in rehabilitation. Implications for rehabilitation Effective implementation of research evidence into rehabilitation practice has many interconnected steps and a roadmap analogy is helpful in defining them. Understanding context for implementation is critically important and using theory can facilitate development of understanding. Research methods for implementation in rehabilitation should be carefully selected and outcomes should evaluate implementation success as well as clinical change. Sustainability requires regular revisiting of the interconnected steps

GenoChemetic strategy for derivatization of the violacein natural product scaffold

H.E.L. was supported by an Imperial College President’s Ph.D. Scholarship. We thank UKRI EPSRC (EP/K038648/1, EP/L011573/1 to P.S.F.) and the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no. 614779 GenoChemetics to R.J.M.G.) for funding. A.M.C.O. receives funding from EPSRC CRITICAT, EP/L016419/1.Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki–Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.Publisher PDFPeer reviewe

Predicting suicide attempts and suicide deaths among adolescents following outpatient visits

BACKGROUND: Few studies report on machine learning models for suicide risk prediction in adolescents and their utility in identifying those in need of further evaluation. This study examined whether a model trained and validated using data from all age groups works as well for adolescents or whether it could be improved. METHODS: We used healthcare data for 1.4 million specialty mental health and primary care outpatient visits among 256,823 adolescents across 7 health systems. The prediction target was 90-day risk of suicide attempt following a visit. We used logistic regression with least absolute shrinkage and selection operator (LASSO) and generalized estimating equations (GEE) to predict risk. We compared performance of three models: an existing model, a recalibrated version of that model, and a newly-learned model. Models were compared using area under the receiver operating curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: The AUC produced by the existing model for specialty mental health visits estimated in adolescents alone (0.796; [0.789, 0.802]) was not significantly different than the AUC of the recalibrated existing model (0.794; [0.787, 0.80]) or the newly-learned model (0.795; [0.789, 0.801]). Predicted risk following primary care visits was also similar: existing (0.855; [0.844, 0.866]), recalibrated (0.85 [0.839, 0.862]), newly-learned (0.842, [0.829, 0.854]). LIMITATIONS: The models did not incorporate non-healthcare risk factors. The models relied on ICD9-CM codes for diagnoses and outcome measurement. CONCLUSIONS: Prediction models already in operational use by health systems can be reliably employed for identifying adolescents in need of further evaluation

Effect of the Tyrosine Kinase Inhibitors (Sunitinib, Sorafenib, Dasatinib, and Imatinib) on Blood Glucose Levels in Diabetic and Non-diabetic Patients in General Clinical Practice (Poster)

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRβ are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRβ or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option

Optically trapped bacteria pairs reveal discrete motile response to control aggregation upon cell–cell approach

Aggregation of bacteria plays a key role in the formation of many biofilms. The critical first step is cell–cell approach, and yet the ability of bacteria to control the likelihood of aggregation during this primary phase is unknown. Here, we use optical tweezers to measure the force between isolated Bacillus subtilis cells during approach. As we move the bacteria towards each other, cell motility (bacterial swimming) initiates the generation of repulsive forces at bacterial separations of ~3 μm. Moreover, the motile response displays spatial sensitivity with greater cell–cell repulsion evident as inter-bacterial distances decrease. To examine the environmental influence on the inter-bacterial forces, we perform the experiment with bacteria suspended in Tryptic Soy Broth, NaCl solution and deionised water. Our experiments demonstrate that repulsive forces are strongest in systems that inhibit biofilm formation (Tryptic Soy Broth), while attractive forces are weak and rare, even in systems where biofilms develop (NaCl solution). These results reveal that bacteria are able to control the likelihood of aggregation during the approach phase through a discretely modulated motile response. Clearly, the force-generating motility we observe during approach promotes biofilm prevention, rather than biofilm formation

Weighing the Association Between BMI Change and Suicide Mortality

OBJECTIVE: Suicide rates continue to rise, necessitating the identification of risk factors. Obesity and suicide mortality rates have been examined, but associations among weight change, death by suicide, and depression among adults in the United States remain unclear. METHODS: Data from 387 people who died by suicide in 2000-2015 with a recorded body mass index (BMI) in the first and second 6 months preceding their death ( index date ) were extracted from the Mental Health Research Network. Each person was matched with five people in a control group (comprising individuals who did not die by suicide) by age, sex, index year, and health care site (N=1,935). RESULTS: People who died by suicide were predominantly male (71%), White (69%), and middle aged (mean age=57 years) and had a depression diagnosis (55%) and chronic health issues (57%) (corresponding results for the control group: 71% male, 66% White, 14% with depression diagnosis, and 43% with chronic health issues; mean age=56 years). Change in BMI within the year before the index date statistically significantly differed between those who died by suicide (mean change=-0.72±2.42 kg/m(2)) and the control group (mean change=0.06±4.99 kg/m(2)) (p\u3c0.001, Cohen\u27s d=0.17). A one-unit BMI decrease was associated with increased risk for suicide after adjustment for demographic characteristics, mental disorders, and Charlson comorbidity score (adjusted odds ratio=1.11, 95% confidence interval=1.05-1.18, p\u3c0.001). For those without depression, a BMI change was significantly associated with suicide (p\u3c0.001). CONCLUSIONS: An increased suicide mortality rate was associated with weight loss in the year before a suicide after analyses accounted for general and mental health indicators