DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

Skin Sensitivity Assessment Using Smartphone Haptic Feedback.

Goal: This work presents a smartphone application to assess cutaneous sensory perception by establishing Vibrational Perception Thresholds (VPTs). Cutaneous sensory perception diagnostics allow for the early detection and symptom tracking of tactile dysfunction. However, lack of access to healthcare and the limited frequency of current screening tools can leave skin sensation impairments undiscovered or unmonitored. Methods: A 23-participant cross-sectional study in subjects with a range of finger sensation tests Smartphone Established VPTs (SE-VPTs) by varying device vibrational intensity. These are compared against monofilament test scores, a clinical measure of skin sensitivity. Results: We find a strong positive correlation between SE-VPTs and monofilament scores ([Formula: see text] = 0.86, p = 1.65e-07). Conclusions: These results demonstrate the feasibility of using a smartphone as a skin sensation screening tool.

A Wearable Testbed for Studying Variable Transmission in Body-Powered Prosthetic Gripping.

For those with upper limb absence, body-powered prostheses continue to be popular for many activities despite being an old technology; these devices can provide both inherent haptic feedback and mechanical robustness. Yet, they can also result in strain and fatigue. Body-powered prosthetic graspers typically consist of a simple lever providing a relatively constant transmission ratio between the input forces from the user's shoulder harness and the grip force of their prosthetic prehensor. In the field of robotic hand design, new continuously varying transmissions demonstrate particular promise in generating a wide range of grasping speeds without sacrificing grip strength. These benefits, if applied to shoulder-driven prosthetic grippers, have the potential to both reduce shoulder exertion and fatigue. This work presents the integration of a continuously variable transmission into a body-powered, voluntary close prosthetic testbed. We introduce the design and validate its performance in a benchtop experiment. We compare constant transmission conditions with a force-dependent, continually varying condition. The device is mounted on a prosthetic emulator for a preliminary wearable demonstration.

Characterizing the Force-Motion Tradeoff in Body-Powered Transmission Design.

Upper-limb prosthesis users continue to reject devices despite continued research efforts. Today, the passive topology of body-powered prehensors, which physically transmits grasp force and position data between user and device, results in improved performance over myoelectric alternatives. However, the loads and postures on the user's body also result in discomfort, fatigue, and worsened grasp force control. Despite the long history and everyday adoption of body-powered prehensors in society, the measurement of how specific body loads and postures affect grasp performance and user experience has yet to be systematically studied. In this work, we present a body-powered prosthesis emulator to independently change required input forces and motions to study the positive and negative effects provided by the inherent haptic feedback. Using a simulated grasping task, we collect functional and qualitative data from 15 participants using a shoulder harness interface. Outcomes show that lowering required input motions and forces independently reduces negative outcomes, with diminishing returns below 1:1 output mappings. Given the tradeoff between force and motion in traditional body-powered transmissions, a transmission ratio of 1:1 balances both requirements. The purpose of this study is to inform future prehensor designs that leverage the transparency of body-power to deliver high functionality while mitigating user discomfort.

Far from Asymptopia: Unbiased High-Dimensional Inference Cannot Assume Unlimited Data.

Inference from limited data requires a notion of measure on parameter space, which is most explicit in the Bayesian framework as a prior distribution. Jeffreys prior is the best-known uninformative choice, the invariant volume element from information geometry, but we demonstrate here that this leads to enormous bias in typical high-dimensional models. This is because models found in science typically have an effective dimensionality of accessible behaviors much smaller than the number of microscopic parameters. Any measure which treats all of these parameters equally is far from uniform when projected onto the sub-space of relevant parameters, due to variations in the local co-volume of irrelevant directions. We present results on a principled choice of measure which avoids this issue and leads to unbiased posteriors by focusing on relevant parameters. This optimal prior depends on the quantity of data to be gathered, and approaches Jeffreys prior in the asymptotic limit. However, for typical models, this limit cannot be justified without an impossibly large increase in the quantity of data, exponential in the number of microscopic parameters.

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing.

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

Information geometry for multiparameter models: new perspectives on the origin of simplicity.

Complex models in physics, biology, economics, and engineering are oftensloppy, meaning that the model parameters are not well determined by the model predictions for collective behavior. Many parameter combinations can vary over decades without significant changes in the predictions. This review uses information geometry to explore sloppiness and its deep relation to emergent theories. We introduce themodel manifoldof predictions, whose coordinates are the model parameters. Itshyperribbonstructure explains why only a few parameter combinations matter for the behavior. We review recent rigorous results that connect the hierarchy of hyperribbon widths to approximation theory, and to the smoothness of model predictions under changes of the control variables. We discuss recent geodesic methods to find simpler models on nearby boundaries of the model manifold-emergent theories with fewer parameters that explain the behavior equally well. We discuss a Bayesian prior which optimizes the mutual information between model parameters and experimental data, naturally favoring points on the emergent boundary theories and thus simpler models. We introduce a 'projected maximum likelihood' prior that efficiently approximates this optimal prior, and contrast both to the poor behavior of the traditional Jeffreys prior. We discuss the way the renormalization group coarse-graining in statistical mechanics introduces a flow of the model manifold, and connect stiff and sloppy directions along the model manifold with relevant and irrelevant eigendirections of the renormalization group. Finally, we discuss recently developed 'intensive' embedding methods, allowing one to visualize the predictions of arbitrary probabilistic models as low-dimensional projections of an isometric embedding, and illustrate our method by generating the model manifold of the Ising model.

Complex dynamics in sustaining clean cooking and food access through a pandemic: A COVID-19 impact study in peri-urban Cameroon.

Access to clean energy for cooking is central to achieving Sustainable Development Goal 7. Latest predictions suggest that this goal will not be met by 2030, with further setbacks due to the COVID-19 pandemic. We investigated the impacts of COVID-19 restrictions on household cooking fuel, practices and dietary behaviours in a peri-urban community in Central Cameroon. Using surveys (n = 333) and qualitative semi-structured interviews (n = 12), we found negative financial impacts and high levels of food insecurity, with 83 % and 56 % of households reporting reduced income and insufficient food, respectively. Households reduced food intake and cooking frequency and relied more heavily on local sources (e.g., farmland) to feed their families. Changes in primary cooking fuel were less pronounced and fuel choice was inherently linked to cooking behaviours, with some households utilising LPG more often for simple tasks, such as reheating food. Local systems were key in sustaining food and fuel access and households demonstrated resilience by employing numerous mechanisms to overcome challenges. Our findings underline the vulnerability of households in maintaining sufficient food intake and sustaining clean cooking, highlighting how policy needs to take a nuanced approach considering food-energy dynamics and strengthening local systems to ensure access to clean energy is resistant to system shocks.

Effect of variable transmission on body-powered prosthetic grasping.

Body-powered upper-limb prostheses remain a popular option for those with limb absence due to their passive nature. These devices typically feature a constant transmission ratio between the forces input by the user and the grasp forces output by the prosthetic gripper. Work incorporating continuously variable transmissions into robotic hands has demonstrated a number of benefits in terms of their motion and forces. In this work, we use a custom prosthesis emulator to evaluate the viability of applying variable transmissions to a body-powered prosthetic context. With this haptics test bed, we measured user performance during a grasping and lift task under a variety of transmission ratio conditions and with three different test objects. Results indicate that use of a variable transmission leads to the successful manipulation of a wider variety of objects than the constant transmission ratio systems, while requiring less shoulder motion. Analysis also shows a potential tendency for users to apply higher grasp forces than necessary, when compared to constant transmission conditions. These findings suggest a multifaceted effect on grasp performance with both benefits and drawbacks when considering a variable approach that supports the continued study of variable transmissions in assisted grasping.

Continuing the sequence? Towards an economic evaluation of whole genome sequencing for the diagnosis of rare diseases in Scotland.

Novel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost-benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts.

Motor-Augmented Wrist-Driven Orthosis: Flexible Grasp Assistance for People with Spinal Cord Injury.

This paper presents the design of a motor-augmented wrist-driven orthosis (MWDO) for improved grasp articulation for people with C6-C7 spinal cord injuries. Based on the traditional passive, wrist-driven orthotic (WDO) mechanism, the MWDO allows for both body-powered and motorized actuation of the grasping output thus enabling more flexible and dexterous operation. Here, the associated control scheme enables active decoupling of wrist and finger articulation, which can be useful during certain phases of manipulation tasks. An additional modification to the traditional WDO is the integration of a magnetic latch at the Distal Interphalangeal (DIP) joint allowing for improved pinching. These abilities are demonstrated with common activities of daily living (ADL).

Comparison of U.S. NRC'S Rascal Emergency Response Code with Noaa's Hyrad Dispersion Model and Tracer Experimental Data.

The U.S. National Oceanic and Atmospheric Administration's Field Research Division uses the HYRad-HYSPLIT dispersion model to assess hypothetical accidental releases of airborne radioactive materials at the Idaho National Laboratory in southeastern Idaho. The State of Idaho Department of Environmental Quality Idaho National Laboratory Oversight Program provides independent assessment of these releases using a different model, RASCAL, which is the U.S. Nuclear Regulatory Commission's primary reactor-emergency response code. To confirm RASCAL is a reasonable independent assessment tool, the Oversight Program compared the two models' output for typical meteorological cases encountered at the Idaho National Laboratory. RASCAL results were also compared to National Oceanic and Atmospheric Administration experimental SF6 tracer data from 2013 at the Idaho National Laboratory. Both RASCAL and HYRad predicted very similar plume shapes and paths for the different meteorological cases. For typical daytime conditions, HYRad predicted slightly higher integrated air concentrations by up to a factor of two at downwind distances of less than about 40 km, then decreased below the RASCAL concentrations. The opposite was true for a nighttime release, with RASCAL giving significantly higher concentrations (by one to two orders of magnitude) at a distance of 20 km. For all the runs, RASCAL predicted significantly less total deposition, except at the outer edges of the plume during a nighttime release. Most of the discrepancies are believed to be due to differences in the models' simulation algorithms and the hard-wired input parameter values used by each model (e.g., deposition velocities). For tracer data comparisons, RASCAL's straight-line Gaussian plume model calculated maximum 2 h predicted-to-observed concentration ratios of 0.8 to 1.8 for unstable conditions and 0.4 to 0.9 for neutral conditions.

Maximizing the information learned from finite data selects a simple model.

We use the language of uninformative Bayesian prior choice to study the selection of appropriately simple effective models. We advocate for the prior which maximizes the mutual information between parameters and predictions, learning as much as possible from limited data. When many parameters are poorly constrained by the available data, we find that this prior puts weight only on boundaries of the parameter space. Thus, it selects a lower-dimensional effective theory in a principled way, ignoring irrelevant parameter directions. In the limit where there are sufficient data to tightly constrain any number of parameters, this reduces to the Jeffreys prior. However, we argue that this limit is pathological when applied to the hyperribbon parameter manifolds generic in science, because it leads to dramatic dependence on effects invisible to experiment.

Celiac Disease and Gluten-Free Oats: A Canadian Position Based on a Literature Review.

This paper provides an overview of the latest scientific data related to the safety of uncontaminated oats (<20 ppm of gluten) in the diet of individuals with celiac disease (CD). It updates the previous Health Canada position posted on the Health Canada website in 2007 and a related paper published in 2009. It considers a number of recent studies published between January 2008 and January 2015. While recognizing that a few people with celiac disease seem to be clinically intolerant to oats, this review concludes that oats uncontaminated by gluten-containing cereals (wheat, rye, and barley) can be safely ingested by most patients with celiac disease and that there is no conclusive evidence that the consumption of uncontaminated or specially produced oats containing no greater than 20 ppm gluten by patients with celiac disease should be limited to a specific daily amount. However, individuals with CD should observe a stabilization phase before introducing uncontaminated oats to the gluten-free diet (GFD). Oats uncontaminated with gluten should only be introduced after all symptoms of celiac disease have resolved and the individual has been on a GFD for a minimum of 6 months. Long-term regular medical follow-up of these patients is recommended but this is no different recommendation to celiac individuals on a GFD without oats.

Two analogues of fenarimol show curative activity in an experimental model of Chagas disease.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

Validation procedures for quantitative gluten ELISA methods: AOAC allergen community guidance and best practices.

The food allergen analytical community is endeavoring to create harmonized guidelines for the validation of food allergen ELISA methodologies to help protect food-sensitive individuals and promote consumer confidence. This document provides additional guidance to existing method validation publications for quantitative food allergen ELISA methods. The gluten-specific criterion provided in this document is divided into sections for information required by the method developer about the assay and information for the implementation of the multilaboratory validation study. Many of these recommendations and guidance are built upon the widely accepted Codex Alimentarius definitions and recommendations for gluten-free foods. The information in this document can be used as the basis of a harmonized validation protocol for any ELISA method for gluten, whether proprietary or nonproprietary, that will be submitted to AOAC andlor regulatory authorities or other bodies for status recognition. Future work is planned for the implementation of this guidance document for the validation of gluten methods and the creation of gluten reference materials.

Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.

BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.

Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease.

We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.