Effect of a daily dose of <i>Lactobacillus brevis</i> CD2 lozenges in high caries risk schoolchildren

Objectives A double-blind, randomised, placebo-controlled clinical trial was performed to validate the hypothesis that the use of lozenges containing Lactobacillus brevis CD2 (Inersan®, CD Investments srl) may reduce plaque pH, salivary mutans streptococci (ms) and bleeding on probing, during a 6-week period, in a sample of high caries risk schoolchildren. Methods A total of 191 children (aged 6–8 years), presenting two to three carious lesions and a salivary ms concentration of ≥105 CFU/ml, were enrolled and divided into two groups, an L. brevis CD2 lozenge group and a no L. brevis lozenge group, and examined at baseline (t0), after 3 weeks (t1), after 6 weeks of lozenge use (t2) and 2 weeks after the cessation of lozenge use (t3). Plaque pH was assessed using the microtouch technique following a sucrose challenge. The area under the curve (AUC5.7 and AUC6.2) was recorded. Salivary ms were counted, and bleeding on probing was assessed. Results At t0, the plaque-pH and ms concentration values were similar in both groups. Mean areas (AUC5.7 and AUC6.2) were significantly greater in the control group at t1, t2 and t3. L. brevis CD2 lozenges significantly reduced salivary ms concentrations and bleeding. The subjects from the test group showed a statistically significant decrease (p=0.01)in salivary ms concentration. At t2, a statistically significantly lower bleeding value was recorded in the test group compared with the control group (p=0.02). Conclusions Six weeks’ use of lozenges containing L. brevis CD2 had a beneficial effect on some important variables related to oral health, including a reduction in plaque acidogenicity, salivary ms and bleeding on probing.</br

Musculoskeletal Injuries and Outcomes Pre- and Post- Emergency Medicine Training Program

Introduction: Musculoskeletal injuries (MSI) comprise a large portion of the trauma burden in low- and middle-income countries (LMIC). Rwanda recently launched its first emergency medicine training program (EMTP) at the University Teaching Hospital-Kigali (UTH-K), which may help to treat such injuries; yet no current epidemiological data is available on MSI in Rwanda.Methods: We conducted this pre-post study during two data collection periods at the UTH-K from November 2012 to July 2016. Data collection for MSI is limited and thus is specific to fractures. We included all patients with open, closed, or mixed fractures, hereafter referred to as MSI. Gathered information included demographics and outcomes including death, traumatic complications, and length of hospital stay, before and after the implementation of the EMTP.Results: We collected data from 3609 patients. Of those records, 691 patients were treated for fractures, and 674 of them had sufficient EMTP data measured for inclusion in the analysis of results (279 from pre-EMTP and 375 from post-EMTP). Patient demographics demonstrate that a majority of MSI cases are male (71.6% male vs 28.4% female) and young (64.3% below 35 years of age). Among mechanisms of injury, major causes included road traffic accidents (48.1%), falls (34.2%), and assault (6.0%). There was also an observed association between EMTP and trends of the three primary outcomes: a reduction of death in the emergency department (ED) from those with MSI by 89.9%, from 2.51% to 0.25% (p = 0.0077); a reduction in traumatic complications for MSI patients by 71.7%, from 3.58% to 1.01% (p = 0.0211); and a reduction in duration of stay in the ED among those with MSI by 52.7% or 2.81 days on average, from 5.33 to 2.52 days (p = 0.0437).Conclusion: This study reveals the current epidemiology of MSI morbidity and mortality for a major Rwandan teaching hospital and the potential impacts of EM training implementation among those with MSI. Residency training programs such as EMTP appear capable of reducing mortality, complications, and ED length of stay among those with MSI caused by fractures. Such findings underscore the efficacy and importance of investments in educating the next generation of health professionals to combat prevalent MSI within their communities

MLPerf Inference Benchmark

Machine-learning (ML) hardware and software system demand is burgeoning. Driven by ML applications, the number of different ML inference systems has exploded. Over 100 organizations are building ML inference chips, and the systems that incorporate existing models span at least three orders of magnitude in power consumption and five orders of magnitude in performance; they range from embedded devices to data-center solutions. Fueling the hardware are a dozen or more software frameworks and libraries. The myriad combinations of ML hardware and ML software make assessing ML-system performance in an architecture-neutral, representative, and reproducible manner challenging. There is a clear need for industry-wide standard ML benchmarking and evaluation criteria. MLPerf Inference answers that call. In this paper, we present our benchmarking method for evaluating ML inference systems. Driven by more than 30 organizations as well as more than 200 ML engineers and practitioners, MLPerf prescribes a set of rules and best practices to ensure comparability across systems with wildly differing architectures. The first call for submissions garnered more than 600 reproducible inference-performance measurements from 14 organizations, representing over 30 systems that showcase a wide range of capabilities. The submissions attest to the benchmark's flexibility and adaptability.Comment: ISCA 202

Drosophila Neurotrophins Reveal a Common Mechanism for Nervous System Formation

Neurotrophic interactions occur in Drosophila, but to date, no neurotrophic factor had been found. Neurotrophins are the main vertebrate secreted signalling molecules that link nervous system structure and function: they regulate neuronal survival, targeting, synaptic plasticity, memory and cognition. We have identified a neurotrophic factor in flies, Drosophila Neurotrophin (DNT1), structurally related to all known neurotrophins and highly conserved in insects.By investigating with genetics the consequences of removing DNT1 or adding it in excess, we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. We show that Spa¨ tzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. Our findings imply that most likely a neurotrophin was present in the common ancestor of all bilateral organisms, giving rise to invertebrate and vertebrate neurotrophins through gene or whole-genome duplications. This work provides a missing link between aspects of neuronal function in flies and vertebrates, and it opens the opportunity to use Drosophila to investigate further aspects of neurotrophin function and to model related diseases

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins

BACKGROUND: Assays detecting human antigen-specific antibodies are medically useful. However, the usefulness of existing simple immunoassay formats is limited by technical considerations such as sera antibodies to contaminants in insufficiently pure antigen, a problem likely exacerbated when antigen panels are screened to obtain clinically useful data. RESULTS: We developed a novel and simple immunoprecipitation technology for identifying clinical sera containing antigen-specific antibodies and for generating quantitative antibody response profiles. This method is based on fusing protein antigens to an enzyme reporter, Renilla luciferase (Ruc), and expressing these fusions in mammalian cells, where mammalian-specific post-translational modifications can be added. After mixing crude extracts, sera and protein A/G beads together and incubating, during which the Ruc-antigen fusion become immobilized on the A/G beads, antigen-specific antibody is quantitated by washing the beads and adding coelenterazine substrate and measuring light production. We have characterized this technology with sera from patients having three different types of cancers. We show that 20–85% of these sera contain significant titers of antibodies against at least one of five frequently mutated and/or overexpressed tumor-associated proteins. Five of six colon cancer sera tested gave responses that were statistically significantly greater than the average plus three standard deviations of 10 control sera. The results of competition experiments, preincubating positive sera with unmodified E. coli-produced antigens, varied dramatically. CONCLUSION: This technology has several advantages over current quantitative immunoassays including its relative simplicity, its avoidance of problems associated with E. coli-produced antigens and its use of antigens that can carry mammalian or disease-specific post-translational modifications. This assay should be generally useful for analyzing sera for antibodies recognizing any protein or its post-translational modifications

Implicit Solvation Using the Superposition Approximation (IS-SPA): Extension to Polar Solutes in Chloroform

Efficient, accurate, and adaptable implicit solvent models remain a significant challenge in the field of molecular simulation. A recent implicit solvent model, IS-SPA, based on approximating the mean solvent force using the superposition approximation, provides a platform to achieve these goals. IS-SPA was originally developed to handle non-polar solutes in the TIP3P water model but can be extended to accurately treat polar solutes in other polar solvents. In this manuscript, we demonstrate how to adapt IS-SPA to include the treatment of solvent orientation and long ranged electrostatics in a solvent of chloroform. The orientation of chloroform is approximated as that of an ideal dipole aligned in a mean electrostatic field. The solvent--solute force is then considered as an averaged radially symmetric Lennard-Jones component and a multipole expansion of the electrostatic component through the octupole term. Parameters for the model include atom-based solvent density and mean electric field functions that are fit from explicit solvent simulations of independent atoms or molecules. Using these parameters, IS-SPA accounts for asymmetry of charge solvation and reproduces the explicit solvent potential of mean force of dimerization of two oppositely charged Lennard-Jones spheres with high fidelity. Additionally, the model more accurately captures the effect of explicit solvent on the monomer and dimer configurations of alanine dipeptide in chloroform than a generalized Born or constant density dielectric model. The current version of the algorithm is expected to outperform explicit solvent simulations for aggregation of small peptides at concentrations below 150 mM, well above the typical experimental concentrations for these materials

A Translation of the East Gothic Law with Explanatory Notes

University of Minnesota Ph.D. dissertation. 1906. Major: History. 1 computer file (PDF); 168 pages