Susceptibility of hamsters to clostridium difficile isolates of differing toxinotype

Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) and BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial and toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression

Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.

Adaptive Endpointing with Deep Contextual Multi-armed Bandits

Current endpointing (EP) solutions learn in a supervised framework, which does not allow the model to incorporate feedback and improve in an online setting. Also, it is a common practice to utilize costly grid-search to find the best configuration for an endpointing model. In this paper, we aim to provide a solution for adaptive endpointing by proposing an efficient method for choosing an optimal endpointing configuration given utterance-level audio features in an online setting, while avoiding hyperparameter grid-search. Our method does not require ground truth labels, and only uses online learning from reward signals without requiring annotated labels. Specifically, we propose a deep contextual multi-armed bandit-based approach, which combines the representational power of neural networks with the action exploration behavior of Thompson modeling algorithms. We compare our approach to several baselines, and show that our deep bandit models also succeed in reducing early cutoff errors while maintaining low latency

Scalable high-precision trimming of photonic resonances by polymer exposure to energetic beams

Integrated photonic circuits (PICs) have seen an explosion in interest, through to commercialization in the past decade. Most PICs rely on sharp resonances to modulate, steer, and multiplex signals. However, the spectral characteristics of high-quality resonances are highly sensitive to small variations in fabrication and material constants, which limits their applicability. Active tuning mechanisms are commonly employed to account for such deviations, consuming energy and occupying valuable chip real estate. Readily employable, accurate, and highly scalable mechanisms to tailor the modal properties of photonic integrated circuits are urgently required. Here, we present an elegant and powerful solution to achieve this in a scalable manner during the semiconductor fabrication process using existing lithography tools: by exploiting the volume shrinkage exhibited by certain polymers to permanently modulate the waveguide’s effective index. This technique enables broadband and lossless tuning with immediate applicability in wide-ranging applications in optical computing, telecommunications, and free-space optics

Stacking disorder in α−RuCl_{3} investigated via x-ray three-dimensional difference pair distribution function analysis

The van der Waals layered magnet α − RuCl_{3} offers tantalizing prospects for the realization of Majorana quasiparticles. Efforts to understand this are, however, hampered by inconsistent magnetic and thermal transport properties likely coming from the formation of structural disorder during crystal growth, postgrowth processing, or upon cooling through the first order structural transition. Here, we investigate structural disorder in α − RuCl_{3} using x-ray diffuse scattering and three-dimensional difference pair distribution function analysis. We develop a quantitative model that describes disorder in α − RuCl_{3} in terms of rotational twinning and intermixing of the high- and low-temperature structural layer stacking. This disorder may be important to consider when investigating the detailed magnetic and electronic properties of this widely studied material

Types of Fish Consumed and Fish Preparation Methods in Relation to Pancreatic Cancer Incidence: The VITAL Cohort Study

The associations of types of fish and fish preparation methods with pancreatic cancer risk remain unknown. The authors conducted a prospective cohort study in western Washington State among 66,616 adults, aged 50–76 years, who participated in the VITamins And Lifestyle cohort study. Diet was assessed by a food frequency questionnaire. Pancreatic cancer cases were identified by linkage to the Surveillance, Epidemiology, and End Results cancer registry. During an average follow-up of 6.8 years, 151 participants developed pancreatic cancer (adenocarcinoma). Long-chain (n-3) polyunsaturated fatty acids (LC-PUFAs) and nonfried fish intake were inversely associated with pancreatic cancer incidence. When the highest and lowest tertiles of exposure were compared, the multivariable-adjusted hazard ratio of pancreatic cancer was 0.62 (95% confidence interval: 0.40, 0.98) (Ptrend = 0.08) for LC-PUFAs and 0.55 (95% confidence interval: 0.34, 0.88) (Ptrend = 0.045) for nonfried fish. Docosahexaenoic acid showed a greater inverse association with pancreatic cancer than eicosapentaenoic acid. No statistically significant associations were observed with fried fish and shellfish consumption. The potential health impact of fish consumption may depend on the types of fish consumed and fish preparation methods. LC-PUFAs, particularly docosahexaenoic acid, and nonfried fish, but not shellfish or fried fish, may be beneficial in the primary prevention of pancreatic cancer

Stacking disorder in α\alpha-RuCl3_3 via x-ray three-dimensional difference pair distribution function analysis

The van der Waals layered magnet $\alpha$-RuCl$_3$ offers tantalizing prospects for the realization of Majorana quasiparticles. Efforts to understand this are, however, hampered by inconsistent magnetic and thermal transport properties likely coming from the formation of structural disorder during crystal growth, postgrowth processing, or upon cooling through the first order structural transition. Here, we investigate structural disorder in $\alpha$-RuCl$_3$ using x-ray diffuse scattering and three-dimensional difference pair distribution function (3D-$\Delta$PDF) analysis. We develop a quantitative model that describes disorder in $\alpha$-RuCl$_3$ in terms of rotational twinning and intermixing of the high and low-temperature structural layer stacking. This disorder may be important to consider when investigating the detailed magnetic and electronic properties of this widely studied material.Comment: 6 pages; 3 figures; accepted in Physical Review

GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors