Search for Heavy Neutral Leptons in Electron-Positron and Neutral-Pion Final States with the MicroBooNE Detector.

We present the first search for heavy neutral leptons (HNLs) decaying into νe^{+}e^{-} or νπ^{0} final states in a liquid-argon time projection chamber using data collected with the MicroBooNE detector. The data were recorded synchronously with the NuMI neutrino beam from Fermilab's main injector corresponding to a total exposure of 7.01×10^{20} protons on target. We set upper limits at the 90% confidence level on the mixing parameter |U_{µ4}|^{2} in the mass ranges 10≤m_{HNL}≤150 MeV for the νe^{+}e^{-} channel and 150≤m_{HNL}≤245 MeV for the νπ^{0} channel, assuming |U_{e4}|^{2}=|U_{τ4}|^{2}=0. These limits represent the most stringent constraints in the mass range 35

'You're not going to give a monkey's chuff': exploring co-production in the design of services for women who have experienced sexual violence.

AIMS: Co-production is an emerging field in public health practice. We aim to present evidence of what works well to support co-production and what can be improved based upon learning from our evaluation of a co-production project implemented by Rape Crisis England and Wales (RCEW). RCEW designed and delivered a national co-production project called Weaving the Web, to inform the development of an online support service for women who have experienced sexual violence. METHODS: We qualitatively evaluated the RCEW co-production approach. The specific objectives of our evaluation were to assess the increased role and voice for women and girls in co-producing services and provide better quality of evidence for what works in empowering women and girls. The evaluation was conducted in two phases: Phase 1 was the observation of co-production events (n = 8), with findings from this used to develop an interview schedule for Phase 2, where semi-structured interviews (n = 26) were conducted with a range of stakeholders (staff, partners and service users). RESULTS: Staff supporting the co-production project were highly committed to the work, investing time, money, and preparation, and having a good understanding of co-production. Service users were less familiar with the approach and felt alienated by some of the language used. Most service users described participation as empowering and, in some instances, important in their own recovery. They were keen to stay involved beyond the creation of the online resource. CONCLUSION: The data from our evaluation illustrate that co-production on a national level is challenging. While RCEW used values-based practice, and provided a supportive culture to underpin the co-production of their online service, transformative engagement and true participation were not achieved. Learning from this project is drawn out here to outline transferrable lessons for practitioners intending to use models of co-production in other public health settings.

Influence of Inhalation Injury on Incidence, Clinical Profile and Recovery Pattern of Dysphagia Following Burn Injury.

Inhalation injury is predictive of dysphagia post burns; however, the nature of dysphagia associated with inhalation burns is not well understood. This study describes the clinical profile and recovery pattern of swallowing following inhalation burn injury. All patients admitted 2008-2017 with confirmed inhalation burns on laryngoscopy and managed by speech-language pathology (SLP) were included. Initial dysphagia presentation and dysphagia recovery pattern were documented using the FOIS. Co-presence of dysphonia was determined clinically and rated present/absent. Persistent laryngeal/pharyngeal injury at 6 months was documented using laryngoscopy. Data were compared to published data from a large adult burn cohort. All patients with confirmed inhalation burns during the study period received SLP input, enabling review of 38 patients (68% male; m = 40.8 years). Percent Total Body Surface Area burn ranged 1-90%, 100% had head and neck burns, 97% required mechanical ventilation (mean 9.4 days), 18% required tracheostomy and 100% had dysphonia. Comparing to non-inhalation burn patients, the inhalation cohort had significantly (p < 0.01) higher dysphagia incidence (89.47% vs 5.6%); more with severe dysphagia at presentation (78.9% vs 1.7%); increased duration to initiate oral intake (m = 24.69 vs 0.089 days); longer duration of enteral feeding (m = 45.03 vs 1.96 days); and longer duration to resolution of dysphagia (m = 29.79 vs 1.67 days). Persistent laryngeal pathology was present in 47.37% at 6 months. This study shows dysphagia incidence in burn patients with inhalation injury is 16 times greater than for those without inhalation injury. Laryngeal pathology due to inhalation injury increases dysphagia severity and duration to dysphagia recovery.

Cardiorespiratory Events Associated With Ophthalmic Surgery: A Single-Center, Retrospective Records Review of 130 775 Patients, 1999-2015.

Purpose: The most recent study of ophthalmic surgery morbidity and mortality was published in 1995, with a patient study population from 1977 to 1988. The present study reports surgical outcomes from a single-center, retrospective analysis of patient records from 1999 to 2015. Methods: Three International Classification of Diseases-9-CM codes for cardiorespiratory events were searched in the discharge diagnoses in an eye hospital over a 16-year period. The overall mortality and preoperative risk factors were analyzed, including the type of anesthetic, type of surgery, medical comorbidities, and bradycardia preceding the cardiac events. Results: Between February 1, 1999 and October 1, 2015, a total of 130 775 patients presented for ophthalmic surgery. Fifty-nine patients (0.45 per 1000) experienced a cardiorespiratory event. Of the 59 patients, 14 patients had a cardiorespiratory arrest, 9 of whom died during the perioperative period. Of the remaining 45 patients, 29 had significant adverse events needing some form of advanced monitoring, evaluation, and/or intervention. There was a significantly greater prevalence of diabetes among patients who had a cardiorespiratory event (P < .001). Conclusions: The major risk factor associated with ophthalmic surgery morbidity and mortality was diabetes with its associated complications of autonomic neuropathy, nephropathy, and retinopathy. Of the 9 patients who died, 8 were diabetic with proliferative diabetic retinopathy and renal insufficiency/failure. The ninth mortality was secondary to a venous air embolism during ocular air infusion. The adage that "the eye is the window to our overall health" seems to be correct.

A field study of a roof bolter canopy air curtain (2nd generation) for respirable coal mine dust control.

A 2nd generation roof bolter canopy air curtain (CAC) design was tested by National Institute for Occupational Safety and Health (NIOSH) at a Midwestern underground coal mine. During the study, the roof bolter never operated downwind of the continuous miner. Using a combination of personal Data Rams (pDR) and gravimetric samplers, the dust control efficiency of the roof bolter CAC was ascertained. Performance evaluation was determined using three methods: (1) comparing roof bolter operator concentrations underneath the CAC to roof bolter concentrations outside the CAC, (2) comparing roof bolter operator concentrations underneath the CAC to the concentrations at the rear of the bolter, and finally, (3) using the gravimetric data directly underneath the CAC to correct roof bolter operator concentrations underneath the CAC and comparing them to the concentrations at the rear of the bolter. Method 1 dust control efficiencies ranged from -53.9% to 60.4%. Method 2 efficiencies ranged from -150.5% to 52.2%, and Method 3 efficiencies ranged from 40.7% to 91%. Reasons for negative and low dust control efficiencies are provided in this paper and include: incorrect sampling locations, large distance between CAC and operator, and contamination of intake air from line curtain. Low dust concentrations encountered during the testing made it difficult to discern whether differences in concentrations were due to the CAC or due to variances inherent in experimental dust measurement. However, the analyses, especially the Method 3 analysis, show that the CAC can be an effective dust control device.

Field investigation to measure airflow velocities of a ram dump car using circular routing at a Midwestern underground coal mine: a case study.

Due to the successful application of roof bolter canopy air curtains (CACs) to protect roof bolter operators from high levels of coal mine respirable dust, a shuttle car CAC is currently being developed. Since a shuttle car consistently trams from the continuous miner to the feeder and back at a speed up to 9.66 kph (6 mph) or 2.68 m/s (528 fpm), it is thought that the shuttle car may encounter very high air velocities (mine ventilation air velocity + max shuttle speed (2.68 m/s (528 fpm)). Past research and preliminary lab testing showed that CAC protection in high interference air velocities is difficult to achieve. Therefore, testing was conducted at a Midwestern US coal mine to determine the air velocities their shuttle car actually encounters. This mine used ram dump cars as their shuttle cars. Results showed that coal mine dust exposure is generally very low at the feeder and when tramming. Elevated concentrations are encountered at the ram dump car operator position when the car is being loaded by the continuous miner. Recorded air velocities while tramming did not reach the max air velocity of mine ventilation air velocity + 2.68 m/s (528 fpm) calculated as 3.32 m/s (653 fpm). High velocities, while encountered, were of low frequency and associated with low respirable coal mine dust concentrations. Therefore, using this new information, designing the shuttle car CAC for maximum interference air velocity may not be as important as previously thought.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance.

A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20' ethyl substituent.

A key series of vinblastine analogs 7-13, which contain modifications to the C20' ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20' side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R=F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R=F (equipotent with H)>N3, CN (10-fold)>Me (50-fold)>Et (100-fold)>OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20'/C15'-fused six-membered ring.

Deuterated Ethanol as a Probe for Measuring Equilibrium Isotope Effects for Hydroxyl Exchange.

Equilibrium deuterium isotope effects for exchange of hydroxyl deuterons and protons among tert-butanol, phenol, ethanethiol, diethylamine, and ethanol were measured by using NMR and also calculated theoretically. Deuterated ethanol could be used as a probe for measuring equilibrium isotope effects (EIE) for hydroxyl exchange; tert-butanol, phenol, ethanethiol, diethylamine, and pyrrole were used as five representive examples. A procedure called the "one-atom isotope effect" was used to save time in the calculations.

Review: Mechanochemistry of the kinesin-1 ATPase.

Kinesins are P-loop NTPases that can do mechanical work. Like small G-proteins, to which they are related, kinesins execute a program of active site conformational changes that cleaves the terminal phosphate from an NTP substrate. But unlike small G-proteins, kinesins can amplify and harness these conformational changes in order to exert force. In this short review I summarize current ideas about how the kinesin active site works and outline how the active site chemistry is coupled to the larger-scale structural cycle of the kinesin motor domain. Focusing largely on kinesin-1, the best-studied kinesin, I discuss how the active site switch machinery of kinesin cycles between three distinct states, how docking of the neck linker stabilizes two of these states, and how tension-sensitive and position-sensitive neck linker docking may modulate both the hydrolysis step of ATP turnover and the trapping of product ADP in the active site. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 476-482, 2016.

Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.

The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

Validity of noninvasive markers of methotrexate-induced hepatotoxicity: a retrospective cohort study.

BACKGROUND: Methotrexate is a cost-effective systemic treatment for moderate-to-severe psoriasis, but the perceived risk of associated liver fibrosis prevents optimal use. Procollagen III aminoterminal propeptide (PIIINP) is a widely adopted noninvasive biomarker of liver fibrosis; however, its clinical utility is narrow owing to limited evidence of performance and the need for serial measurement. The Enhanced Liver Fibrosis (ELF) assay is a validated biomarker of liver fibrosis. OBJECTIVES: To evaluate the diagnostic accuracy of the ELF test compared with PIIINP for the diagnosis of liver fibrosis in a cohort of patients with psoriasis treated with methotrexate. METHODS: A retrospective cohort study comparing the diagnostic accuracy of PIIINP and ELF in detecting liver fibrosis in patients treated with methotrexate. Liver biopsy was the reference standard. RESULTS: Twenty-seven patients were identified and included in the study. The diagnostic accuracies [area under the receiver operating curve (AUROC)] of serial PIIINP and serial ELF were 0·589 [95% confidence interval (CI) 0·379-0·800] and 0·643 (95% CI 0·391-0·895), respectively, for mild fibrosis; and 0·576 (95% CI 0·237-0·916) and 0·674 (95% CI 0·421-0·927) for at least moderate fibrosis. The AUROC values for single PIIINP and single ELF were 0·582 (95% CI 0·363-0·801) and 0·693 (95% CI 0·482-0·904), respectively, for mild fibrosis; and 0·667 (95% CI 0·363-0·971) and 0·806 (95% CI 0·564-1·000) for at least moderate fibrosis. CONCLUSIONS: This pilot study suggests that ELF may be at least equivalent or possibly superior to PIIINP in the detection of liver fibrosis in patients with psoriasis treated with methotrexate, and supports further investigations into the performance of ELF in this clinical setting.

4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-ones prevent the transmission of Plasmodium falciparum to Anopheles freeborni.

Malaria kills approximately 1 million people a year, mainly in sub-Saharan Africa. Essential steps in the life cycle of the parasite are the development of gametocytes, as well as the formation of oocysts and sporozoites, in the Anopheles mosquito vector. Preventing transmission of malaria through the mosquito is necessary for the control of the disease; nevertheless, the vast majority of drugs in use act primarily against the blood stages. The study described herein focuses on the assessment of the transmission-blocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkyl- or 3-phenyl-4(1H)-quinolones (P4Qs), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) were assessed for their transmission-blocking activity against the mosquito stages of the human malaria parasite (Plasmodium falciparum) and the rodent parasite (P. berghei). Results showed that all of the experimental compounds reduced or prevented the exflagellation of male gametocytes and, more importantly, prevented parasite transmission to the mosquito vector. Additionally, treatment with ICI 56,780 reduced the number of sporozoites that reached the Anopheles salivary glands. These findings suggest that 4(1H)-quinolones, which have activity against the blood stages, can also prevent the transmission of Plasmodium to the mosquito and, hence, are potentially important drug candidates to eradicate malaria.

4(1H)-Quinolones with liver stage activity against Plasmodium berghei.

With the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. In this study, a transgenic Plasmodium berghei parasite (1052Cl1; PbGFP-Luc(con)) that expresses luciferase was used to assess the anti-liver stage parasite activity of ICI 56,780, a 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), as well as two 3-phenyl-4(1H)-quinolones (P4Q), P4Q-146 and P4Q-158, by using bioluminescent imaging (BLI). Results showed that all of the compounds were active against liver stage parasites; however, ICI 56,780 and P4Q-158 were the most active, with low nanomolar activity in vitro and causal prophylactic activity in vivo. This potent activity makes these compounds ideal candidates for advancement as novel antimalarials.

Elevation of alanine transaminase and markers of liver fibrosis after a mixed meal challenge in individuals with type 2 diabetes.

BACKGROUND: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. AIM: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). METHODS: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m(2); and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m(2)) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by (1)H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). RESULTS: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). CONCLUSIONS: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.

Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones.

ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50=0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)-4(1H)-quinolone core.

Mechanochemical cell biology.

Eukaryotic systems self-organise by using molecular railways to shuttle specific sets of molecular components to specific locations. In this way, cells are enabled to become larger, more complex and more varied, subtle and effective in their activities. Because of the fundamental importance of molecular railways in eukaryotic systems, understanding how these railways work is an important research goal. Mechanochemical cell biology is a newly circumscribed subject area that concerns itself with the molecular and cell biological mechanisms of motorised directional transport in living systems.

Optimization of 1,2,3,4-tetrahydroacridin-9(10H)-ones as antimalarials utilizing structure-activity and structure-property relationships.

Antimalarial activity of 1,2,3,4-tetrahydroacridin-9(10H)-ones (THAs) has been known since the 1940s and has garnered more attention with the development of the acridinedione floxacrine (1) in the 1970s and analogues thereof such as WR 243251 (2a) in the 1990s. These compounds failed just prior to clinical development because of suboptimal activity, poor solubility, and rapid induction of parasite resistance. Moreover, detailed structure-activity relationship (SAR) studies of the THA core scaffold were lacking and SPR studies were nonexistent. To improve upon initial findings, several series of 1,2,3,4-tetrahydroacridin-9(10H)-ones were synthesized and tested in a systematic fashion, examining each compound for antimalarial activity, solubility, and permeability. Furthermore, a select set of compounds was chosen for microsomal stability testing to identify physicochemical liabilities of the THA scaffold. Several potent compounds (EC(50) < 100 nM) were identified to be active against the clinically relevant isolates W2 and TM90-C2B while possessing good physicochemical properties and little to no cross-resistance.

Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C.

Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.