Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

BACKGROUND & AIMS: Metoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared with placebo in reducing symptoms of diabetic gastroparesis in women. METHODS: This US multicenter, randomized, double-blind, parallel group study enrolled women aged 18-75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy end point was change in mean daily Gastroparesis Symptom Assessment total score from baseline to Week 4. The Gastroparesis Symptom Assessment daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a 5-point ordinal scale. RESULTS: Two hundred and five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared with the placebo group from baseline to Week 4 (P = .881). However, subjects with moderate-to-severe symptoms at baseline had a significant treatment effect from Weeks 1 to 3 (P < .05) and experienced a significant reduction in nausea and upper abdominal pain for all 4 weeks versus placebo (P < .05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. CONCLUSIONS: Although the primary end point was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate-to-severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. (ClinicalTrials.gov identifier: NCT02025725.).

Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665.

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.

Dramatic neurological and biological effects by botulinum neurotoxin type A on SH-SY5Y neuroblastoma cells, beyond the blockade of neurotransmitter release.

BACKGROUND: Gene expression profile analysis on mammalian cell lines and animal models after exposure to botulinum neurotoxin (BoNT) has been investigated in several studies in recent years. Microarray analysis provides a powerful tool for identifying critical signaling pathways involved in the biological and inflammatory responses to BoNT and helps determine the mechanism of the function of botulinum toxins. One of the pivotal clinical characteristics of BoNT is its prolonged on-site effects. The role of BoNT on the blockage of neurotransmitter acetylcholine release in the neuromuscular junction has been well established. However, the effects of the treatment time of BoNT on the human cellular model and its potential mechanism remain to be defined. METHODS: This study aimed to use gene microarray technology to compare the two physiological critical time points of BoNT type A (BoNT/A) treatment of human neuroblastoma cells and to advance our understanding of the profound biological influences that toxin molecules play in the neuronal cellular system. SH-SY5Y neuroblastoma cells were treated with BoNT/A for 4 and 48 h, which represent the time needed for the entrance of toxin into the cells and the time necessary for the initial appearance of the on-site effects after BoNT application, respectively. RESULTS: A comparison of the two time points identified 122 functional groups that are significantly changed. The top five groups are alternative splicing, phosphoprotein, nucleus, cytoplasm, and acetylation. Furthermore, after 48 h, there were 744 genes significantly up-regulated, and 624 genes significantly down-regulated (p< 0.01). These genes fell into the following neurological and biological annotation groups: Nervous system development, proteinaceous extracellular matrix, signaling pathways regulating pluripotency of stem cells, cellular function and signal transduction, and apoptosis. We have also noticed that the up-regulated groups contained neuronal cell development, nervous system development, and metabolic processes. In contrast, the down-regulated groups contained many chromosomes and cell cycle categories. CONCLUSIONS: The effects of BoNT/A on neuronal cells extend beyond blocking the neurotransmitter release, and that BoNT/A is a multifunctional molecule that can evoke profound cellular responses which warrant a more in-depth understanding of the mechanism of the toxin's effects after administration.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665.

Deciphering Genotype-by- Environment Interaction for Targeting Test Environments and Rust Resistant Genotypes in Field Pea (Pisum sativum L.).

Rust caused by Uromyces viciae-fabae is a major biotic constraint to field pea (Pisum sativum L.) cultivation worldwide. Deployment of host-pathogen interaction and resistant phenotype is a modest strategy for controlling this intricate disease. However, resistance against this pathogen is partial and influenced by environmental factors. Therefore, the magnitude of environmental and genotype-by-environment interaction was assessed to understand the dynamism of resistance and identification of durable resistant genotypes, as well as ideal testing locations for rust screening through multi-location and multi-year evaluation. Initial screening was conducted with 250 diverse genotypes at rust hot spots. A panel of 23 promising field pea genotypes extracted from initial evaluation was further assessed under inoculated conditions for rust disease for two consecutive years at six locations in India. Integration of GGE biplot analysis and multiple comparisons tests detected a higher proportion of variation in rust reaction due to environment (56.94%) as an interactive factor followed by genotype × environment interaction (35.02%), which justified the requisite of multi-year, and multi-location testing. Environmental component for disease reaction and dominance of cross over interaction (COI) were asserted by the inconsistent and non-repeatable genotypic response. The present study effectively allocated the testing locations into various categories considering their "repeatability" and "desirability index" over the years along with "discrimination power" and "representativeness." "Mega environment" identification helped in restructuring the ecological zonation and location of specific breeding. Detection of non-redundant testing locations would expedite optimal resource utilization in future. The computation of the confidence limit (CL) at 95% level through bootstrapping strengthened the accuracy of the GGE biplot and legitimated the precision of genotypes recommendation. Genotype, IPF-2014-16, KPMR-936 and IPF-2014-13 identified as "ideal" genotypes, which can be recommended for release and exploited in a resistance breeding program for the region confronting field pea rust.

A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn's Disease.

BACKGROUND AND AIMS: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of Crohn's disease and may serve as a potential biomarker. A phase 2 trial was conducted to examine the efficacy and safety of the anti-MMP9 antibody andecaliximab [GS-5745] in patients with moderately to severely active Crohn's disease. METHODS: Patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo weekly [QW], andecaliximab 150 mg every 2 weeks [Q2W], andecaliximab 150 mg QW, or andecaliximab 300 mg QW.The co-primary study efficacy endpoints were evaluation of a clinical response, defined as liquid or very soft stool frequency and abdominal pain composite [from Patient-Reported Outcome 2] score ≤ 8 at week 8, and an endoscopic response, defined as a ≥ 50% reduction from baseline in the Simple Endoscopic Score for Crohn's Disease, following 8 weeks of treatment. RESULTS: A total of 187 participants were randomized to treatment; 53 participants were randomized to each andecaliximab treatment group and 28 participants were randomized to placebo. Proportions of patients receiving andecaliximab were not different from proportions of patients receiving placebo based on clinical and endoscopic response and Crohn's disease activity index-defined remission at week 8. Rates of adverse events were comparable among the andecaliximab and placebo groups. CONCLUSIONS: Eight weeks of induction treatment with 150 mg andecaliximab Q2W, 150 mg andecaliximab QW, or 300 mg andecaliximab QW in patients with Crohn's disease did not induce a clinically meaningful symptomatic or endoscopic response. Andecaliximab was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02405442.

Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease.

BACKGROUND AND AIMS: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. METHODS: Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. RESULTS: Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. CONCLUSIONS: Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.

Zinc and Iron Concentration as Affected by Nitrogen Fertilization and Their Localization in Wheat Grain.

Nearly half of the world cereal production comes from soils low or marginal in plant available zinc, leading to unsustainable and poor quality grain production. Therefore, the effects of nitrogen (N) rate and application time on zinc (Zn) and iron (Fe) concentration in wheat grain were investigated. Wheat (Triticum aestivum var. Krabat) was grown in a growth chamber with 8 and 16 h of day and night periods, respectively. The N rates were 29, 43, and 57 mg N kg-1 soil, equivalent to 80, 120, and 160 kg N ha-1. Zinc and Fe were applied at 10 mg kg-1 growth media. In one of the N treatments, additional Zn and Fe through foliar spray (6 mg of Zn or Fe in 10 ml water/pot) was applied. Micro-analytical localization of Zn and Fe within grain was performed using scanning macro-X-ray fluorescence (MA-XRF) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The following data were obtained: grain and straw yield pot-1, 1000 grains weight, number of grains pot-1, whole grain protein content, concentration of Zn and Fe in the grains. Grain yield increased from 80 to 120 kg N ha-1 rates only and decreased at 160 kg N ha-1 g. Relatively higher protein content and Zn and Fe concentration in the grain were recorded with the split N application of 160 kg N ha-1. Soil and foliar supply of Zn and Fe (Zn + Fes+f), with a single application of 120 kg N ha-1N at sowing, increased the concentration of Zn by 46% and of Fe by 35%, as compared to their growth media application only. Line scans of freshly cut areas of sliced grains showed co-localization of Zn and Fe within germ, crease and aleurone. We thus conclude that split application of N at 160 kg ha-1 at sowing and stem elongation, in combination with soil and foliar application of Zn and Fe, can be a good agricultural practice to enhance protein content and the Zn and Fe concentration in grain.

Resolution of sub-nanosecond motions in botulinum neurotoxin endopeptidase: An evidence of internal flexibility.

Botulinum neurotoxins (BoNTs) are the most poisonous substances known to mankind, which act on the peripheral nervous system leading to flaccid paralysis. Although co-crystal structure of BoNT/A light chain (LC) reveals some unique features of the biological function of this molecule, structural characteristics in solution reveal its dynamic features, not available through the published crystal structures. In this study, we have examined internal flexibility of this molecule by measuring rotational correlation time as a function of viscosity, using frequency domain fluorescence anisotropy decay technique. Fluorescence anisotropy decay of BoNT/A LC resolved sub-nanosecond local motion (faster component), interpreted as internal flexibility of the molecule was affected significantly with viscosity. Both local and global movements were affected by viscosity, which indicates the accessibility of protein core and flexibility of overall structure. In conclusion, this work demonstrates the presence of flexibility in the internal peptide segments, which appears to play a significant role in BoNT/A LC biological function.

Differential role of molten globule and protein folding in distinguishing unique features of botulinum neurotoxin.

Botulinum neurotoxins (BoNTs) are proteins of great interest not only because of their extreme toxicity but also paradoxically for their therapeutic applications. All the known serotypes (A-G) have varying degrees of longevity and potency inside the neuronal cell. Differential chemical modifications such as phosphorylation and ubiquitination have been suggested as possible mechanisms for their longevity, but the molecular basis of the longevity remains unclear. Since the endopeptidase domain (light chain; LC) of toxin apparently survives inside the neuronal cells for months, it is important to examine the structural features of this domain to understand its resistance to intracellular degradation. Published crystal structures (both botulinum neurotoxins and endopeptidase domain) have not provided adequate explanation for the intracellular longevity of the domain. Structural features obtained from spectroscopic analysis of LCA and LCB were similar, and a PRIME (PReImminent Molten Globule Enzyme) conformation appears to be responsible for their optimal enzymatic activity at 37°C. LCE, on the other hand, was although optimally active at 37°C, but its active conformation differed from the PRIME conformation of LCA and LCB. This study establishes and confirms our earlier finding that an optimally active conformation of these proteins in the form of PRIME exists for the most poisonous poison, botulinum neurotoxin. There are substantial variations in the structural and functional characteristics of these active molten globule related structures among the three BoNT endopeptidases examined. These differential conformations of LCs are important in understanding the fundamental structural features of proteins, and their possible connection to intracellular longevity could provide significant clues for devising new countermeasures and effective therapeutics.

First isolation of dengue virus from the 2010 epidemic in Nepal.

Dengue is an emerging disease in Nepal and was first observed as an outbreak in nine lowland districts in 2006. In 2010, however, a large epidemic of dengue occurred with 4,529 suspected and 917 serologically-confirmed cases and five deaths reported in government hospitals in Nepal. The collection of demographic information was performed along with an entomological survey and clinical evaluation of the patients. A total of 280 serum samples were collected from suspected dengue patients. These samples were subjected to routine laboratory investigations and IgM-capture ELISA for dengue serological identification, and 160 acute serum samples were used for virus isolation, RT-PCR, sequencing and phylogenetic analysis. The results showed that affected patients were predominately adults, and that 10% of the cases were classified as dengue haemorrhagic fever/ dengue shock syndrome. The genetic characterization of dengue viruses isolated from patients in four major outbreak areas of Nepal suggests that the DENV-1 strain was responsible for the 2010 epidemic. Entomological studies identified Aedes aegypti in all epidemic areas. All viruses belonged to a monophyletic single clade which is phylogenetically close to Indian viruses. The dengue epidemic started in the lowlands and expanded to the highland areas. To our knowledge, this is the first dengue isolation and genetic characterization reported from Nepal.

A measurement instrument for spread of quality improvement in healthcare.

OBJECTIVE: The aim of this study was to develop and test a measurement instrument for spread of quality improvement in healthcare. The instrument distinguishes: (i) spread of work practices and their results and (ii) spread practices and effectiveness. Relations between spread and sustainability of changed work practices were also explored to assess convergent validity. DESIGN: We developed and tested a measurement instrument for spread in a follow-up study. The instrument consisted of 18-items with four subscales. SETTING AND PARTICIPANTS: The sample consisted of former improvement teams in a quality improvement program for long-term care (nteams = 73, nrespondents = 127). Data were collected in a questionnaire about 1 year post-pilot site improvement implementation. INTERVENTIONS: Quality improvements in long-term care practices. MAIN OUTCOME MEASURES: Four variables were construed: (i) actions for spread of work practices, (ii) actions for spread of results, (iii) effectiveness of spread of work practices and (iv) effectiveness of spread of results. RESULTS: Psychometric analysis yielded positive results on the item level. The intended four-factor model yielded satisfactory fit. The internal consistency of each scale was fine (Cronbach's α 0.70-0.93). Bivariate correlations revealed that the spread variables were strongly related but distinct, and positively related to the sustainability variables. CONCLUSIONS: The psychometric properties are in line with methodological standards. Convergent validity was confirmed with sustainability. The measurement instrument offers a good starting point for the analysis of spread.

Clinical communication in diagnostic imaging studies: mixed-method study of pre- and post-implementation of a hospital information system.

OBJECTIVE: To examine how and why the quality of clinical communication between radiologists and referring physicians was changed in the inpatient imaging process after implementation of a hospital information system (HIS). METHODS: A mixed-method study of the chest X-ray (CXR) requests and reports, and their involved processes within a pre- and post-HIS implementation setting. RESULTS: Documentation of patient age, patient ward, and name and signature of requesting physician decreased significantly in post-HIS CXR requests (P<0.05). However, documentation of requested position and technique increased significantly (P<0.05). In post-HIS CXR reports, documentation of patient age, patient chart number, urgent/normal status of requisition, position and technique of CXR, name of referring physician, and date of request were increased significantly (P<0.05). However, documentation of discussion for important findings was decreased significantly (P<0.05). The mean number of words in the body text of post-HIS reports was increased significantly (18.65 vs. 16.3, P = 0.00).Our qualitative findings highlighted that involving nursing and radiology staff in the communication loop between physicians and radiologists after the implementation resulted in extra steps in the workflow and more workload for them. To cope with the new workload, they adopted different workarounds that could explain the results seen in the quantitative study. CONCLUSION: The HIS improved communication of administrative and identification information but did not improve communication of clinically relevant information. The reason was traced to the complications that the inappropriate implementation of the system brought to clinical workflow and communication loop.

First Isolation of Dengue Virus from the 2010 Epidemic in Nepal

Dengue is an emerging disease in Nepal and was first observed as an outbreak in nine lowland districts in 2006. In 2010, however, a large epidemic of dengue occurred with 4,529 suspected and 917 serologically-confirmed cases and five deaths reported in government hospitals in Nepal. The collection of demographic information was performed along with an entomological survey and clinical evaluation of the patients. A total of 280 serum samples were collected from suspected dengue patients. These samples were subjected to routine laboratory investigations and IgM-capture ELISA for dengue serological identification, and 160 acute serum samples were used for virus isolation, RT-PCR, sequencing and phylogenetic analysis. The results showed that affected patients were predominately adults, and that 10% of the cases were classified as dengue haemorrhagic fever/ dengue shock syndrome. The genetic characterization of dengue viruses isolated from patients in four major outbreak areas of Nepal suggests that the DENV-1 strain was responsible for the 2010 epidemic. Entomological studies identified <i>Aedes aegypti</i> in all epidemic areas. All viruses belonged to a monophyletic single clade which is phylogenetically close to Indian viruses. The dengue epidemic started in the lowlands and expanded to the highland areas. To our knowledge, this is the first dengue isolation and genetic characterization reported from Nepal.

Melatonin modulates wireless (2.45 GHz)-induced oxidative injury through TRPM2 and voltage gated Ca(2+) channels in brain and dorsal root ganglion in rat.

We aimed to investigate the protective effects of melatonin and 2.45 GHz electromagnetic radiation (EMR) on brain and dorsal root ganglion (DRG) neuron antioxidant redox system, Ca(2+) influx, cell viability and electroencephalography (EEG) records in the rat. Thirty two rats were equally divided into four different groups namely group A1: Cage control, group A2: Sham control, group B: 2.45 GHz EMR, group C: 2.45 GHz EMR+melatonin. Groups B and C were exposed to 2.45 GHz EMR during 60 min/day for 30 days. End of the experiments, EEG records and the brain cortex and DRG samples were taken. Lipid peroxidation (LP), cell viability and cytosolic Ca(2+) values in DRG neurons were higher in group B than in groups A1 and A2 although their concentrations were increased by melatonin, 2-aminoethyldiphenyl borinate (2-APB), diltiazem and verapamil supplementation. Spike numbers of EEG records in group C were lower than in group B. Brain cortex vitamin E concentration was higher in group C than in group B. In conclusion, Melatonin supplementation in DRG neurons and brain seems to have protective effects on the 2.45 GHz-induced increase Ca(2+) influx, EEG records and cell viability of the hormone through TRPM2 and voltage gated Ca(2+) channels.

Quality improvement in long-term mental health: results from four collaboratives.

This multiple case study evaluates four quality improvement collaboratives (QICs) in long-term mental health care focusing on social psychiatric care, recovery oriented care, social participation and somatic co-morbidity of psychiatric patients. The aim is to explore (1) effectiveness in terms of objective outcome indicators and impact of changes as perceived by team members; and (2) associations between collaborative-, organizational- and team-level factors and perceived effectiveness. Most objective outcomes, such as health, loneliness and clients' problem areas, showed significant improvement. Because of the diversity in content no single measure for objective effectiveness could be computed across the four collaboratives. Perceived effectiveness of team members was used as an indicator of the overall impact. In all, 55 of the 94 participating team leaders and 117 remaining team members completed a written survey at the end of each quality improvement collaborative. Multilevel regression analyses indicated that innovation attributes, appropriate measures, usable data collection tools and an innovative team culture could explain variation in perceived effectiveness. In conclusion, overall positive changes for clients were realized as demonstrated by objective outcomes and team members' perceptions of improvements in care processes. The results supported the notion that a layered approach is necessary to achieve improvements in quality of care.

Constructing the social: an evaluation study of the outcomes and processes of a 'social participation' improvement project.

This paper reports on an evaluation of a 'social participation' improvement project in a mental health care and care for the intellectually disabled setting. The main research question is how sociality (i.e. clients' social lives) was constructed and what consequences this had for the project and for the clients. We undertook a dual approach: investigating the predefined outcomes and analysing the improvement processes in terms of how these processes construct sociality. As to the predefined outcomes, clients' social networks were not widened, but clients felt significantly less lonely at the end of the project. In a bottom-up analysis of data gathered on the improvement processes, we articulated two ways of constructing sociality: individualization, in which clients had to verbalize their wishes (verbalization) and to act upon them more actively (enterprising); and normalization, in which a good social life was one embedded in 'normal' community. We argue that this (explorative) way of conceptualizing change corresponds with some of the quantitative findings but also brings to light aspects that would have gone unnoticed by using only the predefined outcomes. Therefore, a mixed methods approach in studying effectiveness is a fruitful addition to the quality improvement literature.

Understanding non-adherence in chronic heart failure: a mixed-method case study.

OBJECTIVES: Understanding non-adherence to guidelines in patients with co-morbidities by supplementing quantitative data through patient-centred qualitative research. It is hypothesised that clinical constraints and patient-related factors explain the vast proportion of non-adherence. DESIGN: Mixed-method case study. SETTING: Primary and secondary acute care hospital, Department for Internal Medicine. PARTICIPANTS: All consecutive patients having chronic heart failure (CHF) being hospitalised within a 2-year period. RESULTS: Quantitative drug prescribing analysis in 348 patients with CHF confirms moderate guideline adherence: the guideline adherence index (GAI) corresponds to 0.7 for the three most important drug classes indicated for CHF and to 0.6 for all five recommended drug classes. Corrections with regard to the most important clinical contraindication (renal insufficiency) for these drugs raise the GAI to 0.8 in both categories. Semistructured interviews in 50 consecutive patients show relevant reasons for non-adherence in half of the remaining patients with non-adherence to guidelines and raise the adjusted GAI to 0.9. Up to 75% of de jure non-adherence can thus be explained by clinical constraints. CONCLUSION: Quantitative data analysis of treatment regimens in patients with CHF is an inaccurate method for measuring guideline adherence. Combining quantitative prescribing data with semistructured interviews shows a 90% match concerning guideline adherence compared to an only 60% match based on quantitative data alone. Thus, neither quality nor economical assessments of the treatment strategy in patients with chronic diseases should be solely based on quantitative analysis. Understanding non-adherence is crucial for defining and improving quality of care.

Evaluation of the impact of a CPOE system on nurse-physician communication--a mixed method study.

OBJECTIVES: To assess the impact of a CPOE system on medication-related communication of nurses and physicians. METHODS: In six internal medicine wards of an academic medical center, two questionnaires were used to evaluate nurses' attitudes toward the impact of a paper-based medication system and then a CPOE system on their communication in medication-related-activities (medication work). The questionnaires were analyzed using t-tests, followed by Bonferroni correction. Nine nurses and six physicians in the same wards were interviewed after the implementation to determine how their communication and their work have been impacted by the system. RESULTS: The total response rates were 54% and 52% for pre- and post-implementation questionnaires. It was shown that after implementation, the legibility and completeness of prescriptions were significantly improved (P <.001) and the administration system had a more intelligible layout (P <.001), with a more reliable overview (P <.001). The analysis of the interviews supported and confirmed the findings of the surveys. Moreover, they showed communication problems that caused difficulties in integrating medication work of nurses into physicians'. To compensate for these, nurses and physicians devised informal interactions and practices (workarounds), which often represented risks for medication errors. CONCLUSION: The introduction of CPOE system with paper-based medication administration system improved prescription legibility and completeness but introduced many workflow impediments and as a result error-inducing conditions. In order to prevent such an effect, CPOE systems have to support the level of communication which is necessary to integrate the work of nurses and physicians.