The Impact of Next-generation Sequencing on Interobserver Agreement and Diagnostic Accuracy of Desmoplastic Melanocytic Neoplasms.

Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant ( P <0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics.

BRAF Mutated and Morphologically Spitzoid Tumors, a Subgroup of Melanocytic Neoplasms Difficult to Distinguish From True Spitz Neoplasms.

Drivers of Spitz neoplasms include activating point mutations in HRAS and Spitz-associated genomic fusions. It has become evident that some BRAF -mutated melanocytic neoplasms can morphologically mimic Spitz tumors (STs). These have been termed BRAF mutated and morphologically spitzoid (BAMS). In this study, 17 experts from the International Melanoma Pathology Study Group assessed 54 cases which included 40 BAMS and 14 true STs. The participants reviewed the cases blinded to the genomic data and selected among several diagnostic options, including BAMS, ST, melanoma, and other. A total of 38% of all diagnostic selections in the BAMS cases were for BAMS, whereas 32% were for ST. In 22 of the BAMS cases, the favored diagnosis was BAMS, whereas in 17 of the BAMS cases, the favored diagnosis was ST. Among the 20 cases in the total group of 54 with the highest number of votes for ST, half were BAMS. Of BAMS, 75% had a number of votes for ST that was within the SD of votes for ST seen among true ST cases. There was poor interobserver agreement for the precise diagnosis of the BAMS (kappa = 0.16) but good agreement that these cases were not melanoma (kappa = 0.7). BAMS nevi/tumors can closely mimic Spitz neoplasms. Expert melanoma pathologists in this study favored a diagnosis of ST in nearly half of the BAMS cases. There are BAMS cases that even experts cannot morphologically distinguish from true Spitz neoplasms.

Clinical, Morphologic, and Molecular Features of MAP3K8 Rearranged Spitz Neoplasms: A Retrospective Study Documenting That Bonafide Spitz Melanomas Are Rare.

Previous studies regarding the clinical behavior of Spitz neoplasms lack genomic characterization. We aim to assess our hypothesis that most MAP3K8 Spitz neoplasms are indolent despite MAP3K8 being the single most common driver of Spitz melanoma. Further, we aim to identify genomic features associated with aggressive behavior and to better characterize the morphology of these cases. We analyzed the outcomes of MAP3K8 Spitz neoplasms. We also performed a meta-analysis of the outcomes of MAP3K8 Spitz from the literature. Morphologic features were compared with other variants of Spitz using a Student t test and χ 2 test. Two of 35 cases resulted in local recurrence and one of these cases had local regional metastasis; all other cases had no evidence of recurrence (mean follow-up time: 33 mo). MAP3K8 Spitz only rarely results in aggressive behavior. Metastatic cases have genomic mutations associated with tumor progression. Morphologically, MAP3K8 Spitz neoplasms frequently showed nodular silhouette, large cell size, epithelioid morphology, and severe nuclear atypia resulting in more frequent diagnosis as Spitz melanoma. Most MAP3K8 Spitz neoplasms have excellent prognoses, apart from rare cases harboring additional genomic abnormalities associated with tumor progression.

Comparison of wheatgrass juices from colored wheat (white, black, blue, and purple) for health promoting phytochemicals.

Wheatgrass juice is a low-acid functional drink extracted from white wheat seedlings. It is cherished by consumers due to its potent health benefits. The present study was conducted to develop and analyze wheatgrass juice from colored wheat lines to meet consumers increasing demand for a novel functional drink. The conventional lyophilized wheatgrass juice powder (WJLP) was found to contain significant chlorophyll content (0.3%), soluble phenolic content (0.6%), protein content (20%), moderate essential amino acid index (EAAI; 86%), high K (RDA; 11.6%) and antioxidant activity. Whereas, black WJLP had 564.2% higher anthocyanins, 30.5% higher chlorophyll, 87.5% higher soluble phenolic content, 10.2% higher proteins, 31.5% higher EAAI, and 112.5% higher antioxidant activity compared to white WJLP. Overall, the biochemical parameters of WJLP were increased in the order of white < blue < purple < black. The findings indicate that a proper cultivar selection can improve the nutritional value of wheatgrass juice.

Physiological and molecular response of colored wheat seedlings against phosphate deficiency is linked to accumulation of distinct anthocyanins.

Anthocyanin rich colored wheat with additional health benefits has created interest among breeders, consumers and policy makers to address the prevailing malnutrition in the vulnerable population. Researchers are exploring how colored wheat could perform under different nutrient conditions for the maintenance of growth and development. The present study was aimed to investigate the differential response of phosphorous (Pi) deficiency at the seedling stage using hydroponics. Our results showed that Pi-deficiency triggered typical response in the wheat along with the changes in the plant root morphology, total biomass, micronutrient concentration and distinct anthocyanin accumulation. Our physiological and biochemical data revealed that these parameters were positively altered under stress in the colored wheat and the adaptation followed the trend of white < blue

Spatial network based model forecasting transmission and control of COVID-19.

The SARS-CoV-2 driven infectious novel coronavirus disease (COVID-19) has been declared a pandemic by its brutal impact on the world in terms of loss on human life, health, economy, and other crucial resources. To explore more about its aspects, we adopted the S E I R D (Susceptible-Exposed-Infected-Recovered-Death) pandemic spread with a time delay on the heterogeneous population and geography in this work. Focusing on the spatial heterogeneity, epidemic spread on the framework of modeling that incorporates population movement within and across the boundaries is studied. The entire population of interest in a region is divided into small distinct geographical sub regions, which interact using migration networks across boundaries. Utilizing the time delay differential equations based model estimations, we analyzed the spread dynamics of disease in India. The numerical outcomes from the model are validated using real time available data for COVID-19 cases. Based on the developed model in the framework of the recent data, we verified total infection cases in India considering the effect of nationwide lockdown at the onset of the pandemic and its unlocking by what seemed to be the end of the first wave. We have forecasted the total number of infection cases in two extreme situations of nationwide no lockdown and strict lockdown scenario. We expect that in future for any change in the key parameters, due to the regional differences, predictions will lie within the bounds of the above mentioned extreme plots. We computed the approximate peak infection in forwarding time and relative timespan when disease outspread halts. The most crucial parameter, the time-dependent generalization of the basic reproduction number, has been estimated. The impact of the social distancing and restricted movement measures that are crucial to contain the pandemic spread has been extensively studied by considering no lockdown scenario. Our model suggests that attaining a reduction in the contact rate between susceptible and infected individuals by practicing strict social distancing is one of the most effective control measures to manage COVID-19 spread in India. The cases can further decrease if social distancing is followed in conjunction with restricted movement.

Cardiovascular Disease in the Indo-Caribbean Population: A Scoping Review.

At the beginning of the 20th century, there was a shift in disease patterns from that of communicable disease to noncommunicable disease (NCD). As a result, cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality worldwide. Its incidence and effect on various populations at a molecular level as well as clinical implications have been heavily studied; however, its role in morbidity and mortality in the Indo-Caribbean population is often overlooked. The Caribbean diaspora is a vibrant and heterogeneous culture, encompassing individuals with ancestries from across the world including the Indian subcontinent and Africa. Abundant research is consistently conducted on these populations, but limited research exists on how the interplay between genetics and environment translates to the manifestation of various diseases in the Indo-Caribbean population. This scoping review aims to identify and assess the current literature within the past 10 years conducted on CVD in Indo-Caribbeans in order to gain a thorough understanding of disease and management to improve health outcomes. Additionally, this review aimed to identify gaps in research that require further study to gain a better understanding of relevant variables affecting disease outcomes in the Indo-Caribbean population. Multiple health databases were queried, and the initial search yielded over 3,000 results. However, after screening with the inclusion and exclusion criteria established, the final search included less than 1% of the papers initially searched. This search yielded data that included treatment and management of myocardial infarction, hypertension, and atherosclerosis, but notably did not yield papers that discussed the relationship between social determinants of health and CVD in Indo-Caribbeans. Florida and New York are prominent states that have robust Indo-Caribbean populations; the lack of research renders these states vulnerable to improving health outcomes in these patients. The authors call for increased focus on this population in research studies and efforts to improve the quality of the data collected through stratification by ethnicity. Robust data may allow for improvement in the treatment and management of CVD in Indo-Caribbeans, which offers a more proactive rather than reactive approach to decreasing morbidity and mortality.

Gene Expression and Proteomics Studies Suggest an Involvement of Multiple Pathways Under Day and Day-Night Combined Heat Stresses During Grain Filling in Wheat.

Recent weather fluctuations imposing heat stress at the time of wheat grain filling cause frequent losses in grain yield and quality. Field-based studies for understanding the effect of terminal heat stress on wheat are complicated by the effect of multiple confounding variables. In the present study, the effect of day and day-night combined heat stresses during the grain-filling stage was studied using gene expression and proteomics approaches. The gene expression analysis was performed by using real-time quantitative PCR (RT-qPCR). The expression of genes related to the starch biosynthetic pathway, starch transporters, transcription factors, and stress-responsive and storage proteins, at four different grain developmental stages, indicated the involvement of multiple pathways. Under the controlled conditions, their expression was observed until 28 days after anthesis (DAA). However, under the day stress and day-night stress, the expression of genes was initiated earlier and was observed until 14 DAA and 7 DAA, respectively. The protein profiles generated using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS/MS) showed a differential expression of the proteins belonging to multiple pathways that included the upregulation of proteins related to the translation, gliadins, and low-molecular-weight (LMW) glutenins and the downregulation of proteins related to the glycolysis, photosynthesis, defense, and high-molecular-weight (HMW) glutenins. Overall, the defense response to the day heat stress caused early gene expression and day-night heat stress caused suppression of gene expression by activating multiple pathways, which ultimately led to the reduction in grain-filling duration, grain weight, yield, and processing quality.

Spotlight on the overlapping routes and partners for anthocyanin transport in plants.

Secondary metabolites are produced by plants and are classified based on their chemical structure or the biosynthetic routes through which they are synthesized. Among them, flavonoids, including anthocyanins and pro-anthocyanidins (PAs), are abundant in leaves, flowers, fruits, and seed coats in plants. The anthocyanin biosynthetic pathway has been intensively studied, but the molecular mechanism of anthocyanin transport from the synthesis site to the storage site needs attention. Although the major transporters are well defined yet, the redundancy of these transporters for structurally similar or dis-similar anthocyanins motivates additional research. Herein, we reviewed the role of membrane transporters involved in anthocyanin transport, including ATP-binding cassette, multidrug and toxic compound extrusion (MATE), Bilitranslocase-homolog (BTL), and vesicle-mediated transport. We also highlight the ability of transporters to cater distinct anthocyanins or their chemically-modified forms with overlapping transport mechanisms and sequestration into the vacuoles. Our understanding of the anthocyanin transporters could provide anthocyanin-rich crops and fruits with a benefit on human health at a large scale.

A null allele of granule bound starch synthase (Wx-B1) may be one of the major genes controlling chapatti softness.

Chapatti (unleavened flatbread) is a staple food in northern India and neighboring countries but the genetics behind its processing quality are poorly understood. To understand the genes determining chapatti quality, differentially expressed genes were selected from microarray data of contrasting chapatti cultivars. From the gene and trait association studies, a null allele of granule bound starch synthase (GBSS; Wx-B1) was found to be associated with low amylose content and good chapatti quality. For validation, near-isogenic lines (NILs) of this allele were created by marker assisted backcross (MAB) breeding. Background screening indicated 88.2 to 96.7% background recovery in 16 selected BC3F5 NILs. Processing quality and sensory evaluation of selected NILs indicated improvement in chapatti making quality. Traits that showed improvement were mouthfeel, tearing strength and softness indicating that the Wx-B1 may be one of the major genes controlling chapatti softness.

Fear Potentiated Startle in Children With Autism Spectrum Disorder: Association With Anxiety Symptoms and Amygdala Volume.

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD.

Evaluation of Anthocyanin Content, Antioxidant Potential and Antimicrobial Activity of Black, Purple and Blue Colored Wheat Flour and Wheat-Grass Juice against Common Human Pathogens.

The present study aimed to analyze the antioxidant and antimicrobial activity of anthocyanins extracted from colored wheat flour and wheat-grass juice against human pathogens. The total anthocyanin content and antioxidant potential in colored wheat flour and wheat-grass juice extracts were significantly higher than white flour and wheat-grass juice extracts. Ultra-performance liquid chromatography showed the maximum number of anthocyanin peaks in black wheat, with delphinidin-3-o-galactoside chloride, delphinidin-3-o-glucoside chloride, and cyanindin-3-o-glucoside chloride as the major contributors. Among flour extracts, maximum zones of inhibition against Staphylococcus aureus (MTCC 1934), Pseudomonas aeruginosa (MTCC 1434), Escherichia coli, and Candida albicans (MTCC 227) were produced by black flour extract, having the highest anthocyanin content. It exhibited a minimum microbicidal concentration (MMC) of 200 mg/mL against E. coli and C. albicans; and 100 and 150 mg/mL against S. aureus and P. aeruginosa, respectively. Black and purple flour extracts exhibited a minimum inhibitory concentration (MIC) of 50 mg/mL against S. aureus and P. aeruginosa. White flour extracts did not show MMC against E. coli and C. albicans. Among wheat-grass juice extracts, black wheat-grass was most effective and showed an MIC of 100-150 mg/mL against all pathogens. It exhibited an MMC of 200 mg/mL against S. aureus and P. aeruginosa. Hence, anthocyanin-rich colored wheat could be of nutraceutical importance.

Influence of Biofortified Colored Wheats (Purple, Blue, Black) on Physicochemical, Antioxidant and Sensory Characteristics of Chapatti (Indian Flatbread).

Biofortified colored wheat (black, blue, and purple) is rich in anthocyanins and phenolic acid compounds that impart positive physiological effects in humans. A large proportion of wheat is consumed in the form of Chapatti in Asian countries. The effect of chapatti cooking on the proximate composition, bioactive compounds (anthocyanins and phenolics), and antioxidant activities of these wheat varieties were checked in this study. Apart from acceptable sensory parameters, good taste, and soft texture of chapatti, biofortified colored wheat chapatti and flour had higher dietary fibers, protein content, and lower carbohydrate content. Higher soluble and insoluble phenolic compounds, anthocyanin content, and antioxidant activity were in the order of black > blue > purple > white. Chapatti making has reduced their antioxidant activity and anthocyanin content in comparison to flour. Moreover, the reduction in antioxidant activity is less as compared to the decrease in anthocyanin content. Our results suggest that colored wheat can be a better alternative to normal wheat for preparing chapatti as it would have additional health-promoting activities.

Pathogenesis of Celiac Disease and Other Gluten Related Disorders in Wheat and Strategies for Mitigating Them.

Wheat is a major cereal crop providing energy and nutrients to the billions of people around the world. Gluten is a structural protein in wheat, that is necessary for its dough making properties, but it is responsible for imparting certain intolerances among some individuals, which are part of this review. Most important among these intolerances is celiac disease, that is gluten triggered T-cell mediated autoimmune enteropathy and results in villous atrophy, inflammation and damage to intestinal lining in genetically liable individuals containing human leukocyte antigen DQ2/DQ8 molecules on antigen presenting cells. Celiac disease occurs due to presence of celiac disease eliciting epitopes in gluten, particularly highly immunogenic alpha-gliadins. Another gluten related disorder is non-celiac gluten-sensitivity in which innate immune-response occurs in patients along with gastrointestinal and non-gastrointestinal symptoms, that disappear upon removal of gluten from the diet. In wheat allergy, either IgE or non-IgE mediated immune response occurs in individuals after inhalation or ingestion of wheat. Following a life-long gluten-free diet by celiac disease and non-celiac gluten-sensitivity patients is very challenging as none of wheat cultivar or related species stands safe for consumption. Hence, different molecular biology, genetic engineering, breeding, microbial, enzymatic, and chemical strategies have been worked upon to reduce the celiac disease epitopes and the gluten content in wheat. Currently, only 8.4% of total population is affected by wheat-related issues, while rest of population remains safe and should not remove wheat from the diet, based on false media coverage.

NF-κB-p62-NRF2 survival signaling is associated with high ROR1 expression in chronic lymphocytic leukemia.

Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1Hi). ROR1Hi CLL cells with elevated NQO1 expression exhibit resistance to drugs that induce ROS accumulation, such venetoclax. However, such cells are more sensitive to compound 29h, a pro-drug that only becomes active after being metabolized by NQO1. Accordingly, 29h sensitizes high NQO1 CLL cells to venetoclax. Collectively, our study unravels a previously unknown signaling network through which the NF-κB-p62-NRF2 axis protects ROR1-high CLL cells from ROS-inducing therapeutics.

Cooperative motor action to regulate microtubule length dynamics.

Motivated by the recent experimental observations on motor induced cooperative mechanism controlling the length dynamics of microtubules (MTs), we examine how plus-end-targeted proteins of the kinesin family regulate MT polymerization and depolymerization routines. Here, we study a stochastic mathematical model capturing the unusual form of collective motor interaction on MT dynamics originating due to the molecular traffic near the MT tip. We provide an extensive analysis of the joint effect of motor impelled MT polymerization and complete depolymerization. The effect of the cooperative action is included by modifying the intrinsic depolymerization rate. We analyze the model within the framework of continuum mean-field theory and the resultant steady-state analytic solution is expressed in terms of Lambert W functions. Four distinct steady-state phases including a shock phase have been reported. The significant features of the shock including its position and height have been analyzed. Theoretical outcomes are supported by extensive Monte Carlo simulations. To explore the system alterations between the regime of growth and shrinkage phase, we consider kymographs of the microtubule along with the length distributions. Finally, we investigated the dependence of MT length kinetics both on modifying factor of depolymerization rate and motor concentration. The overall extensive study reveals that the flux of molecular traffic at the microtubule plus end initiates a cooperative mechanism, resulting in significant change in MT growth and shrinkage regime as also observed experimentally.

Biofortified Crops Generated by Breeding, Agronomy, and Transgenic Approaches Are Improving Lives of Millions of People around the World.

Biofortification is an upcoming, promising, cost-effective, and sustainable technique of delivering micronutrients to a population that has limited access to diverse diets and other micronutrient interventions. Unfortunately, major food crops are poor sources of micronutrients required for normal human growth. The manuscript deals in all aspects of crop biofortification which includes-breeding, agronomy, and genetic modification. It tries to summarize all the biofortification research that has been conducted on different crops. Success stories of biofortification include lysine and tryptophan rich quality protein maize (World food prize 2000), Vitamin A rich orange sweet potato (World food prize 2016); generated by crop breeding, oleic acid, and stearidonic acid soybean enrichment; through genetic transformation and selenium, iodine, and zinc supplementation. The biofortified food crops, especially cereals, legumes, vegetables, and fruits, are providing sufficient levels of micronutrients to targeted populations. Although a greater emphasis is being laid on transgenic research, the success rate and acceptability of breeding is much higher. Besides the challenges biofortified crops hold a bright future to address the malnutrition challenge.

Far-from-equilibrium bidirectional transport system with constrained entrances competing for pool of limited resources.

Motivated by the wide occurrence of limited resources in many real-life systems, we investigate two-lane totally asymmetric simple exclusion process with constrained entrances under finite supply of particles. We analyze the system within the framework of mean-field theory and examine various complex phenomena, including phase separation, phase transition, and symmetry breaking. Based on the theoretical analysis, we analytically derive the phase boundaries for various symmetric as well as asymmetric phases. It has been observed that the symmetry-breaking phenomenon initiates even for very small number of particles in the system. The phases with broken symmetry originates as shock-low density phase under limited resources, which is in contrast to the scenario with infinite number of particles. As expected, the symmetry breaking continues to persist even for higher values of system particles. Seven stationary phases are observed, with three of them exhibiting symmetry-breaking phenomena. The critical values of a total number of system particles, beyond which various symmetrical and asymmetrical phases appear and disappear are identified. Theoretical outcomes are supported by extensive Monte Carlo simulations. Finally, the size-scaling effect and symmetry-breaking phenomenon on the simulation results have also been examined based on particle density histograms.

Muscarinic cholinergic receptor antagonists in the VTA and RMTg have opposite effects on morphine-induced locomotion in mice.

The ventral tegmental area (VTA) and the rostromedial tegmental nucleus (RMTg) each contribute to opiate reward and each receive inputs from the laterodorsal tegmental and pedunculopontine tegmental nuclei, the two principle brainstem cholinergic cell groups. We compared the contributions of VTA or RMTg muscarinic cholinergic receptors to locomotion induced by morphine infusions into the same sites. VTA co-infusion of atropine completely blocked VTA morphine-induced locomotion providing additional support for the important role of VTA muscarinic cholinergic receptors in the stimulant effects of opiates. By contrast, RMTg co-infusion of atropine increased RMTg morphine-induced locomotion. Furthermore, RMTg co-infusion of the M3-selective antagonist 4-DAMP, but not the M4-selective antagonist Tropicamide, strongly increased RMTg morphine-induced locomotion. RMTg infusions of 4-DAMP, but not of Tropicamide, by themselves strongly increased drug-free locomotion. Muscarinic cholinergic receptors in the RMTg thus also contribute to the stimulant effects of morphine, but in a way opposite to those in VTA. We suggest that the net effect of endogenous cholinergic input to the RMTg on drug-free and on RMTg morphine-induced locomotion is inhibitory.

Optimal dosing of angiotensin-converting enzyme inhibitors and ß-blockers for acute coronary syndrome: up-titration remains a challenge.

OBJECTIVES: Suboptimal dosing of angiotensin-converting enzyme inhibitors and ß-blockers limits the mortality benefit for acute coronary syndrome patients. Recent National Institute for Health and Care Excellence (NICE) guidelines emphasise prompt initiation and up-titration from inpatient to community care to achieve this. The aim of this study was to assess the impact of simple interventions on inpatient and community up-titration of bisoprolol and ramipril for acute coronary syndrome patients admitted to Leeds General Infirmary. METHODS: An initial prospective audit of 37 acute coronary syndrome patients admitted to Leeds General Infirmary in January 2013 assessed inpatient up-titration of bisoprolol and ramipril, discharge advice and doses at 6 weeks after discharge. Following a collective multidisciplinary effort with education, posters and discharge advice templates, a re-audit of 34 acute coronary syndrome patients admitted from November to December 2014 assessed the impact of these interventions. The independent samples t test was used to compare the mean difference between doses of ramipril and bisoprolol from initiation to discharge to dose at 6 weeks after discharge before and after intervention. RESULTS: There was a statistically significant improvement in the mean difference from initiation to discharge dose for both ramipril and bisoprolol (p=0.012 and p=0.017, respectively). However, there was little difference in community up-titration despite a 68% improvement in discharge advice. CONCLUSIONS: Simple multidisciplinary interventions improved inpatient up-titration of ramipril and bisoprolol but continued up-titration to achieve the target doses remains a challenge in primary care. Acute coronary syndrome patients are precluded from maximum mortality benefit due to suboptimal dosing after discharge.