Inpatient administration of opioids and risk for post-operative ileus in older adults.

OBJECTIVE: Post-operative ileus (POI) is a common and potentially serious complication after surgery. We assessed the incidence and identified predictors of POI in older surgical patients. DESIGN: A retrospective observational study. SETTING: University of California-San Francisco electronic medical record data. PARTICIPANTS: Opioid-naïve, noncancer patients, aged 65 and older, who underwent elective surgery in the period 2017-2019. EXPOSURE: Administration of opioid analgesics per day of hospitalization in opioid naïve patients. MAIN OUTCOMES MEASURE: Incidence of POI and likelihood of developing POI. RESULTS: In the study period, 3 percent of opioid naïve patients developed POI. Patients with POI used on average 197.1 oral morphine equivalents (OMEs) per day of hospitalization compared to 82.5 OME in patients without POI (p = 0.013). Yet, there were not statistically significant differences in post-operative pain scores between patients with and without POI. General surgery (p = 0.0031), length of surgery (p = 0.0031), and hospital length of stay (p < 0.0001) were significant predictors of the risk for developing POI. Adjusted inpatient administration of more than 90 OME per day of hospitalization was associated with a four times greater risk for developing POI (p = 0.016). Developing POI was associated with 6.5 (95 percent confidence interval: 5.2-7.8) additional days of hospitalization among patients who developed POI compared to patients who did not develop POI (p < 0.0001). CONCLUSIONS: Adjusted inpatient administration of more than 90 OME significantly increased the risk for developing POI in opioid-naïve older patients. Developing POI after surgery significantly increased the hospital length of stay. Optimizing inpatient administration of opioids may prevent opioid use-related POI and longer hospitalizations.

Reconstructing the ecosystem context of a species: Honey-borne DNA reveals the roles of the honeybee.

To assess a species' impact on its environment-and the environment's impact upon a species-we need to pinpoint its links to surrounding taxa. The honeybee (Apis mellifera) provides a promising model system for such an exercise. While pollination is an important ecosystem service, recent studies suggest that honeybees can also provide disservices. Developing a comprehensive understanding of the full suite of services and disservices that honeybees provide is a key priority for such a ubiquitous species. In this perspective paper, we propose that the DNA contents of honey can be used to establish the honeybee's functional niche, as reflected by ecosystem services and disservices. Drawing upon previously published genomic data, we analysed the DNA found within 43 honey samples from Northern Europe. Based on metagenomic analysis, we find that the taxonomic composition of DNA is dominated by a low pathogenicity bee virus with 40.2% of the reads, followed by bacteria (16.7%), plants (9.4%) and only 1.1% from fungi. In terms of ecological roles of taxa associated with the bees or taxa in their environment, bee gut microbes dominate the honey DNA, with plants as the second most abundant group. A range of pathogens associated with plants, bees and other animals occur frequently, but with lower relative read abundance, across the samples. The associations found here reflect a versatile the honeybee's role in the North-European ecosystem. Feeding on nectar and pollen, the honeybee interacts with plants-in particular with cultivated crops. In doing so, the honeybee appears to disperse common pathogens of plants, pollinators and other animals, but also microbes potentially protective of these pathogens. Thus, honey-borne DNA helps us define the honeybee's functional niche, offering directions to expound the benefits and drawbacks of the associations to the honeybee itself and its interacting organisms.

In-Vitro Cell-Induced Corrosion by Macrophages on Cobalt-Chromium-Molybdenum Alloy.

BACKGROUND: Patients have received cobalt-chromium-molybdenum (CoCrMo) implants for their joint replacement for decades. There have been reports of inflammatory cell-induced corrosion (ICIC) of these implants from retrieval studies. The goal of this study is to see if we could recreate ICIC in vitro and whether electrocautery damage to alloy surfaces may hasten this process. METHODS: Murine macrophages were cultured on CoCr disks with and without damage from a monopolar electrocautery. Culture medium was replaced every 12 hours and supernatant was collected every 4 days. After 30 days, cells were removed, counted, and digested. The metal concentrations in the supernatant and within cells were assessed using inductively coupled plasma spectrometry for comparison. RESULTS: The Co supernatant concentration was higher in the undamaged disks with activated macrophages. Higher concentrations of Co and Mo were found in the supernatant of the undamaged disks vs the electrocautery (EC) corrosion damaged disks. There was a significantly higher intracellular Co and Mo concentration with activated cells on CoCrMo disks vs the control group and no difference compared to EC damaged disk group. Scanning electron microscopy displayed microscopic pitting on the surfaces exposed to macrophages without EC damage. CONCLUSION: We found that macrophages could reproduce findings of ICIC pits on the surface of CoCrMo alloy and that the addition of EC damage to the surface did not increase the process. The clinical significance of these findings should be further investigated to determine if this could explain a small number of poor total knee arthroplasty reported outcomes.

A dearth of data: fitting parasitoids into ecological networks.

Studying parasitoids can provide insights into global diversity estimates, climate change impacts, and agroecosystem service provision. However, this potential remains largely untapped due to a lack of data on how parasitoids interact with other organisms. Ecological networks are a useful tool for studying and exploiting the impacts of parasitoids, but their construction is hindered by the magnitude of undescribed parasitoid species, a sparse knowledge of host ranges, and an under-representation of parasitoids within DNA-barcode databases (we estimate <5% have a barcode). Here, we advocate the use of DNA metabarcoding to construct the host-parasitoid component of multilayer networks. While the incorporation of parasitoids into network-based analyses has far ranging applications, we focus on its potential for assessing ecosystem service provision within agroecosystems.

Land-use intensity affects the potential for apparent competition within and between habitats.

Arthropod communities dwelling in adjacent habitats are able to impact one another via shared natural enemies. In agricultural landscapes, drastic differences in resource availability between crop and non-crop habitats cause variation in insect herbivore densities over short distances, potentially driving inter-habitat effects. Moreover, the composition of the landscape in which the habitats are embedded likely affects realised attack rates from natural enemies via impacts on local arthropod community structure. Here, we examine indirect effects between herbivore species within and between habitat types by calculating the potential for apparent competition between multiple populations. Firstly, we aim to determine how disparities in resource availability impact the strength of the potential for apparent competition occurring between habitats, secondly to examine the impact of landscape composition upon these effects, and finally to couch these observations in reality by investigating the link between the potential for apparent competition and realised attack rates. We used DNA metabarcoding to characterise host-parasitoid interactions within two habitat types (with divergent nutrient inputs) at 11 locations with variable landscape composition within an agroecosystem context. We then used these interaction networks to estimate the potential for apparent competition between each host pair and to compare expected versus realised attack rates across the system. Shared natural enemies were found to structure host herbivore communities within and across habitat boundaries. The size of this effect was related to the resource availability of habitats, such that the habitat with high nutrient input exerted a stronger effect. The overall potential for apparent competition declined with increasing land-use intensity in the surrounding landscape and exhibited a discernible impact on realised attack rates upon herbivore species. Thus, our results suggest that increasing the proportion of perennial habitat in agroecosystems could increase the prevalence of indirect effects such as apparent competition among insect herbivore communities, potentially leading to enhanced population regulation via increased attack rates from natural enemies like parasitoid wasps.

DNA traces the origin of honey by identifying plants, bacteria and fungi.

The regional origin of a food product commonly affects its value. To this, DNA-based identification of tissue remains could offer fine resolution. For honey, this would allow the usage of not only pollen but all plant tissue, and also that of microbes in the product, for discerning the origin. Here we examined how plant, bacterial and fungal taxa identified by DNA metabarcoding and metagenomics differentiate between honey samples from three neighbouring countries. To establish how the taxonomic contents of honey reflect the country of origin, we used joint species distribution modelling. At the lowest taxonomic level by metabarcoding, with operational taxonomic units, the country of origin explained the majority of variation in the data (70-79%), with plant and fungal gene regions providing the clearest distinction between countries. At the taxonomic level of genera, plants provided the most separation between countries with both metabarcoding and metagenomics. The DNA-based methods distinguish the countries more than the morphological pollen identification and the removal of pollen has only a minor effect on taxonomic recovery by DNA. As we find good resolution among honeys from regions with similar biota, DNA-based methods hold great promise for resolving honey origins among more different regions.

Corrigendum to: Supporting consulting paediatrics in rural, remote or vulnerable communities in British Columbia: Time for national collaboration.

[This corrects the article DOI: 10.1093/pch/pxab043.].

Supporting consulting paediatrics in rural, remote, or vulnerable communities in British Columbia: Time for national collaboration.

Rural consultant paediatricians in Canada are in short supply. Rural communities across the country could benefit from the implementation of strategies to ensure access to consistent, local consultant paediatric care. Compared to their urban counterparts, rural paediatricians face unique challenges, including significant call requirements, potential risk of burnout and difficulty in recruitment. In response to these challenges, a number of strategies to bolster the provision of paediatric care to rural, remote, and underserved communities have evolved in British Columbia, including virtual support, the development of a rural paediatric network, and new training opportunities. It is time for discussions about the vulnerability of consulting paediatric care in rural or underserved communities to occur at the national level. National engagement will foster collaboration, drive research, and facilitate workforce planning, with the goal of ensuring that all Canadian communities have access to consulting paediatric care.

Electrocautery Induced Damage of Total Knee Implants.

BACKGROUND: Pitting damage on implants has been reported and attributed to the use of electrocautery. This study aimed to determine how different total knee arthroplasty bearing surfaces are susceptible to this type of damage and whether surgeons are aware that this damage can occur. METHODS: A survey was sent to Hip and Knee Society members to determine what percentage of adult reconstructive surgeons use electrocautery after implantation of components. Three bearing surfaces for total knee arthroplasty were selected: cobalt chromium, Oxinium, and zirconium nitride to be damaged by electrocautery with a monopolar (MP) and bipolar (BP) electrocautery with 3 different energy settings. A comparison of surface damage using scanning electron microscopy and elemental differences using energy dispersion spectroscopy was performed. Average roughness (Ra), maximal peak-to-valley height (Rz), kurtosis (Rk), and skewness (Rsk) were recorded for comparison using a profilometer was performed. RESULTS: Median Rz and Ra measurements were larger for BP damaged areas compared to MP for all bearing surfaces. The Oxinium surface had the greatest increase in roughness parameters. Survey results indicate that a significant percentage of adult reconstructive surgeons use the electrocautery after implants are in place and are not aware of this type of damage. Backscatter scanning electron microscopy analysis found significant changes for BP damage compared to MP. CONCLUSION: Surface damage caused by electrocautery can have significant effects on the bearing surfaces of implants but further study needs to be performed to determine if this is a clinical issue. Our survey determined that many arthroplasty experts are unaware that this damage can occur.

The contribution of mitochondrial metagenomics to large-scale data mining and phylogenetic analysis of Coleoptera.

A phylogenetic tree at the species level is still far off for highly diverse insect orders, including the Coleoptera, but the taxonomic breadth of public sequence databases is growing. In addition, new types of data may contribute to increasing taxon coverage, such as metagenomic shotgun sequencing for assembly of mitogenomes from bulk specimen samples. The current study explores the application of these techniques for large-scale efforts to build the tree of Coleoptera. We used shotgun data from 17 different ecological and taxonomic datasets (5 unpublished) to assemble a total of 1942 mitogenome contigs of >3000 bp. These sequences were combined into a single dataset together with all mitochondrial data available at GenBank, in addition to nuclear markers widely used in molecular phylogenetics. The resulting matrix of nearly 16,000 species with two or more loci produced trees (RAxML) showing overall congruence with the Linnaean taxonomy at hierarchical levels from suborders to genera. We tested the role of full-length mitogenomes in stabilizing the tree from GenBank data, as mitogenomes might link terminals with non-overlapping gene representation. However, the mitogenome data were only partly useful in this respect, presumably because of the purely automated approach to assembly and gene delimitation, but improvements in future may be possible by using multiple assemblers and manual curation. In conclusion, the combination of data mining and metagenomic sequencing of bulk samples provided the largest phylogenetic tree of Coleoptera to date, which represents a summary of existing phylogenetic knowledge and a defensible tree of great utility, in particular for studies at the intra-familial level, despite some shortcomings for resolving basal nodes.

Metabarcoding of fungal communities associated with bark beetles.

Many species of fungi are closely allied with bark beetles, including many tree pathogens, but their species richness and patterns of distribution remain largely unknown. We established a protocol for metabarcoding of fungal communities directly from total genomic DNA extracted from individual beetles, showing that the ITS3/4 primer pair selectively amplifies the fungal ITS. Using three specimens of bark beetle from different species, we assess the fungal diversity associated with these specimens and the repeatability of these estimates in PCRs conducted with different primer tags. The combined replicates produced 727 fungal Operational Taxonomic Units (OTUs) for the specimen of Hylastes ater, 435 OTUs for Tomicus piniperda, and 294 OTUs for Trypodendron lineatum, while individual PCR reactions produced on average only 229, 54, and 31 OTUs for the three specimens, respectively. Yet, communities from PCR replicates were very similar in pairwise comparisons, in particular when considering species abundance, but differed greatly among the three beetle specimens. Different primer tags or the inclusion of amplicons in separate libraries did not impact the species composition. The ITS2 sequences were identified with the Lowest Common Ancestor approach and correspond to diverse lineages of fungi, including Ophiostomaceae and Leotiomycetes widely found to be tree pathogens. We conclude that Illumina MiSeq metabarcoding reliably captures fungal diversity associated with bark beetles, although numerous PCR replicates are recommended for an exhaustive sample. Direct PCR from beetle DNA extractions provides a rapid method for future surveys of fungal species diversity and their associations with bark beetles and environmental variables.

Synergistic combination of clinical and imaging features predicts abnormal imaging patterns of pulmonary infections.

We designed and tested a novel hybrid statistical model that accepts radiologic image features and clinical variables, and integrates this information in order to automatically predict abnormalities in chest computed-tomography (CT) scans and identify potentially important infectious disease biomarkers. In 200 patients, 160 with various pulmonary infections and 40 healthy controls, we extracted 34 clinical variables from laboratory tests and 25 textural features from CT images. From the CT scans, pleural effusion (PE), linear opacity (or thickening) (LT), tree-in-bud (TIB), pulmonary nodules, ground glass opacity (GGO), and consolidation abnormality patterns were analyzed and predicted through clinical, textural (imaging), or combined attributes. The presence and severity of each abnormality pattern was validated by visual analysis of the CT scans. The proposed biomarker identification system included two important steps: (i) a coarse identification of an abnormal imaging pattern by adaptively selected features (AmRMR), and (ii) a fine selection of the most important features from the previous step, and assigning them as biomarkers, depending on the prediction accuracy. Selected biomarkers were used to classify normal and abnormal patterns by using a boosted decision tree (BDT) classifier. For all abnormal imaging patterns, an average prediction accuracy of 76.15% was obtained. Experimental results demonstrated that our proposed biomarker identification approach is promising and may advance the data processing in clinical pulmonary infection research and diagnostic techniques.

Diamine-based human histamine H3 receptor antagonists: (4-aminobutyn-1-yl)benzylamines.

A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.

Novel imidazole-based histamine H3 antagonists.

A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.

2-Aryloxymethylmorpholine histamine H(3) antagonists.

The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.

Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity.

5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.

Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling.

Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.

2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists.

The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.

Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.