CFM-ID 4.0 - a web server for accurate MS-based metabolite identification.

The CFM-ID 4.0 web server (https://cfmid.wishartlab.com) is an online tool for predicting, annotating and interpreting tandem mass (MS/MS) spectra of small molecules. It is specifically designed to assist researchers pursuing studies in metabolomics, exposomics and analytical chemistry. More specifically, CFM-ID 4.0 supports the: 1) prediction of electrospray ionization quadrupole time-of-flight tandem mass spectra (ESI-QTOF-MS/MS) for small molecules over multiple collision energies (10 eV, 20 eV, and 40 eV); 2) annotation of ESI-QTOF-MS/MS spectra given the structure of the compound; and 3) identification of a small molecule that generated a given ESI-QTOF-MS/MS spectrum at one or more collision energies. The CFM-ID 4.0 web server makes use of a substantially improved MS fragmentation algorithm, a much larger database of experimental and in silico predicted MS/MS spectra and improved scoring methods to offer more accurate MS/MS spectral prediction and MS/MS-based compound identification. Compared to earlier versions of CFM-ID, this new version has an MS/MS spectral prediction performance that is ∼22% better and a compound identification accuracy that is ∼35% better on a standard (CASMI 2016) testing dataset. CFM-ID 4.0 also features a neutral loss function that allows users to identify similar or substituent compounds where no match can be found using CFM-ID's regular MS/MS-to-compound identification utility. Finally, the CFM-ID 4.0 web server now offers a much more refined user interface that is easier to use, supports molecular formula identification (from MS/MS data), provides more interactively viewable data (including proposed fragment ion structures) and displays MS mirror plots for comparing predicted with observed MS/MS spectra. These improvements should make CFM-ID 4.0 much more useful to the community and should make small molecule identification much easier, faster, and more accurate.

BioTransformer 3.0-a web server for accurately predicting metabolic transformation products.

BioTransformer 3.0 (https://biotransformer.ca) is a freely available web server that supports accurate, rapid and comprehensive in silico metabolism prediction. It combines machine learning approaches with a rule-based system to predict small-molecule metabolism in human tissues, the human gut as well as the external environment (soil and water microbiota). Simply stated, BioTransformer takes a molecular structure as input (SMILES or SDF) and outputs an interactively sortable table of the predicted metabolites or transformation products (SMILES, PNG images) along with the enzymes that are predicted to be responsible for those reactions and richly annotated downloadable files (CSV and JSON). The entire process typically takes less than a minute. Previous versions of BioTransformer focused exclusively on predicting the metabolism of xenobiotics (such as plant natural products, drugs, cosmetics and other synthetic compounds) using a limited number of pre-defined steps and somewhat limited rule-based methods. BioTransformer 3.0 uses much more sophisticated methods and incorporates new databases, new constraints and new prediction modules to not only more accurately predict the metabolic transformation products of exogenous xenobiotics but also the transformation products of endogenous metabolites, such as amino acids, peptides, carbohydrates, organic acids, and lipids. BioTransformer 3.0 can also support customized sequential combinations of these transformations along with multiple iterations to simulate multi-step human biotransformation events. Performance tests indicate that BioTransformer 3.0 is 40-50% more accurate, far less prone to combinatorial 'explosions' and much more comprehensive in terms of metabolite coverage/capabilities than previous versions of BioTransformer.

HMDB 5.0: the Human Metabolome Database for 2022.

The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.

NP-MRD: the Natural Products Magnetic Resonance Database.

The Natural Products Magnetic Resonance Database (NP-MRD) is a comprehensive, freely available electronic resource for the deposition, distribution, searching and retrieval of nuclear magnetic resonance (NMR) data on natural products, metabolites and other biologically derived chemicals. NMR spectroscopy has long been viewed as the 'gold standard' for the structure determination of novel natural products and novel metabolites. NMR is also widely used in natural product dereplication and the characterization of biofluid mixtures (metabolomics). All of these NMR applications require large collections of high quality, well-annotated, referential NMR spectra of pure compounds. Unfortunately, referential NMR spectral collections for natural products are quite limited. It is because of the critical need for dedicated, open access natural product NMR resources that the NP-MRD was funded by the National Institute of Health (NIH). Since its launch in 2020, the NP-MRD has grown quickly to become the world's largest repository for NMR data on natural products and other biological substances. It currently contains both structural and NMR data for nearly 41,000 natural product compounds from >7400 different living species. All structural, spectroscopic and descriptive data in the NP-MRD is interactively viewable, searchable and fully downloadable in multiple formats. Extensive hyperlinks to other databases of relevance are also provided. The NP-MRD also supports community deposition of NMR assignments and NMR spectra (1D and 2D) of natural products and related meta-data. The deposition system performs extensive data enrichment, automated data format conversion and spectral/assignment evaluation. Details of these database features, how they are implemented and plans for future upgrades are also provided. The NP-MRD is available at https://np-mrd.org.

A longitudinal dataset of incidence and intervention policy impacts regarding the COVID-19 pandemic in Canadian provinces.

One year after identifying the first case of the 2019 coronavirus disease (COVID-19) in Canada, federal and provincial governments are still struggling to manage the pandemic. Provincial governments across Canada have experimented with widely varying policies in order to limit the burden of COVID-19. However, to date, the effectiveness of these policies has been difficult to ascertain. This is partly due to the lack of a publicly available, high-quality dataset on COVID-19 interventions and outcomes for Canada. The present paper provides a dataset containing important, Canadian-specific data that is known to affect COVID-19 outcomes, including sociodemographic, climatic, mobility and health system related information for all 10 Canadian provinces and their health regions. This dataset also includes longitudinal data on the daily number of COVID-19 cases, deaths, and the constantly changing intervention policies that have been implemented by each province in an attempt to control the pandemic.

Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats.

OBJECTIVE: To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. ANIMALS: 8 healthy sexually intact male cats. PROCEDURES: A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. RESULTS: Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. CONCLUSIONS AND CLINICAL RELEVANCE: Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.

Evaluation of the Avon Foundation community education and outreach initiative Community Patient Navigation Program.

INTRODUCTION: Black women in the United States experience disproportionate breast cancer mortality. Culturally appropriate community education on the importance of breast health coupled with the availability of free or low-cost mammography screening services may help improve the use of mammography screening services among Black women. The Avon Foundation Community Patient Navigation Program seeks to fill this need. The current study presents a process and outcome evaluation of this program. METHOD: Trained and uniformed community patient navigators (PNs) host breast health education events where they recruit community members to complete a mammography interest form. Participants are referred to a nurse practitioner who determines eligibility for a free or low-cost mammogram. The community PN delivers telephone follow-up to encourage participants to make and keep their mammogram appointments. RESULTS: Over a 15-month period, 22 community PNs hosted 207 breast health events, which included 9,601 attendees. Three hundred and four participants completed a mammography interest form, and 21% of these individuals received mammograms at the collaborating health facility. Participants who reported breast symptoms were twice as likely to get a mammogram as those who did not report symptoms. DISCUSSION: Community patient navigation may be a useful resource for encouraging mammography screening among underserved women.

Multiple endocrine diseases in dogs: 35 cases (1996-2009).

OBJECTIVE: To characterize a population of dogs from a tertiary care center with 2 or more endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. DESIGN: Retrospective case series. ANIMALS: 35 dogs with 2 or more endocrine disorders. PROCEDURES: Medical records were reviewed, and the following was recorded: clinical signs, physical examination findings, and the results of CBC, serum biochemical analysis, urinalysis, aerobic bacterial culture of urine samples, endocrine testing, diagnostic imaging, and necropsy. RESULTS: 35 dogs with more than 1 endocrine disorder were identified. Seventy-seven percent (27/35) of the dogs were male, and the mean age at the time of diagnosis of the first endocrinopathy was 7.9 years. Miniature Schnauzer was the most common breed. Twenty-eight of 35 (80%) dogs had 2 disorders; 7 (20%) had 3 disorders. The most common combinations of disorders included diabetes mellitus and hyperadrenocorticism in 57.1 % (20/35) of dogs; hypoadrenocorticism and hypothyroidism in 22.9% (8/35) of dogs; and diabetes mellitus and hypothyroidism in 28.6% (10/35) of dogs. A mean of 14.5 months elapsed between diagnosis of the first and second endocrine disorders, whereas there was a mean of 31.1 months between diagnosis of the first and third endocrine disorders. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the occurrence of multiple endocrine disorders was uncommon in dogs. The most common combinations of endocrine disorders in this population of dogs were diabetes mellitus and hyperadrenocorticism, followed by hypoadrenocorticism and hypothyroidism.

The use of vascular access ports for blood collection in feline blood donors.

We investigated vascular access ports for feline blood donation. Eight cats were anesthetized for conventional blood collection by jugular venipuncture at the beginning and end of the study. In-between conventional collections, vascular access ports were used for collection with or without sedation every 6 to 8 wk for 6 mo. Ports remained functional except for one catheter breakage, but intermittent occlusions occurred. Systolic blood pressure was lower during conventional collection. Behavioral abnormalities occurred during 3 port collections. Packed red cells prepared from collected blood were stored at 4°C for 25 d and assessed for quality pre- and post-storage. With both collection methods, pH and glucose level declined, and potassium level, lactate dehydrogenase activity and osmotic fragility increased. There were no differences between methods in pre-storage albumin and HCO(3)(-) levels, and pre and post-storage hematocrit, lactate dehydrogenase activity, and glucose and potassium levels. Pre-storage pH and pCO(2) were higher with conventional collection, and pre- and post-storage osmotic fragility were greater with port collection. One port became infected, but all cultures of packed red cells were negative. Tissue inflammation was evident at port removal. In a second study of conventional collection in 6 cats, use of acepromazine in premedication did not exacerbate hypotension. The use of vascular access ports for feline blood donation is feasible, is associated with less hypotension, and may simplify donation, but red cell quality may decrease, and effects on donors must be considered.

Investigation of the use of three electroencephalographic electrodes for long-term electroencephalographic recording in awake and sedated dogs.

OBJECTIVE: To compare electroencephalography (EEG) artifact associated with use of the subdermal wire electrode (SWE), gold cup electrode (GCE), and subdermal needle electrode (SNE) over an 8-hour period in sedated and awake dogs. ANIMALS: 6 healthy dogs. PROCEDURES: 8 EEG channels were recorded during 20-minute video-EEG recording sessions (intermittently at 0.5, 2, 4, 6, and 8 hours) with and without chlorpromazine sedation. Nonphysiologic artifacts were identified. Duration of artifact was summed for each channel. Number of unaffected channels (NUC) was determined. RESULTS: NUC was significantly affected by electrode type and sedation over time; median for SWE (2.80 channels; 95% confidence interval [CI], 0.84 to 5.70 channels) was significantly different from medians for GCE (7.87 channels; 95% CI, 7.44 to 7.94 channels) and SNE (7.60 channels; 95% CI, 6.61 to 7.89 channels). After 4 hours, NUC decreased in awake dogs, regardless of electrode type. In awake dogs, duration of artifact differed significantly between SWE and GCE or SNE; medians at 8 hours were 61.55 seconds (95% CI, 21.81 to 173.65 seconds), 1.33 seconds (95% CI, 0.47 to 3.75 seconds), and 21.01 seconds (95% CI, 6.85 to 64.42 seconds), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The SWE had a significant duration of artifact during recording periods > 2 hours, compared with results for the GCE and SNE, in awake dogs. The GCE, SNE, and sedation resulted in significantly more channels unaffected by artifact. For longer recordings, caution should be exercised in selecting EEG electrodes and sedation state, although differences among electrodes may not be clinically relevant.

Multiple endocrine diseases in cats: 15 cases (1997-2008).

The objective of this retrospective study was to characterize a population of cats from a tertiary care center diagnosed with multiple endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. Medical records of 15 cats diagnosed with more than one endocrine disorder were reviewed. The majority of cats were domestic shorthairs, and the mean age at the time of diagnosis of the first disorder was 10.3 years. The most common combination of disorders was diabetes mellitus and hyperthyroidism. Two cats had concurrent diabetes mellitus and hyperadrenocorticism, one cat had concurrent central diabetes insipidus and diabetes mellitus. A mean of 25.7 months elapsed between diagnoses of the first and second endocrine disorder, but this was variable. This study suggests the occurrence of multiple endocrine disorders is uncommon in cats.

Effects of aspirin, carprofen, deracoxib, and meloxicam on platelet function and systemic prostaglandin concentrations in healthy dogs.

OBJECTIVE: To determine effects of therapeutic dosages of aspirin, carprofen, deracoxib, and meloxicam on platelet function and systemic prostaglandin concentrations in healthy dogs. ANIMALS: 10 hound-crossbred dogs. PROCEDURES: Aspirin (10 mg/kg, PO, q 12 h), carprofen (4.4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), meloxicam (0.1 mg/kg, PO, q 24 h), and a placebo were administered for 7 days in a random order to each of 10 healthy dogs; there was a 21-day washout period between subsequent treatments. One-stage prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, and plasma concentrations of thromboxane (TX)B(2) and 6-keto prostaglandin (PG)F(1alpha) were measured before and after treatment administration. Platelet function was assessed by use of a platelet-function analyzer and aggregation. RESULTS: Aspirin, carprofen, and meloxicam did not significantly affect platelet function. Deracoxib caused a mild decrease in platelet aggregation induced by 50microM ADP. Platelet number, Hct, PT, aPTT, and plasma TXB(2) and 6-keto PGF(1alpha) concentrations were unchanged after NSAID administration. Meloxicam administration resulted in a significant decrease in fibrinogen concentration, but results remained within the laboratory reference interval. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of commonly used NSAIDs at therapeutic dosages in healthy dogs did not alter plasma TXB(2) and 6-keto PGF(1alpha) concentrations. Deracoxib administration resulted in a minor abnormality in platelet aggregation. Anti-inflammatory doses of aspirin did not affect platelet function as measured by use of optical aggregometry and a platelet-function analyzer. Further evaluation of the effects of aspirin and cyclooxygenase-2-selective inhibitors on hemostasis should be performed.

A case of primary hypothyroidism causing central nervous system atherosclerosis in a dog.

A 2-year-old, castrated male, Australian shepherd was presented with a history of chronic mild ataxia, obesity, and lethargy. The dog was treated with levothyroxine, but the ataxia worsened. Cranial nerve abnormalities developed and the dog was euthanized. Postmortem examination revealed marked thyroid gland atrophy and widespread, severe central nervous system atherosclerosis.

Effects of doxycycline, amoxicillin, cephalexin, and enrofloxacin on hemostasis in healthy dogs.

OBJECTIVE: To determine the effects of enteral administration of doxycycline, amoxicillin, cephalexin, and enrofloxacin at therapeutic dosages for a typical duration on hemostatic variables in healthy dogs. ANIMALS: 14 Beagles. PROCEDURE: Doxycycline (10 mg/kg, PO, q 12 h), amoxicillin (30 mg/kg, PO, q 12 h), cephalexin (30 mg/kg, PO, q 12 h), and enrofloxacin (20 mg/kg, PO, q 24 h) were administered in random order to 10 healthy dogs at standard therapeutic dosages for 7 days, with a 7-day washout period between subsequent antimicrobials. In addition, 4 Beagles served as control dogs. Variables were evaluated before and after antimicrobial administration; they included platelet count, Hct, 1-stage prothrombin time (PT), activated partial thromboplastin time (PTT), fibrinogen concentration, and platelet function. Platelet function was assessed via buccal mucosal bleeding time, aggregation, and a platelet-function analyzer. RESULTS: Administration of all antimicrobials caused a slight prolongation of 1-stage PT and activated PTT and slight decrease in fibrinogen concentration. Cephalexin caused a significant increase in 1-stage PT and activated PTT, amoxicillin caused a significant increase in activated PTT, and enrofloxacin caused a significant decrease in fibrinogen concentration. Platelet count or function did not differ significantly after administration of any antimicrobial. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of commonly used antimicrobials in healthy dogs resulted in minor secondary hemostatic abnormalities, with no change in platelet count or function. Although these changes were clinically irrelevant in healthy dogs, additional studies of the effects of antimicrobial administration on hemostasis in animals with underlying disease processes are warranted.

Cutaneous manifestations of disseminated toxoplasmosis in an immunosuppressed dog.

A 3.5-year-old, castrated male, giant schnauzer was presented with alopecic pustular dermatitis. Immune-mediated hemolytic anemia had been diagnosed 45 days previously. At the time of presentation, the dog was receiving prednisone, azathioprine, and cyclosporine. Cutaneous protozoosis was diagnosed, and postmortem examination revealed protozoa within cutaneous, cardiac, pancreatic, and pulmonary tissues. The protozoa divided by endodyogeny, had the morphology of Toxoplasma gondii (T. gondii) tachyzoites, and stained positively with T. gondii polyclonal antibodies but not with antibodies to Neospora caninum or Sarcocystis neurona. Immunosuppression may have predisposed this dog to disseminated toxoplasmosis.

Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs.

OBJECTIVE: To identify the normal gastric acid secretion profile in dogs and determine the degree of gastric acid suppression associated with 4 gastric acid suppressants. ANIMALS: 12 healthy Beagles. PROCEDURE: Intragastric pH was measured continuously for 24-hour periods with a digital recording system placed via a gastrostomy tube. Baseline measurements were obtained when food was withheld and when dogs were fed a standard diet. Dogs were then treated with ranitidine (2 mg/kg, IV, q 12 h), famotidine (0.5 mg/kg, IV, q 12 h), pantoprazole (1 mg/kg, IV, q 24 h), omeprazole (1 mg/kg, PO, q 24 h), or saline solution for 7 days; intragastric pH was recorded on days 0, 2, and 6. Subsequently, the effects of administering famotidine (0.5 mg/kg, IV, q 8 h; 6 dogs) and omeprazole as a suspension (1 mg/kg, PO, q 12 h; 6 dogs) were evaluated. Median 24-hour intragastric pH, percentage of time pH was > or = 3, and percentage of time pH was > or = 4 were determined. RESULTS: Median pH, percentage of time pH was > or = 3, and percentage of time pH was > or = 4 were all significantly higher when food was withheld than when dogs were fed. Famotidine, pantoprazole, and omeprazole significantly suppressed gastric acid secretion, compared with saline solution, as determined on the basis of median 24-hour pH and percentages of time pH was > or = 3 or > or = 4. However, ranitidine did not. Omeprazole suspension suppressed gastric acid secretion. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in healthy dogs, famotidine, pantoprazole, and omeprazole significantly suppress gastric acid secretion. Twice daily administration of a suspension of omeprazole, was the only regimen tested that approached the potential therapeutic efficacy for acid-related disease when assessed by criteria used for human patients.