Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (µ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

A new species of amphipod of the genus Parhyale Stebbing, 1897 from Chilika Lagoon, India.

A new species of the genus Parhyale, Stebbing 1897 was collected from the intertidal region of Chilika Lagoon associated with the seaweed Gracilaria sp. Parhyale odian sp. nov. differs from other species of the genus by having a stout robust seta on the surface of the propodus near to dactyl hinge of male gnathopod 1. With the new description of P. odian sp. nov., the global species number in the genus rises to 16.

Talorchestia buensis sp. nov. (Senticaudata, Talitridae), a new species of amphipod from West Bengal, east coast of India.

In coastal regions, Talitrids are found among decaying material in the supralittoral zone of sandy beach, mangroves and delta regions. Five genus and five species of the family Talitridae have been reported so far from Indian coastal waters. A new species of the amphipod genus Talorchestia Dana, 1852, Talorchestia buensis sp. nov. was collected from Kadirabad Char, West Bengal, east coast of India. The species was collected from a sandy beach, beneath dead leaves. The new species can be distinguished from other described species of the genus by the presence of a double rows of setae on the endopod of uropod 2, the presence of more than 10 robust setae in each lobe of the telson, antenna 2 reaching more than half the body length, pereopod 7 longer than pereopod 6 and by the absence of a distal protuberance on the palm of male gnathopod 2. The present article increases the total number of world species in the genus to 26.

A new species and a new record of the amphipod genus Cymadusa Savigny, 1816 (Senticaudata, Ampithoidae) from India.

The present study recorded Cymadusa filosa Savigny 1816 for the first time from India along with the description of a new species Cymadusa kaureshi n. sp. The newly described species C. kaureshi n. sp. can be differentiated from its closely related congeners C. setosa (Haswell, 1879) and C. tattersalli Peart, 2004 in having 3 articulated accessory flagellum of antenna 1 and male gnathopod 2 palm with small proximal knob-like process. The record of Cymadusa filosa Savigny, 1816 by Rabindranath (1972) from Tamil Nadu does not match with the description and illustrations of C. filosa sensu stricto in having mid palmar tooth on male gnathopod 2; antenna 1 with 3 articulated accessory flagellum and gnathopod 1 significantly longer and slender than gnathopod 2. Since the record of Rabindranath (1972) significantly differs from C. filosa sensu stricto, we assume that the Tamil Nadu specimen could be an undescribed species. Moreover, all the previous reports from India of C. filosa are erroneous, and here in this study we report the first confirmed record of C. filosa from India.

Soluble and insoluble α-glucan synthesis in yeast by enzyme suites derived exclusively from maize endosperm.

Molecular mechanisms that distinguish the synthesis of semi-crystalline α-glucan polymers found in plant starch granules from the synthesis of water-soluble polymers by nonplant species are not well understood. To address this, starch biosynthetic enzymes from maize (Zea mays L.) endosperm were isolated in a reconstituted environment using yeast (Saccharomyces cerevisiae) as a test bed. Ninety strains were constructed containing unique combinations of 11 synthetic transcription units specifying maize starch synthase (SS), starch phosphorylase (PHO), starch branching enzyme (SBE), or isoamylase-type starch debranching enzyme (ISA). Soluble and insoluble branched α-glucans accumulated in varying proportions depending on the enzyme suite, with ISA function stimulating distribution into the insoluble form. Among the SS isoforms, SSIIa, SSIII, and SSIV individually supported the accumulation of glucan polymer. Neither SSI nor SSV alone produced polymers; however, synergistic effects demonstrated that both isoforms can stimulate α-glucan accumulation. PHO did not support α-glucan production by itself, but it had either positive or negative effects on polymer content depending on which SS or a combination thereof was present. The complete suite of maize enzymes generated insoluble particles resembling native starch granules in size, shape, and crystallinity. Ultrastructural analysis revealed a hierarchical assembly starting with subparticles of approximately 50 nm diameter that coalesce into discrete structures of approximately 200 nm diameter. These are assembled into semi-crystalline α-glucan superstructures up to 4 µm in length filling most of the yeast cytosol. ISA was not essential for the formation of such particles, but their abundance was increased dramatically by ISA presence.

Provider-directed analgesia for dental pain.

INTRODUCTION: Extraction of impacted molar teeth is a common procedure performed by oral surgeons and general dentists, with postoperative pain being a significant adverse event post-surgery. If mismanaged, pain can lead to complications that impact oral and systemic health. The current scourge of the opioid epidemic has ushered in a new era of provider-directed analgesic (PDA) therapy in dentistry. AREAS COVERED: This article provides an in-depth review on the major pharmacological and therapeutic properties of established and alternative analgesics used to manage dental pain. EXPERT OPINION: Substantial evidence-based literature shows a combination of a non-steroidal anti-inflammatory drug (NSAID; e.g. ibuprofen) and acetaminophen provides superior pain relief than single-agent or combination opioid regimens. However, there are clinical scenarios (e.g. severe pain) where a short-course opioid prescription is appropriate in select patients, for which a 2-3-day treatment duration is typically sufficient. Alternative agents (e.g. caffeine, gabapentin, phytotherapies), typically in combination with established agents, can mitigate postoperative dental pain. Some evidence suggests preemptive therapies (e.g. corticosteroids, NSAIDs) reduce amounts of postsurgical analgesic consumption and might lessen opioid prescription burden. In summary, this comprehensive review provides an opportune update on the evolving landscape of pharmacotherapy for acute postsurgical dental pain, informing best practices for PDA in the dental setting.

A new species of the amphipod genus Quadrivisio (Senticaudata, Maeridae) from Chilika Lagoon, India.

A new species of the amphipod genus Quadrivisio Stebbing, 1907, Quadrivisio chilikensis sp. nov. was collected from the Chilika Lagoon, east coast of India. The species was collected from seaweed Chaetomorpha sp.. The new species can be distinguished from other described species of the genus by the presence of a carina on pleonites and urosome, by the flagellum of antenna 2 being twice the length of peduncle article 5 and by pereopods 6 and 7 being equal in length.

Interactions of Betel Quid Constituents with Drug Disposition Pathways: An Overview.

Global estimates indicate that over 600 million individuals worldwide consume the areca (betel) nut in some form. Nonetheless, its consumption is associated with a myriad of oral and systemic ailments, such as precancerous oral lesions, oropharyngeal cancers, liver toxicity and hepatic carcinoma, cardiovascular distress, and addiction. Users commonly chew slivers of areca nut in a complex consumable preparation called betel quid (BQ). Consequently, the user is exposed to a wide array of chemicals with diverse pharmacokinetic behavior in the body. However, a comprehensive understanding of the metabolic pathways significant to BQ chemicals is lacking. Henceforth, we performed a literature search to identify prominent BQ constituents and examine each chemical's interplay with drug disposition proteins. In total, we uncovered over 20 major chemicals (e.g., arecoline, nicotine, menthol, quercetin, tannic acid) present in the BQ mixture that were substrates, inhibitors, and/or inducers of various phase I (e.g., CYP, FMO, hydrolases) and phase II (e.g., GST, UGT, SULT) drug metabolizing enzymes, along with several transporters (e.g., P-gp, BCRP, MRP). Altogether, over 80 potential interactivities were found. Utilizing this new information, we generated theoretical predictions of drug interactions precipitated by BQ consumption. Data suggests that BQ consumers are at risk for drug interactions (and possible adverse effects) when co-ingesting other substances (multiple therapeutic classes) with overlapping elimination mechanisms. Until now, prediction about interactions is not widely known among BQ consumers and their clinicians. Further research is necessary based on our speculations to elucidate the biological ramifications of specific BQ-induced interactions and to take measures that improve the health of BQ consumers.

The impact of coronavirus disease 2019 pandemic on dental school assessments - Current status and future perspectives.

PURPOSE: To evaluate course directors' feedback on the assessment methods used during the coronavirus disease 2019 (COVID-19) pandemic and identify effective approaches for future assessments in dental education. METHODS: Course directors at the US dental schools were surveyed for changes in assessments implemented during the early stages of the pandemic (March-July 2020) using the Qualtrics platform. The survey questions addressed assessment methods utilized in didactic, preclinical, and clinical arenas pre-COVID-19 (before March 2020) and during the early phase of the pandemic (between March and July 2020) and identified any sustained changes in assessments post-COVID-19. Of the 295 responses for the type of courses directed, 48%, 22%, and 30% responses were for didactic, pre-clinical, and clinical assessments, respectively. Chi-square tests and 95% confidence intervals were used to assess quantitative differences. RESULTS: Computer-based un-proctored and remote- proctored assessments increased whereas paper-based in-person proctored assessments decreased during an early pandemic. For pre-clinical and clinical courses, objective-structured clinical exams and case-based assessments increased whereas, for didactic courses, the number of presentations, short-answer, and multiple-choice questions-based assessments increased. Specimen-based assessments and patient-based encounters decreased significantly in didactic and clinical courses, respectively. Manikin-based exams increased in clinical but not in pre-clinical courses. Survey respondents disagreed that alternative assessments helped students learn better, resulted in better course evaluations, or were an equivalent replacement for pre-COVID-19 assessments. Interestingly, 49% of respondents indicated a likelihood of continuing alternative assessments whereas 36% were unlikely and 15% were neutral. CONCLUSIONS: A combination of effective pre-pandemic and innovative alternative assessments developed during the pandemic may be the new normal in the dental education curriculum.

Annotated Checklist of Marine Amphipods (Crustacea: Amphipoda) of India.

An annotated checklist of the marine amphipods recorded from Indian waters is compiled from the available peer-reviewed literature. A total of 266 species belonging to 133 genera and 56 families are listed. The maximum numbers of species were recorded from the South Indian Ecoregion (177 species, 98 genera, 47 families), followed by the Western India Ecoregion (101 species, 72 genera, 36 families), the Eastern Indian Ecoregion (99 species, 65 genera, 35 families), the Northern Bay of Bengal Ecoregion (92 species, 53 genera, 29 families), the Maldives Ecoregion (32 species, 24 genera, 16 families), and the Andaman and Nicobar Islands Ecoregion (31 species, 22 genera, 18 families). Notes on the questionable identifications and records of some amphipods are also provided.

Effect of imatinib on oral wound healing after extraction: A rare case report.

BACKGROUND: Proper tissue repair and healing after oral surgery are vital to achieve optimal outcomes. Certain medications may interfere with wound healing, but this debilitating adverse drug reaction is often not reported in the literature. It is unknown whether imatinib (Gleevec; Novartis Pharmaceuticals) interferes with gingival healing after oral surgery. CASE DESCRIPTION: A 58-year-old man with a dislodged crown and core buildup of tooth no. 19 sought treatment at a prosthodontic clinic. After examination, the patient consented to extraction, ridge preservation, and future implant placement. He had previous surgical resection of a gastrointestinal stromal tumor and was taking 400 mg of imatinib daily. After extraction and ridge preservation, delayed soft-tissue healing and loss of the coronal portion of bone graft were observed at 8 weeks after surgery. Delayed wound healing was observed again after revision surgery. After imatinib therapy was paused, the adverse effect subsided and the wound healed properly. On the basis of causality assessment and clinical judgment, the authors determined that imatinib was the probable cause of this adverse drug reaction. To their best knowledge, this is the first report of delayed gingival healing after oral surgery secondary to imatinib. PRACTICAL IMPLICATIONS: Dental practitioners should consider the possibility of impaired healing among their patients taking imatinib, especially before procedures that damage gingival tissue, although this adverse drug reaction is not reported in the drug's package insert. Consult with the patient's oncologist is advised before dental manipulations; temporary discontinuation (or dose reductions) of imatinib may be warranted until wounded tissue heals properly.

Metabolism of the areca alkaloids - toxic and psychoactive constituents of the areca (betel) nut.

Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include N-oxidation, glutathionylation, nitrosamine conversion, and carbon-carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field.

A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation.

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3-70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted. Median follow-up was 66 months (interquartile range: 58-80). Three-year relapse incidence (RI), 25% with FCB, vs. 39% with Flu-Bu (p = 0.018), offset by higher non-relapse mortality, 22.6% (95%CI: 16-30.2%) vs. 12.3% (95%CI: 6.5-19%). Three-year PFS was 52% (95%CI: 44-62%) (FCB), vs. 48% (95%CI: 41-58%) (Flu-Bu). FCB benefited CR patients less, NCR patients age ≤ 60 had 3-year 34% RI (95%CI: 19-49%) (FCB) vs. 56% (95%CI: 38-70%) after Flu-Bu (p = 0.037). NCR patients >60 years had 3-year RI 10.0% (FCB), vs. 56.0%, after Flu-Bu (p = 0.003). Bayesian regression analysis including treatment-covariate interactions showed FCB superiority in NCR patients with low HCT-CI (0-2). Serious adverse event profiles were similar for the regimens. Conditioning with FCB did not improve PFS overall, but improved disease control in NCR patients, mandating confirmatory trials. Remission status and HCT-CI should be considered when using FCB.

A revision of the genus Pontocrates Boeck, 1871 (Amphipoda, Oedicerotidae) with the description of P. moorei sp. nov. and the re-establishment of P. norvegicus (Boeck, 1860).

The genus Pontocrates Boeck, 1871 is revised. Pontocrates norvegicus Boeck (1860), is re-established and a new species, P. moorei sp. nov., is described. An illustrated key to the species of the genus is provided.

The conquest of land by the Amphipoda (Senticaudata, Talitroidea) explained by global tectonics and vicariance.

The Talitroidea originated from a marine ancestor in the amphipod family Hyalidae that colonised marshy land flooded occasionally by the sea. From there, some descendants migrated inland along river catchments, as their terrestrial adaptations evolved, becoming riparian. Over time they colonised moist habitats in fields and forests. The superfamily Talitroidea comprises all known terrestrial amphipods and it has an almost worldwide distribution, but families have discrete distributions. Because all amphipods release fully formed young and have no dispersive phase in their life history, their potential for dispersal is extremely limited. Terrestrial talitroids are particularly constrained on a global scale, because their adaptations for terrestrial life prevent them from crossing seas or oceans. It has been hypothesised that Talitridae living on marine shores might traverse oceans on rafts of detached wrack. Support for this might be the fact that beach hoppers are the most widely distributed of the Talitroidea. However, they have been shown to abandon floating objects actively and several attempts to explain specific cases of talitrid distributions by implicating rafting have been falsified. The broad distributions of Talitroidea across the globe can be explained parsimoniously only by vicariance. The family Arcitalitridae is, with one exception, endemic to Australasia and South Africa, which have been separated from one another since the late Jurrasic c.150Ma. The exception is provided by two genera in Indochina, which probably arrived in Laurasia when India, which had been part of east Gondwana, accreted to Laurasia in the Miocene. However, terranes separated from the margins of Gondwana in the late Triassic-early Jurrasic and then accreted as allochthonous terranes to Laurasia, so the possibility of arcitalitrids arriving in Laurasia at that time, cannot be excluded. The family Makawidae, which is endemic to Zealandia and Tasmania, probably attained it's current distribution through the expansion of the Tasman Sea in the Cretaceous.

Chemical Degradation of Intravenous Chemotherapy Agents and Opioids by a Novel Instrument.

Purpose: To assess chemical degradation of various liquid chemotherapy and opioid drugs in the novel RxDestruct™ instrument. Methods: Intravenous (IV) drug solutions for chemotherapy and pain management were prepared using 0.9% normal saline in Excel® bags to a final volume of 500 mL. We investigated duplicate IV solutions of methotrexate (0.1 mg/mL), etoposide (0.4 mg/mL), doxorubicin (0.25 mg/mL), cladribine (12.4 µg/mL), fentanyl (1.0 µg/mL), and hydromorphone (12.0 µg/mL) in this study. Solutions were poured into an automated instrument to undergo pulsatile chemical treatment (Fenton reactions) for 20 minutes, and then discharged from the instrument through a waste outlet. Extent of intact drug degradation was determined by measuring concentrations of drugs before entry into the instrument and after chemical treatment in the filtrate using high-performance liquid-chromatography with ultraviolet detection (HPLC-UV). Results: Following chemical reactions (Fenton processes) in the automated instrument, infusion solutions containing methotrexate, etoposide, doxorubicin, and cladribine had levels below the HPLC-UV limit of quantification (LOQ), indicating <50 ppb of each. This equated to >99.5%, 99.99%, 99.9%, and 99.8% intact drug loss, respectively. Likewise, processed samples of fentanyl and hydromorphone contained levels below the LOQ (78 and 98 ng/mL, respectively), indicating extensive degradation (>92.2% and 99.2% intact drug loss, respectively). Conclusion: The novel instrument was capable of degrading intact chemotherapy and opioid drugs prepared in infusion solutions to undetectable quantities by HPLC-UV. RxDestruct™ is a possible alternative for disposal of aqueous medication waste.

Genome assembly and population genomic analysis provide insights into the evolution of modern sweet corn.

Sweet corn is one of the most important vegetables in the United States and Canada. Here, we present a de novo assembly of a sweet corn inbred line Ia453 with the mutated shrunken2-reference allele (Ia453-sh2). This mutation accumulates more sugar and is present in most commercial hybrids developed for the processing and fresh markets. The ten pseudochromosomes cover 92% of the total assembly and 99% of the estimated genome size, with a scaffold N50 of 222.2 Mb. This reference genome completely assembles the large structural variation that created the mutant sh2-R allele. Furthermore, comparative genomics analysis with six field corn genomes highlights differences in single-nucleotide polymorphisms, structural variations, and transposon composition. Phylogenetic analysis of 5,381 diverse maize and teosinte accessions reveals genetic relationships between sweet corn and other types of maize. Our results show evidence for a common origin in northern Mexico for modern sweet corn in the U.S. Finally, population genomic analysis identifies regions of the genome under selection and candidate genes associated with sweet corn traits, such as early flowering, endosperm composition, plant and tassel architecture, and kernel row number. Our study provides a high-quality reference-genome sequence to facilitate comparative genomics, functional studies, and genomic-assisted breeding for sweet corn.

Retail Availability and Characteristics of Addictive Areca Nut Products in a US Metropolis.

Consumption of the areca (betel) nut is the world's fourth-most common addictive habit, only after caffeine, alcohol, and nicotine. Mastication of the nut releases psychoactive alkaloids that produce greater alertness, a tingling sensation in the body, and euphoria. Consumption is prevalent in many Asia-Pacific countries, but also within immigrant populations in Europe and North America. Regarding use/abuse in the US, data are limited to mostly case/anecdotal reports, and some published literature. Little is known about the retail availability and product characteristics of areca products in the US. In this field observational study, we found that areca products were relatively inexpensive, readily available, and easily purchased in grocery stores visited in Houston, TX. Almost entirely, no hindrances or warnings for purchasing occurred, which is concerning since it is well-established that consumption is associated with substance abuse and untoward oral/systemic health effects. Several products contained the sweetening agent sodium cyclamate, a substance currently banned by the FDA. Others products contain menthol, the role of which in areca addiction is unknown. Collectively, our findings support the need for future psychopharmacological and public health research, as well as closer investigation by US policy makers and statewide/federal regulatory agencies.