A Slug Flow Platform with Multiple Process Analytics Facilitates Flexible Reaction Optimization.

Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low-volume optimization experiments are reported. A Buchwald-Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self-optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor.

The Rocky Road to a Digital Lab.

The pharmaceutical industry has begun incorporating continuous manufacturing technology in synthetic routes toward active pharmaceutical ingredients (APIs). The development of smart manufacturing routes can be accelerated by utilizing digitalization, process analytical technology (PAT), and data-rich experimentation from an early stage. Here, we present the key aspects of implementing automated flow chemistry reactor platforms with real-time process analytics. Based on our experiences in this field, we aim to highlight the potential of these platforms to conduct self-optimization, automated reaction model building, dynamic experiments and to implement advanced process control strategies.

Rediscovering Cyanogen Gas for Organic Synthesis: Formation of 2-Cyanothiazole Derivatives.

The expeditious synthesis of an API building block, 2-cyanothiazole, from cyanogen gas and a readily available dithiane is reported. A previously undisclosed partially saturated intermediate is formed, which can be further functionalized and isolated by the acylation of the hydroxy group. Dehydration using trimethylsilyl chloride furnished 2-cyanothiazole, which could be further converted to the corresponding amidine. The sequence provided a 55% yield over 4 steps. We envision that this work will spark further interest in cyanogen gas as a reactive and cost-effective synthetic reagent.

Active ascent accelerates the time course but not the overall incidence and severity of acute mountain sickness at 3,600 m.

Acute mountain sickness (AMS) typically peaks following the first night at high altitude (HA) and resolves over the next 2-3 days, but the impact of active ascent on AMS is debated. To determine the impact of ascent conditions on AMS, 78 healthy Soldiers (means ± SD; age = 26 ± 5 yr) were tested at baseline residence, transported to Taos, NM (2,845 m), hiked (n = 39) or were driven (n = 39) to HA (3,600 m), and stayed for 4 days. AMS-cerebral (AMS-C) factor score was assessed at HA twice on day 1 (HA1), five times on days 2 and 3 (HA2 and HA3), and once on day 4 (HA4). If AMS-C was ≥0.7 at any assessment, individuals were AMS susceptible (AMS+; n = 33); others were nonsusceptible (AMS-; n = 45). Daily peak AMS-C scores were analyzed. Ascent conditions (active vs. passive) did not impact the overall incidence and severity of AMS at HA1-HA4. The AMS+ group, however, demonstrated a higher (P < 0.05) AMS incidence in the active vs. passive ascent cohort on HA1 (93% vs. 56%), similar incidence on HA2 (60% vs. 78%), lower incidence (P < 0.05) on HA3 (33% vs. 67%), and similar incidence on HA4 (13% vs. 28%). The AMS+ group also demonstrated a higher (P < 0.05) AMS severity in the active vs. passive ascent cohort on HA1 (1.35 ± 0.97 vs. 0.90 ± 0.70), similar score on HA2 (1.00 ± 0.97 vs. 1.34 ± 0.70), and lower (P < 0.05) score on HA3 (0.56 ± 0.55 vs. 1.02 ± 0.75) and HA4 (0.32 ± 0.41 vs. 0.60 ± 0.72). Active compared with passive ascent accelerated the time course of AMS with more individuals sick on HA1 and less individuals sick on HA3 and HA4.NEW & NOTEWORTHY This research demonstrated that active ascent accelerated the time course but not overall incidence and severity of acute mountain sickness (AMS) following rapid ascent to 3,600 m in unacclimatized lowlanders. Active ascenders became sicker faster and recovered quicker than passive ascenders, which may be due to differences in body fluid regulation. Findings from this well-controlled large sample-size study suggest that previously reported discrepancies in the literature regarding the impact of exercise on AMS may be related to differences in the timing of AMS measurements between studies.

A review of the endoparasitic isopods (Epicaridea: Entoniscidae) from hermit crabs, including description of the new subfamily Diogenioninae and a new species of Paguritherium Reinhard, 1945 from the Philippines.

Entoniscid isopods (Entoniscidae) are obligate endoparasites of other crustacean species. They have an indirect lifestyle, usually with two hosts and multiple larval stages; as adults they are found living within decapod hosts. Hermit crabs were previously known to be definitive hosts of only two species of entoniscid parasites: Paguritherium alatum, from the east coast of the United States in Pagurus spp. and Diogenion vermifactus from the Red Sea in Diogenes senex. Little beyond the original descriptions of these species has been reported in the literature. Recently, two species of entoniscids were found parasitizing hermit crabs (mostly Calcinus spp.) collected from shallow water coral reef areas in the Philippines. The goal of this study was to describe the morphology of both the adult and larval stages of these entoniscids through light and scanning electron microscopy and compare them to the previously described species that infest hermit crabs. One of these entoniscids is tentatively identified as D. vermifactus, which infested 0.95% (5 of 527) of the hermit crabs sampled. All specimens of D. cf. vermifactus were found in the abdomens of specimens of Calcinus gaimardii, C. minutus, C. pulcher and Pagurojacquesia polymorpha. Examination of D. vermifactus shows that this taxon belongs in its own subfamily: Diogenioninae n. subfam. The second entoniscid is a new species of the genus Paguritherium and infested 0.94% (7 of 744) of the hermit crabs (C. gaimardii and C. latens) sampled. Females of P. manggagaway n. sp. are characterized by a highly vaulted head, a slender body and long pleopods and males by a blunt head and stump-like pereopods covered in scales; the new species can be distinguished from P. alatum based on the specialized fan-like setae on the first five pereopods of the epicaridium larvae. A key to all entoniscid genera is provided.

Nomenclatural and taxonomic changes in parasitic isopods (Isopoda: Epicaridea), including two new families and note on the questionable association between monogeneans and bopyrids.

Several long-standing taxonomic and nomenclatural problems in bopyroid and cryptoniscoid isopods are addressed. Within Bopyroidea we propose five new synonomies, three new combinations, a correction of the spelling of one species and a replacement name for another. In addition, the likely erroneous conclusion that a monogenean is an associate of bopyrids is discussed. Within Cryptoniscoidea, we determined the familial placement of three genera that were previously designated as incertae sedis (Capitoniscus Bourdon, 1972 and Carocryptus Schultz, 1977) or of doubtful affiliation (Cumoechus Hansen, 1916). In total, five species of cryptoniscoids are placed into two new families (Capitoniscidae n. fam. and Cumoechidae n. fam.), each containing at least one species known from both female and cryptoniscus larvae/paedomorphic male stages. Finally, the status of two cryptoniscoid genera is addressed: Gorgoniscus Grygier, 1981 is placed in Hemioniscidae, and Leponiscus Giard, 1887, is synonymized with Hemioniscus Buccholz, 1866.

An Umpolung Approach to Acyclic 1,4-Dicarbonyl Amides via Photoredox-Generated Carbamoyl Radicals.

A method for the generation and reaction of carbamoyl radicals from oxamate salts, followed by reaction with electron-poor olefins, is described. The oxamate salt acts as a reductive quencher in the photoredox catalytic cycle, allowing mild and mass-efficient formation of 1,4-dicarbonyl products; a challenging transformation in the context of functionalized amide formation. Increased understanding has been obtained by the use of ab initio calculations, in support of experimental observations. Furthermore, steps have been taken towards an environmentally-friendly protocol, by utilizing sodium as a cheap and low mass counterion, and demonstrating successful reactions using a metal-free photocatalyst and a sustainable, non-toxic solvent system.

Disposable laryngoscope intubation to reduce equipment failure in an emergency out of OR setting - a quality control case study.

BACKGROUND: Reusable laryngoscopes have been reported to be superior to disposable laryngoscopes with plastic blades during emergent intubations. Surprisingly, at our institution a quality reporting system revealed a high number of equipment failures with reusable laryngoscopes in an emergency out-of-OR (operating room) setting. As recent studies indicated an improved quality of disposable laryngoscopes, we hypothesized that a thoroughly evaluated disposable laryngoscope would result in less equipment failure in an emergency out-of-OR setting. METHODS: To perform a more standardized and time efficient analysis, four distinct disposable laryngoscope blade/handle configurations were trialed during standard intubations (n = 4 × 30) in the OR by experienced anesthesia providers who completed a 6-question, Likert-scale/open-ended survey for product evaluation. The 'best' disposable blade was implemented in an emergency out-of-OR setting and equipment failure rates were monitored over a 3-year period. RESULTS: Different disposable laryngoscopes were equal regarding sturdiness, illumination and airway visualization. The laryngoscope with the highest overall score was significantly higher scored than the laryngoscope with the lowest overall score. All disposable laryngoscopes were more cost effective than the reusable ones, and the top scored laryngoscope demonstrated the highest 5-year cost-saving ($210 K). Implementation of the top scored disposable laryngoscope into an emergency out-of-OR setting reduced the equipment failure incidence from high 20s to 0. CONCLUSION: Disposable laryngoscopes are cost effective and superior to reusable laryngoscopes in an emergency out-of-OR setting. We demonstrate that the implementation of a disposable laryngoscope in the emergency out-of-OR setting resulted in a near elimination of equipment related quality submissions which ultimately enhances patient safety.

Photochemical Deracemization of a Medicinally-Relevant Benzopyran using an Oscillatory Flow Reactor.

Dynamic deracemization processes, such as crystallization-induced diastereomer transformations (CIDTs), offer the opportunity to combine racemization and resolution processes, to provide high yields of enantiomerically pure compounds. To date, few of these processes have incorporated photochemical racemization. By combining batch crystallization with a flow photoreactor for efficient irradiation, it is possible to perform such deracemization in an effective, scalable and high yielding manner. After applying design of experiment (DoE) principles and mathematical modelling, the most efficient parameter set could be identified, leading to excellent results in just 4 h reaction time: isolated yield of 82 % and assay ee of 96 %. Such photochemical racemization methods can serve to open new avenues for preparation of enantiomerically pure functional molecules on both small and industrially-relevant scales.

Autonomous Multi-Step and Multi-Objective Optimization Facilitated by Real-Time Process Analytics.

Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single-step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self-optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two-step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L-1 h-1 space-time yield for this pharmaceutically relevant product.

A Review of the Parasitic Isopod Genus Epicepon Nierstrasz & Brender à Brandis, 1931 (Crustacea: Isopoda: Epicaridea), Parasites of Cyclodorippoid Crabs (Crustacea: Decapoda: Brachyura), with Description of a New Species from New Caledonia.

A new species of the parasitic isopod genus Epicepon Nierstrasz & Brender à Brandis, 1931 (Isopoda: Bopyridae) found parasitizing the cyclodorippoid crab host Tymolus hirtipes Tan & Huang, 2000 is described from New Caledonia. Females of Epicepon belema n. sp. can be distinguished from those of the other two species in the genus in length to width ratio, pleopodal endopod morphology, and structure of the barbula. We review the two previously described species of Epicepon from Tymolus Stimpson, 1858 hosts based on type specimens of E. indicum Nierstrasz & Brender à Brandis, 1931 from Indonesia and type specimens plus new material of E. japonicum Nierstrasz & Brender à Brandis, 1931 from Japan. New details previously omitted from the original descriptions and a key to species of Epicepon based on female and male specimens are provided.

Segmented worms (Phylum Annelida): a celebration of twenty years of progress through Zootaxa and call for action on the taxonomic work that remains.

Zootaxa has been the leading journal on invertebrate systematics especially within Annelida. Our current estimates indicate annelids include approximately 20,200 valid species of polychaetes, oligochaetes, leeches, sipunculans and echiurans. We include herein the impact of Zootaxa on the description of new annelid species in the last two decades. Since 2001, there have been over 1,300 new annelid taxa published in about 630 papers. The majority of these are polychaetes (921 new species and 40 new genera) followed by oligochaetes (308 new species and 10 new genera) and leeches (21 new species). The numerous papers dealing with new polychaete species have provided us a clear picture on which polychaete families have had the most taxonomic effort and which authors and countries have been the most prolific of descriptions of new taxa. An estimated additional 10,000+ species remain to be described in the phylum, thus we urge annelid workers to continue their efforts and aid in training a new generation of taxonomists focused on this ecologically important group.

Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow*.

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations. Advanced data analysis models were developed (indirect hard modeling, deep learning and partial least squares regression), to quantify the desired products, intermediates and impurities in real time, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data-driven continuous flow synthesis.

Continuous flow synthesis of arylhydrazines via nickel/photoredox coupling of tert-butyl carbazate with aryl halides.

Nickel/photoredox catalyzed C-N couplings of hydrazine-derived nucleophiles provide a powerful alternative to Pd-catalyzed methods. This continuous-flow photochemical protocol, optimized using design of experiments, achieves these couplings in short residence times, with high selectivity. A range of (hetero)aryl bromides and chlorides are compatible and understanding of process stability/reactor fouling has been discerned.

Confirmation of the shell-boring oyster parasite Polydora websteri (Polychaeta: Spionidae) in Washington State, USA.

Invasions by shell-boring polychaetes such as Polydora websteri Hartman have resulted in the collapse of oyster aquaculture industries in Australia, New Zealand, and Hawaii. These worms burrow into bivalve shells, creating unsightly mud blisters that are unappealing to consumers and, when nicked during shucking, release mud and detritus that can foul oyster meats. Recent findings of mud blisters on the shells of Pacific oysters (Crassostrea gigas Thunberg) in Washington State suggest a new spionid polychaete outbreak. To determine the identity of the polychaete causing these blisters, we obtained Pacific oysters from two locations in Puget Sound and examined them for blisters and burrows caused by polychaete worms. Specimens were also obtained from eastern oysters (Crassostrea virginica Gmelin) collected in New York for morphological and molecular comparison. We compared polychaete morphology to original descriptions, extracted DNA and sequenced mitochondrial (cytochrome c oxidase I [mtCOI]) and nuclear (small subunit 18S rRNA [18S rRNA]) genes to determine a species-level molecular identification for these worms. Our data show that Polydora websteri are present in the mud blisters from oysters grown in Puget Sound, constituting the first confirmed record of this species in Washington State. The presence of this notorious invader could threaten the sustainability of oyster aquaculture in Washington, which currently produces more farmed bivalves than any other US state.

A new species of Crinoniscus Pérez, 1900 (Crustacea: Isopoda: Crinoniscidae) parasitising the pedunculate barnacle Heteralepas newmani Buhl-Mortensen & Mifsud (Cirripedia: Heteralepadidae) with notes on its ecology and a review of the genus.

The new species Crinoniscus stroembergi n. sp. belonging to the parasitic isopod family Crinoniscidae Bonnier, 1900, is described from a pedunculate barnacle host collected in the Mediterranean Sea. This is the first species of Crinoniscus Pérez, 1900 described from a host in the genus Heteralepas Pilsbry. The male cryptoniscus larva is distinguished from congeneric species by having a dorsoventrally flattened body with the posterolateral margins of the cephalon scarcely extending beyond the anterior margin of pereomere 1 (in contrast to C. cephalatus Hosie, 2008 with extended margins); articles 1 and 2 of the antennule being subequal in width and the anterodistal angle of antennule article being low and rounded; propodus of pereopods 6 and 7 having a sinuous dorsal margin that is distally narrowing and the posterior margin of the pleotelson being short and rounded. The mature females of species in Crinoniscus are of two basic forms: those with ventrolateral lobes on the pereomeres (C. alepadis (Gruvel, 1901) n. comb., and C. politosummus Hosie, 2008) and those lacking such lobes (C. cephalatus and C. stroembergi n. sp.). The mature females of C. stroembergi n. sp. can be distinguished from other species of Crininiscus based on their lacking lobes on the anterior end. The material examined includes the male and three female developmental stages of the parasite in the host, Heteralepas newmani Buhl-Mortensen & Mifsud. The mouthparts of the immature female are described and the feeding biology and effects on the host are discussed along with a review of feeding modes in species of the Cryptoniscoidea. Leponiscus alepadis is transferred to Crinoniscus; the latter genus now contains five species. A modified diagnosis of Crinoniscus is provided.

Continuous-Flow Synthesis of ZIF-8 Biocomposites with Tunable Particle Size.

Zeolitic imidazolate framework (ZIF) biocomposites show the capacity to protect and deliver biotherapeutics. To date, the progress in this research area is based on laboratory batch methods. Now, the first continuous flow synthetic method is presented for the encapsulation of a model protein (bovine serum albumin, BSA) and a clinical therapeutic (α1-antitrypsin, AAT) in ZIF-8. The in situ kinetics of nucleation, growth, and crystallization of BSA@ZIF-8 were studied by small-angle X-ray scattering. By controlling the injection time of ethanol, the particle growth could be quenched by ethanol-induced crystallization from amorphous particles to ZIF-8 crystals. The particle size of the biocomposite was tuned in the 40-100 nm range by varying residence time prior to introduction of ethanol. As a proof-of-concept, this procedure was used for the encapsulation of AAT in ZIF-8. Upon release of the biotherapeutic from the composite, the trypsin inhibitor function of AAT was preserved.

Towards a Scalable Synthesis of 2-Oxabicyclo[2.2.0]hex-5-en-3-one Using Flow Photochemistry.

Cyclobutene lactones hold great potential as synthetic building blocks, yet their preparation by photochemical rearrangement in batch can often be a bottleneck in synthetic studies. We report the use of flow photochemistry as a tool to enable a higher-throughput approach to the synthesis of 2-oxabicyclo[2.2.0]hex-5-en-3-one, which reduces reaction times from 24 h to 10 min. Accordingly, a significantly improved throughput of 144 mg/h (vs 14-21 mg/h in batch) was achieved. Scale-out experiments showed problematic reactor fouling and steps were taken to explore and minimize this effect.