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.

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.

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.

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.

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.

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.

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.

Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection.

BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.27 kg L-1 h-1.

A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology.

The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high-yielding, mass-efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2 , this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.

Development of quantitative PCR assay for detection of the trematode parasite Proctoeces maculatus in the blue mussel Mytilus edulis.

The digenean trematode Proctoeces maculatus is an important parasite of the blue mussel Mytilus edulis. The parasite reduces mussel quality and yield, negatively impacting mussel aquaculture efforts. Typically, the trematode is detected by visual observation. To provide a better diagnostic tool able to detect this parasite at any life stage and at low intensities, we designed a species-specific molecular assay to detect P. maculatus in M. edulis tissue. Primers targeting the 18S nuclear ribosomal DNA (rDNA) from P. maculatus were used to develop an end-point polymerase chain reaction assay and a quantitative polymerase chain reaction (qPCR) assay. Analytical specificity of the assays was demonstrated using DNA from 4 other digenean trematodes. The qPCR assay was linear from 6.79 × 102 to 6.79 × 107 copies of the cloned target DNA and had a conservative detection limit of 68 copies. The qPCR assay detected single cercariae, and the number of isolated cercariae was linearly correlated with the threshold cycle (CT). Diagnostic sensitivity of the PCR-based methods was 100%. The assays also detected the parasite in 6 additional samples from the 57 tested through microscopy. We used the assays to verify the presence of encapsulated sporocysts in the mantle and to document infected mussels from Dover, New Hampshire, extending the previously described northern range of the species. Thus, this work has important implications for detection of the parasite in aquaculture and in monitoring its potential spread with climate change.

First documentation and molecular confirmation of three trematode species (Platyhelminthes: Trematoda) infecting the polychaete Marenzelleria viridis (Annelida: Spionidae).

Polychaete worms are hosts to a wide range of marine parasites; yet, studies on trematodes using these ecologically important species as intermediate hosts are lacking. During examination of the spionid polychaete Marenzelleria viridis collected on the north shore of Long Island, New York, putative trematode cysts were discovered in the body cavity of these polychaetes. In order to verify these cysts as metacercariae of trematodes, specimens of the eastern mudsnail Ilyanassa obsoleta (a very common first intermediate host of trematodes in the region) were collected for molecular comparison. DNA barcoding using cytochrome C oxidase I regions confirmed the presence of three species of trematodes (Himasthla quissetensis, Lepocreadium setiferoides, and Zoogonus lasius) in both M. viridis and I. obsoleta hosts. Brown bodies were also recovered from polychaetes, and molecular testing confirmed the presence of L. setiferoides and Z. lasius, indicating an immune response of the polychaete leading to encapsulation of the cysts. From the 125 specimens of M. viridis collected in 2014, 95 (76.8 %) were infected with trematodes; of these 95 infected polychaetes, 86 (90.5 %) contained brown bodies. This is the first confirmation that trematodes use M. viridis as a second intermediate host and that this intermediate host demonstrates a clear immune response to metacercarial infection. Future research should explore the role of these polychaetes in trematode life cycles, the effectiveness of the immune response, and transmission pathways to vertebrate definitive hosts.

Occupational skin disease in Victoria, Australia.

OBJECTIVES: To describe the characteristics of patients with occupational skin disease (OSD) in a tertiary referral clinic in Victoria, Australia. METHODS: A retrospective review was conducted of records from patients seen at the Occupational Dermatology Clinic in Melbourne, Australia between 1 January 1993 and 31 December 2010. RESULTS: Of the 2894 people assessed in the clinic during the 18-year period, 44% were women and 56% were men. In all, 2177 (75%) were diagnosed with occupational skin disease (OSD). Of the patients with a work-related skin condition, 45% (n = 979) were considered to be atopic. The most common diagnosis in those with OSD was irritant contact dermatitis (ICD) (44%), followed by allergic contact dermatitis (33%) and endogenous eczema (11%). Women were significantly more likely to have soaps and detergents (P < 0.001) and water/wet work (P < 0.001) as causes of their ICD than men. Men were significantly more likely to have oils and coolants (P < 0.001) and solvent exposures (P < 0.001) as causes of their ICD. Occupational groups with the highest incidence of OSD were the hair and beauty professions (70 per 100 000), followed by machine and plant operators (38 per 100 000) and health-care workers (21 per 100 000). CONCLUSION: We confirm the importance of occupational contact dermatitis as the most common cause of OSD, with ICD being the most common diagnosis. There are differences in the causes of ICD between our group of male and female workers. For the first time in Australia, rates of OSD in certain industries have been calculated.

A new genus for Entophilus mirabiledictu Markham & Dworschak, 2005 (Crustacea: Isopoda: Cryptoniscoidea: Entophilidae) with remarks on morphological support for epicaridean superfamilies based on larval characters.

A detailed reexamination of male and female Entophilus mirabiledictu Markham & Dworschak, 2005 (an endoparasite of callianassid shrimp), resulted in recognition of seven female and five male characters that separate the species from its sole congener, E. omnitectus Richardson, 1903 (an endoparasite of munidid squat lobsters). These characters show that the two species are so different as to warrant E. mirabiledictu being placed in its own genus within the Entophilidae. Additionally, a review of the morphological features of entophilid cryptoniscus larvae led to the finding that the number of flagellar segments on the second antenna offers morphological support for a recent molecular phylogeny of epicaridean taxa that rearranged the component families within the two recognised superfamilies. This work highlights the power of using larval characters in testing hypotheses on the evolutionary relationships of epicaridean taxa.

Effectiveness of an intensive outpatient program for disruptive children: initial findings.

There are currently no manualized, intensive outpatient programs (IOP), for diagnostically heterogeneous pediatric samples that simultaneously intervene with youth and parents. Such a program was developed and has been operating at Children's Hospital Colorado since January 2006. The current study was conducted to characterize the patient sample and evaluate clinical outcomes for this novel program. The study used a method of retrospective chart review to examine demographic and diagnostic information of youth and their families, who participated in IOP. Clinical outcomes were similarly assessed, using paired-samples t test comparisons of the baseline and endpoint parent-report versions of the Ohio Youth Outcome Scales. Results indicated that there were statistically significant differences in each of the Subscale scores on the Ohio Youth Scales from baseline to endpoint of IOP. Preliminary findings suggest that participation in the IOP program was associated with improved clinical outcomes, at the end of treatment.

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.

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.

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.

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.