Further assessment of the clinical relevance of anatomical structures through PubMed and other measures.

A previous paper has demonstrated a statistically significant moderate correlation between the number of citations obtained from PubMed and a Delphi study for 251 anatomical structures of the Head and Neck region, suggesting that clinical significance is a major driver of research involving anatomical structures. This raises the possibility that these ranks could be an objective measure of clinical relevance of individual anatomical structures. In the present study, we revisited the rankings of the PubMed results from the previous paper and compared it with a Delphi study for 450 musculoskeletal structures. PubMed ranks were derived using different search parameters; a PubMed search with quotations yielded a moderate, statistically significant correlation coefficient of 0.639 with the musculoskeletal dataset. Additionally, we developed a Python tool, PDF Term Search, to calculate the frequency of anatomical terms in four authoritative textbooks, and these frequencies exhibited moderate significant correlations ranging (0.549-0.646) with our PubMed-derived ranks. We further explored strategies to improve the accuracy of our PubMed results by addressing limitations identified in the previous paper. We refined the syntax of search queries for 500 anatomical structures, resulting in marked improvement in the correlation coefficients with the musculoskeletal dataset, demonstrating clear avenues for future iterations of PubMed-derived ranks. We also created a spreadsheet of 2181 anatomical structures ranked using PubMed, published Delphi studies, and authoritative texts, providing a resource for anatomical educators who are adjusting their curricula to better train future healthcare practitioners.

Quantifying research on anatomical structures, a potential new metric for assessing clinical relevance.

Human anatomy remains an integral part of medical education, and recent studies have documented an emerging consensus on the key anatomical learning objectives for physicians and other health professionals in training, both at the graduate and postgraduate levels. Despite this progress, less attention has been given to assessing the clinical relevance of individual anatomical structures, and which structures students should master to achieve these learning objectives. In this study we hypothesized that published research involving individual anatomical structures is largely driven by the clinical relevance of these structures, and that tabulating the number of such publications can provide an up-to-date, evolving metric of clinical relevance. To test this hypothesis, we developed a semi-automated search routine that uses the PubMed database to quantify the publication frequency of anatomical structures and compared that to a previous study that assessed the importance of structures of the head and neck using the Delphi method, a formal procedure of generating expert consensus. Using our new approach, we were able to rank the research intensity of 2182 anatomical structures included in Grant's Dissector, a widely used textbook for anatomical dissection. Furthermore, a sample of these PubMed-derived ranks had a highly significant, positive correlation with ranks derived from a consensus of experts. Similar results were obtained when PubMed searches were restricted to journals that focus on applying knowledge in a clinical setting. Our study provides a potential new tool for anatomical educators who are aligning their basic science curricula with the clinical knowledge expected of medical graduates.

Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers.

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects.

Safety and Pharmacokinetics of Intranasally Administered Heparin.

PURPOSE: Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity. METHODS: Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 µg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects. RESULTS: UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 h, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 h. CONCLUSIONS: UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 h after dosing.

Safety and Pharmacokinetics of Intranasally Administered Heparin.

PURPOSE: Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity. METHODS: Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 µg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects. RESULTS: UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 hours, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 hours. CONCLUSIONS: UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 hours after dosing.

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration.

Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ's enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days' treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7-14 days washout period in between: R-(-) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects.

Hydrogen Bonds Dictate O2 Capture and Release within a Zinc Tripod.

Six directed hydrogen bonding (H-bonding) interactions allow for the reversible capture and reduction of dioxygen to a trans-1,2-peroxo within a tripodal zinc(II) framework. Spectroscopic studies of the dizinc peroxides, as well as on model zinc diazides, suggest H-bonding contributions serve a dominant role for the binding/activation of these small molecules.

Second sphere ligand modifications enable a recyclable catalyst for oxidant-free alcohol oxidation to carboxylates.

Modification of the classic terpyridine pincer ligand with pendent NHR (R = mesityl) groups provides enhanced activity and stability in Ru-catalyzed dehydrogenation catalysis. These second sphere modifications furnish highly active catalysts for the oxidant-free dehydrogenative oxidation of primary alcohols to carboxylates and facilitate catalyst recycling.

Hydrogen Bonds Dictate the Coordination Geometry of Copper: Characterization of a Square-Planar Copper(I) Complex.

6,6''-Bis(2,4,6-trimethylanilido)terpyridine (H2Tpy(NMes)) was prepared as a rigid, tridentate pincer ligand containing pendent anilines as hydrogen bond donor groups in the secondary coordination sphere. The coordination geometry of (H2 Tpy(NMes))copper(I)-halide (Cl, Br and I) complexes is dictated by the strength of the NH-halide hydrogen bond. The Cu(I)Cl and Cu(II)Cl complexes are nearly isostructural, the former presenting a highly unusual square-planar geometry about Cu(I) . The geometric constraints provided by secondary interactions are reminiscent of blue copper proteins where a constrained geometry, or entatic state, allows for extremely rapid Cu(I)/Cu(II) electron-transfer self-exchange rates. Cu(H2 Tpy(NMes))Cl shows similar fast electron transfer (≈10(5)  m(-1) s(-1)) which is the same order of magnitude as biological systems.

Beyond H2: exploiting 2-hydroxypyridine as a design element from [Fe]-hydrogenase for energy-relevant catalysis.

The unique primary and secondary coordination environments surrounding the active site of hydrogenase enzymes play a crucial role in H2 activation and transfer reactions. [Fe]-hydrogenase contains a 2-hydroxypyridine ligand motif, and many researchers have incorporated this design element into synthetic catalysts. Transition metal complexes supported by 2-hydroxypyridine scaffolds are catalysts for chemical conversion schemes relevant to alternative energy applications and, in addition to hydrogenase-type reactivity, find new uses in other chemical domains. In this review, the current status of 2-hydroxypyridine-derived catalysts is described with an emphasis on design features that lead to lower energy catalytic pathways.

The functional model complex [Fe2(BPMP)(OPr)(NO)2](BPh4)2 provides insight into the mechanism of flavodiiron NO reductases.

Flavodiiron nitric oxide reductases (FNORs), found in many pathogenic bacteria, are able to detoxify NO by reducing it to N2O. In this way, FNORs equip these pathogens with immunity to NO, which is a central immune defense agent in humans. Hence, FNORs are thought to promote infection of the human body, leading to chronic diseases. Despite this importance of FNORs for bacterial pathogenesis, the mechanism of NO reduction by these enzymes is not well understood. Here we present the synthesis and spectroscopic characterization of the diiron dinitrosyl model complex [Fe2(BPMP)(OPr)(NO)2](BPh4)2. The crystal structure of this complex shows two end-on-coordinated {FeNO}(7) units that, based on spectroscopic and electrochemical results, are only weakly electronically coupled. Importantly, reduction of this complex by two electrons leads to the clean formation of N2O in quantitative yield. This complex therefore represents the first example of a functional model system for FNORs. The results provide key mechanistic insight into the mechanism of FNORs and, in particular, represent strong support for the proposed "super-reduced" mechanism for these enzymes.

Nanoliter droplet viscometer with additive-free operation.

Measurement of a solution's viscosity is an important analytic technique for a variety of applications including medical diagnosis, pharmaceutical development, and industrial processing. The use of droplet-based (e.g., water-in-oil) microfluidics for viscosity measurements allows nanoliter-scale sample volumes to be used, much smaller than those either in standard macro-scale rheometers or in single-phase microfluidic viscometers. By observing the flow rate of a sample plug driven by a controlled pressure through an abrupt constriction, we achieve accurate and precise measurement of the plug viscosity without addition of labels or tracer particles. Sample plugs in our device geometry had a volume of ~30 nL, and measurements had an average error of 6.6% with an average relative standard deviation of 2.8%. We tested glycerol-based samples with viscosities as high as 101 mPa s, with the only limitation on samples being that their viscosity should be higher than that of the continuous oil phase.

Flexible casting of modular self-aligning microfluidic assembly blocks.

The recent shift among developers of microfluidic technologies toward modularized "plug and play" construction reflects the steadily increasing realization that, for many would-be users of microfluidic tools, traditional clean-room microfabrication is prohibitively complex and/or expensive. In this work, we present an advanced modular microfluidic construction scheme in which pre-fabricated microfluidic assembly blocks (MABs) can be quickly fashioned, without expertise or specialized facilities, into sophisticated microfluidic devices for a wide range of applications. Specifically, we describe three major advances to the MAB concept: (1) rapid production and extraction of MABs using flexible casting trays, (2) use of pre-coated substrates for simultaneous assembly and bonding, and (3) modification of block design to include automatic alignment and sealing structures. Finally, several exemplary applications of these MABs are demonstrated in chemical gradient synthesis, droplet generation, and total internal reflection fluorescence microscopy.

Microfluidic chemical analysis systems.

The field of microfluidics has exploded in the past decade, particularly in the area of chemical and biochemical analysis systems. Borrowing technology from the solid-state electronics industry and the production of microprocessor chips, researchers working with glass, silicon, and polymer substrates have fabricated macroscale laboratory components in miniaturized formats. These devices pump nanoliter volumes of liquid through micrometer-scale channels and perform complex chemical reactions and separations. The detection of reaction products is typically done fluorescently with off-chip optical components, and the analysis time from start to finish can be significantly shorter than that of conventional techniques. In this review we describe these microfluidic analysis systems, from the original continuous flow systems relying on electroosmotic pumping for liquid motion to the large diversity of microarray chips currently in use to the newer droplet-based devices and segmented flow systems. Although not currently widespread, microfluidic systems have the potential to become ubiquitous.