Bipolar fracture of clavicle mimicking fracture dislocation of sternoclavicular joint: A case report.

INTRODUCTION AND IMPORTANCE: Bipolar fractures involving segmental fractures of the lateral and proximal clavicles are exceptionally rare, with only isolated cases documented in the literature. Such fractures may easily be overlooked during the initial presentation. CASE PRESENTATION: We present the case of a 35-year-old male with deformation in the middle segment of the clavicle following a road traffic accident (RTA). On radiography, the injury was initially thought to be a lateral clavicle fracture combined with sternoclavicular joint dislocation but was later changed to a bipolar clavicle fracture intraoperatively. The patient had an uneventful postoperative course with excellent functional outcomes 14 months after surgery. CLINICAL DISCUSSION: A bipolar clavicle fracture is the result of direct trauma to the shoulder region commonly following RTA. Bipolar injuries can be diagnosed based on clinical findings and radiographic evaluation using plain X-rays and aided by computed tomography (CT) scans in doubtful scenarios. With a paucity of guidelines regarding the management of bipolar clavicle fractures most reported cases have been managed operatively with open reduction and internal fixation using locking plates and screws. CONCLUSIONS: Due to its rarity, bipolar clavicle fractures can be easily missed, necessitating a high index of suspicion and detailed evaluation of suspected cases. Appropriate initial and definitive management through operative fixation can lead to optimal outcomes.

Workplace absenteeism due to COVID-19 and influenza across Canada: A mathematical model.

The continual distress of COVID-19 cannot be overemphasized. The pandemic economic and social costs are alarming, with recent attributed economic loss amounting to billions of dollars globally. This economic loss is partly driven by workplace absenteeism due to the disease. Influenza is believed to be a culprit in reinforcing this phenomenon as it may exist in the population concurrently with COVID-19 during the influenza season. Furthermore, their joint infection may increase workplace absenteeism leading to additional economic loss. The objective of this project will aim to quantify the collective impact of COVID-19 and influenza on workplace absenteeism via a mathematical compartmental disease model incorporating population screening and vaccination. Our results indicate that appropriate PCR testing and vaccination of both COVID-19 and seasonal influenza may significantly alleviate workplace absenteeism. However, with COVID-19 PCR testing, there may be a critical threshold where additional tests may result in diminishing returns. Regardless, we recommend on-going PCR testing as a public health intervention accompanying concurrent COVID-19 and influenza vaccination with the added caveat that sensitivity analyses will be necessary to determine the optimal thresholds for both testing and vaccine coverage. Overall, our results suggest that rates of COVID-19 vaccination and PCR testing capacity are important factors for reducing absenteeism, while the influenza vaccination rate and the transmission rates for both COVID-19 and influenza have lower and almost equal affect on absenteeism. We also use the model to estimate and quantify the (indirect) benefit that influenza immunization confers against COVID-19 transmission.

Discovery of small-molecule enzyme activators by activity-based protein profiling.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

N-Acyl pyrazoles: Effective and tunable inhibitors of serine hydrolases.

A series of N-acyl pyrazoles was examined as candidate serine hydrolase inhibitors in which the active site acylating reactivity and the leaving group ability of the pyrazole could be tuned not only through the nature of the acyl group (reactivity: amide > carbamate > urea), but also through pyrazole C4 substitution with electron-withdrawing or electron-donating substituents. Their impact on enzyme inhibitory activity displayed pronounced effects with the activity improving substantially as one alters both the nature of the reacting carbonyl group (urea > carbamate > amide) and the pyrazole C4 substituent (CN > H > Me). It was further demonstrated that the acyl chain of the N-acyl pyrazole ureas can be used to tailor the potency and selectivity of the inhibitor class to a targeted serine hydrolase. Thus, elaboration of the acyl chain of pyrazole-based ureas provided remarkably potent, irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki = 100-200 pM), dual inhibitors of FAAH and monoacylglycerol hydrolase (MGLL), or selective inhibitors of MGLL (IC50 = 10-20 nM) while simultaneously minimizing off-target activity (e.g., ABHD6 and KIAA1363).

DNA binding of Pd(TC3), a conformable cationic porphyrin with a long-lived triplet state.

The goal of this work has been to synthesize and investigate Pd(TC3), an intercalating porphyrin that has conformable substituents capable of groove binding to B-form DNA. (TC3 denotes the doubly deprotonated form of 5,10,15,20-tetra[3-(3'-methylimidazolium-1'-yl)prop-1-yl]porphyrin.) Palladium(ii) is an apt choice for the central metal ion because it remains strictly four-coordinate and provides for a luminescent triplet excited state with a long lifetime. The DNA hosts are hairpin-forming sequences programmed to differ in base composition. Luminescence, absorbance, and circular dichroism results are consistent with the idea that congruent structural reorganization takes place at the host and ligand during uptake. Photoexcitation of DNA-bound Pd(TC3) generates a comparatively modest steady state concentration of singlet oxygen, due to a relatively slow reaction with molecular oxygen in solution. The sheer size of the substituent groups disfavors quenching, but groove-binding interactions compound the problem by inhibiting mobility. The results show how ligand design affects adduct structure as well as function.

Regeneration of Light-Harvesting Complexes via Dynamic Replacement of Photodegraded Chromophores.

All-synthetic molecular donor-acceptor complexes are designed, which are capable of counteracting the effect of photoinduced degradation of donor chromophores. Anionic gallium protoporphyrin IX (GaPP) and semiconducting carbon nanotube (CNT) are used as a model donor-acceptor complex, which is assembled using DNA oligonucleotides. The GaPP-DNA-CNT complex produces an anodic photocurrent in a photoelectrochemical cell, which steadily decays due to photo-oxidation. By modulating the chemical environment, we showed that the photodegraded chromophores may be dissociated from the complex, whereas the DNA-coated carbon nanotube acceptors are kept intact. Reassociation with fresh porphyrins leads to the full recovery of GaPP absorption and photocurrents. This strategy could form a basis for improving the light-harvesting performance of molecular donor-acceptor complexes and extending their operation lifetime.

DNA-binding studies of a tetraalkyl-substituted porphyrin and the mutually adaptive distortion principle.

This investigation explores DNA-binding interactions of various forms of an alkyl-substituted cationic porphyrin, H2TC3 (5,10,15,20-tetra[3-(3'-methylimidazolium-1'-yl)]porphyrin). The motivating idea is that incorporating alkyl rather than aryl substituents in the meso positions will enhance the prospects for intercalative as well as external binding to DNA hosts. The ligands may also be applicable for photodynamic and/or anticancer therapy. Methods employed include absorbance, circular dichroism, and emission spectroscopies, as well as viscometry and X-ray crystallography. By comparison with the classical H2T4 system, H2TC3 exhibits a higher molar extinction coefficient but is more prone to self-association. Findings of note include that the copper(II)-containing form Cu(TC3) is adept at internalizing into single-stranded as well as B-form DNA, regardless of the base composition. Surprisingly, however, external binding of H2TC3 occurs within domains that are rich in adenine-thymine base pairs. The difference in the deformability of H2TC3 versus Cu(TC3) probably accounts for the reactivity difference. Finally, Zn(TC3) binds externally, as the metal center remains five-coordinate.

Internal versus external binding of cationic porphyrins to single-stranded DNA.

Absorbance, induced circular dichroism, and emission studies establish that the tetrasubstituted cationic porphyrin Cu(T4) preferentially binds externally to single-stranded (ss) DNA sequences, except in a purine-rich system like 5'-(dA)10-3' where a degree of internalization occurs. On the other hand, the sterically friendly, disubstituted Cu(tD4) system exclusively binds to ss DNA by internalization, that is, pseudointercalation. By and large the results show that double-stranded DNA hosts decisively outcompete more flexible ss hosts for the uptake of a porphyrin, regardless of the binding motif. The findings are relevant because ss domains of DNA appear during replication, in different types of DNA-secondary structure, and as products of the disassembly of multistranded forms.