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The superacid-promoted electrophilic Csp3–H bond activation of aliphatic amines generates superelectrophilic species that can be subsequently fluorinated. Demonstrated by low-temperature in situ NMR experiments, the ammonium–carbenium dications, crucial for this reaction, can also react with C–H bonds opening future synthesis perspectives for this mode of activation. [ABSTRACT FROM AUTHOR]

The hydrolysis of glycosides is a biochemical transformation that occurs in all living organisms, catalyzed by a broad group of enzymes, including glycoside hydrolases. These enzymes cleave the glycosidic bond via a transition state with substantial oxocarbenium ion character, resulting in short-lived oxocarbenium ion-like species. While such transient species have been inferred through theoretical studies and kinetic isotope effect measurements, their direct spectroscopic characterization remains challenging. In this study, we exploit a superacid environment to generate, accumulate, and fully characterize nonprotected 2-deoxy glycosyl cations in the d-glucopyranose, d-galactopyranose, and l-arabinofuranose series using low-temperature NMR spectroscopy, supported by DFT calculations. Additionally, QM/MM MD simulations reveal that the properties of these glycosyl cations in superacid closely resemble those within the active sites of glycosidase enzymes, particularly in terms of conformation and anomeric charge distribution. These findings highlight a parallel between the stabilizing effect of counterions in superacid media and the network of multidentate noncovalent interactions within glycosidase active sites, which stabilize transition states with pronounced oxocarbenium ion character.

Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the N -propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.

Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C-H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients., (© 2024. The Author(s).)

The accumulation of chiral ammonium-oxocarbenium dications in superacid is evidenced by low-temperature NMR spectroscopy, X-ray diffraction analysis and confirmed by DFT calculations. Its potential for the diastereoselective remote hydrofunctionalization of non-activated alkene is also explored., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Harnessing the acidity of HF/base reagents is of paramount importance to improve the efficiency and selectivity of fluorination reactions. Yet, no general method has been reported to evaluate their acidic properties, and experimental designs are still relying on a trial-and-error approach. We report a new method based on 19 F NMR spectroscopy which allows highly sensitive measures and short-time analyses. Advantageously, the basic properties of the indicators can be determined upstream by DFT calculations, affording a simple yet robust semiempirical approach. In particular, the indicators used in this study were rationally designed to fit on the conceptually appealing and commonly used Hammett scale. This method has been applied to commercially available and recently developed HF/base reagents.

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen-containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N-isopropyl systems allows for the selective formal C sp3 -H activation/cyclization or homologation / functionalization of nitrogen-containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C-N bond cleavage, isopropyl cation generation and subsequent C-N bond and C-C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Both local anesthesia (LA) and brachial plexus (BP) anesthesia are commonly used in hand surgery. LA has increased efficiency and reduced costs, but BP is often favored for more complex hand surgery, despite requiring greater time and resources. The primary objective of this study was to assess the quality of recovery of patients who received LA or BP block for hand surgery. Secondary objectives were to compare postoperative pain and opioid use., Methods: This randomized, controlled, noninferiority study enrolled patients undergoing surgery distal to the carpal bones. Patients were randomized to either LA (wrist or digital block) or BP block (infraclavicular block) before surgery. Patients completed the Quality of Recovery-15 questionnaire on postoperative day (POD) 1. Pain level was assessed with a numeric pain rating scale, and narcotic consumption was recorded on POD1 and POD3., Results: A total of 76 patients completed the study (LA, n = 46, BP, n = 30). No statistically significant difference was found for median Quality of Recovery-15 score between LA [127.5 (interquartile range, 28)] and BP block [123.5 (interquartile range, 31)]. The inferiority margin of LA to BP block at the 95% confidence interval was less than the minimal clinically important difference of 8, demonstrating noninferiority of LA compared with BP block. There was no statistically significant difference between LA and BP block for numeric pain rating scale scores or narcotic consumption on POD1 and POD3 ( P > 0.05)., Conclusion: LA is noninferior to BP block for hand surgery with regard to patient-reported quality of recovery, postoperative pain, and narcotic use., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Although the origins of procedures now falling under the scope of modern plastic surgery date back thousands of years, it was only fairly recently that these were grouped under the umbrella term "plastic" surgery. However, mainly due to the industrialization period, the popular understanding of the term "plastic" would soon change-making way for the addition of the term "reconstructive" to the specialty's name. Through a careful look at historical trends, the authors illustrate how this unintentionally led to an ideological divide between the aesthetic and reconstructive portions of our work, prompting a recent push to unify the field under the one, original, lexical choice: "plastic" surgery., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Background: The COVID-19 pandemic has led to increased barriers for medical students seeking to engage with plastic surgery. Traditional approaches such as pursuing clinical electives broadly are no longer feasible and medical students are seeking innovative approaches for engagement. The current study evaluated the efficacy of online information sessions on medical student perception and proposed a timeline for longitudinal medical student recruitment. Methods: The McGill Plastic and Reconstructive Surgery residency program held an online information session for medical students focusing on a wide array of topics related to plastic surgery and residency. Following the session, an anonymous survey was sent to participants gauging their satisfaction with the event and potential effects it had on career planning. Results: Thirty-four participants completed the survey, comprising more than 60% of annual applicants to Canadian plastic surgery programs. 94% of participants stated that their view of McGill's training program improved and reported a desire for additional sessions from other training programs. 68% of respondents reported being more likely to consider training at McGill and 100% agreed that such sessions could influence their decision to pursue a given training program. Social media was the most common resource used by participants to gain information on training programs. Conclusion: Online information sessions are valuable tools for medical student recruitment and can directly influence their views of a specific training program and affect career planning. Investing in generating high quality content through online forms of communication is paramount as most medical students are turning to these platforms amidst the pandemic., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Introduction: One of the important factors in achieving gender equity is ensuring equitable surgical training for all. Previous studies have shown that females get significantly lower surgical exposure than males in certain surgical specialties. Gender gap in surgical exposure has never been assessed in plastic surgery. To that end, the goal of this study was to assess if there are any differences in plastic surgery training between male and female residents. Methods: A survey was sent to all plastic surgery residency programs in Canada to assess the No. of surgeries residents operated on as a co-surgeon or primary assistant during their training. The survey also assessed career goals, level of interest in the specialty, and subjective perception of gender bias. Results: A total of 89 plastic surgery residents (59.3% participation rate) completed the survey and were included in the study. The average No. of reconstructive cases residents operated on as a co-surgeon or primary assistant was 245 ± 312 cases. There was no difference in either reconstructive or aesthetic surgery case logs between male and female residents ( p  > .05). However, a significantly larger proportion of females (39%) compared to males (4%) felt that their gender limited their exposure to surgical cases and led to a worsening of their overall surgical training ( p  < .001). Finally, a larger proportion of male residents were interested in academic careers while a larger proportion of female residents were interested in a community practice ( p  = .024). Conclusion: While there is no evidence of differences in the volume of logged cases between genders, female surgical residents still feel that their respective gender limits their overall surgical training. Gender inequalities in training should be addressed by residency programs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Since the pioneer reports of the groups of Akiyama and Terada on Brønsted acid organocatalysis, this field never stopped growing with the development of ingenious strategies for the activation of challenging poorly reactive substrates. The development of superacidic organocatalysts is an important way to selectively functionalize reluctant electrophiles and other approaches have also emerged such as the combination of Lewis and Brønsted acids as well as the consecutive organocatalysis and superacid activation. This Concept aims to highlight these different strategies and demonstrate their complementarity., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Understanding the influence of emerging fluorinated motifs is of a crucial importance in the context of the exponentially growing exploitation of fluorine in many fields. Herein, we report on the dramatic effect of a local partial charge inversion by replacing a CHCH 3 group by a CFCF 3 . This strategy allows the diastereoselective reduction of 5-membered ring oxocarbenium ions to access highly substituted tetrahydrofurans.

Purpose: The purpose of this study was to determine if the use of postoperative therapeutic dose intravenous heparin (POTDIVH) was indicated in digital replantation and revascularization by assessing digit survival and complications associated with heparin., Methods: All patients with amputation distal to the carpal tunnel treated at our center from 2004 to 2020 were included for chart review. Digit survival and complication rates were compared between patients who received POTDIVH (group A) and those who did not (group B). Logistic regression analysis and subgroup analysis were conducted., Results: A total of 795 patients (1,155 digits) were included in this study (248 patients/374 digits in group A and 547 patients/781 digits in group B). The overall revascularization and replantation success rate was 79.9% in the POTDIVH group and 92.8% in the non-POTDIVH group. In our retrospective regression and subgroup analyses, group A demonstrated increased odds of failure compared with group B and was associated with increased bleeding-related complications. Subgroup analyses stratified by the mechanism of injury and vein grafting also showed a significantly decreased survival in the POTDIVH group., Conclusions: Our retrospective data seem to indicate that heparin in digit replantation and revascularization appears to have no benefit on digit survival across all subgroups, including crush and avulsion injuries, and is associated with a significantly increased rate of complications., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2023. Published by Elsevier Inc.)

Background: Local anesthesia has shown to be safe and cost-effective for elective hand surgery procedures performed outside of the operating room. The economic benefits of local anesthesia compared to regional anesthesia for hand surgeries performed in the operating room involving repair of tendons, nerves, arteries, or bones are unclear. This study aimed to compare costs pertinent to hand surgeries performed in the main operating room under local anesthesia (LA) or brachial plexus (BP) block., Methods: We performed a cross-sectional study on the first 70 randomized patients from a prospective controlled trial of anesthesia modalities for hand surgery. The primary objective was to determine the mean anesthesia-related cost, and the secondary objectives were to analyze block performance time, block onset time, duration of anesthesia, duration of surgery, and time in the recovery room., Results: The mean anesthesia-related cost of performing hand surgery under LA as a wrist and/or digital block was $236 ± 30, compared to $435 ± 43 for BP, a difference of $199 per case. The mean block performance time was shorter for LA (1.3 minutes) versus BP (7.0 minutes). The mean anesthesia-related time was longer in BP (30.7 ± 16 minutes) compared to LA (17.7 ± 6.7 minutes), and consequently the total anesthesia time was longer in BP., Conclusions: We demonstrated that local anesthesia compared to brachial plexus block achieved substantial cost savings in complex hand surgeries by decreasing major expenses. In an era of cost-consciousness, the use of LA represents an important modality for health systems to optimize patient flow and increase cost-effectiveness.

The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium-modified drugs directly from their non-labeled parents. While most of the recent studies focus on metal-catalyzed C-H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late-stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures., (© 2022 Wiley-VCH GmbH.)

Background: Digital replants and revascularization (DRV) have been performed since the 1960s but there are no recognized standard peri-operative anticoagulation practices. A narrative systematic review of the clinical effectiveness and safety of therapeutic peri-operative unfractionated heparin following DRV was undertaken., Methods: A review of the literature from 1985 to March 2022 was conducted using Medline, Embase, CINAHL and EBM reviews. Unfractionated heparin (UFH) use following DRV was compared to low-molecular weight heparin, other anticoagulants or no anticoagulation. Randomized trials, observational studies as well as guidelines were selected and independently screened. The Revised Cochrane risk-of-bias (RoB 2) tool and ROBINS-I were used to appraise risk of bias., Results: While the search strategy identified 1490 references, only six studies met the inclusion criteria. Significant heterogeneity and the low methodological quality of the evidence precluded a meta-analysis. Among the four studies that documented the surgical success rate associated with the use of a therapeutic dose of UFH post DRV, only two reported improved clinical outcomes. Evidence of a higher complication rate related to UFH use was found in four studies. Low quality evidence suggests that a therapeutic dose of unfractionated heparin leads to a higher risk of complications when compared with heparin given as an intermittent bolus of unfractionated heparin or subcutaneous heparin, or prostaglandin E1 or no heparin., Conclusions: Current evidence suggests that IV UFH use following DRV has no significant impact on the success of the intervention. Heparin use may not be innocuous as some studies showed increased bleeding complications., (© 2022 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic has challenged health care systems. We sought to comprehend the impact of the COVID-19 pandemic on surgical residents' education and mental well-being across Canada., Methods: An online 51-question survey was distributed to surgical residents across all 17 Canadian post- graduate surgical residency programs. The questionnaire contained questions concerning demographic factors, perceived effects of COVID-19 pandemic on surgical training and residents' mental health (categorically demonstrating whether it improved, stayed the same, or worsened). Health habits were measured as continuous variables and compared before and during the pandemic. Additionally, participants reported the performance of wellness offices' response to their needs during this crisis., Results: A total of 122 out of 650 (19%) residents from all surgical specialities anonymously completed the survey. The majority (68%) reported a worsening in their surgical training. 94% of participants favored online teaching as a complementary method to in-person teaching. As to health habits, 38% reported a rise in their alcohol consumption and time spent seated. Only a minority (25%) felt happier and 41% reported experiencing more anxiety in comparison to surgical training pre-COVID-19. Merely 14% reported benefitting from wellness programs., Conclusion: The COVID-19 pandemic had a negative effect on the perceived quality of surgical training, education, and resident mental health. There is an urgent need to reconsider the implemented measures in medical education and urge us to develop better agendas to face the current or future waves., Competing Interests: None, (© 2022 Alam, Salimi, ElHawary, Sioufi, Papanastasiou, Thibaudeau; licensee Synergies Partners.)

Enantioenriched complex fused-tricyclic azepanes or bridged-polycyclic azocanes were constructed via a two-step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa-bridged azepane acts as a key hidden heptacyclic chiral N-acyl iminium ion triggering a chemo- and diastereoselective intramolecular mono- or di-arylation., (© 2022 Wiley-VCH GmbH.)

Functional recovery after peripheral nerve injury is often suboptimal despite the intrinsic permissive growth environment of the peripheral nervous system. The objective of this systematic review is to explore the use of electrical stimulation (ES) for peripheral nerve regeneration., Methods: A systematic literature search was conducted from inception to March 2, 2021 to retrieve articles on ES for peripheral nerve regeneration using the PubMed, Ovid MEDLINE, and Embase databases. Primary outcome measures included objective measures of motor and sensory nerve function., Results: Four randomized control trials, two case reports, and three case series that addressed the aims were identified. The stimulation parameters varied greatly between studies, without an apparent commonality for a given electrical conduit. Outcomes measured included motor (n = 8) and sensory (n = 7) modalities (cold detection, static two-point discrimination, tactile discrimination, and pressure detection), nerve-specific muscle function and bulk, and electromyography (EMG) motor and sensory terminal latency. Different parameters for measurement were utilized and improvement was observed across the studies compared with controls (n = 4) or pre-intervention measurements (n = 5). One randomized control trial reported no benefit of ES and attributed their findings to their stimulation protocol. Complications were documented in three patients only and included wire remnant removal, skin pigmentation, and bone formation., Conclusions: ES in peripheral nerve regeneration is beneficial in improving and accelerating recovery. A meta-analysis was not performed due to the heterogeneity, but all studies showed positive findings and minor to no complications. These results provide a primer for further development of delivery methods., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: The role of ultrasound in plastic surgery practice has grown significantly over the past decade, with notable applications for conditions of the upper extremity. Its utility for the management of de Quervain disease, however, remains to be established, and the prevalence of first dorsal compartment anatomical variations needs to be adequately assessed., Methods: A systematic review was performed to evaluate the role of ultrasound in the diagnosis, anatomical characterization, and clinical management of de Quervain disease. A meta-analysis was conducted to establish the prevalence of first dorsal compartment anatomical variations in the de Quervain disease and general population, along with the diagnostic accuracy of ultrasound for their detection. Outcomes were documented and compared to alternative treatment options., Results: Extensor retinaculum thickening, tendon sheath swelling, peritendinous edema, and tendon enlargement were the most common sonographic features of de Quervain disease. The prevalence of an intercompartmental septum in the de Quervain disease surgical population was shown to be significantly greater than in the general cadaveric population (67 percent versus 35 percent, respectively). Although the efficacy of energy-based therapeutic ultrasound remains elusive, ultrasound-guided corticosteroid injections were shown to be more accurate than manual injections (90 to 100 percent versus 40 to 100 percent), and to confer significantly better treatment outcomes (73 to 100 percent versus 59 to 83 percent success rates, respectively)., Conclusions: Ultrasound use is essential to achieve the best evidence-based outcomes in the management of de Quervain disease. The varied prevalence of first dorsal compartment anatomical variations and high accuracy of ultrasound for their detection carry significant prognostic implications., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Under superacid conditions, aromatic amines are directly and regioselectively 1,1-difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α-fluoronium and α-chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late-stage functionalization of natural alkaloids and active pharmaceutical ingredients., (© 2021 Wiley-VCH GmbH.)

Background: Growing use of pyrocarbon implants in upper extremity arthroplasty has culminated in a breadth of literature ascertaining outcomes and complications at long-term follow-up. However, at present, the literature remains devoid of studies synthesizing the available evidence for upper extremity surgeons to adequately assess the safety and utility of these implants relative to other available options., Methods: A systematic search of the National Library of Medicine, MEDLINE, and Embase databases was performed to determine clinical outcomes and complication and reoperation rates following pyrocarbon arthroplasties in the upper extremity. A breakdown of complication and reoperation rates for each independent joint (shoulder, elbow, wrist, and hand joints), and according to specific causes necessitating surgery, was also compiled., Results: A comprehensive summary of functional outcomes following upper extremity pyrocarbon arthroplasties is presented. Overall complication and reoperation rates in the hand and wrist were determined to be 28.2 percent and 17 percent, respectively. The proximal interphalangeal joint was associated with the highest complication rate (42.7 percent), followed by carpometacarpal joint (18.8 percent), metacarpophalangeal joint (17.6 percent), wrist (16 percent), elbow (15.7 percent), and shoulder (12.9 percent). In the hand and wrist, major complications included dislocations and subluxations (8.4 percent), stiffness and limited motion (4.4 percent), deformity (3.1 percent), hardware failure (1.9 percent), fractures (1.7 percent), persistent pain (1.7 percent), and infections (0.9 percent)., Conclusion: In the absence of large clinical trials, systematic reviews such as these can help inform clinical guidelines and provide practitioners with an evidence-based reference to improve informed consent., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Despite the success of composite tissue allograft (CTA) such as face and hand transplant at improving recipients' quality of life, organ donors' hesitation needs to be better understood. The aim of the study was to assess Canadian organ donors' willingness to donate their face and hands, and the efficacy of an educational intervention., Methods: Canadians registered for organ donation were invited to complete an online survey about CTA. An interactive vignette was introduced part way through to clarify transplant-related concepts, with repeat of questions post-vignette exposure to assess attitudes pliability., Results: A total of 942 participants completed the survey. Fifty-two percent of donors were willing to donate their face after passing, whereas 80% were willing to donate their hands. Reasons to refuse CTA donation included the risk of upsetting their family, having someone look like them, and wanting their body to remain intact. Donors' willingness to donate their face (38%, P < 0.001) and hands (79%, P = 0.67) decreased following vignette exposure. Comparative analysis of our interventional vignette with a similar study where donors' donation readiness increased after an educational intervention revealed that our vignette lacked a strong enough emotional component to positively impact donors' attitude to CTA, and may have exposed participants to alternatives to transplant they were not previously aware of., Conclusions: Canadian organ donors surveyed were willing to donate their face and hands following death, a willingness reduced after watching our informative vignette. Further qualitative work is required to better understand the educational needs and areas to address to increase donors' acceptance of CTA., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Despite lower extremity polydactyly (LEP) representing the most common congenital foot anomaly with functional and psychosocial implications, the literature is devoid of comprehensive, synthesizing reviews. The purpose of the current review is to identify an evidence-based approach to guide clinical management and shed light on reported functional and esthetic outcomes for postaxial polydactyly., Methods: A scoping systematic review of primary clinical studies was performed. Baseline patient characteristics, diagnostic, and surgical approaches were recorded. Main outcomes included immediate postoperative pain, infections, callouses, scar cosmesis, residual deformities, and difficulty with shoe-wear or mobility. A qualitative synthesis of outcomes was performed, and a therapeutic algorithm was developed., Results: Nine primary studies were identified representing 375 cases of LEP; mean age was 28.8 months (range: 20-40.6 months), and mean follow-up: 42.7 months (range: 1 month-41 years). Ray dominance and the presence of syndactyly were identified as the most important factors for surgical planning; age at surgery was insignificant. A lateral incision approach was used in 78% of cases. Postoperative callouses occurred in 22.1% of cases, infections in 2.5%, and intermittent pain in 11.9%. Significant issues with shoe-wear or mobilization and esthetic residual deformities were reported for 0.78% and 41.2% of cases, respectively. The incidence of residual valgus was 10.6%., Conclusion: LEP is most commonly managed with excision of the non-dominant ray and carries excellent long-term functional outcomes, as presented herein. Numerous techniques are discussed to minimize the risk of esthetic sequalae, although the presence of residual valgus remains a concern. A therapeutic algorithm is proposed for the optimal management of LEP., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein-ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand-protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X-ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand-based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future., (© 2021 Wiley-VCH GmbH.)

Predestined to be transient theoretical species, phenonium ions can now be considered as cationic intermediates of choice in organic synthesis. Here, we demonstrate that under non-nucleophilic and superacidic conditions, CF 3 -substituted phenonium ions can be generated to furnish original CF 3 -substituted dihydrostilbenes of interest., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Canadian medical school curriculums have undergone major restructuring during the COVID-19 pandemic. This study's goal was to assess the perceived impact of COVID-19 on medical students' education and wellbeing., Methods: An online survey was distributed to Canadian medical students. Descriptive analyses and ANOVAs were used to assess changes in mental health, health habits and quality of education during the pandemic., Results: 248 medical students from 13 schools across Canada participated in this study. 74% reported a reduction in the quality of their education since COVID-19. 58% of students found online to be inferior to in-person teaching. 65% of students had more time for wellness and leisure activities, about half of the cohort felt more depressed (48%) and lonelier (52%). Student's overall health habits worsened after the start of the pandemic (F=37.4, p < 0.001). Alcohol drinking, time spent seated, and screen time also increased since the pandemic ( p < 0.001). During the pandemic, students with a prior history of depression or anxiety expressed increased depressive symptoms (66% vs. 42%, p =0.003), increased anxiety (69% vs. 41%, p < 0001), worse sleep quality (34% vs. 18%, p = 0.031), and poorer quality of life (55% vs. 65%, p = 0.024) versus those with no prior history., Conclusion: Canadian medical student's education and wellbeing has been negatively impacted during the pandemic., Competing Interests: Conflicts of Interest: None, (© 2021 ElHawary,Salimi, Barone, Alam, Thibaudeau; licensee Synergies Partners.)

Under superacidic conditions, aniline and indole derivatives are sulfonylated at low temperature with easy-to-access arenesulfonic acids or arenesulfonyl hydrazides. By modification of the functional-group directing effect through protonation, this method allows nonclassical site functionalization by overcoming the innate regioselectivity of electrophilic aromatic substitution. This superacid-mediated sulfonylation of arenes is complementary to existing methods and can be applied, through protection by protonation, to the late-stage site-selective functionalization of natural alkaloids and active pharmaceutical ingredients.

Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity.We also highlight that, from a chemical perspective, the glycosylation reaction can be described as a continuum, from unimolecular S N 1 with naked oxocarbenium cations as intermediates to bimolecular S N 2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-separated ion pairs, solvent-equilibrated ion pairs) with bimolecular features in most reactions is also highlighted.The role of theoretical calculations to predict the conformation, dynamics, and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under S N 1-like conditions.Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterization of the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid solution by NMR spectroscopy.We also pay special attention to the reactivity of these glycosyl ions, which depends on the conditions, including the counterions, the possible intra- or intermolecular participation of functional groups that may stabilize the cation and the chemical nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different experimental perspectives, which identified the involved ionic intermediates, estimating their lifetimes and reactivities and studying their interactions with other molecules. In this context, we also emphasize the relationship between the chemical methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of molecules that regulate the stability and reactivity of glycosyl cations.

"The extraordinary instability of such an "ion" accounts for many of the peculiarities of organic reactions" - Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations - carbocations substituted with electron-withdrawing groups - are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF 3 -substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations., (Copyright © 2021, Fernandes et al.)

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively., (© 2020 Wiley-VCH GmbH.)

Introduction: Trapezoidal fractures account for only 0.4% of all carpal bone fractures. Owing to their rarity, there is paucity in the literature regarding the clinical findings and treatment. This paper aims to summarize the current understanding of trapezoidal fractures and present a novel classification algorithm., Methods: A diagnostic classification algorithm was created based on the known blood supply and ligamentous attachment of the trapezoid. The proposed treatment algorithm was then applied to trapezoidal fractures in the literature to validate the algorithm and determine whether patients received treatment that was in accordance., Results: A total of 19 articles, representing 22 trapezoidal fractures were included, with two additional cases presented by the authors. Presenting symptoms were pain (n = 21) and swelling (n = 12). Diagnosis was made on CT in a majority of the time, 79.2% (n = 18). All outcomes were favorable with symptomatic resolution and full range of motion after treatment, except in four patients that had co-existing wrist injuries. When the algorithm was applied, 89.5% (n = 17) of the patients received treatment in accordance with the proposed algorithm and demonstrated good outcomes. In the remaining patients (n = 2) whose treatment differed, one had diminished grip strength and the other was lost to follow-up., Conclusions: Given a degree of clinical suspicion including a history of blunt trauma to the hand and persisting pain, trapezoidal fractures should remain on the differential when plain radiographs fail to identify any fracture. Operative treatment is suggested if there is any significant displacement, compromise of the dorsal surface, or breech of the trapezoidal ligaments causing possible dislocation., Level of Evidence: IV - Diagnostic., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Exploiting superacid activation, the reactivity of aminonitriles was enhanced through the transient formation of highly reactive ammonium-nitrilium superelectrophiles. Demonstrated by using in situ low-temperature NMR experiments and confirmed by X-ray diffraction analysis, these dications can be intramolecularly trapped by non-activated alkenes to generate unsaturated piperidinones, including enantioenriched ones, in a straightforward way.

Functionalized angular cycloalkane-fused naphthalenes were prepared using a two-step process involving a Pd-catalyzed Suzuki-Miyaura coupling of aryl pinacol boronates and vinyl triflates followed by a boron trifluoride etherate-catalyzed cycloaromatization.