Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same.N-Heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C–C and C–H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives  was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation,  Molecular insights on the formation, detection, and even isolation of the Breslow intermediate, which is the most important species in N-heterocyclic carbene (NHC) catalysis, as obtained from experimental and computational studies, are presented. Albeit being scattered, many pieces of experimental evidence and a good number of computational studies on the generation of Breslow intermediates in NHC catalyzed transformations can be found in the literature. The lacuna in the burgeoning area of NHCs is the lack of a compendium on Breslow intermediates, focusing on their formation, detection, and isolation. It is therefore quite timely to give these aspects of NHCs their deserving attention in the form of a review article.The topic of N-heterocyclic carbenes (NHCs) has been richly reviewed in recent years, with most of those reviews narrating their translational impact from a fleeting intermediate to a versatile organocatalyst for an unprecedented array of reactions.2 which signifies reversal of polarity, is utilized in several organic reactions. The carbonyl carbon of an aldehyde is an electrophilic site, which upon reaction with a cyanide ion can be made nucleophilic, effectively leading to a reversal of polarity. More than a century ago, Wöhler and Liebig discovered the homodimerization of aldehydes in the presence of cyanide ions that leads to benzoin products.3 The Lapworth mechanism for such cyanide catalyzed benzoin reaction contributed to the early rationalization of umpolung reactivity.4 Decades later, Ukai and co-workers observed that thiazolium salts are also capable of catalyzing the benzoin reaction.5 In a landmark article in the year 1958, Breslow proposed a mechanism, as shown in 6 The thiazolium catalyst precursor 1 is deprotonated at the most acidic position by the action of a base to generate carbene 2. The nucleophilic carbene 2 can then add to the electrophilic benzaldehyde 3 to form a zwitterionic intermediate, 4. A critical proton transfer from the aldehydic carbon to the geminal oxygen atom can then provide the diamino enol intermediate 5, which in more recent years came to be known as the Breslow intermediate. The nucleophilic Breslow intermediate can then combine with a second molecule of benzaldehyde to form the benzoin product (7) with the expulsion of the free carbene. While the formation of the diamino enol intermediate was suggested quite a few years ago, renewed attention to such intermediates was triggered due to the emergence of NHCs as promising organocatalysts in recent times.1,9The textbook concept of umpolung,7 In a seminal report back in 1991, Arduengo and co-workers disclosed the crystal structure of an isolable N-adamantyl substituted NHC. Conspicuously, a chemist's ability to ‘see’ the molecular structure of a free NHC, which otherwise remained an elusive intermediate back then, served as an impetus to subsequent developments in this domain.8 In particular, the ensuing years witnessed an unprecedented growth in the use of NHCs as organocatalysts for a gamut of organic transformations. Especially, in such NHC catalyzed reactions, there has been the implicit assumption of participation of the Breslow intermediate. As one reads this article, it will become increasingly clear how systematic efforts helped researchers in taming this fleeting intermediate and eventually to make it amenable to detection and characterization.It is interesting to note that even decades before the transformative phase of NHCs, from an esoteric species to a ubiquitous catalyst, efforts on their isolation by Wanzlick and others led to dimerized products. The ability of such dimers to dissociate and to react with different electrophiles offered some early signs of promise toward developing the reactivity of NHCs.9 These NHC catalyzed asymmetric transformations not only demonstrate their versatile role in diverse range of reactions, but also convey the synergism of density functional theory computations in faithfully reproducing the experimental enantioselectivities. One of the vital details encompassing the whole domain of NHC organocatalysis that demands attention is the mechanism of formation of Breslow intermediates. In the following section, an overview of the current understanding on the formation of Breslow intermediates under different catalytic conditions that vary in terms of the presence/nature of certain types of additive is provided.The formation of the Breslow intermediate, in transient or detectable forms, is vital to the catalytic applications of NHCs. Different reaction conditions have been employed in NHC catalysis, particularly due to their higher-level utilization such as that in asymmetric transformations. Computational studies were effectively employed in gaining valuable molecular understanding on the origin of stereoselectivities in such reactions, as evident from a representative set of examples shown in e.g., aldehyde, enal, etc.) generates a zwitterionic intermediate (8) first (8) via a highly strained three-membered transition state. In the second alternative, the zwitterionic intermediate undergoes a 1,2-hydride transfer to form the keto intermediate (11) followed by a tautomerization to the Breslow intermediate (10), again via a strained four-membered transition state. Along the expected lines, the computed barriers for the 1,2-direct proton transfer in 8 to form 10 are generally found to be very high, indicating that this pathway is not feasible  first . A critie.g., DBU, iPr2NEt, K2CO3), (ii) Brønsted acids, or (iii) other protic additives . There have been interesting density functional theory studies demonstrating the role of different additives in the formation of Breslow intermediates. In this section, we provide the energetic details on the formation of Breslow intermediates using a few representative examples as listed in 10 Note that most of our discussions in the latter sections make use of the reactions listed in this table.An assisted proton transfer invokes a more direct role for (i) the base present in the reaction mixture (10 The proposed mechanism for the formation of the Breslow intermediate (16) is shown in 13) between the NHC and acetaldehyde. A likely two-step bimolecular proton transfer between intermediates 14 and 15 was invoked.10 An overall activation barrier of 25.4 kcal mol−1 was found at the B3LYP/6-311+G level of theory, which is 13.7 kcal mol−1 lower than that for the unassisted 1,2-proton transfer in 13 .10 While this pathway appears energetically reasonable, it is instructive to consider that an encounter between two activated species  under the reaction conditions is less likely than that between the zwitterionic intermediate and any other molecule abundantly available in the medium. Hence, alternative routes for the generation of the Breslow intermediate need to be considered (vide infra).In 2008, Yates and co-workers employed density functional theory computations to study the mechanism of a Stetter reaction between acetaldehyde and a Michael acceptor R1, .10a The 10 Interesting examples were reported wherein methanol, catechol, etc. assisted the critical proton transfer leading to the formation of the Breslow intermediate.9 As part of their mechanistic investigation on NHC catalyzed ring expansion of 4-formyl-β-lactam /B3LYP/6-31G** level of theory  was 24.7 kcal mol−1 lower than that for the unassisted pathway viaTS3.10 Diminished strain in the transition state geometry as well as the additional specific interaction with the methanol can be considered as the origin of the lower barrier in the methanol assisted pathway.The presence of protic additives is known to be beneficial in certain reactions as they can facilitate easier proton transfer.ctam R2, , Domingof theory .10c On t9 The energetically preferred pathway obtained at the SMD(toluene)/M06-2X/6-31+G** level of theory was suggested to begin with a nucleophilic addition of quinuclidine to DMAD as shown in 17).In another recent study, Sunoj and co-workers reported the mechanism and origin of enantioselectivity in an asymmetric Michael–Stetter cascade reaction catalyzed by a chiral NHC and quinuclidine leading to the formation of benzofuran R3, .9f The e17 to form a zwitterionic species 19. As with previous cases, a crucial proton transfer would convert 19 to the desired Breslow intermediate 21. Here, a 1,2-direct proton transfer was predicted to encounter a barrier of 48.0 kcal mol−1 prompting the authors to consider two types of assisted pathway, one with the involvement of the additive catechol and the other with an explicitly included water molecule. It was noted that catechol assists the proton transfer through a stepwise process involving the catecholate as the key species (formed by the action of quinuclidine on catechol). Shown in TS5), wherein the alkoxy oxygen abstracts the phenolic proton of the catecholate while the proton on the alkoxy carbon is simultaneously abstracted by the phenoxide end of the catecholate. The predicted barrier was 24.0 kcal mol−1 for the catecholate assisted proton transfer, half of that for the 1,2-direct proton transfer. They also evaluated the efficacy of water assisted proton transfer en route to the Breslow intermediate. The energy of relay proton transfer, assisted by two explicit water molecules, as shown in TS6, was incidentally the same as that of the catechol assisted pathway. The barrier for the assisted proton transfer, mediated by one water molecule, was found to be 32.1 kcal mol−1 /M06-2X/6-311+G**//M06-2X/6-31+G** level of theory. A subsequent keto–enol tautomerization viaTS8 was suggested toward the formation of the desired Breslow intermediate. A high barrier for this unassisted keto–enol tautomerization prompted the authors to consider a DBU assisted relay proton transfer viaTS9. Interestingly, the barrier was found to be about 27 kcal mol−1 for the DBU assisted pathway wherein DBU abstracts the proton from the NHC carbon and delivers it to the enolate oxygen. As would become more apparent in the ensuing sections of this article, both the keto and enol variants of the Breslow intermediate are inherently appealing and thus deserve additional attention, primarily owing to the ease of detection of the former (vide infra).There have been reports that invoked the participation of bases such as DBU, KOions R4, .10d The 10 the Sunoj group has identified that KOtBu played a pivotal role in the formation of the Breslow intermediate. As with the previous examples, once the initial adduct between the aldehyde and NHC is generated, a proton transfer in the zwitterionic intermediate can take place through (a) a 1,2-direct process, or (b) a KOtBu assisted pathway /M06-2X/6-31G** level of theory. Additional analysis of the geometric features by using the intrinsic reaction coordinate computations on TS10 indicated that the t-butoxide first abstracts the proton from the enolate carbon to generate tBuOH and a potassium ion, thus leading to a potassium bound Breslow intermediate.In another density functional theory study on a chiral NHC catalyzed intermolecular Stetter reaction R5, ,10e the  pathway . The aut pathway , as kine2CO3 as the base , were examined /M06-2X/6-31G** level of theory, which is obviously far more favorable than the direct proton transfer process .10 Similarly, the barrier for the water assisted proton transfer viaTS12 was found to be 21.4 kcal mol−1, higher than that for the HCO3− assisted pathway. These data suggest that the kinetics of Breslow intermediate formation is likely to be sensitive to the nature of base employed during the course of its generation.In 2015, Tang and co-workers reported the mechanism and enantioselectivity of an NHC catalyzed [4 + 2] annulation reaction between enals and azodicarboxylates in the presence of Kbase R6, .10f,14 Texamined . In the 10 Sunoj and co-workers found that a DBU-assisted 1,2 proton transfer in the zwitterionic intermediate  is critical to the formation of the Breslow intermediate. In this process, the basic nitrogen of DBU abstracts the C–H proton and subsequently transfers it to the alkoxide oxygen in a concerted manner (TS13 in −1) was energetically more preferred over the 1,2-direct proton transfer with a prohibitively large barrier  at the SMD(THF)/B3LYP-D3/6-31G** level of theory. Through all the above-mentioned examples, we hope to have conveyed the significance of the base assisted proton transfer in the formation of the Breslow intermediate.In another computational study on a cooperative NHC–LiCl catalyzed reaction toward the synthesis of spirooxindole lactone R7, ,10g Suno TS13 in . As in t9 Acid additives have generally been considered as being capable of lowering the barrier for the formation of Breslow intermediates.9 Recently, Wei and co-workers have examined the mechanistic features and stereoinduction of a chiral NHC catalyzed [4 + 2] cycloaddition reaction at the IEF-PCM(THF)/B3LYP/6-31G** level of theory  than the corresponding five-membered alternative  as well as that in a direct proton transfer pathway .17 In the acid assisted proton transfer transition states, a stronger O–H⋯O hydrogen bonding interaction was noted in the seven-membered case than in the five-membered analogue.Acids such as acetic acid, benzoic acid, and other Brønsted acids have been employed as additives in various NHC catalyzed asymmetric reactions.eory R8, .10j Theyer TS14,  had a lo3CN) was 11.7 kcal mol−1 . Benzoic acid assisted proton transfer was found to be a concerted process as confirmed through IRC calculations. In another interesting study, Tang and co-workers probed the mechanism of a cooperative catalytic protocol involving an NHC and a Brønsted acid (TMEDA-H+) in a [3 + 2] annulation between enals and α-ketoamides /M06-2X/6-31G level of theory  was suggested to be far more favorable than the TMEDA assisted  as well as an unassisted proton transfer  route to the Breslow intermediate. It was noted that in TS16 the proton transfer from TMEDA-H+ is almost complete  as compared to the removal of C1–H4 (1.51 Å) by the amino end of the protonated base. Importantly, the O2–H3⋯N6 hydrogen bonding interaction stabilizes both the intermediate and transition states (TS16). The overall process was highly exergonic and irreversible. Furthermore, the barrier for the abstraction of the H4 proton by N5 of TMEDA viaTS16 was 13.4 kcal mol−1, which in turn leads to the Breslow intermediate and TMEDA-H+.Very recently, Sunoj and co-workers have examined the mechanism and origin of stereoinduction in cooperative asymmetric catalysis involving an NHC and Brønsted acid yielding γ-lactams by using SMDions R9, .9l In thal mol−1 . The bendes R10, .10k On tf theory , the Brø10 The barrier for the first proton transfer between two zwitterionic intermediates was 25.4 kcal mol−1 while that for the second proton transfer was 22.1 kcal mol−1. A two-step process involving the initial formation of a zwitterionic intermediate and a subsequent 1,2-hydride transfer to a keto-type intermediate was also noted in reaction R4. The barrier for DBU-assisted proton transfer in the keto–enol tautomerization was found to be much lower  as compared to that for the corresponding unassisted alternative .10 Although this two-step mechanism of formation of Breslow intermediates was proposed in certain systems, it should be noted that the single step pathways are energetically more feasible . Proton transfer assisted by K2CO3 was reported as energetically more favorable than other bases, acids, water, or alcohol. These findings collectively indicate that the choice of additive is likely to have a direct bearing on the efficiency of formation of the Breslow intermediate and hence on its subsequent catalytic abilities as well. Apart from the environmental influences exerted by various additives on the energetics of formation of Breslow intermediates, it would also be important to consider intrinsic factors such as the nature of the NHC and the substituents therein. In the following section, we wish to present one such interesting example for specific attention and more in the latter part of this thesis.A summary of the activation barriers for the formation of Breslow intermediates, under different reaction conditions, is compiled in N-substituents in the formation of Breslow intermediates. The geometric proximity and the ability of such substituents in altering the electron donating ability of the nitrogen to the carbenic carbon are of significance to the energetics of formation of the Breslow intermediate. One such study that sheds light on the effect of N-aryl substituent in NHC catalyzed reactions was from the Bode group. Noteworthy conclusions gathered from their control experiments and kinetic measurements conveyed that the Breslow intermediate formation is irreversible with N-mesityl carbene while with the N–C6F5 analogue it is reversible  through the reaction between alkyl halides and thiazolium salts, which are a close analogue of the Breslow intermediate , while excess aldehyde led to a spiro-dioxolane (43a). The latter could potentially be a resting state in the catalytic cycle, from where dissociation to the monomeric form should take place for its active participation in catalysis. In the presence of an acid, the reversible formation of an isolable intermediate, 43b, was noticed.As we begin discussing the isolation and characterization of Breslow intermediates, it is prudent to acknowledge the pioneering contributions from the Berkessel group, by taking one of their examples as a starting point. As the earliest step in this front, back in 2010, they could perform NMR characterization of the keto variant of a Breslow intermediatealdehyde . It was 45 (−1 higher in energy than the corresponding keto form 44 (when R = Ph). While the keto form was found to be catalytically inactive, attempts at tautomerization to the active enol form by using various acids, bases, and silylating agents also remained unsuccessful (44 to an enaminol (45a) or to an enol (45b) was in vain too, even in the presence of a catalytic amount of acid . Interestingly, the use of a catalytic amount of NaH base in the presence of a silylating agent, BSA acetamide), did provide access to a silylated enol ether, 46b, while the formation of an active enaminol, 46a, could not be established. It is likely that 46a was either not formed or was not amenable to detection under the conditions employed.The B3LYP/6-31G computations revealed that the enol intermediate 45  is 14 kcccessful . The tau24 Two key pathways for the proton transfer in the initially formed zwitterionic intermediate 47 were envisaged, (a) facilitated by the –OR group of the substrate (via intermediate 48) and (b) by engaging the N-aryl group of the catalyst (involving 50). Carefully designed kinetic experiments using substrates 51 and 53, as shown in 51 bearing an ether linkage was considered as evidence for an intramolecular substrate-assisted proton transfer  confirmed that the proton was not transferred via the catalyst as shown in 53 lacking an ether linkage , their own catalytic activity was demonstrated in an asymmetric Stetter reaction. Intermediates 57 and 59 are respectively an acyl anion and a homoenolate equivalent, which are typically seen in native NHC catalysis involving Breslow intermediates.Similar to the interest in native Breslow intermediates, there have been efforts toward the synthesis of other analogues such as aza-Breslow intermediates. A recent report by the Rovis group is particularly noteworthy where they disclosed the synthesis, detection, and characterization of aza-Breslow intermediates using a combination of UV-Vis, NMR, and X-ray crystallography  tools.25O-methylated Breslow intermediate by the deprotonation of the corresponding azolium salt in the presence of NaH and catalytic amounts of KOtBu as shown in 26 The thiazole derived intermediates 60 and 61 were formed as a mixture of Z and E isomers (Z/E = 2 : 1) while triazole analogue 64 resulted in Z/E of 1 : 10 (65 as the electrophile (O-methylated Breslow intermediates as the nucleophilic partners. It was found that the thiazole O-methylated Breslow intermediate (61) was less nucleophilic than the corresponding deoxy-Breslow intermediate (66). The relative rates between 62 and 61 indicated that the O-methylated Breslow intermediate derived from thiazole was 2 to 3 orders of magnitude less reactive than the structurally analogous imidazole family.In another study, Mayr and co-workers isolated an f 1 : 10 . An intetrophile  and a ra31 or dihydro-imidazolidine-2,6-bis(2-propyl)phenyl (SIPr) 68 with benzaldehyde or 2,4-bis(trifluoromethyl)benzaldehyde, respectively, yielded Breslow intermediates 67 and 69 (44), while the latter offered access to the desired enaminol variants 67 and 69. These Breslow intermediates were further examined using in situ NMR spectroscopy.27 A characteristic peak at δ = 4.40 ppm in the 1H NMR spectrum of 69 benzaldehyde (13CHO) resulted in a coupling between 13C (labeled as C6) and the OH group (2JC–OH = 3.23 Hz). The other characteristic 13C peaks observed were at δ = 145.8 ppm  and δ = 142.5 ppm . These spectral features confirmed the formation of diamino enol between the saturated carbene SIPr and 2,4-bis(trifluoromethyl)benzaldehyde. These pieces of unequivocal evidence are noteworthy inroads toward a long-standing goal of establishing the true nature of Breslow intermediates.Along similar lines, Berkessel and co-workers reported the synthesis of diamino enols using saturated carbenes. The reaction of dihydro-imidazolidine-2,4,6-trimethylphenyl (SIMes) 7 and 69 . A compa7 and 69  and thatum of 69  was conf70 exists in equilibrium with the free carbene 68 and benzaldehyde. The use of a more electrophilic 2,4-bis(trifluoromethyl) benzaldehyde exhibited rapid equilibrium between 70, 68, and 71. The formation of a cross benzoin product (72) as the major product was considered as a tangible indication of a fully reversible equilibrium operating between Breslow intermediates 70 and 71. Experiments of such kind that were able to identify an equilibrium between a free NHC and the corresponding Breslow intermediate do convey a gratifying message that our quest for studying enaminol intermediates has come a long way.Interesting crossover experiments were performed to gather additional details regarding the equilibrium of Breslow intermediate formation . It was 28 Intermediates such as diamino enol 76 , diamino dienols 77 and 79 , azolium enolate 78 , and azolium enol 80 could be identified. Each of these intermediates hold a prominent place in NHC catalysis as they are known to react with a range of different electrophiles to furnish a good number of valuable products.In keeping with their continued interest in Breslow intermediates, Berkessel and co-workers characterized a set of key intermediates involved in the NHC catalyzed umpolung reactions of various aldehydes by using X-ray crystallography .28 Inter82 was noticed in the case of triphenyltriazolylidene carbenes (42), while the saturated imidazolylidene carbenes (68) yielded the enol tautomer (84) in their stoichiometric reaction with benzaldehyde //M06-L-D3/6-31+G level of theory for the enol was found to be 2 kcal mol−1 lower when 2,6-bis(iso-propyl)phenyl was the N-R substituent as compared to that of a simple phenyl substituted NHC  could also be accomplished.30The electronic energy computed at the M06-2X-D3/def2-TZVPP/IEFPCMuted NHC . The ele31 The ammonium charge-tag was introduced either on the NHC or aldehyde moiety, as shown in 68 existed as a diamino enol, 87. The presence of IR stretching frequencies at 1538 cm−1  and 1524 cm−1 (computed) was attributed to the enol C PBM data was replaced with SVG by xgml2pxml:<glyph-data id="z.dbd" format="PBM" resolution="300" x-size="8" y-size="10" xml:space="preserve">00000000000000000000000000000000111111110000000011111111000000000000000000000000</glyph-data><svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="13.200000pt" height="16.000000pt" viewBox="0 0 13.200000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata>Created by potrace 1.16, written by Peter Selinger 2001-2019</metadata><g transform="translate scale" fill="currentColor" stroke="none"><path d="M0 440 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z M0 280 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z"/></g></svg>C(OH) functionality of diamino enol 87. The detection of diamino enol was in concert with the computed energetic preference of 12 kcal mol−1 toward 87 as compared to the corresponding keto form at the M06-2X-D3/def2-TZVPPD//M06-L-D3/6-31+G level of theory. On the other hand, attempts to obtain the Breslow intermediate using 1,2,4-triazolin-5-ylidenes 42 and thiazolin-2-ylidenes 89 resulted in keto structures, shown respectively as 88 and 90. Both the experimental and calculated IR spectra showed the presence of a carbonyl CO stretching band at 1720 cm−1 and at 1670 cm−1 for 88 and 90, respectively.After their successful series of reports on the characterization of various Breslow intermediates, both in the solution and in the solid state, Berkessel and co-workers have most recently disclosed a gas phase study of an ammonium charge-tagged Breslow intermediate by using ESI-MS IR ion spectroscopy in conjunction with quantum-chemical calculations.Breslow intermediates occupy a unique position in the contemporary literature owing to the remarkable popularity of N-heterocyclic carbene (NHC) catalysis. In due cognizance of the central role of Breslow intermediates in a myriad of NHC organocatalytic reactions and the lack of a single consolidated resource on their formation, isolation, and characterization, we have compiled the available knowledge in this review and have provided a critical assessment of their developmental strides. As the title implies, this treatise is philosophically organized from ‘then’ to ‘now’, and thus provides chronological details of the evolution of Breslow intermediates.The age-old concept of umpolung, invoked for understanding the homo-dimerization of aldehydes in the presence of cyanide, bears noteworthy semblance to certain catalytic protocols employed in recent times. The suggested role of NHCs in promoting a similar umpolung reactivity became a conspicuous landmark when Ukai and co-workers identified that thiazolium salts could catalyze the benzoin reaction. A few decades later, Breslow proposed the involvement of a nucleophilic amino enol intermediate in the mechanism of a thiazolium catalyzed benzoin reaction. While this putative intermediate remained rather dormant for long, the renaissance in organocatalysis in the last two decades appears to have provided the much-needed impetus. Obviously, recent years witnessed an unprecedented series of applications of such amino enols in NHC catalyzed organocatalytic reactions. In honor of his pioneering work, amino enols have been termed as “Breslow intermediates”.N-substituents on the carbene backbone were identified to influence the formation as well as the subsequent reactivity of nucleophilic Breslow intermediates under different reaction conditions. Experimental endeavors probing the formation of Breslow intermediates were ably complemented by computational studies that helped in gaining key molecular insights. Importantly, computations revealed that after the initial addition of the NHC to a suitable enal/enone or similar electrophilic partner, the ensuing proton/hydride transfer encountered high barriers. A direct proton transfer in the initial zwitterionic intermediate through a strained three-membered transition state, or a 1,2-hydride transfer first to a keto intermediate that tautomerizes via a strained four-membered transition state to the corresponding Breslow intermediate, had a prohibitively high kinetic barrier. Computational studies demonstrated that the vital proton transfer could be assisted by an explicit participation of additives/solvent. Assisted proton transfer promoted by various additives (such as K2CO3) exhibited lower barriers than the corresponding unassisted pathways in the formation of Breslow intermediates, with a general preference for the assisted 1,2-proton transfer than the alternative keto–enol mechanism. Hence, the single step mechanism of formation of Breslow intermediates, with barriers in the range of 7 to 24 kcal mol−1 (depending on the molecular system), was recommended as more favorable over the two-step mechanism .In the years that followed, efforts toward the generation of structural analogues of Breslow intermediates became an attractive endeavor. The characterization of Breslow intermediates derived from saturated imidazolylidene, unsaturated benzimidazolin-2-ylidenes, and thiazolin-2-ylidenes was realized. The electronic features of the in situ detection of Breslow intermediates under a plethora of diverse reaction conditions has significantly improved, certain subtle issues related to the energetics of formation that leads to the keto form with imidazolylidene carbenes and enaminol variants with dihydro imidazolylidene seem to demand more careful scrutiny. In summary, we have enunciated the state-of-the-art understanding on the formation and nature of Breslow intermediates in NHC organocatalysis, which is expected to serve as a single source of valuable knowledge on this important topic.Besides the work on the energetic origin of formation of Breslow intermediates, inexorable efforts led to successful elucidation of their structure by using X-ray crystallography in the solid state, NMR studies in the solution phase, and more recently ESI-MS IR ion spectroscopy in the gas phase. While our ability to perform All authors conceptualised the review, M. P. and Y. R. wrote the first draft supervised by R. B. S., who edited the manuscript.There are no conflicts of interest to declare.


We designed a questionnaire and asked two groups of veterinarians: (1) subject matter experts, who had published on calving management and (2) veterinary practitioners) for their opinion about aspects of calving management. Participants recommended to differentiate between the two stages of parturition and emphasized signs of imminent parturition, such as “restlessness” and “visibility of fetal parts”. There was no consensus on the right time to move the cow to the maternity pen. Almost half of the respondents recommended a 6-h observation interval for prepartum cows in the maternity pen. The two veterinary groups differed little in their knowledge of calving management.n = 80) and non-SMEs, veterinary practitioners  for their opinions. For this, we designed a questionnaire on the significance of signs of imminent parturition (SIP), the frequency of calving observation, and influencing factors for the timing of cow movement to a maternity pen. The response rate was 67.5% in the online survey and 100% in the workshop survey. The majority (89.7%) of all respondents agreed that it is beneficial for successful calving management to differentiate between stage I and II of parturition. Of 12 signs of imminent parturition (for stage I and II), “restlessness” and “visibility of fetal parts in vulva” were cited by 56.5% and 73.3% of SME and non-SME respondents, respectively. There was no consensus on the right time to move the cow to the maternity pen; recommendations varied from one to over 21 days. Almost half of the respondents (45.7%) recommended a 6-h observation interval for prepartum cows in the maternity pen. This study identified a strong consensus on the SIP and how and when to observe cows prior to parturition. SMEs and non-SMEs provided broadly similar recommendations, while the SMEs and the non-SMEs differed significantly in the number of publications on calving they authored, they differed little in their knowledge of calving management.Accurate detection of the onset of parturition is a key factor in the prevention of dystocia. In order to establish current best practice recommendations for calving management, we asked subject matter experts (SME) who had published on calving management (by online survey,  Between 2 and 10% of all calves are born dead or die in the next 48 h after birth . ManagemMaternity pens  not only provide a lower risk of spreading infections , but theSpecific recommendations regarding the prediction of calving time and consequent movement to the maternity pen are rare. Relaxation of the pelvic ligaments  or the cThis raises the generic issue of how subject matter experts (SMEs), e.g., academics, might differ from non-SME, e.g., veterinary practitioners, in their recommendations. An adjacent study of causes of perinatal calf mortality revealed a surprising consensus between SME and non-SME . Any potGiven this paucity and diversity of opinion in the literature and the knowledge gap of what veterinary practitioners recommend, the objective of this survey was to elicit current veterinary opinions on calving management in order to provide farmers with best practice recommendations for managing the prepartum cow. Furthermore, we wanted to find out, if there is a difference in opinion between SMEs and non-SMEs.n = 18) were either open (n = 6), semi-open (n = 4), multiple-choice (n = 1), or closed (n = 7). Four questions covered general information on the participants and 14 questions comprised a selection of signs of imminent parturition (SIP), definitions of stages of calving, and information on influencing factors during calving, technical devices, and management of dystocia. The original questionnaire is provided in the Supplementary Online A comprehensive questionnaire in English was developed by a team of veterinary researchers focusing on calving management. The questionnaire was assessed for readability, clarity, and logical structure by 12 research associates before administration. Questions  and veterinary practitioners (non-SMEs). To identify SMEs, two comprehensive literature searches were conducted, and the corresponding authors of publications were contacted. Three different search strategies were applied.https://www.ncbi.nlm.nih.gov/pubmed/) was accessed (on 28 June 2018), using the keyword combination “Calving Management OR Calving Prediction” for relevant publications (n = 1283). Results were filtered by applying the following exclusion criteria (n = 1252), published between 1998 and 2018 (n = 1045) with the subject: veterinary science (n = 1031) and available as full text (n = 973). Publications with a title that was off-topic  (n = 801), published in a book (n = 1) or a journal with a 5-year citation index (IF) of ≤1.0 (n = 1), and dealt with beef cattle (n = 64) or species other than cattle (n = 24) were excluded. The 82 remaining publications were examined in more detail and selected as reference publications based on the study objective (n = 30). Corresponding authors that were named twice or more (n = 8) were filtered out. Given the limited number of corresponding authors (n = 22) identified in the Pubmed search, another search engine (https://scholar.google.com/) was accessed on 15 July 2018, and publications before 1998, with an IF ≤ 1, and publications dealing with beef cattle were included, resulting in an additional 39 corresponding authors. The systematic literature research via Pubmed and Google Scholar resulted in 61 corresponding authors that were included in the survey.First, the Pubmed database (criteria . Publican = 319) in a convenience sample of 5 of the 22 selected publications  were excluded. Publications with a title that was off-topic (n = 215), published before 1998 (n = 15), published in a journal with an IF ≤ 1 (n = 1) and not peer-reviewed (n = 1) were excluded. In addition, corresponding authors who were cited multiple times in the reference list of the 5 selected publications (n = 36) and corresponding authors who are members of our working group (n = 3) were excluded. This supplementary search resulted in 19 additional corresponding authors that were included in the final survey.Secondly, a supplementary search of the references  was conIn total, 80 corresponding authors were invited to participate as subject matter experts (SMEs) in the field of calving management in the survey.For the non-SMEs, 24 participants in a workshop on bovine perinatology organized by the Ontario Association of Bovine Practitioners (OABP) delivered by J.F. Mee and held in Guelph, Canada on 2nd May 2019 were surveyed as a convenience sample of large animal practitioners.https://www.unipark.com/), (online survey) (accessed on 10 July–26 September 2018)] and veterinary participants in a workshop on bovine perinatology [using a paper copy of the questionnaire (workshop survey)].The same questionnaire was administered to the two veterinary groups; corresponding authors of peer-review papers on calving management  to observe cows for signs of parturition and potential movement to the maternity pen ranged from more than 21 days to one day before ECD ; the other 9 participants  disagreed with this practice . The recommendations of SMEs and non-SMEs did not differ significantly.p = 0.04).Twenty-two SMEs and 21 non-SMEs named 21 important signs of parturition . “Abdomip = 0.009) stated “Gestation length” was a recommendable parameter. Some of those recommended 3 weeks (n = 5) or 1 week (n = 3), others 2 weeks (n = 1) or three days (n = 1) before ECD. All 39 respondents estimated the predictive value of their recommended SIPs in the upper range , but only 10.3% of respondents  considered the predictive value of their selection to be very certain . Most respondents  estimated the predictive value of their recommendation at 61–80%. There was no significant difference between SMEs and non-SMEs.In question 11 we offered a choice of ten signs of parturition to determine the right time to move a cow to the maternity pen. The most common responses were “Relaxation of the pelvic ligaments”,  and “Behavioral changes”  . Thirteep = 0.02), and “Vaginal discharge with bloody traces”  were very important to check on a regular basis as signs of parturition. “Tripping” was found to be very important by SMEs only  , “Tail raising” , tail-mounted accelerometers  or cameras in the maternity pen .When asked to rate on a 5-point Likert scale the importance of influencing factors on the right time of moving a cow to the maternity pen  who fully agreed and 16  who agreed. The influence of cow movement on the duration of parturition was supported by 27/45 participants, who fully agreed (26.7%) and agreed (33.3%), whereas 8 (17.8%) voted neutral and 4 (8.9%) disagreed, and 2 (4.4%) fully disagreed. Most participants agreed  that the timing of moving cows to the maternity pen also affects the ease of calving. Answers of SMEs and non-SMEs on influencing factors did not differ significantly.When asked whether participants would recommend a vaginal examination to rule out dystocia and when they would recommend such an examination  or once abdominal contractions  have commenced were indices for vaginal examination. Bloody vaginal discharge was considered an immediate indicator for a vaginal examination  but others recommended waiting up to 24 h . Regarding the interval from observation of abdominal contractions to vaginal examination, the time period with the highest agreement  was 1 h, with variation from 30 min to 24 h. Five participants  recommended not to perform a vaginal examination at all, only if no calving progress is apparent, bleeding or placenta prolapse.Besides after the appearance of the amniotic sac (AS) or feet of the calf outside the vulva; bloody vaginal discharge  was higher in the workshop (62.5%) than in the online survey (28.8%). However, the login rate  in the online survey (67.5%) is comparable with other online surveys  considered the predictive value of their selection to be very certain . However, this 10.3% of participants all selected different signs which they named to be very predictive. This suggests over-confidence in experts’ ante judgment, failure to recognize objective ignorance, and perhaps lack of experts post evaluation. The favorite signs rated as important for imminent parturition were “Abdominal contractions” and “Vaginal discharge”. Overall, signs selected were consistent with the literature ,49,51,52Respondents recommended increased frequency of daily observations once the cows were in the maternity pen, most commonly every 2 or 6 h. These recommendations are similar to those published by Mee  who suggThe benefits of technical devices for detecting calving and deciding when to move cows were not unanimously accepted by study participants. Various devices for calving surveillance have been developed and evaluated ,63,73,74When asked about the importance of factors influencing the timing of cow movement to the maternity pen, study participants’ assessments regarding the expertise of the personnel are consistent with the literature where comprehensive training on calving management practices has been identified as a top priority in order to reduce the incidence of calving difficulties ,3,78. ThMost participants agreed (26.66% fully agreed and 33.33% agreed) that the timing of moving cows to the maternity pen has an influence on the duration of parturition. Stress caused by moving the cow to the maternity pen during the first stage of parturition can stop or delay the calving process  and causMost participants agreed (22.2% fully agreed and 42.2% agreed) that the timing of moving cows to the maternity pen also affects the ease of calving. Other studies reported that moving primiparous cows to the maternity pen in stage two of parturition resulted in lower average calving ease scores compared to stage one . A vaginal examination can help to rule out dystocia. The majority (89.4%) of study participants recommended such an examination and only five (10.6%) did not recommend examining the cow or only in cases of no calving progress or if blood or the placenta came out. In some studies, cows were given a vaginal examination if no progress of parturition was observed two hours after AS burst  or feet The objective of this survey was to elicit current recommendations on calving management from both SMEs and non-SMEs in order to provide farmers with best practice advice for managing the periparturient cow. There was good consensus between SMEs and non-SMEs apart from using ECD as a good sign for moving cows into maternity pens. It seems that some information found in the literature lacked high clinical utility due to the imprecision in either their definition, , measurement , or timing  or their poor evidential base . Thus, it can be concluded that it makes sense to differentiate between stages 1 and 2 of parturition. There is a broad agreement on how to identify imminent signs of parturition, but skilled and motivated personnel is needed to recognize those. However, more research is warranted to determine the best time for moving cows to the maternity pen. To rule out dystocia a vaginal examination of the calving cow was recommended. Technical devices are recommended to identify the onset of calving, without a clear recommendation of the best technique.


In the last decade, there have been significant advances in our understanding of anterior cruciate ligament (ACL) reconstruction. Recent prospective cohort studies have identified risk factors for ACL reconstruction graft failure such as younger patient age, increased activity level, nonanatomic tunnel placement, and the use of allograft. Among these, the most easily modifiable risk factor is graft choice. Given that the surgeon's recommendation has been shown to be one of the most important factors behind patients' graft choice, it is critical that the operating surgeon have a thorough understanding of all the ACL graft options available to choose the graft that would be most suitable for the patient's personalized reconstruction . The purpose of this review is to provide an up-to-date understanding of the current ACL graft reconstruction options. The indications, advantages, and disadvantages of the different ACL reconstruction graft options available will be discussed. It is thus imperative that the ACL surgeon has a complete understanding of the graft options available given that his or her recommendation will strongly influence a patient's ultimate graft choice.2Injury to the anterior cruciate ligament (ACL) is one of the most common sports-related injuries, and its incidence has been increasing at all levels of competition. In the United States alone, the rates of ACL reconstruction (ACLR) have increased significantly in a 12-year period from 10.36 to 18.06 and from 22.58 to 25.42 per 100,000 person-years for females and males, respectively.3 These bundles work synergistically to stabilize the knee in response to anterior tibial and rotary loads.3 Biomechanical studies have shown that the PL bundle contributes the most to rotatory stability to the knee in lower degrees of flexion, and the anteromedial bundle provides more sagittal stability in higher degrees of flexion.3Before performing ACLR with autograft or allograft, knowledge of the anatomy and biomechanics of the native ACL is essential. The ACL functions to provide anteroposterior and rotary stability to the knee. It comprises two functional bundles based on their tibial insertion sites, the anteromedial and posterolateral (PL) bundles.3 It comprises a highly organized collagen matrix with 20-μm-thick bundles of collagen fibers surrounded by loose connective tissue.3 Its sporadic fiber arrangement allows for a higher tensile strength than many other ligaments, with a maximum tensile strength reported as high as 2160 N (mean tensile strength approximately 1725 N), with a stiffness of 242 N/mm (mean stiffness 182 N/mm) and a strain rate of approximately 20% before failure4  with an average thickness of 3.9 mm and a cross-sectional area of 40.9 ± 3 mm.7 Iliotibial band autografts have also been described for use in both primary ACLR and as an augmentation technique, largely in the skeletally immature patient population.8 For allografts, the most common choices include BPTB, tibialis anterior or posterior, HS, and Achilles tendon.7 Iliotibial band and peroneal allografts have also been described for ACLR.9There are many graft choices for ACLR, including autografts and allografts. The autograft choices most commonly used include hamstring (HS), bone–patellar tendon–bone (BPTB), and quadriceps tendon (QT) with or without a bone block.4 The choice of graft should also be individualized to the patient's risk factors for failure, anatomy, sport, level of competition, age, and graft used in previous ACL surgery for cases of revision reconstruction.10 Graft size is an important consideration, as larger grafts may provide improved strength, but have also been shown to increase the risk of postoperative arthrofibrosis.11 Overall, graft size, rather than graft type, seems to be more associated with the risk of arthrofibrosis after ACLR.11 Recent prospective cohort studies have identified several risk factors for ACLR graft failure.7The ideal graft for use in ACLR should have similar properties to those of the native ligament, limit donor site morbidity, and allow for secure fixation and rapid incorporation.7 Higher activity level at the time of ligament injury has been associated with an increased risk of graft rupture.7 Studies have also clearly demonstrated that tunnel malposition is associated with higher rates of reconstruction failure.12 The use of allograft in comparison to autograft has also been identified as a risk factor for reconstruction failure, especially in younger more active patients.7 It is important to note that regardless of graft type, anatomic ACLR is considered the benchmark, reconstructive technique,13 as it has been shown that anatomic ACLRs reduce the risk of posttraumatic osteoarthritis (OA) at long-term follow-up.14 Given the multitude of graft options and risk factors for failure, it is critical that the operating surgeon have a comprehensive discussion with the patient regarding which graft option(s) would be most suitable for the patient's individualized reconstruction, particularly given that the surgeon's recommendation has been shown to be one of the most important factors behind the patient's graft choice.2 A summary of the indications, advantages, and disadvantages of the different ACLR graft options is shown in Table Younger patient age has been consistently shown to portend a higher risk of reconstruction failure, which is likely in part related to increased activity level and demands on the reconstructed graft.4 Autograft options include HS, BPTB, and QT with or without a bone block.10 Autografts can be harvested from the ipsilateral/injured side or from the contralateral or uninjured extremity. There are advantages and disadvantages to the different types of autografts, which will be discussed in detail. As previously mentioned, it is imperative to tailor graft choice to the patient's anatomy, sport, age, level of competition, and graft used in previous ACL surgery.10Autografts remain the preferred graft choice in the young athletic patient population due to higher rates of failure, increased costs, and risk of repeat rupture associated with ACL allograft reconstruction.7The BPTB autograft consists of a portion of the central aspect of the patellar tendon with its corresponding bone plugs from the patella and tibia Figure , A. The 15 Other long-term outcome studies have demonstrated a higher incidence of post-traumatic OA after ACLR when using BPTB autograft in comparison with HS autografts. The rates of OA have been reported to be as high as 39% at 10 years after BPTB compared to 18% at 10 years after HS autograft and the relative risk for OA for BPTB versus HS has been reported to be 1.61.17 More recent studies and meta-analyses have found that BPTB autografts have lower failure rates and higher return-to-sport rates compared with HS autografts, especially in the young athletic patient population.18-20 These studies have reported graft rupture rates between 1.9% and 6.6% after BTB autografts compared with 4.9% and 17.5% after HS autografts. Some studies have also found less residual anterior knee laxity and improved stability with the use of BPTB autograft versus HS autograft at longer-term follow-up.19 Proponents of BPTB also cite the advantages of bone-to-bone healing compared with soft-tissue allografts. In a sense, bone-to-bone healing is similar to fracture healing and is faster and stronger than soft-tissue healing.4 Although bone grafts have been shown to heal to host bone within 6 weeks, soft-tissue grafts take 8 to 12 weeks to fully incorporate.4Past randomized controlled trials of primary ACLRs comparing HS versus. BPTB autografts have shown similar results, patient-reported outcomes, and incidences of postoperative OA on follow-up radiographs.4 It should be noted that intraoperative and postoperative patellar fractures and patellar tendon ruptures are uncommon complications after BTB harvest.6 One of the most common complications after ACLR that has been associated with BPTB autograft use is anterior knee pain.19 In a meta-analysis of 21 studies, BPTB autografts had an incidence of anterior knee pain of 17.4% versus 11.5% in HS autografts.19 The cause of postoperative anterior knee pain has not been well elucidated, but it has been hypothesized that anterior knee pain is related to the harvesting method of the BPTB graft. Studies have shown that patients who kneel for a profession or sport  experience more postoperative anterior knee complications—making BPTB autograft a relatively contraindicated graft choice in these patient populations.16 There is some evidence that anterior knee pain after ACL surgery may be more related to loss of motion and poor rehabilitation rather than graft choice, and studies have demonstrated a decrease in anterior knee symptoms after initiation of an accelerated rehabilitation program that emphasizes knee extension.4 BPTB autograft is also contraindicated in skeletally immature individuals as the graft harvest and fixation methods would violate the physes and increase the risk of growth arrest.16Although outcomes with BPTB autograft are consistently good, there are complications associated with BPTB that are almost exclusively related to the graft harvesting technique. These harvest-related complications include patellar fractures 0% to 2%), patellar tendon rupture (0.25%), and patellar tendonitis as shown in Table %, patell16 HS autografts are typically folded on themselves to increase graft diameter and strength and can be folded to form two- to six-strand grafts.3 Although larger grafts are biomechanically stronger, grafts that are too large can cause impingement. Quadrupled HS grafts are most commonly used as they provide a balance between strength, stiffness, and mobility.3 A quadrupled HS autograft after harvest and preparation is shown in Figure 16 Disadvantages include prolonged healing times, unpredictable graft size, higher failure rates in certain patient populations, and knee flexion weakness.16 HS autografts have been known to cause bone tunnel enlargement due to a windshield wiper effect from the suspensory fixation.24 There is also a risk of residual HS weakness,16 making the graft a relative contraindication for athletes who heavily rely on their HSs for their athletic performance . HS autografts have also been shown to have higher infection rates than BPTB autografts; a registry study from Kaiser Permanente demonstrated that patients who had HS autograft ACLR were 8.24 times more likely to develop a deep surgical site infection than patients who had a BTB autograft (0.6% compared with 0.07%).23Given the complications and disadvantages associated with BPTB autografts, HS autografts (semitendinosus and/or gracilis muscle tendons) are a viable option for ACLR in certain patient populations.18 In particular, HS autograft seems to fail more among younger female patients, with graft rupture reported at 17.5% after HS autograft compared with 6.4% after BTB autograft in females aged 15 to 20 years.20 Interestingly, a recent randomized controlled trial showed that the addition of a lateral extra-articular tenodesis (LET) to HS autograft ACLRs resulted in a clinically relevant and statistically significant reduction in graft failure and persistent rotatory laxity at two years after surgery.26 Despite the improvements in graft rupture rates and postoperative laxity, there were no clinically important differences noted in patient-reported outcome meausures in this study. This is a promising result, and further research is currently being performed with regard to indications and long-term outcomes after LET.The main concern after HS autograft ACLR is graft failure. As previously discussed, recent studies and meta-analyses have found that HS autografts have higher failure rates compared with BPTB autografts.13 Harvesting with a bone block can provide a longer graft if needed. The QT is a reliable and robust graft with a cross-sectional area up to twice that of a BPTB autograft.5 The graft is longer and wider, has a higher tensile strength, about 50% more mass than a BPTB autograft, and has been shown to be biomechanically similar to the six-strand HS autograft with regard to ultimate load to failure.10 It can be used in both primary and revision ACLRs based on tunnel size, tunnel position, previous graft used, etc.13 QT harvest is associated with less damage at the tendon harvest site than BPTB harvest, with similar patient-reported outcomes.10 In addition, it can be harvested with a minimally invasive technique using a small incision with or without the assistance of an arthroscope.27The QT autograft is an option for ACLR in the primary and revision setting and has recently gained popularity due to its versatility and more recent outcome data Figure , C. The 13 The all soft-tissue QT has become increasingly used in skeletally immature patients and is a good alternative to the traditional HS autograft with improved outcomes, as previously discussed. Despite its advantages, QT autograft ACLR is not without its associated complications , less injury to the infrasaphenous nerve branch (1.5% versus 53.3% BTB), less donor site morbidity (zero to 15% versus 18% to 51% BTB), and a low rate of quad strength deficit for both FT and partial-thickness (PT) grafts .27 In a systematic review of clinical studies  that evaluated QT versus BPTB and HS, no significant differences were found in laxity, patient-reported outcomes, or patient satisfaction between QT and either BPTB or HS.25 In addition, a more recent meta-analysis evaluating 27 clinical studies with 2856 patients (Level of Evidence II) concluded that QT had similar graft survival rates and comparable functional and clinical outcomes when compared with BPTB and HS autografts.28 In this meta-analysis QT also showed improved functional outcomes compared with HS autograft and significantly less harvest site pain compared with BPTB autograft. Numerous studies have also shown no significant differences in knee stability testing  between QT versus HS or BPTB.25 A recent registry study did show a higher revision rate for QT (4.7%) versus HS and BPTB (2.3% versus 1.5%. respectively), although QT patients in this study comprised only 3.2% of the patient sample and graft size, fixation technique, and bone block use were not available for analysis.29 Because the QT is historically the least used autograft option for ACLR, further research is required to better understand its long-term outcomes.7Whereas initial outcome data were unfavorable for QT autografts, more recent data using newer harvest techniques have provided support for the use of QT autografts in both the primary and revision settings.9 An example of a prepared Achilles tendon allograft for ACLR is shown in Figure 30 Disadvantages of allografts include concerns for disease transmission, immune responses, weakening of graft tissues that occurs due to sterilization and processing techniques, and delayed incorporation and healing.31 Other disadvantages are that allografts are more costly than autografts4 and that they are not as widely available in other countries outside of the United States.30As discussed previously, a variety of fresh-frozen allograft options exist such as patellar tendon, tibialis anterior or posterior tendons, HS tendons, peroneal tendons, iliotibial band, and Achilles tendon.32 Allograft processing begins with careful screening of the donor patient to minimize the risk of communicable diseases.31 After allograft harvest, grafts must be sterilized before they can be stored for eventual transport and usage for ACLR. There are a number of sterilization methods including ethylene oxide, low- or high-dose gamma irradiation, and supercritical carbon monoxide among other techniques. All methods of allograft sterilization have been found to compromise the structural integrity of the allograft to varying degrees.21 Gamma irradiation has been found to have a dose-dependent relationship with delayed graft healing and increased risk of failure.32 Newer sterilization techniques including supercritical carbon dioxide and the use of gamma irradiation in conjunction with antioxidants have been developed and have yet to demonstrate significant improvement in mechanical properties of the grafts in comparison to previous methods.32 With graft processing and sterilization, risk of disease transmission with allografts is extremely small, and risk of surgical infection has not been shown to differ markedly in comparison with autografts.31 Allografts can be stored as fresh frozen, freeze dried, or cryopreserved and typically remain frozen for approximately 2 to 4 weeks until serologic studies are complete to confirm that the grafts are disease free.Before proceeding with allograft ACLR, it is imperative that surgeons be familiar with graft processing techniques and infection risk, as different techniques have been shown to affect risks of graft failure and subsequent revision surgery.33 A recent systematic review demonstrated that in active patients aged <25 years, there was a 9.6% graft rupture rate with autograft versus 25.0% with allograft.33 There is also evidence that athletes have an improved return-to-sport rate when undergoing ACLR with autograft compared with allograft, with one study demonstrating a return-to-sport rate of 43.3% after BTPB allograft compared with 75.0% after BTPB autograft.34Regarding outcomes after ACLR with allograft, studies have consistently shown that allografts have a higher rerupture rate than autografts in young, athletic individuals.7 In addition to decreased morbidity, easier recovery, and shorter surgical times,30 studies have demonstrated that outcomes and revision rates after allograft use in patients who are aged >40 years are consistently similar to those after autograft ACLRs.35 There are special circumstances in which allografts can be useful, particularly in younger patients. These include multiligament knee injuries, multiple-revised ACLRs with limited autograft options, patient preference, and cases in which autograft tissue is inadequate.31 A summary of relative indications for allograft ACLR is shown in Table Although the literature demonstrates higher failure rates with allograft in young, active athletes, there is a compelling role for allograft use in the older, less active patient population.23 it is important to note that comparison of absolute values among these studies is difficult due to differences in donor age, graft size, and testing methodology.The biomechanical profiles of the native ACL, as well as autografts and allografts used for ACLR, are shown in Table 5 , suspensory fixation with fixed or adjustable loops, buttons, or a combination of aperture fixation for one side of the graft and suspensory fixation for the other. Both fixation types can be used for soft-tissue grafts and grafts with bone blocks.36 In light of these issues, nonmetallic interference screws have been developed as an alternative fixation method.Historically, interference screws were metallic, most often titanium. Titanium interference screws in ACLR have been associated with a low complication profile and excellent long-term results. Despite their initial widespread use, metallic interference screws have unique disadvantages including the possibility of iatrogenic graft damage with screw insertion, limitations in postoperative advanced imaging related to metal artifact, and retention causing potential difficulties in the event of revision surgery.36 Despite the initial appeal, these interference screws have raised concerns due to reports of screw breakage, increased postoperative effusion, and diminished pullout strength in comparison to metallic screws. A recent prospective, randomized controlled trial evaluated long-term outcomes of ACLR using either PLLA-HA screws versus titanium screws and found equivalent clinical results lasting up to 13 years postoperatively.36Nonmetallic interference screws use a variety of materials including polyglycolic acid, poly-L-lactic acid (PLLA), poly-D,L-lactic acid, poly-D,L-lactic acid with trimethylene carbonate, polyglycolic acid with trimethylene carbonate, and PLLA with β-tricalcium phosphate.37 Suspensory fixation is also advantageous in pediatric patients to avoid the potential damage to the physis that an interference screw placed across the physis can cause. Concerns with suspensory fixation devices are that when grafts are placed nonanatomically, there can be bone tunnel enlargement due to a windshield wiper motion of the graft.24 A recent prospective study demonstrated that both fixed loop and adjustable loop suspensory devices are equally effective fixation methods for ACLR.37Given that interference screws have the potential for graft damage and for hindering graft-to-bone healing, a variety of suspensory fixation devices have been developed, including fixed and adjustable suspensory devices.The ideal graft choice for ACLR depends on many patient factors and should be individualized to best match the patient's anatomy, age, needs, and expectations. A number of autograft and allograft options are available that can achieve satisfactory results if applied appropriately. The treating surgeon should thus be familiar with all the ACLR reconstruction options available to individualize and optimize each patient's treatment and outcomes.


JACC: CardioOncology launched in September 2019, and has emerged as the premier journal and essential resource in the field, receiving an impact factor of 6.25 in under 2 years of publication.Increasing awareness and knowledge surrounding the prevention, screening, diagnosis, and management of cardiovascular injury associated with cancer therapies has ushered in the dedicated subspecialty of cardio-oncology. A rise in cancer survivorship has resulted in growing numbers of aging survivors with cardiovascular disease who also need specific and informed cardiovascular care . These pJACC: CardioOncology's launch, a focused and multimodal social media (SoMe) strategy was created with the overarching goal to augment the dissemination of cardio-oncology knowledge for both patients and health care professionals , clicks, link clicks to pandemic . AlthougJACC: CardioOncology on WeChat with Chinese language translations. Content is also featured on LinkedIn.To place this SoMe engagement in context, we have promoted new issues and podcasts on SoMe each quarter. Twitter threads are frequently used, complementing 3-5 posts daily. Twitter’s microblogging interface allows for short communications, is the platform widely used by health professionals in cardio-oncology, and has emerged as an important medical education tool in the Americas and Europe. Disease process diagrams are routinely used on Instagram, with 1 post daily. Instagram is well-suited for cardiovascular image-centric communications. New clinical studies are also shared on Facebook, with 1-3 posts daily. Facebook has the largest global user base; allows for text-based interactions with photo, video, and link embedding capability; and has many engaged followers in Asia. Additionally, and primarily to further engage our international audience, we have leveraged a “live” video journal club series, and cross-promotion of In 2019, the overall journal Altmetric Attention Score was 1,350, with 2,029 Twitter mentions and 41 Facebook Mentions. The most talked-about paper was “Pre-Diagnosis Exercise and Cardiovascular Events in Primary Breast Cancer: Women's Health Initiative,” with an Altmetric score of 145 . In 2020To place these data in context, we looked at SoMe analytics for all ACC journals for 2020. As of December, the @JACCJournals Twitter account had >925,000 tweet engagements in 2020 compared with >490,000 in 2019, showing an increase of ∼90%. The total number of times Twitter users saw content was >18.5 million. A review of audience demographics revealed that it was 70% men and 30% women.JACC Journals Facebook page had ∼120,000 followers, a >9% increase over the previous year. There were >770,000 engagements in 2020 vs >840,000 in 2019, indicating a decrease of 8%, with ∼16.5 million impressions. Demographic review of the JACC Journals Facebook page revealed 62% men and 38% women. The top 5 countries in the audience were India, the United States, Mexico, Brazil, and Egypt. The top 5 cities were Mexico City (Mexico), Cairo (Egypt), Bangkok (Thailand), Lima (Peru), and Delhi (India).As of December 2020, the overall JACC Journals’ presence on Instagram was launched in October of 2019. As of December 2020, the page had ∼70,000 followers, with ∼60,000 new followers in 2020. There were >230,000 engagements in 2020, and the total number of times content was seen by users was >8 million. Demographic review revealed 54% men and 45% women; 1% was unspecified. The top 5 countries in the audience were United States, Brazil, India, Mexico, and Colombia. The top 5 cities were Mexico City (Mexico), Sao Paulo (Brazil), New York (United States), Bogota (Colombia), and Buenos Aires (Argentina).The Interestingly, most followers on Twitter, Facebook, and Instagram were men between the ages of 25 and 34 years, although a much larger percentage of women are followers on Instagram compared with Twitter and Facebook. Globally, female physicians remain substantially under-represented in both cardiology (<20%)  and oncoTaken together, these metrics indicate that our SoMe engagement continues to grow as we consistently share educational content and expand our presence on various platforms. Notably, several papers suggest an association between journal paper SoMe posts and subsequent journal paper downloads and citations, which drives journal impact factor . In JanuJACC: CardioOncology, with a vision of becoming the primary scientific source of cardio-oncology globally through publishing high-quality and impactful science. JACC: CardioOncology also seeks to be the “go to resource” through the dissemination of knowledge and learning through How to Series, International Perspectives and Leadership Pages, Case Challenges, Viewpoints, State-of-the-Art Reviews, and Primers, along with hosting online international multilingual collaborative journal clubs, podcasts, and webinars.Our SoMe team aims to increase our international audience, including in the Middle East, Latin America, and East Asia, by 10%. We also intend to increase @JACCJournals engagement/mentions on all of our SoMe platforms. We will continue to employ relevant hashtags and relevant tagging of individuals to increase mentions and engagements, especially among key demographics, including women, early-career cardiovascular professionals, specific clinical areas, and/or key countries/regions. These goals are aligned with To maintain momentum, we continue to direct efforts to establish the journal as a premier scientific resource in cardio-oncology. We aim to publish excellent, rigorous, and impactful science to advance clinical medicine and improve patient care. Since the journal’s inception, SoMe has served to augment our reach, putting the new journal on par with other major cardiology journals that have been in existence for a longer time. Our goal is to enhance the global community in cardio-oncology and to continue to use SoMe as a tool to increase our reach.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


N-butyl-2-cyanoacrylate (NBCA).Simultaneous pancreas and kidney transplantation (SPK) is a treatment option for patients with end-stage renal disease due to type 1 diabetes mellitus. We report a patient with a refractory fistula due to leakage from the duodenal stump of the pancreas graft after an SPK with bladder drainage who was successfully treated with a percutaneous direct injection of A 60-year-old female with a 33-year history of type 1 diabetes mellitus and a 10-year history of renal replacement therapy underwent an SPK in 2015. At the time of transplantation, an abdominal aortic aneurysm with a high risk of rupture was treated by a Y-graft replacement prior to the SPK. Bladder drainage of the pancreas graft was chosen to avoid a vessel graft infection. The patient’s postoperative course was uneventful. The patient was discharged on postoperative day 93 with good-functioning pancreas and kidney grafts. One and a half years after the operation, the patient was found to have acute graft pancreatitis and a leak from the duodenal stump of the pancreas graft due to a paralytic neurogenic bladder. The insertion of an indwelling catheter into the bladder and the endoscopic-guided insertion of a catheter into the graft pancreatic duct through the duodenum/bladder anastomosis did not result in the closure of the fistula. Therefore, NBCA was injected at the site of the leak point using CT-guided technique. The fistula was completely closed immediately after the injection, with no recurrences of leaks.A percutaneous direct injection of NBCA is one of the treatment options to treat intractable fistulas. N-butyl-2-cyanoacrylate (NBCA).Simultaneous pancreas and kidney transplantation (SPK) is a treatment option for patients with chronic renal failure due to type 1 diabetes mellitus. However, the duodenal stump of the pancreas graft may leak, requiring complicated treatments. We present a patient with a refractory fistula due to leakage from the duodenal stump of the pancreas graft after SPK with bladder drainage who was successfully treated using percutaneous direct injection of A 60-year-old female with a 33-year history of type 1 diabetes mellitus and a 10-year history of renal replacement therapy underwent an SPK in 2015 Fig. . HoweverIn cadaveric pancreas transplantations, the pancreas graft is ectopically transplanted into the retroperitoneal space or at the iliac fossa, and the duodenum of the pancreas graft is anastomosed to the small bowel  or the bladder  to provide pancreatic exocrine drainage. The ED of pancreatic exogenous fluid is the more physiologic technique and has a lower risk of urinary tract infections (UTI) , 2. HoweThis patient had a concomitant spindle-shaped abdominal aortic aneurysm with a diameter of 3.3 cm at the time of the SPK, and an annual growth of 0.5 cm indicated the requirement of treatment. We performed an artificial vascular graft replacement to the aneurysm prior to the pancreas and kidney implantations in order to avoid low blood flow to the grafts when the aneurysm replacement was performed after the SPK. The BD method was selected on the pancreas engrafting as it has a lower risk of intraperitoneal infection compared to ED. The vascular graft infection is one of the serious complications with high mortality and morbidity rate. Once infected, early mortality rate has been reported 24 to 45% –13, and Following the SPK with BD, our patient was followed up with monthly blood tests and urine amylase checks. One and a half years after the transplantation, the patient presented with lower abdominal pain, which we diagnosed as pancreatitis and leakage from the duodenal stump of the pancreas graft into the peritoneal cavity caused by urinary retention related to a neurogenic bladder. While a urodynamic study can be used to evaluate bladder function, we do not regularly perform this study in the posttransplant period . There aUrinary drainage with an indwelling catheter is the standard first-line treatment for leaks from the duodenal stump after SPK with BD. Surgical repair is not always necessary to treat late-onset leakage or fistulas after SPK . HoweverIn conclusion, leaks from the duodenal stump of a pancreas graft can occur after an SPK. The percutaneous direct injection of NBCA to the site of the leak can be used to treat this complication.