Site-selective benzylic C-H hydroxylation in electron-deficient azaheterocycles.

Benzylic C-H bonds can be converted into numerous functional groups, often by mechanisms that involve hydrogen atom transfer as the key bond breaking step. The abstracting species is most often an electrophilic radical, which makes these reactions best suited to electron-rich C-H bonds to achieve appropriate polarity matching. Thus, electron deficient systems such as pyridine and pyrimidine are relatively unreactive, and therefore underrepresented in substrate scopes. In this report, we describe a new method for heterobenzylic hydroxylation-essentially an unknown reaction in the case of pyrimidines-that makes use of an iodine(III) reagent to afford very high selectivity towards electron-deficient azaheterocycles in substrates with more than one reactive position and prevents over-oxidation to carbonyl products. The identification of key reaction byproducts supports a mechanism that involves radical coupling in the bond forming step.

Remolding and Deconstruction of Industrial Thermosets via Carboxylic Acid-Catalyzed Bifunctional Silyl Ether Exchange.

Convenient strategies for the deconstruction and reprocessing of thermosets could improve the circularity of these materials, but most approaches developed to date do not involve established, high-performance engineering materials. Here, we show that bifunctional silyl ether, i.e., R'O-SiR2-OR'', (BSE)-based comonomers generate covalent adaptable network analogues of the industrial thermoset polydicyclopentadiene (pDCPD) through a novel BSE exchange process facilitated by the low-cost food-safe catalyst octanoic acid. Experimental studies and density functional theory calculations suggest an exchange mechanism involving silyl ester intermediates with formation rates that strongly depend on the Si-R2 substituents. As a result, pDCPD thermosets manufactured with BSE comonomers display temperature- and time-dependent stress relaxation as a function of their substituents. Moreover, bulk remolding of pDCPD thermosets is enabled for the first time. Altogether, this work presents a new approach toward the installation of exchangeable bonds into commercial thermosets and establishes acid-catalyzed BSE exchange as a versatile addition to the toolbox of dynamic covalent chemistry.

An Improved PIII/PV═O-Catalyzed Reductive C-N Coupling of Nitroaromatics and Boronic Acids by Mechanistic Differentiation of Rate- and Product-Determining Steps.

Experimental, spectroscopic, and computational studies are reported that provide an evidence-based mechanistic description of an intermolecular reductive C-N coupling of nitroarenes and arylboronic acids catalyzed by a redox-active main-group catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide, i.e., 1·[O]). The central observations include the following: (1) catalytic reduction of 1·[O] to PIII phosphetane 1 is kinetically fast under conditions of catalysis; (2) phosphetane 1 represents the catalytic resting state as observed by 31P NMR spectroscopy; (3) there are no long-lived nitroarene partial-reduction intermediates observable by 15N NMR spectroscopy; (4) the reaction is sensitive to solvent dielectric, performing best in moderately polar solvents (viz. cyclopentylmethyl ether); and (5) the reaction is largely insensitive with respect to common hydrosilane reductants. On the basis of the foregoing studies, new modified catalytic conditions are described that expand the reaction scope and provide for mild temperatures (T ≥ 60 °C), low catalyst loadings (≥2 mol%), and innocuous terminal reductants (polymethylhydrosiloxane). DFT calculations define a two-stage deoxygenation sequence for the reductive C-N coupling. The initial deoxygenation involves a rate-determining step that consists of a (3+1) cheletropic addition between the nitroarene substrate and phosphetane 1; energy decomposition techniques highlight the biphilic character of the phosphetane in this step. Although kinetically invisible, the second deoxygenation stage is implicated as the critical C-N product-forming event, in which a postulated oxazaphosphirane intermediate is diverted from arylnitrene dissociation toward heterolytic ring opening with the arylboronic acid; the resulting dipolar intermediate evolves by antiperiplanar 1,2-migration of the organoboron residue to nitrogen, resulting in displacement of 1·[O] and formation of the target C-N coupling product upon in situ hydrolysis. The method thus described constitutes a mechanistically well-defined and operationally robust main-group complement to the current workhorse transition-metal-based methods for catalytic intermolecular C-N coupling.

Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic-inorganic inhibitors.

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.

Combined Iron/Hydroxytriazole Dual Catalytic System for Site Selective Oxidation Adjacent to Azaheterocycles.

This report details a new method for site-selective methylene oxidation adjacent to azaheterocycles. A dual catalysis approach, utilizing both an iron Lewis acid and an organic hydroxylamine catalyst, proved highly effective. We demonstrate that this method provides complementary selectivity to other known catalytic approaches and represents an improvement over current heterocycle-selective reactions that rely on stoichiometric activation.

Intermolecular Reductive C-N Cross Coupling of Nitroarenes and Boronic Acids by PIII/PV═O Catalysis.

A main group-catalyzed method for the synthesis of aryl- and heteroarylamines by intermolecular C-N coupling is reported. The method employs a small-ring organophosphorus-based catalyst (1,2,2,3,4,4-hexamethylphosphetane) and a terminal hydrosilane reductant (phenylsilane) to drive reductive intermolecular coupling of nitro(hetero)arenes with boronic acids. Applications to the construction of both Csp2-N (from arylboronic acids) and Csp3-N bonds (from alkylboronic acids) are demonstrated; the reaction is stereospecific with respect to Csp3-N bond formation. The method constitutes a new route from readily available building blocks to valuable nitrogen-containing products with complementarity in both scope and chemoselectivity to existing catalytic C-N coupling methods.

Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron Transfer to Selectfluor.

A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C-F bond formation. This mechanism enables high intra- and intermolecular selectivity for aza-heterocycles over other benzylic components with similar C-H bond-dissociation energies.

Inhibiting prolyl isomerase activity by hybrid organic-inorganic molecules containing rhodium(II) fragments.

A small molecule containing a rhodium(II) tetracarboxylate fragment is shown to be a potent inhibitor of the prolyl isomerase FKBP12. The use of small molecules conjugates of rhodium(II) is presented as a general strategy for developing new protein inhibitors based on distinct structural and sequence features of the enzyme active site.

Examining the validity of the Delis-Kaplan Executive Function System (D-KEFS) in traumatic brain injury.

This study examines the validity of the Delis-Kaplan Executive Function System (D-KEFS) in a traumatic brain injury (TBI) population compared to participants with orthopaedic injuries and normative controls. The utility of the D-KEFS was examined using a between groups design. One hundred patients with mild uncomplicated to severe TBI were recruited from a consecutive cohort of patients admitted as inpatients to a UK Major Trauma Centre and compared to 823 participants from the D-KEFS normative sample and 26 participants with orthopaedic injuries. Data were filtered for performance validity. Sample discrimination was calculated from D-KEFS subtest scores and derived index scores. Sensitivity to TBI severity was established. The TBI participants performed significantly lower on the D-KEFS Trail Making Test, Colour Word Interference, Colour Word Switching, Letter Fluency and Verbal Fluency Category Switching Total Words Correct. The D-KEFS index scores discriminated between TBI, orthopaedic and normative participants with large and moderate effect sizes, respectively. The D-KEFS demonstrated a dose-response relationship with TBI severity. These effects were robust to differences in premorbid intellectual functioning; however, D-KEFS performance was sensitive to performance on tests of mental processing speed. The use of a D-KEFS index score provides a robust and reliable discrimination of TBI patients from healthy control participants. This discrimination is not accounted for by premorbid intellect or the non-specific effects of trauma. The clinical and conceptual implications of these findings are considered.

Reprocessability in Engineering Thermosets Achieved Through Frontal RingOpening Metathesis Polymerization.

While valued for their durability and exceptional performance, crosslinked thermosets are challenging to recycle and reuse. Here, inherent reprocessability in industrially relevant polyolefin thermosetsis unveiled. Unlike prior methods, this approach eliminates the need to introduce exchangeable functionality to regenerate the material, relying instead on preserving the activity of the metathesis catalyst employed in the curing reaction. Frontal ring-opening metathesis polymerization (FROMP) proves critical to preserving this activity. Conditions controlling catalytic viability are explored to successfully reclaim performance across multiple generations of material, thus demonstrating long-term reprocessability. This straightforward and scalable remolding strategy is poised for widespread adoption. Given the anticipated growth in polyolefin thermosets, these findings represent an important conceptual advance in the pursuit of a fully circular lifecycle for thermoset polymers.

Semi-extended extra-synovial (SEES) tibial intramedullary nailing technique: Up to 10 year retrospective analysis of outcomes and anterior knee pain rates.

Background: Tibial intramedullary nailing is a common method of fixation for fractures of the tibia, with several approaches described. Anterior knee pain is a common complication following nailing, but the reported incidence of knee pain varies in the literature between 10 % and 86 %. There is considerable variation in incidence between nailing techniques, with an exact aetiology still unknown. We investigated the reported incidence of anterior knee pain in patients undergoing tibial nailing using the semi-extended extra synovial (SEES) technique at a Major Trauma Centre (MTC) in the UK. Methods: A retrospective review of tibial fractures treated with the SEES technique between December 2012 to February 2021. Data collected included patient demographics, mechanism of injury, fracture characteristics, length of stay, union rates and re-operation rates. Primary outcomes were anterior knee pain rates and patient reported outcome measures (PROM), the Kujala Score. Secondary outcomes were rates of union and complications. Results: 55 fractures were identified in 53 patients. Male: Female ratio was 32:21. The average age was 45.5 years. 96 % were unilateral fractures; with 53 % being right-sided. 21(38 %) fractures were open. Prior to definitive nailing 21 fractures had temporary stabilisation with an external fixator (Ex-Fix) ± wound debridement whilst the rest received plaster backslab immobilisation. 13 of the open fractures required soft tissue cover. 75 % of patients had initial surgery (SEES Nailing/Ex-Fix) within 4 days. There was a 91 % union rate with a median time to full radiographic union of 14 months. One post-operative complication of wound dehiscence was recorded. The mean follow-up time was 13.6 months. 15 % of patients reported anterior knee pain in the postoperative follow-up period. The average Kujala PROM score was 85 (Range: 52-100). Conclusion/findings: The SEES technique had favourable PROM scores and displayed a lower incidence of anterior knee pain than the traditional infrapatellar approach. Knee pain rates were comparable to suprapatellar approaches without violating the knee joint. Disclosures: None.

A Model Ensemble Approach Enables Data-Driven Property Prediction for Chemically Deconstructable Thermosets in the Low-Data Regime.

Thermosets present sustainability challenges that could potentially be addressed through the design of deconstructable variants with tunable properties; however, the combinatorial space of possible thermoset molecular building blocks (e.g., monomers, cross-linkers, and additives) and manufacturing conditions is vast, and predictive knowledge for how combinations of these molecular components translate to bulk thermoset properties is lacking. Data science could overcome these problems, but computational methods are difficult to apply to multicomponent, amorphous, statistical copolymer materials for which little data exist. Here, leveraging a data set with 101 examples, we introduce a closed-loop experimental, machine learning (ML), and virtual screening strategy to enable predictions of the glass transition temperature (Tg) of polydicyclopentadiene (pDCPD) thermosets containing cleavable bifunctional silyl ether (BSE) comonomers and/or cross-linkers with varied compositions and loadings. Molecular features and formulation variables are used as model inputs, and uncertainty is quantified through model ensembling, which together with heavy regularization helps to avoid overfitting and ultimately achieves predictions within <15 °C for thermosets with compositionally diverse BSEs. This work offers a path to predicting the properties of thermosets based on their molecular building blocks, which may accelerate the discovery of promising plastics, rubbers, and composites with improved functionality and controlled deconstructability.

Fracture of pubic rami during hip fracture fixation: a rare case of traction table-related injury.

We present a case of an elderly and comorbid patient who was scheduled to undergo a hip fracture fixation using an intramedullary nail. Unfortunately, this was delayed by 3 weeks as the patient was unfit to undergo this procedure. She was placed onto the traction table and intraoperatively sustained a superior and inferior pubic rami fracture while attempting reduction on the traction table. Closed-reduction techniques using traction tables and perineal posts are not without morbidity. Risk factors such as osteoporosis and delayed-fixation should be accounted for when managing this complex and often frail group of patients.

Mortality risk of surgically managing orthopaedic trauma during the COVID-19 pandemic.

AIMS: It is imperative to understand the risks of operating on urgent cases during the COVID-19 (SARS-Cov-2 virus) pandemic for clinical decision-making and medical resource planning. The primary aim was to determine the mortality risk and associated variables when operating on urgent cases during the COVID-19 pandemic. The secondary objective was to assess differences in the outcome of patients treated between sites treating COVID-19 and a separate surgical site. METHODS: The primary outcome measure was 30-day mortality. Secondary measures included complications of surgery, COVID-19 infection, and length of stay. Multiple variables were assessed for their contribution to the 30-day mortality. In total, 433 patients were included with a mean age of 65 years; 45% were male, and 90% were Caucasian. RESULTS: Overall mortality was 7.6% for all patients and 15.9% for femoral neck fractures. The mortality rate increased from 7.5% to 44.2% in patients with fracture neck of femur and a COVID-19 infection. The COVID-19 rate in the 30-day postoperative period was 11%. COVID-19 infection, age, and Charlson Comorbidity Index were independent risk factor for mortality. CONCLUSION: There was a significant risk of contracting COVID-19 due to being admitted to hospital. Using a site which was not treating COVID-19 respiratory patients for surgery did not identify a difference with respect to mortality, nosocomial COVID-19 infection, or length of stay. The COVID-19 pandemic significantly increases perioperative mortality risk in patients with fractured neck of femora but patients with other injuries were not at increased risk. Cite this article: Bone Jt Open 2021;2(5):330-336.

Identification of Loci That Confer Resistance to Bacterial and Fungal Diseases of Maize.

Crops are hosts to numerous plant pathogenic microorganisms. Maize has several major disease issues; thus, breeding multiple disease resistant (MDR) varieties is critical. While the genetic basis of resistance to multiple fungal pathogens has been studied in maize, less is known about the relationship between fungal and bacterial resistance. In this study, we evaluated a disease resistance introgression line (DRIL) population for the foliar disease Goss's bacterial wilt and blight (GW) and conducted quantitative trait locus (QTL) mapping. We identified a total of ten QTL across multiple environments. We then combined our GW data with data on four additional foliar diseases (northern corn leaf blight, southern corn leaf blight, gray leaf spot, and bacterial leaf streak) and conducted multivariate analysis to identify regions conferring resistance to multiple diseases. We identified 20 chromosomal bins with putative multiple disease effects. We examined the five chromosomal regions (bins 1.05, 3.04, 4.06, 8.03, and 9.02) with the strongest statistical support. By examining how each haplotype effected each disease, we identified several regions associated with increased resistance to multiple diseases and three regions associated with opposite effects for bacterial and fungal diseases. In summary, we identified several promising candidate regions for multiple disease resistance in maize and specific DRILs to expedite interrogation.

Removal of broken solid femoral nail: a modified bent tip guide wire technique.

A broken solid femoral nail can be challenging to remove. We describe a modified bent tip guide wire technique for extraction of a broken solid retrograde femoral nail from the proximal femur. The broken nail was removed successfully through the original retrograde entry point to allow for an exchange femoral nailing in a patient with a hypertrophic non-union. This novel technique avoids any additional exposure other than that required to remove and insert the nail.

Abdominal pain in a patient with ankylosing spondylitis under treatment with infliximab.

In patients suffering from ankylosing spondylitis, silent inflammatory bowel disease (IBD) is frequent. Furthermore, spondylarthritis may be the first manifestation of IBD.We describe the case of a patient suffering from ankylosing spondylitis who presented with abdominal pain. The patient had been treated over 2(1/2) years with infliximab. Although the initial clinical presentation seemed to suggest new-onset IBD as the cause of the abdominal pain, it eventuated that the patient was suffering from a severe abdominal manifestation of tuberculosis likely due to reactivation of latent tuberculosis by the anti-TNF agent.

Genome-Wide Analysis and Prediction of Resistance to Goss's Wilt in Maize.

Goss's bacterial wilt and leaf blight is one of the most important foliar diseases of maize ( L.). To date, neither large-effect resistance genes, nor practical chemical controls exist to manage the disease. Thus, the importance of discovering durable host resistance necessitates additional genetic mapping for this disease. Unfortunately, because of the biology of the pathogen and the highly significant genotype-by-environment interaction effect observed with Goss's wilt, consistent phenotyping across multiple years poses a hurdle for genetic studies and conventional breeding methods. The objective of this study was to perform a genome-wide association study (GWAS) to identify regions of the genome associated with Goss's wilt resistance as well as to use genomic prediction models to evaluate the utility of genomic selection (GS) in predicting Goss's wilt phenotypes in a panel of diverse maize lines. Using genome-wide association mapping, we were unable to identify any variants significantly associated with Goss's wilt. However, using genomic prediction we were able to train a model with an accuracy of 0.69. Taken together, this suggests that resistance to Goss's wilt is highly polygenic. In addition, when evaluating the accuracy of our prediction model under reduced marker density, it was shown that only 10,000 single nucleotide polymorphisms (SNPs), or ∼20% of our total marker set, was necessary to achieve prediction accuracies similar to the full marker set. This is the first report of genomic prediction for a bacterial disease of maize, and these results highlight the potential of GS for disease resistance in maize.