Completion of Patient-Reported Outcome Measures Improved With Use of a Mobile Application in Arthroplasty Patients: Results From a Randomized Controlled Trial.

BACKGROUND: The collection of patient-reported outcome measures (PROMs) has historically been reported as costly and time-consuming, with low compliance rates that may impact reimbursement. Little research has reported the effects of mobile applications to support PROMs collection following arthroplasty. METHODS: Secondary analysis of data from a multicenter randomized controlled trial was performed. Patients undergoing knee and hip arthroplasty were randomized to utilize a smartphone-based care management platform (app) for self-directed rehabilitation and completed joint-specific PROMs (Hip Dysfunction and Osteoarthritis Outcome Score, Joint Replacement or Knee Injury and Osteoarthritis Score, Joint Replacement) via the application at prescribed intervals or on paper during clinic visits. Control patients received practice standard of care, and completed PROMs via emailed hyperlink or during clinic visits following lower limb arthroplasty. Overall, 455 patients underwent knee arthroplasty procedures (245 control, 210 app group) and 380 underwent total hip arthroplasty (206 control, 174 app group). Compliance with expected PROMs completion was calculated through one year postoperatively. RESULTS: Compliance was higher in the app group preoperatively in both knee (98.1 versus 86.9%, P < .0001) and hip cohorts (96.0 versus 88.4%, P = .008), and postoperatively, including at one year (knees, 72.2 versus 53.7%, P < .0001; hips, 71.1 versus 49.2%, P < .0001). On log-binomial regressions, intervention arm was the strongest predictor of completion of all PROMs, where app users undergoing knee (Relative Risk 2.039, 95% confidence interval (CI) 1.595 to 2.607, P < .000) and hip arthroplasty (2.268 95% CI 1.742 to 2.953, P < .0001) were more likely to be compliant at all timepoints. The majority of patients in the app group, including those over 65 years of age, completed PROMs using the application as opposed to paper methods. CONCLUSIONS: A smartphone mobile application that engages patients during recovery after knee and hip joint arthroplasty improved compliance with completion of preoperative and postoperative PROMs compared to other electronic and paper methods.

Response and Overall Survival for Yttrium-90 Radioembolization of Hepatic Sarcoma: A Multicenter Retrospective Study.

PURPOSE: To evaluate the effectiveness and safety of yttrium-90 transarterial radioembolization (TARE) for the treatment of primary and metastatic soft tissue sarcoma (STS) of the liver. MATERIALS AND METHODS: A retrospective review of 39 patients with primary (n = 2) and metastatic (n = 37) hepatic STS treated with TARE at 4 institutions was performed. Fourteen STS subtypes were included, with leiomyosarcoma being the most common (51%). TARE with glass (22 patients) or resin (17 patients) microspheres was performed, with single lobe (17 patients) or bilobar treatment (22 patients) based on disease burden. Adverse events of treatment, overall survival (OS), and tumor response at 3, 6, and 12 months after TARE were assessed per the Response Evaluation Criteria in Solid Tumors. RESULTS: Fourteen patients demonstrated either partial or complete response to therapy, with an objective response rate of 36%. Thirty patients (77%) demonstrated disease control (DC)-either stable disease or response to treatment. Median OS was 30 months (95% confidence interval 12-43 months) for all patients. DC at 3 months was associated with an increased median OS (44 months) compared with progressive disease (PD) (7.5 months; P < .0001). Patients with DC at 6 months also demonstrated an increased median OS (38 months) compared to patients with PD (17 months; P = .0443). Substantial adverse events included 1 liver abscess, 1 gastric ulceration, and 1 pneumonitis. CONCLUSIONS: Patients with hepatic STS treated with TARE demonstrated a high rate of DC and a median OS of 30 months, which suggests a role for TARE in the palliation of hepatic STS.

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome.

Negamycin is a natural product with broad-spectrum antibacterial activity and efficacy in animal models of infection. Although its precise mechanism of action has yet to be delineated, negamycin inhibits cellular protein synthesis and causes cell death. Here, we show that single point mutations within 16S rRNA that confer resistance to negamycin are in close proximity of the tetracycline binding site within helix 34 of the small subunit head domain. As expected from its direct interaction with this region of the ribosome, negamycin was shown to displace tetracycline. However, in contrast to tetracycline-class antibiotics, which serve to prevent cognate tRNA from entering the translating ribosome, single-molecule fluorescence resonance energy transfer investigations revealed that negamycin specifically stabilizes near-cognate ternary complexes within the A site during the normally transient initial selection process to promote miscoding. The crystal structure of the 70S ribosome in complex with negamycin, determined at 3.1 Å resolution, sheds light on this finding by showing that negamycin occupies a site that partially overlaps that of tetracycline-class antibiotics. Collectively, these data suggest that the small subunit head domain contributes to the decoding mechanism and that small-molecule binding to this domain may either prevent or promote tRNA entry by altering the initial selection mechanism after codon recognition and before GTPase activation.

Crystal structure of A. aeolicus LpxC with bound product suggests alternate deacetylation mechanism.

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is the first committed step to form lipid A, an essential component of the outer membrane of Gram-negative bacteria. As it is essential for the survival of many pathogens, LpxC is an attractive target for antibacterial therapeutics. Herein, we report the product-bound co-crystal structure of LpxC from the acheal Aquifex aeolicus solved to 1.6 Å resolution. We identified interactions by hydroxyl and hydroxymethyl substituents of the product glucosamine ring that may enable new insights to exploit waters in the active site for structure-based design of LpxC inhibitors with novel scaffolds. By using this product structure, we have performed quantum mechanical modeling on the substrate in the active site. Based on our results and published experimental data, we propose a new mechanism that may lead to a better understanding of LpxC catalysis and inhibition.

Negishi cross-coupling enabled synthesis of novel NAD(+)-dependent DNA ligase inhibitors and SAR development.

Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency.

Copper-associated hepatitis in a Pembroke Welsh corgi.

A 6-year-old spayed female Pembroke Welsh corgi dog was diagnosed with copper-associated hepatitis; an uncommon disease to which a variety of breeds are predisposed. This case report describes copper-associated hepatitis in a breed in which the disease has not previously been reported.

Hépatite associée au cuivre chez un Corgi Pembrokeshire. Une chienne Corgi du Pembrokeshire stérilisée âgée de 6 ans a été diagnostiquée avec une hépatite associée au cuivre; une maladie rare à laquelle diverses races sont prédisposées. Ce rapport de cas décrit l'hépatite associée au cuivre chez une race où la maladie n'a pas déjà été signalée.(Traduit par Isabelle Vallières).

Arthroplasty for femoral neck fractures is at risk for under restoration of lateral femoral offset.

PURPOSE: The aim of the study was to determine the restoration of hip biomechanics through lateral offset, leg length, and acetabular component position when comparing non-arthroplasty surgeons (NAS) to elective arthroplasty surgeons (EAS). METHODS: 131 patients, with a femoral neck fracture treated with a THA by 7 EAS and 20 NAS, were retrospectively reviewed. 2 blinded observers measured leg-length discrepancy, femoral offset, and acetabular component position. Multivariate logistic regression models examined the association between the surgeon groups and restoration of lateral femoral, acetabular offset, leg length discrepancy, acetabular anteversion, acetabular position, and component size, while adjusting for surgical approach and spinal pathology. RESULTS: NAS under-restored 4.8 mm of lateral femoral offset (43.9 ± 8.7 mm) after THA when compared to the uninjured side (48.7 ± 7.1 mm, p = 0.044). NAS were at risk for under-restoring lateral femoral offset when compared to EAS (p = 0.040). There was no association between lateral acetabular offset, leg length, acetabular position, or component size and surgeon type. CONCLUSIONS: Lateral femoral offset is at risk for under-restoration after THA for femoral neck fractures, when performed by surgeons that do not regularly perform elective THA. This indicates that lateral femoral offset is an under-appreciated contributor to hip instability when performing THA for a femoral neck fracture. Lateral femoral offset deserves as much attention and awareness as acetabular component position since a secondary analysis of our data reveal that preoperative templating and intraoperative imaging did not prevent under-restoration.

Host and microbial characteristics associated with recurrent prosthetic joint infections.

Approximately 20% of patients after resection arthroplasty and antibiotic spacer placement for prosthetic joint infection develop repeat infections, requiring an additional antibiotic spacer before definitive reimplantation. The host and bacterial characteristics associated with the development of recurrent infection is poorly understood. A case-control study was conducted for 106 patients with intention to treat by two-stage revision arthroplasty for prosthetic joint infection at a single institution between 2009 and 2020. Infection was defined according to the 2018 Musculoskeletal Infection Society criteria. Thirty-nine cases ("recurrent-periprosthetic joint infection [PJI]") received at least two antibiotic spacers before clinical resolution of their infection, and 67 controls ("single-PJI") received a single antibiotic cement spacer before infection-free prosthesis reimplantation. Patient demographics, McPherson host grade, and culture results including antibiotic susceptibilities were compared. Fifty-two (78%) single-PJI and 32 (82%) recurrent-PJI patients had positive intraoperative cultures at the time of their initial spacer procedure. The odds of polymicrobial infections were 11-fold higher among recurrent-PJI patients, and the odds of significant systemic compromise (McPherson host-grade C) were more than double. Recurrent-PJI patients were significantly more likely to harbor Staphylococcus aureus. We found no differences between cases and controls in pathogen resistance to the six most tested antibiotics. Among recurrent-PJI patients, erythromycin-resistant infections were more prevalent at the final than initial spacer, despite no erythromycin exposure. Our findings suggest that McPherson host grade, polymicrobial infection, and S. aureus infection are key indicators of secondary or persistent joint infection following resection arthroplasty and antibiotic spacer placement, while bacterial resistance does not predict infection-related arthroplasty failure.

Exploring the UDP pocket of LpxC through amino acid analogs.

Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs.

A Case of Cutaneous Vasculitis in the Setting of Systemic Lupus Erythematosus and Cocaine Use.

Cocaine, one of most prevalent illicit substances in the United States, affects a multitude of organ systems and precedes numerous negative health outcomes. Many of the consequences of cocaine are linked to induction of vasoconstriction. For this reason, cocaine users are placed at considerable risk of ischemic stroke, myocardial infarction, and cardiac arrhythmias. Furthermore, a prominent contaminant, levamisole, has been widely implicated in predisposing individuals to developing or exacerbating cutaneous vasculitides. This report details a 31-year-old woman with acute, localized necrotic skin lesions after cocaine use. Her clinical picture was complicated by a 17-year history of systemic lupus erythematosus (SLE) and Raynaud's phenomenon. This case examines the challenge of forming a differential diagnosis, initiating an appropriate workup, and interpreting serologic-based and immunologic-based studies to differentiate between SLE and drug-based etiologies of skin necrosis. Finally, we discuss appropriate treatment plans to mitigate symptoms and reduce future instances of drug-induced vasculitis.

Assessment of Team Dynamics and Operative Efficiency in Hip and Knee Arthroplasty.

Importance: Surgical team communication is a critical component of operative efficiency. The factors underlying optimal communication, including team turnover, role composition, and mutual familiarity, remain underinvestigated in the operating room. Objective: To assess staff turnover, trainee involvement, and surgeon staff preferences in terms of intraoperative efficiency. Design, Setting, and Participants: Retrospective analysis of staff characteristics and operating times for all total joint arthroplasties was performed at a tertiary academic medical center by 5 surgeons from January 1 to December 31, 2018. Data were analyzed from May 1, 2021, to February 18, 2022. The study included cases with primary total hip arthroplasties (THAs) and primary total knee arthroplasties (TKAs) comprising all primary total joint arthroplasties performed over the 1-year study interval. Exposures: Intraoperative turnover among nonsurgical staff, presence of trainees, and presence of surgeon-preferred staff. Main Outcomes and Measures: Incision time, procedure time, and room time for each surgery. Multivariable regression analyses between operative duration, presence of surgeon-preferred staff, and turnover among nonsurgical personnel were conducted. Results: A total of 641 cases, including 279 THAs (51% female; median age, 64 [IQR, 56.3-71.5] years) and 362 TKAs (66% [238] female; median age, 68 [IQR, 61.1-74.1] years) were considered. Turnover among circulating nurses was associated with a significant increase in operative duration in both THAs and TKAs, with estimated differences of 19.6 minutes (SE, 3.5; P < .001) of room time in THAs and 14.0 minutes (SE, 3.1; P < .001) of room time in TKAs. The presence of a preferred anesthesiologist or surgical technician was associated with significant decreases of 26.5 minutes (SE, 8.8; P = .003) of procedure time and 12.6 minutes (SE, 4.0; P = .002) of room time, respectively, in TKAs. The presence of a surgeon-preferred vendor was associated with a significant increase in operative duration in both THAs (26.3 minutes; SE, 7.3; P < .001) and TKAs (29.6 minutes; SE, 9.6; P = .002). Conclusions and Relevance: This study found that turnover among operative staff is associated with procedural inefficiency. In contrast, the presence of surgeon-preferred staff may facilitate intraoperative efficiency. Administrative or technologic support of perioperative communication and team continuity may help improve operative efficiency.

Influence of team composition on turnover and efficiency of total hip and knee arthroplasty.

AIMS: Surgical costs are a major component of healthcare expenditures in the USA. Intraoperative communication is a key factor contributing to patient outcomes. However, the effectiveness of communication is only partially determined by the surgeon, and understanding how non-surgeon personnel affect intraoperative communication is critical for the development of safe and cost-effective staffing guidelines. Operative efficiency is also dependent on high-functioning teams and can offer a proxy for effective communication in highly standardized procedures like primary total hip and knee arthroplasty. We aimed to evaluate how the composition and dynamics of surgical teams impact operative efficiency during arthroplasty. METHODS: We performed a retrospective review of staff characteristics and operating times for 112 surgeries (70 primary total hip arthroplasties (THAs) and 42 primary total knee arthroplasties (TKAs)) conducted by a single surgeon over a one-year period. Each surgery was evaluated in terms of operative duration, presence of surgeon-preferred staff, and turnover of trainees, nurses, and other non-surgical personnel, controlling cases for body mass index, presence of osteoarthritis, and American Society of Anesthesiologists (ASA) score. RESULTS: Turnover among specific types of operating room staff, including the anaesthesiologist (p = 0.011), circulating nurse (p = 0.027), and scrub nurse (p = 0.006), was significantly associated with increased operative duration. Furthermore, the presence of medical students and nursing students were associated with improved intraoperative efficiency in TKA (p = 0.048) and THA (p = 0.015), respectively. The presence of surgical fellows (p > 0.05), vendor representatives (p > 0.05), and physician assistants (p > 0.05) had no effect on intraoperative efficiency. Finally, the presence of the surgeon's 'preferred' staff did not significantly shorten operative duration, except in the case of residents (p = 0.043). CONCLUSION: Our findings suggest that active management of surgical team turnover and composition may provide a means of improving intraoperative efficiency during THA and TKA. Cite this article: Bone Joint J 2021;103-B(2):347-352.

A quantum mechanical study of methacrylate free-radical polymerizations.

Theoretical calculations at the semiempirical and ab initio levels of theory have been completed for a series of methacrylate compounds reported in the literature as measured by pulsed-laser initiated polymerization in conjunction with size-exclusion chromatography (PLP-SEC). Modeling includes calculation of the Gibb's free energies (ΔG(‡)) and activation energies (E(a)). These results were then compared to experimental results. Semiempirical ΔG(‡) using AM1-CI calculations successfully predicted relative activation energies (R(2) = 0.89). HF and DFT methods more accurately predicted absolute activation energies, but the relative values were less reliable. Accurate quantitative structure property relationship (QSAR) models for propagation rate coefficients, k(p), were developed using AM1-CI and DFT. The semiempirical model included two charge descriptors, partial negatively charged surface area (PNSA), and minimum net atomic charge for oxygen (R(2) = 0.959). The DFT information, which included two quantum chemical descriptors (1-electron reactivity index for carbon and point charge component of the molecular dipole) calculated from the ground state structure, had improved statistics (R(2) = 0.979). A second DFT model is reported for 10 hydrocarbon methacrylate structures based on the 1-electron reactivity index for carbon (R(2) = 0.979). Theoretical results were also analyzed to provide an explanation for the unexpectedly large experimental k(p) values observed in the case of larger methacrylate monomers.

Leishmaniasis in a dog native to Colorado.

CASE DESCRIPTION: A 1-year-old 32.5-kg (71.5-lb) sexually intact male foxhound-Treeing Walker Coonhound cross was evaluated because of a 2.5-month history of dermatologic lesions, weight loss, and diarrhea. CLINICAL FINDINGS: Physical examination revealed muscle wasting, lymphadenopathy, and multifocal pruritic dermatologic lesions of alopecia, thickening, erythema, and follicular casting. Hematologic and serum biochemical analyses revealed nonregenerative anemia, mono-cytosis, hypercalcemia, hyperproteinemia, and hyperglobulinemia. Proteinuria was identified on urinalysis. Hepatomegaly, splenomegaly, and diffuse abdominal lymphadenomegaly were detected on abdominal ultrasonography. A diagnosis of leishmaniasis was confirmed by ELISA detection of serum antibodies against Leishmania spp, a high serum indirect fluorescent antibody titer (1:1,024) against Leishmania infantum, amplification of Leishmania DNA on PCR assay of a whole blood sample and a lymph node aspirate, and histologic identification of suspected Leishmania amastigotes in skin specimens. In addition, the dog had a low CD4+:CD8+ lymphocyte ratio of 1:1. TREATMENT AND OUTCOME: The dog was euthanized because of the severity of leishmaniasis and poor prognosis. This dog was from a litter of 10 puppies that included 4 stillborn puppies, 2 puppies that died as neonates, and 1 littermate that was euthanized at 1 year of age because of a high serum antibody titer against Leishmania spp. Eventually the foxhound dam was euthanized because of a high serum antibody titer against Leishmania spp. The dog had been raised with an unaffected littermate, its sire, and an unrelated Treeing Walker Coonhound female that were seronegative for Leishmania infection. CLINICAL RELEVANCE: Although vertical disease transmission was suspected, it is possible that L infantum is now endemic in Colorado. Leishmaniasis should be considered in dogs with scaly dermatoses.

Diagnostic use of cytologic examination of bone marrow from dogs with thrombocytopenia: 58 cases (1994-2004).

OBJECTIVE: To determine the diagnostic use of cytologic examination of bone marrow from dogs with thrombocytopenia. DESIGN: Retrospective case series. ANIMALS: 58 dogs with thrombocytopenia. PROCEDURES: Medical records were searched and reviewed for dogs with thrombocytopenia. Dogs that had thrombocytopenia and cytologic examination of bone marrow were included in the study. Dogs with other hematologic abnormalities, with a previous diagnosis of hematopoietic neoplasia, or that had previous treatment with cytotoxic drugs were excluded. Bone marrow cytologic findings were reviewed. Results were compared between dogs with severe thrombocytopenia (< 20,000 platelets/microL) and dogs with mild to moderate thrombocytopenia (20,000 to 200,000 platelets/microL). RESULTS: 58 dogs met the inclusion criteria. Of 55 dogs with diagnostic bone marrow aspirates, 36 had severe thrombocytopenia. Cytologic evaluation of bone marrow did not reveal substantial nonmegakaryocytic bone marrow abnormalities or result in a definitive diagnosis in any of these dogs. Nineteen dogs with mild to moderate thrombocytopenia had diagnostic bone marrow aspirates. Bone marrow cytologic findings revealed nonmegakaryocytic abnormalities in 4 of these dogs. Significantly fewer dogs with severe thrombocytopenia had abnormalities identified on cytologic examination of bone marrow, compared with dogs with mild to moderate thrombocytopenia. CONCLUSIONS AND CLINICAL RELEVANCE: Cytologic examination of bone marrow is unlikely to provide specific diagnostic or prognostic information in dogs with severe thrombocytopenia.

Quantum-Mechanical QSPR Models for Polymerization Volume Change of Epoxides and Methacrylates Based on Mercury Dilatometry Results.

Polymerization volume change (PVC) was measured systematically using mercury dilatometry for 41 epoxide and methacrylate monomers with quartz filler. Quantitative structure property relationship (QSPR) models were developed based on this previously unreported data to gain insight in the data collection method for future models. Successful models included only data from those samples which polymerized to hardness. The most significant descriptors in these models related to monomer reactivity. In contrast, PVC data collected under experimental conditions which maximized monomer conversion resulted in descriptors describing size and branching, indicating conversion must be considered for future PVC measurements. A Rule of Mixtures (ROM) correction term improved correlations of the dilatometer data with varying quartz content, and an adjustment for conversion may similarly enable inclusion of data which had not polymerize to hardness.

Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens.

Negamycin is a natural product with antibacterial activity against a broad range of Gram-negative pathogens. Recent revelation of its ribosomal binding site and mode of inhibition has reinvigorated efforts to identify improved analogues with clinical potential. Translation-inhibitory potency and antimicrobial activity upon modification of different moieties of negamycin were in line with its observed ribosomal binding conformation, reaffirming stringent structural requirements for activity. However, substitutions on the N6 amine were tolerated and led to N6-(3-aminopropyl)-negamycin (31f), an analogue showing 4-fold improvement in antibacterial activity against key bacterial pathogens. This represents the most potent negamycin derivative to date and may be a stepping stone toward clinical development of this novel antibacterial class.

Polymer-brush stationary phases for open-tubular capillary electrochromatography.

Synthesis of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes from the inside of silica capillaries by surface-initiated atom transfer radical polymerization (ATRP) yields unique stationary phases for open-tubular capillary electrochromatography (OT-CEC). Although PHEMA brushes have only a small effect on the separation of a set of phenols and anilines, derivatization of PHEMA with ethylenediamine (en) allows baseline resolution of several anilines that co-elute from bare silica capillaries. Derivatization of PHEMA with octanoyl chloride (C8-PHEMA films) affords even better resolution in the separation of a series of phenols and anilines. Increasing the thickness of C8-PHEMA coatings by a factor of 2 enhances resolution for several solute pairs, presumably because of an increase in the effective stationary phase to mobile phase volume ratio. Thus, this work demonstrates that thick polymer brushes provide a tunable stationary phase with a much larger phase ratio than is available from monolayer wall coatings. Through appropriate choice of derivatizing reagents, these polymer brushes should allow separation of a wide range of neutral molecules as well as compounds with similar electrophoretic mobilities.

Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.

In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.

Alkylidene Oxapenem ß-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges.

We present a comprehensive study of C6-alkylidene containing oxapenems. We show that this class of ß-lactamase inhibitors possesses an unprecedented spectrum with activity against class A, C, and D enzymes. Surprisingly, this class of compounds displayed significant photolytic instability in addition to the known hydrolytic instability. Quantum mechanical calculations were used to develop models to predict the stability of new analogues.