Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly.

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 µM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

Adult William's Syndrome: The Cause of an Unusual Vasculopathy and Biliary Abnormalities.

A man in his 50s was diagnosed with William's syndrome (WS) following the investigation of severe vasculopathy and bile duct abnormalities. The vascular lesions included: right carotid artery hypoplasia, tortuous dilated left carotid artery, severe aortic hypoplasia, and pulmonary branch arterial stenoses. The bile ducts were dilated with damaged and inflamed intrahepatic ducts. The patient had been labeled with fetal alcohol syndrome as a consequence of his mother's alcohol addiction. The etiology is thought to be the combined effects and his genetic condition and prenatal alcohol exposure.

Dilemmas in anticoagulation and use of inferior vena cava filters in venous thromboembolism; a survey of Respiratory Physicians, Haematologists and Medical Oncologists and a review of the literature.

Twenty percent of patients with Cancer Associated Thrombosis receive an inferior vena cava filter annually. Insertion is guided by practice guidelines, which do not specify or discuss the use of inferior vena cava filters in malignancy. Adherence to these guidelines is known to be variable. We aimed to see if there was consistent management of venous thromboembolism among Medical Oncologists/Haematologists and Respiratory Physicians, with respect to inferior vena cava filter use in the setting of suspected and confirmed malignancy. Medical Oncologists, Haematologists and Respiratory Physicians were surveyed with four theoretical cases. Case 1 concerns a patient who develops a pulmonary embolism following spinal surgery. Cases 2 and 4 explore the use of inferior vena cava filters in the setting of malignancy. Case 3 covers the role of inferior vena cava filters in recurrent thrombosis despite systemic anticoagulation. There were 56 responses, 32 (57%) Respiratory Physicians and 24 (43%) Haematologists/Oncologists. Respiratory Physicians were significantly more likely to insert an inferior vena cava filter in case 1 (p = 0.04) whilst Haematologists/Medical Oncologists were more likely to insert an inferior vena cava filter in case 3 (p = 0.03). No significant differences were found in cases 2 and 4. There were significant disparities in terms of type and timing of anticoagulation. Consistency of recommendations with guidelines was variable likely in part because guidelines are themselves inconsistent. The heterogeneity in responses highlights the variations in venous thromboembolism management, especially in Cancer Associated Thrombosis. International Societies should consider addressing inferior vena cava filter use specifically in the setting of Cancer Associated Thrombosis. Collaboration between interested specialities would assist in developing consistent, evidence-based guidelines for the use of inferior vena cava filters in the management of venous thromboembolism.

2,7-Diazabicyclo[2.2.1]heptanes: novel asymmetric access and controlled bridge-opening.

Organocatalysed asymmetric Michael additions of substituted triketopiperazines to enones afford products in high yield and enantiomeric ratio (er). Further modification delivers products possessing natural product (NP) scaffolds including diazabicyclo[2.2.1]heptane, prolinamide and harmicine.

Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling.

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki-Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD-obtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki-Miyaura cross-coupling products, from which 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns.

Inferior vena cava filters (IVCFs): a review of uses and application to international guidelines at a single Australian center; implications of venous thromboembolism associated with malignancy.

Venous thromboembolism (VTE) is a potentially lethal event. Anticoagulation is the cornerstone of treatment. Inferior vena cava filters (IVCFs) may be used in circumstances when anticoagulation is contraindicated or as an adjunct to anticoagulation. IVCF use is not without controversy due to concerns over their safety profile, differences in guidelines from international societies, and a limited randomized control trial evidence. We retrospectively undertook a review of IVCF use over a three-year period (2014-2016) at our center, which has a large oncology service but no trauma unit. There were 44 patients with successful IVCF insertion and one patient with an unsuccessful attempt. Indications for insertion included: a contraindication to anticoagulation (n = 28); recurrent VTE on anticoagulation (n = 10); and extensive VTE (n = 7). There were 13 retrieval attempts, of which ten were successful. There were five documented IVCF complications (tilting: n = 2, IVC thrombus: n = 3) with one episode of IVCF failure and two episodes of deep vein thrombosis during the follow-up period. Of the patients, 71% had an active malignancy (of whom 71% had metastatic disease). Seventeen patients died due to progressive malignancy during the study period. There were no life-threatening VTEs or IVCF-associated mortalities. Adherence with published international guidelines was variable. Patients with malignancy were less likely to undergo IVCF retrieval and had a reduced rate of retrieval success. None of the international guidelines comment on the use of IVCFs in patients with malignancy despite being commonly used. IVCF use may be an underappreciated tool in this group.

Realisation of small molecule libraries based on frameworks distantly related to natural products.

The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

A biosynthesis-inspired approach to over twenty diverse natural product-like scaffolds.

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels-Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

A divergent synthetic approach to diverse molecular scaffolds: assessment of lead-likeness using LLAMA, an open-access computational tool.

Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.

Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries.

The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.

Diagnosis of appendicitis by bedside ultrasound in the ED.

BACKGROUND: Computed tomography (CT) has largely become standard of care for diagnosing appendicitis at the expense of increased patient radiation exposure, cost, and time to surgical intervention. To date, there are very limited data on the accuracy of bedside ultrasound (BUS) for the diagnosis of appendicitis in adults. OBJECTIVE: The objective of this study is to evaluate test characteristics of BUS for diagnosis of acute appendicitis in the emergency department. METHODS: Data were prospectively collected on 97 cases of suspected appendicitis, which had BUS performed by trained residents with attending supervision between August 2011 and November 2013. All BUS interpretation and additional diagnostic imaging were left to the discretion of the physician or surgical consultants. A blinded ultrasound fellowship-trained physician reviewed all images after clinical treatment. Bedside ultrasound findings and patient outcomes were reported. RESULTS: A total of 97 adult cases underwent diagnostic ultrasound scans for suspected appendicitis. Of 97 cases, 34 had acute appendicitis by surgery/pathology report. Twenty-four BUS were positive for acute appendicitis and 11 were nondiagnostic. Of 24 positive ultrasounds, 23 had appendicitis on pathology report. There was 1 false-positive result, yielding a sensitivity of 67.65% (95% confidence limits, 49.5%-82.6%) and a specificity of 98.41% (95% confidence limits, 91.4%-99.7%). Of 23 positive BUS, 12 cases went to the Operating Room without an abdominal CT yielding a 12% reduction in CT utilization. If all positive BUS went to the OR without a CT scan, this would yield a 24% reduction in CT utilization. CONCLUSIONS: Bedside ultrasound may be an appropriate initial test to evaluate patients with suspected acute appendicitis in the emergency department.

Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries.

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

Prospective, 10-year evaluation of the impact of Hispanic ethnicity on pain management practices in the ED.

INTRODUCTION: Hispanic ethnicity has been reported as an independent risk factor for oligoanalgesia in the emergency department (ED). OBJECTIVES: The objectives are to compare pain management practices in White and Hispanic patients in the ED to determine whether treatment differences exist. METHODS: Prospective analysis of a convenience sample of patients presenting to an urban, academic, tertiary-care ED over the 10-year period from 2000 to 2010. We compared patients with pain-related complaints of any nature, who self-identified their race as White or Hispanic, and evaluated initial morphine administration/dosing, arrival/disposition pain scores, and overall ED satisfaction scores (0-10 scale). RESULTS: Fifteen thousand sixty patients were enrolled. Eighty-one point 2 percent (n, 12 232) of the patients were White and 11.2% (n, 1680), Hispanic. White and Hispanic patients reported similar pain at presentation (6.7 vs 7.3, P < .001) and discharge/admission (4.6 vs 4.8, P = .14). Hispanic patients were not less likely to receive an analgesic during the ED visit (odds ratio, 1.06; confidence interval, 0.96-1.17; P = .62), nor less likely to receive an opioid analgesic (odds ratio, 0.97; confidence interval, 0.88-1.08; P = .70). Hispanic patients, on average, received similar initial doses of morphine (4.1 vs 4.3 mg, P = .29) and had similar wait times from arrival to initial dose of morphine (82 vs 86 minutes). Overall ED satisfaction scores were the same (8.7 vs 8.7, P = .65). CONCLUSION: White and Hispanic patients were similar in rates of initial morphine administration for pain-related complaints. These findings contrast with previous studies reporting lower rates of initial analgesia administration among Hispanic patients in the ED.

Patient anxiety may influence the efficacy of ED pain management.

OBJECTIVE: The aim of this study was to evaluate the incidence of anxiety and rates of anxiety treatment in emergency department (ED) patients presenting with pain-related complaints. METHODS: We prospectively evaluated patients in an urban academic tertiary care hospital ED from 2000 through 2010. We enrolled a convenience sample of adult patients presenting with pain and recorded patient complaint, medication administration, satisfaction, and pain and anxiety scores throughout their stay. We stratified patients into 4 different groups according to anxiety score at presentation (0, none; 1-4, mild; 5-7, moderate; 8-10, severe). RESULTS: We enrolled 10 664 ED patients presenting with pain-related complaints. Patients reporting anxiety were as follows: 25.7%, none; 26.1%, mild; 23.7%, moderate; and 24.5%, severe. Although 48% of patients described moderate to severe anxiety at ED presentation and 60% were willing to take a medication for anxiety, only 1% received anxiety treatment. Thirty-five percent of patients still reported moderate/severe anxiety at discharge. Severe anxiety at ED presentation was associated with increased demand for pain medication (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.10-1.79) and anxiety medication (OR, 4.34; 95% CI, 3.68-5.11) during the ED stay and decreased satisfaction with the treatment of pain (ß coefficient = -0.328; P < .001). After adjusting for age, sex, and presentation pain scores, patients who reported severe anxiety were more likely to receive an analgesic (OR, 1.33; 95% CI, 1.19-1.50) and an opioid (OR, 1.25; 95% CI, 1.11-1.41) during the ED stay. CONCLUSION: Anxiety may be underrecognized and undertreated in patients presenting with pain-related complaints. Patients reporting severe anxiety were less likely to report satisfaction with the treatment of their pain, despite higher rates of analgesic administration.