Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

General Versus Regional Anaesthesia for Lower Limb Arthroplasty and Associated Patient Satisfaction Levels: A Prospective Service Evaluation in the Oxford University Hospitals.

Introduction Lower limb arthroplasty is performed under general anaesthesia (GA) or regional anaesthesia (RA). There is increasing evidence of the surgical and anaesthetic benefits of RA. National Institute for Health and Care Excellence (NICE) guidelines advise using either but highlight a lack of data comparing outcomes of RA and GA for these procedures. We conducted a service evaluation, prospectively analysing elective orthopaedic cases performed at the Nuffield Orthopaedic Centre, Oxford, UK from 19/11/2018 to 03/04/2019. We aimed to compare data on anaesthetic assessment, intra-operative parameters and patient satisfaction for RA and GA cases. Methods We selected elective patients, aged above 18, undergoing total hip, total knee or unilateral knee arthroplasties. Prospective quantitative and qualitative data were collected using two forms. Firstly, anaesthetists completed a case report recording demographic data, intra-operative details and reason for anaesthetic choice. Secondly a questionnaire gathered patient satisfaction data. This was analysed using descriptive statistics and presented in tables. Results Data for 132 patients were collected over the service evaluation period. After exclusion, 99 patients were included for final analysis; 59 underwent GA and 40 had RA. GA was used predominantly due to patient preference (74.6%). RA was used primarily due to anaesthetic preference (75%); most commonly due to speed of list and duration of operation. Overall patients had low pain scores (0.3/10) and high pre-operative anxiety levels (4.6/10) regardless of anaesthetic. Conclusion Our results show high patient satisfaction with GA and RA for lower limb arthroplasty; however, pre-operative anxiety was common for both. Patient preference and comfort influenced choice of anaesthesia, highlighting the importance of pre-operative counselling and education to facilitate shared decision making, leading to favourable post-operative outcomes.

Hydroamination of Dihapto-Coordinated Benzene and Diene Complexes of Tungsten: Fundamental Studies and the Synthesis of γ-Lycorane.

Reactions are described for complexes of the form WTp(NO)(PMe3)(η2-arene) and various amines, where the arene is benzene or benzene with an electron-withdrawing substituent (CF3, SO2Ph, SO2Me). The arene complex is first protonated to form an η2-arenium species, which then selectively adds the amine. The resulting η2-5-amino-1,3-cyclohexadiene complexes can then be subjected to the same sequence with a second nucleophile to form 3-aminocyclohexene complexes, where up to three stereocenters originate from the arene carbons. Alternatively, 1,3-cyclohexadiene complexes containing an ester group at the 5 position (also prepared from an arene) can be treated with acid followed by an amine to form trisubstituted 3-aminocyclohexenes. When the amine is primary, ring closure can occur to form a cis-fused bicyclic γ-lactam. Highly functionalized cyclohexenes can be liberated from the tungsten through oxidative decomplexation. The potential utility of this methodology is demonstrated in the synthesis of the alkaloid γ-lycorane. An enantioenriched synthesis of a lactam precursor to γ-lycorane is also described. This compound is prepared from an enantioenriched version of the tungsten benzene complex. Regio- and stereochemical assignments for the reported compounds are supported by detailed 2D-NMR analysis and 13 molecular structure determinations (SC-XRD).

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review.

BACKGROUND: Rapid and widespread increases in carbapenem resistance (CR) necessitate identification of risk factors to guide appropriate interventions. OBJECTIVES: We aimed to identify risk factors for CR Gram-negative infection through a systematic literature review. DATA SOURCES: We searched MEDLINE (via OvidSP and PubMed) and Embase (via OvidSP) databases and the Cochrane Central Register of Controlled Trials. STUDY ELIGIBILITY CRITERIA: Prospective or retrospective cohort and case-control studies reporting quantitative data on risk factors associated with infections due to CR Gram-negative pathogens in hospitalized patients were eligible. PARTICIPANTS: Studies included hospitalized patients with CR infection caused by Gram-negative bacterial pathogens (Enterobacterales and non-fermenters). METHODS: Searches were conducted in January 2018/December 2019 to identify studies published since 2007. Risk factor data were extracted and grouped by factor. The primary metric was proportion of studies reporting a significant association with CR infection for each factor. RESULTS: In total, 92 studies were identified. Risk factors most frequently reported as significantly associated with CR infection (>10 studies) were previous antibiotic use (91.1%; 72/79 studies); previous carbapenem use (82.6%; 57/69); previous colonization (72.7%; 8/11); mechanical ventilation (66.7%; 36/54); previous intensive care unit stay (64.4%; 38/59); dialysis (61.1%; 11/18); catheter (58.0%; 40/69); length of stay in hospital (54.5%; 30/55); comorbidities (52.7%; 39/74); APACHE II (51.7%; 15/29); and intubation (51.4%; 18/35). Risk factors were mostly consistent across different species and sites of infection. CONCLUSIONS: Several variables, particularly previous antibiotic use, are strong risk factors for CR infection. Interventions to mitigate against CR infection should target these factors.

Patients' reported experiences and outcomes following surgical excision of lower limb osteomyelitis and microvascular free tissue reconstruction under 'awake' epidural anaesthesia and sedation.

BACKGROUND: Orthoplastic operations for lower limb osteomyelitis (LLOM) involving microvascular free tissue reconstructions ("free-flaps") are usually performed under general anaesthesia (GA), with or without epidural anaesthesia (EA) due to concerns about the discomfort associated with prolonged surgery. However, our clinical experience supports "awake" epidural anaesthesia with sedation (EA + Sed) rather than EA + GA as a technique of choice for this type of surgery. METHODS: We used a standardised postoperative questionnaire to formally assess the experiences and outcomes for 50 patients who underwent free-flaps for LLOM under EA + Sed. FINDINGS: The mean duration of surgery was 522 min (8.7 h), range 240-875 min. There were no ITU admissions or flap failures. Postoperatively, fifty patients completed a standardised questionnaire about their experiences before the operation, in the anaesthetic room and theatre. 80% were aware of the procedure at least "some of the time". 72.5% patients and 75% respectively, did not have any concerns in the anaesthetic room and theatre. Concerns expressed by the remaining patients were manageable. 97.5% of those patients who recalled their operation reported their overall experience as "comfortable" or "very comfortable". 92% of respondents had undergone previous lower limb surgery under GA ± EA. In this subgroup, 91.3% reported the recovery after EA + Sed as "quicker" than GA, and 89.4% reported their experience with EA + Sed as "better". All fifty patients (100%) were "satisfied" or "very satisfied" with their experience and all but one (98%) would recommend this technique to others. CONCLUSIONS: Our study showed that despite prolonged duration, the patients' reported experiences and outcomes were excellent when EA + Sed was used for orthoplastic operations involving free-flaps for LLOM. We recommend EA + Sed as the anaesthetic technique of choice for such patients.

A systematic review and indirect treatment comparison of perampanel versus brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization.

PURPOSE: To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods. METHODS: A systematic review was conducted to identify RCTs that evaluated either one of perampanel or brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between perampanel and brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted. RESULTS: Eight RCTs (four comparing perampanel to placebo, four comparing brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a significantly better responder rate compared to brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found. CONCLUSION: Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

Spatial Recognition Within Terpenes: Redox and H-bond Promoted Linkage Isomerizations and the Selective Binding of Complex Alkenes.

A method for the resolution of η 2-alkene-complex isomers of the type MoTp(NO)(DMAP)(η 2-alkene) and WTp(NO)(PMe3)(η 2-alkene) (where Tp = hydridotris(pyrazolyl)-borate and DMAP = 4-(dimethylamino)pyridine) has been explored. Alkene and polyene compounds form as a mixture of kinetically trapped isomers. For both types of complexes, it was found that addition of either a fluorinated alcohol or one-electron oxidant reduces the number of isomers in solution. Accelerated ligand exchange was also observed, although these reactions were accompanied by significant decomposition.

Highly Functionalized Cyclohexenes Derived from Benzene: Sequential Tandem Addition Reactions Promoted by Tungsten.

The dihapto-coordination of benzene to the π-basic fragment {TpW(NO)(PMe3)} (Tp = hydridotris(pyrazolyl)-borate) enhances the basicity of the arene ligand to the point that it can be protonated with a mild Brønsted acid (diphenylammonium triflate; p Ka ∼ 1). The resulting η2-benzenium complex reacts with a wide range of nucleophiles including protected enolates, cyanide, amines, methoxide, and aromatic nucleophiles to form 5-substituted 3,4-η2-1,3-cyclohexadiene complexes in good yield (42-70%). These coordinated dienes were successfully taken through a second protonation and nucleophilic addition with a similar scope of nucleophiles (54-80%). The resulting cis-3,4- and cis-3,6-disubstituted η2-cyclohexene complexes were prepared with high regio- and stereocontrol, as governed by the asymmetric nature of π-allyl intermediates. In some cases, a diene linkage isomerization from 3,4-η2 to 1,2-η2 could be effected with a redox catalyst, and reactions of the latter species led to cis-3,5-disubstituted cyclohexene products exclusively. Oxidative decomplexation afforded the free cyclohexene products in moderate yield (37-68%). Additionally, when a single enantiomer of the chiral dearomatization agent was used, the elaborated cyclohexenes were able to be synthesized in enantioenriched forms (86-90% enantiomeric excess). Full characterization of 40 new compounds is provided that includes two-dimensional NMR, IR, electrochemical and in some cases crystallographic data.

Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis.

BACKGROUND: Ocrelizumab was approved for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) by the US Food and Drug Administration in March 2017 and by the European Medicines Agency in January 2018. These approvals were based on two pivotal randomized controlled trials (RCTs), OPERA I and OPERA II, comparing ocrelizumab 600 mg with an active comparator, interferon ß-1a 44 µg (Rebif), and the first trial with positive results in patients with PPMS, which compared ocrelizumab with placebo. However, direct evidence of the efficacy and safety of ocrelizumab in RMS compared with other disease-modifying therapies (DMTs) approved for RMS is not available from RCTs. In the absence of such RCTs, network meta-analyses (NMAs) were conducted to compare indirectly the relative efficacy and safety of ocrelizumab with all other approved DMTs for the treatment of RMS. METHODS: Systematic literature searches were conducted in MEDLINE, Embase, the Cochrane Library, trial registers, relevant conference websites and health technology assessment agency websites. Eligible RCTs evaluated approved treatments for multiple sclerosis (MS) in which more than 75% of patients had a relapsing form of MS. NMAs were conducted for four efficacy and three safety outcomes, and treatment hierarchies were generated for each outcome using surface under the cumulative ranking curve (SUCRA) values. RESULTS: Results suggest that ocrelizumab has superior efficacy to 10 of the 17 treatments in the 12-week confirmed disability progression network and 12 of the 17 treatments in the annualized relapse rate network (both including placebo). The efficacy of ocrelizumab was comparable with the other treatments in both networks. In the serious adverse events and discontinuation due to adverse events networks, ocrelizumab demonstrated a safety profile comparable with all other treatments (including placebo). SUCRA values consistently ranked ocrelizumab among the most effective or tolerable treatments across all outcomes. CONCLUSIONS: Results suggest that ocrelizumab has an efficacy superior to or comparable with all other currently approved DMTs across all endpoints analyzed, and a similar safety profile, indicating it offers a valuable package for the treatment of patients with RMS.

Sequential Tandem Addition to a Tungsten-Trifluorotoluene Complex: A Versatile Method for the Preparation of Highly Functionalized Trifluoromethylated Cyclohexenes.

The effects of an electron-withdrawing group on the organic chemistry of an η2-bound benzene ring are explored using the complex TpW(NO)(PMe3)(η2-PhCF3). This trifluorotoluene complex was found to undergo a highly regio- and stereoselective 1,2-addition reaction involving protonation of an ortho carbon followed by addition of a carbon nucleophile. The resulting 1,3-diene complexes can undergo a second protonation and nucleophilic addition with a range of nucleophiles including hydrides, amines, cyanide, and protected enolates. Interestingly, the addition of the second proton and nucleophile occurs in a 1,4-fashion, again with a high degree of regio- and stereocontrol. Oxidation of the metal allows for the isolation of highly substituted trifluoromethylcyclohexenes with as many as four stereocenters set by the metal. The ability to synthesize enantio-enriched organics was also demonstrated for a diene and a trisubstituted cyclohexene. Substitution from an enantio-enriched η2-dimethoxybenzene complex in neat trifluorotoluene yielded enantio-enriched trifluorotoluene complex, which was elaborated into cyclohexadienes and cyclohexenes with ee's ranging from 92 to 99%.

Molybdenum(0) Dihapto-Coordination of Benzene and Trifluorotoluene: The Stabilizing and Chemo-Directing Influence of a CF3 Group.

The preparation of the complexes TpMo(NO)(DMAP)(η2-PhCF3) (5) and TpMo(NO)(DMAP)(η2-benzene) (3) is described. The CF3 group is found to stabilize the metal-arene bond strength in 5 by roughly 3 kcal/mol compared to that in 3, allowing the large-scale synthesis and isolation of the trifluorotoluene analogue (5, 37 g, 70%). When a benzene solution of 5 is allowed to stand, clean conversion to the benzene analogue 3 occurs, and this complex may be precipitated from solution upon the addition of pentane and isolated. The trifluorotoluene complex is shown to be a synthetic precursor to functionalized cyclohexadienes: In solution, it selectively protonates at the ortho position, and the resulting η2-arenium species undergoes reactions with nucleophiles at the adjacent meta carbon. Thus, reactions of 5, triflic acid, and either N-methylpyrrole or 1-methoxy-2-methyl-1-(trimethylsilyloxy)-1-propene result in 5-substituted-1,3-cyclohexadienes after removal of the metal.

Trends in the golden state: small-group premiums rise sharply while actuarial values for individual coverage plummet.

Using multiple databases, this paper examines recent trends in the affordability and comprehensiveness of small-group and individual health insurance markets in California. Both became less affordable over the study period. In 2006, a single person age 32-52 earning the median income who purchased individual insurance spent on average 16 percent of income on premiums and out-of-pocket medical expenses. For individual insurance, the share of medical expenses paid by insurance as opposed to patients declined from 2002 to 2006. In the small-group market, premiums rose more than 50 percent from 2003 to 2006, but the proportion of claims paid by insurers for a standardized population remained constant.