Identification of "Structural Pin" Interactions and their Significance for the Conformational Control of Macrocyclic Scaffolds.

While peptide macrocycles with rigidified conformations have proven to be useful in the design of chemical probes of protein targets, conformational flexibility and rapid interconversion can be equally vital for biological activity and favorable physicochemical properties. This study introduces the concept of "structural pin", which describes a hydrogen bond that is largely responsible for stabilizing the entire macrocycle backbone conformation. Structural analysis of macrocycles using nuclear magnetic resonance (NMR), molecular modelling and X-ray diffraction indicates that disruption of the structural pin can drastically influence the conformation of the entire ring, resulting in novel states with increased flexibility. This finding provides a new tool to interrogate dynamic behaviour of macrocycles. Identification of structural pins offers a useful conceptual framework to understand positions that can either be modified to give flexible structures or retained to maintain the rigidity of the scaffold.

Laparoscopic Cholecystectomy in Jos: Prospects and Perspectives.

Laparoscopic cholecystectomy is now done in a lot more private and public hospital settings presently in low-income countries, particularly sub-Saharan Africa. Though it is not routinely done in these centres, the percentage of cholecystectomies done laparoscopically has increased over the years. Laparoscopic surgery services were introduced at our hospital in 2011 and this retrospective study reviews our outcomes with the procedure over a 6-year period. A total of 87 cholecystectomies were done in the period under review. Forty-eight (55.2%) were laparoscopic cholecystectomies, 30 (44.8%) were open cholecystectomies, and 9 (10.3%) were mini-laparotomy cholecystectomies. There were 32 (66.7%) women and 16 (33.3%) men who had laparoscopic cholecystectomy giving a male-to-female ratio of 1:2. The mean age of the patients was 41.0 years (SD = 14.3 years). The most common indication for laparoscopic cholecystectomy was calculous cholecystitis. The most common co-morbidity was hypertension in 23 (47.9%) patients, followed by sickle cell anaemia in 10 (20.8%) patients. The operating time ranged from 70 min to 120 min with a mean of 86.6 (SD = 14.5). There were three conversions and two intra-operative complications. Twenty-five patients (52.1%) were discharged within 24 h, 16 (33.3%) within 48 h and the rest (14.6%) were discharged later. The duration of surgery had a significant association with duration of hospital stay. There was 1 mortality in our study. Laparoscopic cholecystectomy offers unique advantages over open such as decreased length of hospital stay and reduced wound complications. Most of the cholecystectomies in our setting are now performed laparoscopically with a low conversion rate and low incidence of bile duct injuries. Patients with sickle cell disease constitute a significant percentage of patients requiring this procedure.

Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease.

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.

Meat quality of Sasso T44 and Koekoek cockerels exposed to temperature variation with supplementary coriander seed powder.

This experiment was conducted to evaluate the effects of ambient temperature and coriander seed supplementations on meat quality of Sasso T44 and Koekoek. Both breeds were exposed to two temperature rooms with a heated room of 32 ± 1.2 °C from 11:00 am to 16:00 pm and the normal room temperature of average maximum and minimum of 23.8 ± 3 °C and 16.6 ± 1.6 °C, respectively, with a relative humidity between 34.5 ± 4 and 44.8 ± 3%. Both breeds were also further randomly allocated to three levels of 0 g/kg, 5 g/kg and 10 g/kg coriander seed powder supplementations. The experiment was conducted from 9 to 20 weeks of age. There was a slight variation in breast lightness (L*; P < 0.05) due to temperature at 48 h after slaughtered. At 48 h after slaughtered, breast from cockerels reared in a heated room became slightly lighter compared to groups reared at normal temperature. However, the overall meat colour did not categorized under the paled colour of meat; rather, it can be in the darker than normal category. Moreover, breast of Koekoek at 1 h after slaughtered was more yellow (P < 0.05) in colour and higher chroma values, while at 48 h, Sasso T44 had redder meat (P < 0.05) than Koekoek. In addition, the thigh meat of Koekoek had more total ash than Sasso T44 (P < 0.05). However, Sasso T44 breast had better water holding capacity due to lower in drip loss percentage (P < 0.05) than Koekoek. This research indicated that some meat quality variations were shown between breeds, while temperature had no effect on the meat quality parameters conducted except the L* value at 48 h, which was higher in groups of cockerels placed in a heated room. However, further insights into other physical meat qualities and sensory evaluations may also reveal to the meat quality of these breeds.

How do we measure unmet need within sexual and reproductive health? A systematic review.

BACKGROUND: Addressing health inequality with sexual and reproductive health requires an understanding of unmet need within a range of populations. This review examined the methods and definitions that have been used to measure unmet need, and the populations most frequently assessed. METHODS: Five databases (PubMed, Web of Science, Scopus, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Health Management and Policy Database (HMIC)) were searched for studies that described quantitative measurement of unmet need within sexual and/or reproductive health between 2010 and 2021. A narrative synthesis was then undertaken to ascertain themes within the literature. RESULTS: The database search yielded 19,747 papers; 216 papers were included after screening. 190 studies assessed unmet reproductive health need, of which 137 were analyses of trends among people living in low/lower-middle income countries; 181 used cross-sectional data, with only nine analyses being longitudinal. Eighteen studies analysed unmet sexual health need, of which 12 focused on high and upper-middle income populations. 16 papers used cross-sectional analyses. The remaining 10 studies examined unmet need for a combination of sexual and reproductive health services, eight among populations from upper-middle or high income countries. All were cross-sectional analyses. 165 studies used the Demographic and Health Surveys (DHS) definition of unmet need; no other standardised definition was used among the remaining papers. DISCUSSION: There is a significant focus on unmet need for contraception among women in low income countries within the published literature, leaving considerable evidence gaps in relation to unmet need within sexual health generally and among men in particular, and unmet reproductive health need in high income settings. In addition, using an increased range of data collection methods, analyses and definitions of unmet need would enable better understanding of health inequality in this area.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

Discovery of a new series of PI3K-δ inhibitors from Virtual Screening.

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.

Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles.

We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast in 17, 18, 19-membered rings but slows down in 16-membered rings. The analysis by NMR and MD simulation experiments is consistent with the maintenance of rare cis-amide motifs during conformational interconversion. Taken together, our investigation demonstrates that heterocyclic rearrangement reactions can be used to control macrocyclic backbones and provides fundamental insights that may be applicable to the development of a wide range of other conformational control elements.

Associations among temporal and large artery abnormalities on vascular ultrasound in giant cell arteritis.

Objectives: Giant cell arteritis (GCA) can manifest in cranial and/or extracranial arteries. We investigated the distribution of affected arteries on vascular ultrasound (VUS) among patients with new-onset or prior-onset GCA.Method: We retrospectively studied patients with either new-onset or prior-onset GCA and an abnormal VUS, from 2013 to 2017. Trained vascular technologists imaged the bilateral temporal arteries and carotid, axillary, and subclavian arteries. Vascular medicine physicians interpreted the images. Vasculitis-related abnormalities in individual vessels and their distribution (temporal artery, large artery, or both) were evaluated. Phi coefficients (φ) and Fisher's exact test were used to assess correlations among individual abnormal arteries.Results: Among 66 GCA patients, 28.8% had prior-onset GCA (median duration 17.8 months). Acute arteritis on VUS was observed in the majority of patients with both new-onset (72.3%) and prior-onset GCA (68.4%); the remainder had hyperechoic wall thickening without acute arteritis. Involvement of the temporal arteries only (45.5%) or large arteries only (34.8%) was more common than involvement of both (19.7%); this finding was similar in new-onset and prior-onset GCA. There were moderate positive correlations among temporal artery branches (φ = 0.51-0.58, p < 0.003) and among axillary and subclavian arteries (φ = 0.51-0.77, p < 0.003), and moderate negative correlations between abnormalities in the temporal and large arteries (φ = -0.46 to -0.58, p < 0.003).Conclusion: On VUS, vasculitis-related abnormalities in the temporal arteries only or large arteries only were more common than concurrent temporal and large artery abnormalities in patients with both new-onset GCA and prior-onset GCA.

Illuminating the dark conformational space of macrocycles using dominant rotors.

Three-dimensional conformation is the primary determinant of molecular properties. The thermal energy available at room temperature typically equilibrates the accessible conformational states. Here, we introduce a method for isolating unique and previously understudied conformations of macrocycles. The observation of unusual conformations of 16- to 22-membered rings has been made possible by controlling their interconversion using dominant rotors, which represent tunable atropisomeric constituents with relatively high rotational barriers. Density functional theory and in situ NMR measurements suggest that dominant rotor candidates for the amino-acid-based structures considered here should possess a rotational energy barrier of at least 25 kcal mol-1. Notable differences in the geometries of the macrocycle conformations were identified by NMR spectroscopy and X-ray crystallography. There is evidence that amino acid residues can be forced into rare turn motifs not observed in the corresponding linear counterparts and homodetic rings. These findings should unlock new avenues for studying the conformation-activity relationships of bioactive molecules.

Healing of erosions in rheumatoid arthritis remains elusive: results with 24 months of the anabolic agent teriparatide.

Objective: Erosion healing in rheumatoid arthritis (RA) is difficult to demonstrate. This extension study aimed to determine whether 2 years of teriparatide (TPTD) produces erosion healing. Method: Subjects in a previous 12 month randomized controlled trial of TPTD in RA were invited to receive 12 additional months of open-label TPTD. Eleven of the 24 original subjects were enrolled in the extension study, six of whom received TPTD in the final 12 months only. Subjects receiving 24 months of TPTD were assessed for reduction in erosion volume from baseline using computed tomography. We also compared erosion volumes between 12 and 24 months of TPTD. Large erosions in subjects receiving TPTD for 24 months were examined for volume change. Results: In the six patients who received 24 months of TPTD, there was no significant change in erosion volume at the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints compared with baseline. The six subjects who received 24 months of TPTD had similar changes in erosion volume to the five who received 12 months of TPTD, in MCP (p = 0.17) and PIP (p = 0.63) joints. Assessment of large erosions in those receiving TPTD for 24 months showed no evidence of erosion healing. Conclusion: While this extension study was too small to be conclusive, we observed no evidence of reduction in erosion volume with the addition of TPTD for 24 months in subjects with RA in whom disease activity was controlled on a tumour necrosis factor inhibitor. This is consistent with our negative findings at 12 months.

Amidine Functionality As a Conformational Probe of Cyclic Peptides.

The amidine functionality switches between hydrogen bond donor and acceptor roles depending on pH. Herein, the amidine was incorporated to select amides in cyclo(d-Ala-Pro-d-Phe-Pro-Gly). The unprotonated amidine-containing macrocyclic conformation resembles its oxoamide counterpart. Upon protonation, minimal alterations in the macrocyclic conformation were observed despite changes to the hydrogen bond network. The amidine disrupts hydrogen bonding at minimal steric cost, making it a useful functionality to study the effect of hydrogen bonding on the macrocyclic conformation.

Oxadiazole-Containing Macrocyclic Peptides Potentiate Azole Activity against Pathogenic Candida Species.

Opportunistic pathogens of the genus Candida reign as the leading cause of mycotic disease and are associated with mortality rates greater than 40%, even with antifungal intervention. This is in part due to the limited arsenal of antifungals available to treat systemic fungal infections. Azoles have been the most widely deployed class of antifungal drug for decades and function by targeting the biosynthesis of ergosterol, a key component of the fungal cell membrane. However, their utility is compromised by their fungistatic nature, which favors the development of resistance. Combination therapy has the potential to confer enhanced efficacy as well as mitigate the evolution of resistance. Previously, we described the generation of structurally diverse macrocyclic peptides with a 1,3,4-oxadiazole and an endocyclic amine grafted within the peptide backbone. Importantly, this noncanonical backbone displayed high membrane permeability, an important attribute for compounds that need to permeate across the fungal cell wall and membrane in order to reach their intracellular target. Here, we explored the bioactivity of this novel chemical scaffold on its own and in combination with the azole fluconazole. Although few of the oxadiazole-containing macrocyclic peptides displayed activity against Candida albicans on their own, many increased the efficacy of fluconazole, resulting in a synergistic combination that was independent of efflux inhibition. Interestingly, these molecules also enhanced azole activity against several non-albicans Candida species, including the azole-resistant pathogens Candida glabrata and Candida auris This work characterizes a novel chemical scaffold that possesses azole-potentiating activity against clinically important Candida species.IMPORTANCE Fungal infections, such as those caused by pathogenic Candida species, pose a serious threat to human health. Treating these infections relies heavily on the use of azole antifungals; however, resistance to these drugs develops readily, demanding novel therapeutic strategies. This study characterized the antifungal activity of a series of molecules that possess unique chemical attributes and the ability to traverse cellular membranes. We observed that many of the compounds increased the activity of the azole fluconazole against Candida albicans, without blocking the action of drug efflux pumps. These molecules also increased the efficacy of azoles against other Candida species, including the emerging azole-resistant pathogen Candida auris Thus, we describe a novel chemical scaffold with broad-spectrum bioactivity against clinically important fungal pathogens.

Discovery of a chemical probe for PRDM9.

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

Diffusion Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3-K27M Mutation Using Apparent Diffusion Coefficient Histogram Analysis.

BACKGROUND AND PURPOSE: Diffuse midline gliomas with histone H3 K27M mutation are biologically aggressive tumors with poor prognosis defined as a new diagnostic entity in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. There are no qualitative imaging differences (enhancement, border, or central necrosis) between histone H3 wildtype and H3 K27M-mutant diffuse midline gliomas. Herein, we evaluated the utility of diffusion-weighted imaging to distinguish H3 K27M-mutant from histone H3 wildtype diffuse midline gliomas. MATERIALS AND METHODS: We identified 31 pediatric patients (younger than 21 years of age) with diffuse gliomas centered in midline structures that had undergone assessment for histone H3 K27M mutation. We measured ADC within these tumors using a voxel-based 3D whole-tumor measurement method. RESULTS: Our cohort included 18 infratentorial and 13 supratentorial diffuse gliomas centered in midline structures. Twenty-three (74%) tumors carried H3-K27M mutations. There was no difference in ADC histogram parameters (mean, median, minimum, maximum, percentiles) between mutant and wild-type tumors. Subgroup analysis based on tumor location also did not identify a difference in histogram descriptive statistics. Patients who survived <1 year after diagnosis had lower median ADC (1.10 × 10-3mm2/s; 95% CI, 0.90-1.30) compared with patients who survived >1 year (1.46 × 10-3mm2/s; 95% CI, 1.19-1.67; P < .06). Average ADC values for diffuse midline gliomas were 1.28 × 10-3mm2/s (95% CI, 1.21-1.34) and 0.86 × 10-3mm2/s (95% CI, 0.69-1.01) for hemispheric glioblastomas with P < .05. CONCLUSIONS: Although no statistically significant difference in diffusion characteristics was found between H3-K27M mutant and H3 wildtype diffuse midline gliomas, lower diffusivity corresponds to a lower survival rate at 1 year after diagnosis. These findings can have an impact on the anticipated clinical course for this patient population and offer providers and families guidance on clinical outcomes.

Conformationally stable peptide macrocycles assembled using the Petasis borono-Mannich reaction.

Macrocyclization of linear peptide precursors using the Petasis borono-Mannich reaction affords a diverse range of macrocycles with an endocyclic amine. Analysis of the corresponding macrocyclic structures underscores that the hydrogen bond between an endocyclic amine and the adjacent amide NH is a powerful control element for conformationally homogenous peptide macrocycles.

Conformational Control of Macrocycles by Remote Structural Modification.

The conformational analysis of macrocycles is a complex and challenging problem. There are many factors that contribute to this complexity. These include a large number of degrees of freedom, transannular interactions such as hydrogen bonds and hydrophobic interactions, and a range of steric interactions, along with ring strain effects. To a greater extent than within acyclic molecules, these interactions within macrocycles are coupled such that changing one dihedral angle can significantly affect other dihedral angles, further complicating the situation. However, this coupling of bond rotations and transannular interactions enables the transmission of three-dimensional information from one side of a macrocycle to the other. Making relatively small structural modifications to a macrocycle can result in local conformational changes that propagate along the ring to affect distal structural features. The factors that control how such changes can propagate are poorly understood, and it is difficult to predict which modifications will result in significant conformational reorganizations of remote regions of a macrocycle. This review discusses examples where small structural modifications to macrocyclic scaffolds change the conformational preferences of structurally remote regions of the ring. We will highlight evidence provided for conformational changes triggered by remote substituents and explanations of how these changes might occur in an effort to further understand the factors that control such phenomena.

Patterns of prescription opioid use before total hip and knee replacement among US Medicare enrollees.

OBJECTIVE: To examine patterns of prescription opioid use before total joint replacement (TJR) and factors associated with continuous use of opioids before TJR. DESIGN: We conducted an observational cohort study among Medicare enrollees aged ≥65 years who underwent TJR between 2010 and 2014. Preoperative opioid use was defined as having any opioid prescription in the 12-month period before TJR. Patients who had an opioid prescription every month for a 12-month period were defined as continuous users. We examined patients' demographics, pain-related conditions, medication use, other comorbidities, healthcare utilization and their association with use of opioids before TJR. RESULTS: A total of 473,781 patients underwent TJR:,155,516 THR and 318,265 TKR. Among the total cohort, 60.2% patients had any use of opioids and of those, 12.4% used opioids at least once a month continuously over the 12-month baseline period. Correlates of continuous opioid use included African American race (OR = 2.14, 95% confidence intervals (CI) = 2.01-2.28, compared to White patients), history of drug abuse (OR = 5.18, 95% CI = 3.95-6.79) and back pain (OR = 2.32, 95% CI = 2.24-2.39). CONCLUSIONS: In this large cohort of patients undergoing TJR, over 60% ever used opioids and 12.4% of them continuously used opioids in the 12-month prior to surgery. Utilization of opioids became more frequent and high-dosed near the surgery. History of drug abuse, back pain, and African American race were strongly associated with continuous use of opioids preoperatively. Further research is needed to determine short-term and long-term risks of preoperative use of opioids in TJR patients and to optimize pre- and post-TJR pain management of patients with arthritis.

Preoperative MR Imaging to Differentiate Chordoid Meningiomas from Other Meningioma Histologic Subtypes.

BACKGROUND AND PURPOSE: Chordoid meningiomas are uncommon WHO grade II primary intracranial neoplasms that possess unique chordoid histology and follow an aggressive clinical course. Our aim was to assess the utility of qualitative MR imaging features and quantitative apparent diffusion coefficient values as distinguishing preoperative MR imaging metrics to identify and differentiate chordoid histology from other meningioma histologic subtypes. MATERIALS AND METHODS: Twenty-one patients with meningiomas with chordoid histology, which included both chordoid meningiomas (>50% chordoid histology) and meningiomas with focal chordoid histology (<50% chordoid histology) with available preoperative MR imaging examinations, including diffusion-weighted imaging, were identified. Qualitative imaging features and quantitative ADC values were compared between meningiomas with chordoid histology and 42 nonchordoid meningiomas (29 WHO grade I, eleven WHO grade II, and 2 WHO grade III). RESULTS: The median ADC (10-3mm2/s) of meningiomas with chordoid histology was significantly higher than nonchordoid meningiomas (1.16 versus 0.92, P < .001), as was the median normalized ADC (1.60 versus 1.19, P < .001). In subgroup analysis, the median and normalized ADC values of chordoid meningiomas (n = 11) were significantly higher than those in meningiomas with focal chordoid histology (n = 10, P < .001 and P < .001, respectively) or nonchordoid meningiomas (n = 42, P < .001 and <0.001, respectively). Median and normalized ADC values were not significantly different between the meningiomas with focal chordoid histology and nonchordoid meningiomas (P = .816 and .301, respectively). Among the qualitative imaging features, only DWI signal intensity was significantly associated with meningiomas with chordoid histology diagnosis. CONCLUSIONS: ADC values are higher in chordoid compared with nonchordoid meningiomas and may be used to discriminate the degree of chordoid histology in meningiomas. While qualitative MR imaging features do not strongly discriminate chordoid from nonchordoid meningiomas, DWI may allow preoperative identification of chordoid meningiomas.