Breast vibro-acoustography: initial experience in benign lesions

Background

Functional magnetic resonance imaging (fMRI) analysis is commonly done with cross-correlation analysis (CCA) and the General Linear Model (GLM). Both CCA and GLM techniques, however, typically perform calculations on a per-voxel basis and do not consider relationships neighboring voxels may have. Clustered voxel analyses have then been developed to improve fMRI signal detections by taking advantages of relationships of neighboring voxels. Mean-shift clustering (MSC) is another technique which takes into account properties of neighboring voxels and can be considered for enhancing fMRI activation detection.

Methods

This study examines the adoption of MSC to fMRI analysis. MSC was applied to a Statistical Parameter Image generated with the CCA technique on both simulated and real fMRI data. The MSC technique was then compared with CCA and CCA plus cluster analysis. A range of kernel sizes were used to examine how the technique behaves.

Results

Receiver Operating Characteristic curves shows an improvement over CCA and Cluster analysis. False positive rates are lower with the proposed technique. MSC allows the use of a low intensity threshold and also does not require the use of a cluster size threshold, which improves detection of weak activations and highly focused activations.

Conclusion

The proposed technique shows improved activation detection for both simulated and real Blood Oxygen Level Dependent fMRI data. More detailed studies are required to further develop the proposed technique.     

Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein‐coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain‐of‐function to loss‐of‐function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein‐coding variants (i.e., the residuals were reduced), and approximately one‐third of these individuals (12/39) were re‐assigned from normal to slow metabolizer status. Rare coding variants can alter an individual’s CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Common CYP2A6 variants (minor allele frequency >1%) explain 30–35% of the variation in CYP2A6 activity, despite high heritability estimates (60–80%) in the CYP2A6 activity biomarker measure. One hypothesis is that rare coding variants (minor allele frequency <1%) may explain a portion of the missing heritability from pharmacogenes, including CYP2A6.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the relative contribution of rare coding variants in explaining variation in CYP2A6 activity? How necessary is the incorporation of rare coding variants in predicting individual metabolic status, and consequent tailoring of treatment?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Rare coding variants may explain only a small fraction of the variation on a population level; however, their role may be important on an individual level, altering the predicted metabolic status in a third of the individuals with these rare coding variants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Evaluating rare coding variants in pharmacogenes, such as CYP2A6, will be valuable in enhancing the investigation of CYP2A6’s influence on tobacco addiction and disease pathogenesis, by providing a more accurate reflection of the phenotypic metabolic status through improved genetic assessments.     

Factors Associated with Physician Tolerance of Uncertainty: an Observational Study

BackgroundPhysicians need to learn and work amidst a plethora of uncertainties, which may drive burnout. Understanding differences in tolerance of uncertainty is an important research area.ObjectiveTo examine factors associated with tolerance of uncertainty, including well-being metrics such as burnout.DesignOnline confidential survey.SettingThe Massachusetts General Physicians Organization (MGPO).ParticipantsAll 2172 clinically active faculty in the MGPO.Main MeasuresWe examined associations for tolerance of uncertainty with demographic information, personal and professional characteristics, and physician well-being metrics.Key ResultsTwo thousand twenty (93%) physicians responded. Multivariable analyses identified significant associations of lower tolerance of uncertainty with female gender (OR, 1.23; 95% CI, 1.03–1.48); primary care practice (OR, 1.56; 95% CI, 1.22–2.00); years since training (OR, 0.99; 95% CI, 0.98–0.995); and lacking a trusted advisor (OR, 1.25; 95% CI, 1.03–1.53). Adjusting for demographic and professional characteristics, physicians with low tolerance of uncertainty had higher likelihood of being burned-out (OR, 3.06; 95% CI, 2.41–3.88), were less likely to be satisfied with career (OR, 0.37; 95% CI, 0.26–0.52), and less likely to be engaged at work (RR, 0.87; 95% CI, 0.84–0.90).ConclusionAt a time when concern about physician well-being is high, with much speculation about causes of burnout, we found a strong relationship between tolerance of uncertainty and physician well-being, across specialties. Particular attention likely needs to be paid to those with less experience, those in specialties with high rates of undifferentiated illness and uncertainty, such as primary care, and ensuring all physicians have access to a trusted advisor. These results generate the potential hypothesis that efforts focused in understanding and embracing uncertainty could be potentially effective for reducing burnout. This concept should be tested in prospective trials.KEY WORDS: uncertainty, burnout, well-being, faculty development, continuing medical education     

Pilot Study to Quantify Palladium Impurities in Lead-like Compounds Following Commonly Used Purification Techniques

Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis. The products have a range of uses, including as intermediates in total synthesis and as screening compounds for drug discovery or agrochemical projects. Despite the known and potentially deleterious effects of low-level metal impurities in biological assays, the quantification of metal remaining in reaction products to verify the effective removal of the transition element is rarely reported. Using palladium as an exemplar, we describe a pilot study that for the first time quantifies residual metal levels in reaction products following increasingly rigorous purification protocols. Our results demonstrate that significant levels of residual palladium can remain in isolated reaction products following chromatographic purification, and only by using a subsequent metal scavenging step are they reliably reduced to a low level. Finally, we provide a set of simple guidelines that should minimize the potential for issues associated with residual palladium in reaction products.     

Social Phobia Among Depressed Individuals Entering Residential Rehabilitation Programmes: Prevalence and Correlates

Social phobia commonly co-occurs with substance use disorders and depression; however, the prevalence and correlates of social phobia among individuals with both of these disorders remain unknown. Interviews were conducted with 120 individuals entering residential rehabilitation for substance use treatment, who endorsed criteria for major depression and were recruited to a randomised controlled trial. Nearly three quarters (72.5%) of the sample met diagnostic criteria for social phobia. These individuals were more likely to report problematic drinking, more severe anxiety and depressive rumination, and lower distress tolerance, compared to individuals without social phobia. When examining the impact of applying diagnostic exclusion rules for social phobia among this cohort, results indicate that one third (32.2%) of those with social phobia specified their fear was related to a co-occurring mental health and/or substance use disorder. This group—who would not have met diagnostic criteria for social phobia if exclusion rules were strictly followed—experienced more severe depression, anxiety, depressive rumination, and repetitive negative thinking than those who did not make such attributions. The high prevalence and burden associated with social phobia among depressed substance users highlight the importance of screening for, assessing, and treating the disorder upon entry to treatment, irrespective of whether symptoms are related to other conditions.

     

Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results

The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9–1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.Subject terms: Drug development, Cancer therapy, Cancer therapy     

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP^R155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages that infiltrate the muscles of VCP^R155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP^R155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80⁽⁺⁾Ly6C⁽⁺⁾IL-1β⁽⁺⁾ macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.     

Preliminary evidence for an association between a dopamine D3 receptor gene variant and obsessive-compulsive personality disorder in patients with major depression.

We have previously reported that the Ser9Gly dopamine D3 receptor (DRD3) polymorphism was associated with increased rates of obsessive-compulsive personality disorder (OCPD) symptomology. We tested the replicability of this association within a further two independent groups of individuals with a history of depression, from a clinical sample (n = 149) and a family study (n = 213). The data from the replication samples and the original sample, within which the association was found, were compiled within a meta-analysis. Although the independent samples did not replicate the original finding, the meta-analysis elucidated significant evidence supporting the association. An individual with Gly/Gly genotype is 2.4 (P = 0.017) times more likely to be diagnosed with OCPD. Male gender was also found to be a significant predictor of OCPD diagnosis (OR = 2.82, P = 0.001). An exploration of an association of DRD3 with Axis I anxiety disorder diagnoses and Temperament and Character Inventory (TCI) traits, in particular persistence, revealed no support for an association. We conclude that DRD3 may contribute to the development of OCPD.