A Plant-Centered Diet is Inversely Associated With Radiographic Emphysema: Findings from the CARDIA Lung Study.

Background: Chronic obstructive pulmonary disease (COPD) is a significant public health concern and intercepting the development of emphysema is vital for COPD prevention. Smokers are a high-risk population for emphysema with limited prevention strategies. We aimed to determine if adherence to a nutritionally rich, plant-centered diet among young ever-smokers is associated with reduced risk of future radiographic emphysema. Methods: We studied participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Prospective Cohort Study who were 18-30 years old at enrollment and followed for 30 years. We analyzed 1706 adults who reported current or former smoking by year 20. Repeated measures of diet history were used to calculate A Priori Diet Quality Scores (APDQSs), and categorized into quintiles, with higher quintiles representing higher nutritionally rich plant-centered food intake. Emphysema was assessed at year 25 (n=1351) by computed tomography (CT). Critical covariates were selected, acknowledging potential residual confounding. Results: Emphysema was observed in 13.0% of the cohort, with a mean age of 50.4 ± 3.5 years. The prevalence of emphysema was 4.5% in the highest APDQS quintile (nutritionally rich), compared with 25.4% in the lowest quintile. After adjustment for multiple covariates, including smoking, greater adherence to a plant-centered diet was inversely associated with emphysema (highest versus lowest quintile odds ratio: 0.44, 95% CI 0.19-0.99, ptrend=0.008). Conclusion: Longitudinal adherence to a nutritionally rich, plant-centered diet was associated with a decreased risk of emphysema development in middle adulthood, warranting further examination of diet as a strategy for emphysema prevention in a high-risk smoking population.

Right Bundle Branch and Bifascicular Blocks: Insensitive Prognostic Indicators for Acute Myocardial Infarction.

The clinical significance of right bundle branch block (RBBB) or bifascicular block (BFB) in the setting of acute myocardial infarction (AMI) is uncertain. RBBB was found in 211 of 7,626 patients (2.8%), presenting to the ED (emergency department) with chest pain, of which 18 (8.5%) also had acute coronary syndrome (ACS). Incidences of ACS were not significantly different between new or presumed new RBBB and prior known RBBB or new or presumed new BFB and prior known BFB. In 2 patients, baseline ST-segment depression in leads V1-3 masked anterior ST-elevation detected on electrocardiogram (ECG). In opposition to the guidelines, the presence of RBBB or BFB does not appear to offer any clinical utility when evaluating patients with suspected AMI. Patients with suspected AMI who present with RBBB and any ST-elevation in leads V1-3 should be considered for emergent coronary angiography rather than RBBB alone.

Open-Source Browser-Based Tools for Structure-Based Computer-Aided Drug Discovery.

We here outline the importance of open-source, accessible tools for computer-aided drug discovery (CADD). We begin with a discussion of drug discovery in general to provide context for a subsequent discussion of structure-based CADD applied to small-molecule ligand discovery. Next, we identify usability challenges common to many open-source CADD tools. To address these challenges, we propose a browser-based approach to CADD tool deployment in which CADD calculations run in modern web browsers on users' local computers. The browser app approach eliminates the need for user-initiated download and installation, ensures broad operating system compatibility, enables easy updates, and provides a user-friendly graphical user interface. Unlike server apps-which run calculations "in the cloud" rather than on users' local computers-browser apps do not require users to upload proprietary information to a third-party (remote) server. They also eliminate the need for the difficult-to-maintain computer infrastructure required to run user-initiated calculations remotely. We conclude by describing some CADD browser apps developed in our lab, which illustrate the utility of this approach. Aside from introducing readers to these specific tools, we are hopeful that this review highlights the need for additional browser-compatible, user-friendly CADD software.

Abnormalities in Cardiac Structure and Function among Individuals with CKD: The COMBINE Trial.

Background: Individuals with CKD have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age- and sex-matched healthy volunteers. Among COMBINE participants, we examined the associations of eGFR, urine albumin-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (SD) ages of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years, respectively. The mean (SD) baseline eGFR values in COMBINE participants were 32.1 (8.0) and 85.9 (16.0) ml/min per 1.73 m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3-540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared with healthy volunteers (for CKD versus non-CKD, ß estimate, -0.13; 95% CI, -0.24 to -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (ß estimate per 1 unit increase in natural-log UACR, -0.06; 95% CI, -0.09 to -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction, as assessed by mitral valve E/A ratio, in individuals with CKD with and without clinical CVD. Albuminuria was not associated with change in any cMRI parameter.

A Cohort Analysis of Statin Treatment Patterns Among Small-Sized Primary Care Practices.

BACKGROUND: Small-sized primary care practices, defined as practices with fewer than 10 clinicians, delivered the majority of outpatient visits in the USA. Statin therapy in high-risk individuals reduces atherosclerotic cardiovascular disease (ASCVD) events, but prescribing patterns in small primary care practices are not well known. This study describes statin treatment patterns in small-sized primary care practices and examines patient- and practice-level factors associated with lack of statin treatment. METHODS: We conducted a retrospective cohort analysis of statin-eligible patients from practices that participated in Healthy Hearts in the Heartland (H3), a quality improvement initiative aimed at improving cardiovascular care measures in small primary care practices. All statin-eligible adults who received care in one of 53 H3 practices from 2013 to 2016. Statin-eligible adults include those aged at least 21 with (1) clinical ASCVD, (2) low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL, or (3) diabetes aged 40-75 and with LDL-C 70-189 mg/dL. Eligible patients with no record of moderate- to high-intensity statin prescription are defined by ACC/AHA guidelines. RESULTS: Among the 13,330 statin-eligible adults, the mean age was 58 years and 52% were women. Overall, there was no record of moderate- to high-intensity statin prescription among 5,780 (43%) patients. Younger age, female sex, and lower LDL-C were independently associated with a lack of appropriate intensity statin therapy. Higher proportions of patients insured by Medicaid and having only family medicine trained physicians (versus having at least one internal medicine trained physician) at the practice were also associated with lower appropriate intensity statin use. Lack of appropriate intensity statin therapy was higher in independent practices than in Federally Qualified Health Centers (FQHCs) (50% vs. 40%, p value < 0.01). CONCLUSIONS: There is an opportunity for improved ASCVD risk reduction in small primary care practices. Statin treatment patterns and factors influencing lack of treatment vary by practice setting, highlighting the importance of tailored approaches to each setting.

AL Amyloidosis Presenting With Crescentic Glomerulonephritis.

Kidney amyloidosis typically presents with nephrotic-range proteinuria. Rare cases of crescentic glomerulonephritis have been reported in patients with kidney amyloidosis but most cases were in the setting of patients with AA amyloidosis from long-standing inflammation and malignancy. We present a case of a previously healthy man in his 70s who was admitted with severe acute kidney injury, nephrotic-range proteinuria, and nephritic urinary sediment. Initial serologic testing for causes of rapidly progressive glomerulonephritis were negative. Kidney biopsy demonstrated the presence of active cellular and fibrocellular crescents with Congo red-positive staining in glomeruli and microvasculature on light microscopy and amyloid fibrils in glomerular basement membrane on electron microscopy. Urinary protein electrophoresis revealed monoclonal λ light chains, leading to a diagnosis of kidney AL amyloidosis, which was confirmed with bone marrow biopsy. Our case illustrates that AL amyloidosis can present with findings suspicious for rapidly progressive glomerulonephritis and crescent formation on kidney biopsy specimens.

Is peripartum magnesium sulfate associated with a reduction in postpartum depressive symptoms?

BACKGROUND: The prevention of postpartum depression is an important area of investigation given its association with major maternal and neonatal sequelae, yet few evidence-based treatments to reduce the frequency of postpartum depression are used. Recent data suggest that N-methyl-D-aspartate receptor antagonists may lead to rapid improvement of depressive symptoms lasting up to 2 weeks. We hypothesized that the N-methyl-D-aspartate receptor antagonist magnesium sulfate would elicit antidepressant effects subsequent to its receipt by women receiving peripartum seizure prophylaxis for a hypertensive disorder of pregnancy. OBJECTIVE: This study aimed to compare the frequency of depressive symptoms at 2 weeks and 6 weeks after delivery between women who did and did not receive peripartum magnesium sulfate for a hypertensive disorder of pregnancy. STUDY DESIGN: This prospective cohort study included women with a hypertensive disorder of pregnancy at ≥34 weeks' gestation with singleton gestations. Magnesium sulfate for seizure prophylaxis was administered at the obstetrician's discretion. The Quick Inventory of Depressive Symptomatology survey was administered before hospital discharge and again at 2 weeks and 6 weeks after delivery to assess for postpartum depressive symptoms. The primary outcome for this study was the change in Quick Inventory of Depressive Symptomatology score from baseline to 2 weeks after delivery, which was analyzed both continuously and categorically (any symptom worsening vs stability or improvement). Secondary outcomes included the change in Quick Inventory of Depressive Symptomatology score from baseline to 6 weeks after delivery and the proportion of women who experienced an increase in Quick Inventory of Depressive Symptomatology score at 6 weeks after delivery. RESULTS: Of the 342 women enrolled, 39% (n=134) received magnesium sulfate. Compared with women who did not receive magnesium, women who received magnesium had a significantly smaller change in their mean Quick Inventory of Depressive Symptomatology score (0.6±3.4 vs 1.6±3.0; P=.015) and also were less likely to have an increase in Quick Inventory of Depressive Symptomatology score at 2 weeks after delivery (52% vs 67%; P=.022). These differences were not present at 6 weeks after delivery. After controlling for potential confounders, women who received magnesium continued to have a lower odds of having an increased Quick Inventory of Depressive Symptomatology score from baseline at 2 weeks after delivery than women who did not receive magnesium (adjusted odds ratio, 0.88; 95% confidence interval, 0.78-0.98). CONCLUSION: Peripartum magnesium was associated with less of an exacerbation in depressive symptoms in the immediate postpartum period. Given the implications of postpartum depression on maternal and child health and the lack of existing prophylaxis, randomized trials should examine this novel potential prophylactic therapy.

Does coaching matter? Examining the impact of specific practice facilitation strategies on implementation of quality improvement interventions in the Healthy Hearts in the Heartland study.

BACKGROUND: Practice facilitation is a multicomponent implementation strategy used to improve the capacity for practices to address care quality and implementation gaps. We sought to assess whether practice facilitators use of coaching strategies aimed at improving self-sufficiency were associated with improved implementation of quality improvement (QI) interventions in the Healthy Hearts in the Heartland Study. METHODS: We mapped 27 practice facilitation activities to a framework that classifies practice facilitation strategies by the degree to which the practice develops its own process expertise (Doing Tasks, Project Management, Consulting, Teaching, and Coaching) and then used regression tree analysis to group practices by facilitation strategies experienced. Kruskal-Wallis tests were used to assess whether practice groups identified by regression tree analysis were associated with successful implementation of QI interventions and practice and study context variables. RESULTS: There was no association between number of strategies performed by practice facilitators and number of QI interventions implemented. Regression tree analysis identified 4 distinct practice groups based on the number of Project Management and Coaching strategies performed. The median number of interventions increased across the groups. Practices receiving > 4 project management and > 6 coaching activities implemented a median of 17 of 35 interventions. Groups did not differ significantly by practice size, association with a healthcare network, or practice type. Statistically significant differences in practice location, number and duration of facilitator visits, and early study termination emerged among the groups, compared to the overall practice population. CONCLUSIONS: Practices that engage in more coaching-based strategies with practice facilitators are more likely to implement more QI interventions, and practice receptivity to these strategies was not dependent on basic practice demographics.

Racial and gender inequities in the implementation of a cannabis criminal justice diversion program in a large and diverse metropolitan county of the USA.

BACKGROUND: Diversion programs are considered alternatives to the arrest and incarceration of non-violent drug offenders, including those found in possession of smaller amounts of cannabis in states with prohibitive laws. Despite the progressive nature of such programs, the inability to complete diversion program requirements can often result in greater involvement with the criminal justice system than traditional case adjudication. Few studies have evaluated racial group differences in cannabis diversion program completion. METHODS: The current study examined a sample of 8323 adult participants in Harris County, Texas' Marijuana Misdemeanor Diversion Program (MMDP) between March 2017 and July 2019. Gender, age, and race/ethnicity were examined as predictors of program completion and time to completion using Chi square, Kruskal Wallis tests, and Cox proportional hazard regression models. RESULTS: Both males and African Americans were over-represented (80 % and 50 %, respectively) among participants of Harris County's MMDP. African American (HR = 0.782, 95 % CI [.735-.832], p < .001) and Latino American MMDP participants (HR = .822, 95 % CI [.720-.937], p = .003) had significantly lower odds of MMDP completion and a longer interval to program completion as compared to non-Latino White participants. CONCLUSIONS: The current study identified racial/ethnic and gender disparities in a large county's cannabis diversion program. These findings may be related to law enforcement disparities which disproportionately target males and people of color. Findings may serve to inform the continued reform of the criminal justice system, particularly laws relating to cannabis.

Identifying Practice Facilitation Delays and Barriers in Primary Care Quality Improvement

OBJECTIVE: Practice facilitation is an effective approach to implementing quality improvement (QI) interventions in practice-based research networks (PBRNs). Regular facilitator-practice interactions are necessary for successful facilitation, and missed engagements may hinder the process of practice improvement. This study employs a mixed-methods approach to characterize the dynamics of practice facilitation and examine facilitation delays and barriers, as well as their association with the achievement of QI program goals in a PBRN initiative. METHODS: This study presents a secondary analysis of data from 226 primary care practices that participated in the Healthy Hearts in the Heartland (H3) initiative. We performed a time series analysis to identify delays in facilitation activities, and then qualitatively analyzed practice facilitators' notes (n = 4358) to uncover facilitation barriers. Finally, we assessed the relationship between delays, barriers, and QI intervention completion. RESULTS: While most facilitation activities occurred at regular, practice-specific tempos, nearly all practices experienced at least 1 delay. Practices with more delays had lower QI intervention completion rates. Practices with more delays were more likely to have encountered barriers such as lack of time and staff, lack of staff engagement, technical issues, and staff turnover. DISCUSSION AND CONCLUSION: This study is the first to quantify irregular intervals between facilitation activities and demonstrate their negative association with project completion. The analytic method can be applied to identify at-risk practices and to accelerate timely interventions in future studies. Our delay detection algorithm could inform the design of a decision support system that notifies facilitators which practices may benefit from timely attention and resources.

Race and Ethnicity and Satisfaction With Communication in the Intensive Care Unit.

PURPOSE: Racial and ethnic minority patients receive poorer quality end-of-life (EoL) care compared with white patients. Differences in quality of communication (QOC) with clinicians may contribute to these disparities. We measured differences in satisfaction with communication in the intensive care unit (ICU) by race and ethnicity. MATERIALS AND METHODS: This is a cross-sectional survey of family members of patients in ICUs of an academic medical center serving a diverse urban population using The Family Satisfaction with the ICU (FS-ICU) and QOC scales. RESULTS: One hundred surveys were completed (18.8% white, non-Hispanic; 34.4% black, non-Hispanic; 31.3% Hispanic; 15.6% other race/ethnicity). Mean FS-ICU score was 84.2 (standard deviation [SD] 20.5) for white patients, 83.3 (SD 16.2) for black patients, 82.7 (SD 17.8) for Hispanic or Latino patients, and 80.9 (SD 18.8) for patients with other race/ethnicity (Kruskal-Wallis, P = .92). Differences remained insignificant when controlling for patient and respondent characteristics. The QOC scale was not scored due to nonresponse levels on questions about EoL communication. CONCLUSIONS: Uniformly high ratings may have been influenced by avoidance of EoL discussion. This study is inconclusive regarding whether QOC influences disparities in EoL care since quality of EoL communication was not captured.

Septic arthritis in a previously healthy man with pan-negative infectious and rheumatologic work-up.

Neisseria gonorrhoeae is the causative organism in 0.6%-1.2% of septic arthritis cases in North America and Europe, and classically presents as migratory polyarthralgias and tenosynovitis, with later development of septic oligoarthritis. In men, urine gonorrhoea nucleic amplification testing (NAAT) is the preferred diagnostic test, as its sensitivity surpasses that of joint and blood culture in disseminated infections. We present a case of a previously healthy man who presented with septic arthritis of the wrist. He denied any sexual activity in the previous year. Urine gonorrhoea NAAT and cultures were negative. However, N. gonorrhoeae was later identified via 16s PCR of the patient's synovial fluid, leading to a delayed diagnosis of gonococcal arthritis. In patients with septic arthritis, gonococcal infection should remain on the differential despite reported sexual history and negative urine NAAT. Clinicians should continue to follow cultures and provide antibiotic coverage until a causative organism is identified.

Barriers to receipt of novel oral oncolytics: A single-institution quality improvement investigation.

INTRODUCTION: Novel oral oncolytic agents have become the standard of care and first-line therapies for many malignancies. However, issues impacting access to these drugs are not well explored. As part of a quality improvement project in a large tertiary academic institution, we aim to identify potential barriers that delay treatment for patients who are prescribed novel oral oncolytics. METHODS: This was a retrospective review of adults who were newly prescribed a novel oral oncolytic for Food and Drug Administration-approved indications at a single tertiary care center. Patients were identified via electronic prescription data (e-Scribe). Demographics, insurance information, and prescription dates were extracted from the electronic medical record and pharmacy claims data. Statistical analyses were performed to determine whether time-to-receipt was associated with insurance category, pharmacy transfers, cost assistance, and drug prescribed. RESULTS: Of the 270 successfully filled prescriptions, the mean time-to-receipt was 7.3 ± 10.3 days (range: 0-109 days). Patients with Medicare experienced longer time-to-receipt (9.1 ± 13.1 days) compared to patients with commercial insurance (4.4 ± 3.3). Uninsured patients experienced the longest time-to-receipt (15.7 ± 7.8 days) overall. Pharmacy transfers and cost assistance programs were also significantly associated with longer time-to-receipt. Ten prescriptions remained unfilled 90 days after the study period and were considered abandoned. CONCLUSION: Insurance has a significant effect on the time-to-receipt of newly prescribed novel oral oncolytics. Pharmacy transfers and applying for cost assistance are also associated with longer wait times for patients. Our retrospective analysis identifies areas of improvement for future interventions to reduce wait times for patients receiving novel oral oncolytics.

Better With Ultrasound: Arterial Line Placement.

Arterial catheterization is frequently performed in ICUs to facilitate hemodynamic monitoring and frequent blood sampling. Overall, arterial catheterization has high success and low complication rates, but in patients who are critically ill, the incidence of failure is higher because of hypotension, peripheral edema, and obesity. Ultrasound guidance significantly increases the likelihood of successful cannulation and decreases complications compared with traditional landmark-based techniques. Multiple ultrasound techniques for radial and femoral arterial catheter insertion have been described; this paper presents an approach for incorporating these tools into bedside practice, including illustrative figures and narrated video presentations to demonstrate the techniques described.

Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery.

Heart failure is the leading cause of death in the western world and as such, there is a great need for new therapies. Heart failure has a variable presentation in patients and a complex etiology; however, it is fundamentally a condition that affects the mechanics of cardiac contraction, preventing the heart from generating sufficient cardiac output under normal operating pressures. One of the major issues hindering the development of new therapies has been difficulties in developing appropriate in vitro model systems of human heart failure that recapitulate the essential changes in cardiac mechanics seen in the disease. Recent advances in stem cell technologies, genetic engineering, and tissue engineering have the potential to revolutionize our ability to model and study heart failure in vitro. Here, we review how these technologies are being applied to develop personalized models of heart failure and discover novel therapeutics.

Basal Plate Myometrial Fibers and Hypertensive Disorders of Pregnancy: A Case-Control Study.

Introduction Basal plate myometrium (BPMYO), the pathological presence of myometrial fibers in the basal plate, is a common finding on pathological examination of the placenta, yet its clinical correlates are not well studied. As myometrial fibers are frequently located in proximity to poorly converted maternal spiral arteries, our objective was to determine whether BPMYO is associated with hypertensive disorders of pregnancy (HDP), a well-known clinical sequela of abnormal maternal artery remodeling. Methods This case-control study included women who delivered a live-born singleton gestation whose placentas were sent for pathological examination. Cases were women with HDP (gestational hypertension, preeclampsia, or HELLP syndrome) as defined by American College of Obstetricians and Gynecologists. Controls were women without HDP. Women with chronic hypertension were excluded. The primary outcome was the presence of BPMYO. Secondary outcomes included the pathologic stage of BPMYO and the incidence of pathologically defined accreta. Each outcome was compared between cases and controls in bivariable and multivariable analyses. Results Of the 306 women who met inclusion criteria, 230 (75%) had HDP. BPMYO was present in 99 (32%) of placentas. Compared to controls, cases were younger, had higher body mass index, and were more likely to have diabetes, be nulliparous, deliver preterm, and have had a prior cesarean. There were no differences in the incidence of BPMYO, stage of BPMYO, or incidence of pathologically defined accreta between cases and controls. These findings persisted after controlling for potential confounders. Conclusions Although BPMYO may be more common in the setting of abnormal placental vasculature, there is no significant association between BPMYO and HDP.

Construction of Comprehensive Dosage-Matching Core Histone Mutant Libraries for Saccharomyces cerevisiae.

Saccharomyces cerevisiae contains two genes for each core histone, which are presented as pairs under the control of a divergent promoter, i.e., HHT1-HHF1, HHT2-HHF2, HTA1-HTB1 and HTA2-HTB2HHT1-HHF1, and HHT2-HHF2 encode histone H3 and H4 with identical amino acid sequences but under the control of differently regulated promoters. Previous mutagenesis studies were carried out by deleting one pair and mutating the other one. Here, we present the design and construction of three additional libraries covering HTA1-HTB1, HTA2-HTB2, and HHT1-HHF1 respectively. Together with the previously described library of HHT2-HHF2 mutants, a systematic and complete collection of mutants for each of the eight core S. cerevisiae histone genes becomes available. Each designed mutant was incorporated into the genome, generating three more corresponding libraries of yeast strains. We demonstrated that, although, under normal growth conditions, strains with single-copy integrated histone genes lacked phenotypes, in some growth conditions, growth deficiencies were observed. Specifically, we showed that addition of a second copy of the mutant histone gene could rescue the lethality in some previously known mutants that cannot survive with a single copy. This resource enables systematic studies of function of each nucleosome residue in plasmid, single-copy, and double-copy integrated formats.

Engineering the ribosomal DNA in a megabase synthetic chromosome.

We designed and synthesized a 976,067-base pair linear chromosome, synXII, based on native chromosome XII in Saccharomyces cerevisiae SynXII was assembled using a two-step method, specified by successive megachunk integration and meiotic recombination-mediated assembly, producing a functional chromosome in S. cerevisiae. Minor growth defect "bugs" detected in synXII, caused by deletion of tRNA genes, were rescued by introducing an ectopic copy of a single tRNA gene. The ribosomal gene cluster (rDNA) on synXII was left intact during the assembly process and subsequently replaced by a modified rDNA unit used to regenerate rDNA at three distinct chromosomal locations. The signature sequences within rDNA, which can be used to determine species identity, were swapped to generate a Saccharomyces synXII strain that would be identified as Saccharomyces bayanus by standard DNA barcoding procedures.

Synthesis, debugging, and effects of synthetic chromosome consolidation: synVI and beyond.

We describe design, rapid assembly, and characterization of synthetic yeast Sc2.0 chromosome VI (synVI). A mitochondrial defect in the synVI strain mapped to synonymous coding changes within PRE4 (YFR050C), encoding an essential proteasome subunit; Sc2.0 coding changes reduced Pre4 protein accumulation by half. Completing Sc2.0 specifies consolidation of 16 synthetic chromosomes into a single strain. We investigated phenotypic, transcriptional, and proteomewide consequences of Sc2.0 chromosome consolidation in poly-synthetic strains. Another "bug" was discovered through proteomic analysis, associated with alteration of the HIS2 transcription start due to transfer RNA deletion and loxPsym site insertion. Despite extensive genetic alterations across 6% of the genome, no major global changes were detected in the poly-synthetic strain "omics" analyses. This work sets the stage for completion of a designer, synthetic eukaryotic genome.

Individual and Combined Associations of Genetic Variants in CYP3A4, CYP3A5, and SLCO1B1 With Simvastatin and Simvastatin Acid Plasma Concentrations.

Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.