THRB Gene Mosaicism Confirmed by Next-Generation Sequencing in a Clinically Symptomatic Infant.

A 4-day-old infant was admitted for neonatal jaundice. He had persistent tachycardia and tachypnea. Initial workup showed a serum free T4 of 75.6 pmol/L (5.87 ng/dL) (reference range: 11.5-28.3 pmol/L; 0.89-2.20 ng/dL) and a nonsuppressed TSH 3.76 mIU/L (reference range: 0.72-11.0 mIU/L). A TRH stimulation test showed an exaggerated TSH response with a peak of 92.1 mIU/L at 30 minutes after TRH injection, which suggested the diagnosis of resistance to thyroid hormone ß syndrome. Sanger sequencing showed a questionable pathogenic variant in the THRB gene with low signal amplitude. Restriction fragment length polymorphism was consistent with its presence. The variant was originally reported as heterozygous. Next-generation sequencing was performed on blood and buccal swab samples of the patient and his parents, which confirmed this de novo mosaic variant NM_000461.5:c.1352T > C p.(Phe451Ser) in the patient but not in his asymptomatic parents. As it was in a mosaic state, only the offspring, but not other first-degree relatives, of the patient would have the risk of inheriting that variant.

Population Pharmacokinetic Modeling of Cotadutide: A Dual Agonist Peptide of Glucagon-Like Peptide and Glucagon Receptors Administered to Participants with Type II Diabetes Mellitus, Chronic Kidney Disease, Obesity and Non-Alcoholic Steatohepatitis.

BACKGROUND: Cotadutide is a dual glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor agonist peptide. The objective of this analysis was to develop a population pharmacokinetic (popPK) model of cotadutide, and to identify any potential effect on the PK from intrinsic and extrinsic covariates. METHODS: The popPK analysis utilized a non-linear mixed-effects modeling approach using the data from 10 clinical studies in different participant categories following once-daily subcutaneous dose administration ranging from 20 to 600 µg. Additionally, the covariates affecting cotadutide exposure were quantified, and the model performance was evaluated through the prediction-corrected visual predictive checks. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the data as confirmed via visual predictive check plots and parameter plausibility. The mean values for cotadutide apparent clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (Ka), and half-life were 1.05 L/h, 20.0 L, 0.38 h-1, and 13.3 hours, respectively. Covariate modeling identified body weight, alanine transaminase, albumin, anti-drug antibody (ADA) titer values, formulation strength and injection device, and participant categories as significant covariates on PK parameters, where ADAs have been identified to decrease cotadutide clearance. The model demonstrated that a 150-kg participant was estimated to have 30% lower for both AUC and Cmax and a 66 kg participant was estimated to have 35% higher for both AUC and Cmax relative to a reference individual with a median weight of 96 kg. CONCLUSIONS: A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure-response relationships for cotadutide clinical data.

Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse.

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells.

Cannabis, the most consumed illicit psychoactive drug in the world, is increasingly used by pregnant women. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is lacking. Here, we leverage a stepwise in vitro differentiation system that captures the early embryonic developmental cascade to investigate the impact of exposure to the most abundant phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). We demonstrate that Δ9-THC increases the proliferation of naive mouse embryonic stem cells (ESCs) but not of their primed counterpart. Surprisingly, this increased proliferation, dependent on the CB1 receptor binding, is only associated with moderate transcriptomic changes. Instead, Δ9-THC capitalizes on ESCs' metabolic bivalence by increasing their glycolytic rates and anabolic capabilities. A memory of this metabolic rewiring is retained throughout differentiation to Primordial Germ Cell-Like Cells in the absence of direct exposure and is associated with an alteration of their transcriptional profile. These results represent the first in-depth molecular characterization of the impact of Δ9-THC exposure on early stages of germline development.

Cannabis is the most widely used illicit drug in the world, with 4.3% of the global adult population estimated to have used it in the previous year. In particular, the consumption of cannabis by pregnant women has almost doubled in recent years and is particularly increased in those aged under 18. The main psychoactive component in cannabis, known as Δ9-THC, activates cannabinoid receptors in the brain, including the receptor CB1. Recent research has shown that CB1 is also active in the mouse embryo, but it remained unclear if Δ9-THC could also affect the development of an embryo. To better understand the potential effects of this exposure, scientists can study stem cells that develop into germ cells (which go on to form egg and sperm), which have been grown in the laboratory. Emerging research has shown that germ cells are particularly sensitive to changes in their environment and due to their role in reproduction, changes can have knock-on effects for embryos. Verdikt et al. studied the effects of Δ9-THC on mouse embryonic stem cells, finding that it caused them to multiply more quickly. This was dependent on both Δ9-THC binding to the CB1 receptor that causes the psychoactive effects of cannabis in the brain and an increased energy metabolism. Blocking an important metabolic pathway called glycolysis caused the Δ9-THC-treated cells to return to a normal multiplication rate. The exposed stem cells also gave rise to germ cells with abnormal metabolism and altered gene expression, suggesting that this metabolic 'memory' can be passed on to cells in the next developmental stage. Overall, the findings indicate that exposure to Δ9-THC alters the metabolism in early embryonic cells of mice and that these effects can be lasting. This emphasises the need for further research on the impact of cannabis use during pregnancy, particularly as the drug's availability is expected to increase significantly with changes in regulation. The work also contributes to research highlighting the inheritance of metabolism.

Gene Regulatory Networks in Coronary Artery Disease.

PURPOSE OF REVIEW: Coronary artery disease is a complex disorder and the leading cause of mortality worldwide. As technologies for the generation of high-throughput multiomics data have advanced, gene regulatory network modeling has become an increasingly powerful tool in understanding coronary artery disease. This review summarizes recent and novel gene regulatory network tools for bulk tissue and single cell data, existing databases for network construction, and applications of gene regulatory networks in coronary artery disease. RECENT FINDINGS: New gene regulatory network tools can integrate multiomics data to elucidate complex disease mechanisms at unprecedented cellular and spatial resolutions. At the same time, updates to coronary artery disease expression data in existing databases have enabled researchers to build gene regulatory networks to study novel disease mechanisms. Gene regulatory networks have proven extremely useful in understanding CAD heritability beyond what is explained by GWAS loci and in identifying mechanisms and key driver genes underlying disease onset and progression. Gene regulatory networks can holistically and comprehensively address the complex nature of coronary artery disease. In this review, we discuss key algorithmic approaches to construct gene regulatory networks and highlight state-of-the-art methods that model specific modes of gene regulation. We also explore recent applications of these tools in coronary artery disease patient data repositories to understand disease heritability and shared and distinct disease mechanisms and key driver genes across tissues, between sexes, and between species.

Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse.

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

Simultaneous quantitation of urine aldosterone and tetrahydroaldosterone in healthy Chinese subjects using a validated LC-MS/MS method.

Aldosterone (ALD) is excreted in urine mainly as glucuronide conjugates of ALD and tetrahydroaldosterone. Measuring these urinary metabolites might be an alternative screening test to plasma ALD for primary aldosteronism. We report a validated LC-MS/MS method to measure both analytes simultaneously. Urine samples underwent enzymatic hydrolysis to release the analytes from their glucuronide conjugates followed by organic solvent extraction and LC-MS/MS. The analytical performance of this method was evaluated. The within-batch and between-batch coefficients of variation for urine ALD and urine THA were all ≤5.2 and ≤3.7%. The lower limit of quantification was 0.5 nmol/L, and the linearity was up to at least 2770 nmol/L for both analytes. No significant matrix interference and carryover were observed. Both analytes in urine were stable for at least 48 h at 10°C and at least 18 months at -80°C. Local reference intervals were established from 126 healthy normotensive Chinese subjects (53% women, age: 20-65 years). Reference intervals for urine ALD and tetrahydroaldosterone were 2-38 and 9-139 nmol/day, respectively. This validated method can be applied to screening and diagnosing primary aldosteronism.

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells.

Cannabis, the most consumed illicit psychoactive drug in the world, is increasingly used by pregnant women. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is lacking. Here, we leverage a stepwise in vitro differentiation system that captures early embryonic developmental cascade to investigate the impact of exposure to the most abundant phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). We demonstrate that Δ9-THC increases the proliferation of naïve mouse embryonic stem cells (ESCs) but not of their primed counterpart. Surprisingly, this increased proliferation, dependent on the CB1 receptor binding, is only associated with moderate transcriptomic changes. Instead, Δ9-THC capitalizes on ESCs' metabolic bivalence by increasing their glycolytic rates and anabolic capabilities. A memory of this metabolic rewiring is retained throughout differentiation to Primordial Germ Cell-Like Cells in the absence of direct exposure and is associated with an alteration of their transcriptional profile. These results represent the first in-depth molecular characterization of the impact of Δ9-THC exposure on early stages of germline development.

GCK-MODY in pregnancy: A pregnant woman with diabetes and a small-for-gestational-age fetus.

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is often misdiagnosed as other forms of diabetes. A 42-year-old pregnant lady with pre-existing diabetes was treated with insulin during first trimester. Fetal growth restriction was noted since mid-second trimester. Genetic testing suggested the diagnosis of GCK-MODY.

Chinese normotensive and essential hypertensive reference intervals for plasma aldosterone and renin activity by liquid chromatography-tandem mass spectrometry.

OBJECTIVES: The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure. Plasma renin activities (PRA) and plasma aldosterone concentrations (PAC) are biomarkers related to RAAS. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based measurements for PRA and PAC have become popular. Method-specific reference intervals (RIs) are required. METHODS: Routine PRA and PAC services in a Hong Kong teaching hospital were based on LC-MS/MS methods. PRA and PAC RIs were developed for normotensive subjects and essential hypertensive (EH) patients. Healthy volunteers were recruited to establish normotensive RIs. PRA and PAC results of hypertensive patients with urine aldosterone tests for primary aldosteronism (PA) screening were retrieved from the laboratory information system. Patients without PA were included. Patients with secondary hypertension and patients on medications affecting the RAAS were excluded. The central 95% RIs were established based on the recommendations of the Clinical and Laboratory Standards Institute guideline C28-A3. RESULTS: PRA and PAC of 170 normotensive volunteers and 362 EH patients were analysed. There was no sex-specific difference in PRA and PAC for normotensive and EH reference subjects. Differences for PRA and PAC were noted between normotensive subjects aged below 45 and their older counterparts. However, such a difference was only identified for PRA but not PAC in EH patients. Age-specific RIs were established accordingly. CONCLUSIONS: This study presented age-specific LC-MS/MS RIs of PRA and PAC for both normotensive and EH populations for local Chinese in Hong Kong.

Negative Pressure Pulmonary Edema Related to Laryngospasm and Upper Airway Obstruction in a Patient With Treacher Collins Syndrome.

Laryngospasm is an uncommon complication of anesthesia in adults but more common in pediatric anesthesia, which could present similarly to supraglottic upper airway obstruction. The management of such airway complications is even more difficult in patients with difficult mask ventilation and intubation. Our case illustrated the management of laryngospasm and negative pressure pulmonary edema in a patient with Treacher Collins syndrome. A literature search revealed few previous similar reports. We demonstrated an algorithm to differentiate between the true laryngospasm from the supraglottic upper airway obstruction, the management of laryngospasm in patients with difficult airways, and the recognition and management of negative pressure pulmonary edema as a complication of laryngospasm.

A Case Report of a Successful Percutaneous Trial and Surgical Placement of a Spinal Cord Stimulator in a Patient With Severe Thoracolumbar Scoliosis.

Spinal cord stimulation has been demonstrated as a therapeutic option for patients with persistent lumbar radicular pain secondary to failed back surgery syndrome. This case report demonstrates a successful percutaneous spinal cord stimulator (SCS) trial followed by surgical placement of a permanent SCS to treat lumbar radicular pain and axial low back pain in a patient with severe thoracolumbar scoliosis status after laminectomy and spinal fusion surgery. Currently, there is a paucity of literature on this topic.

Enhanced Bioavailability by Orally Administered Sirolimus Nanocrystals.

Nanocrystallization can improve the dissolvability of insoluble medicines in water, making them easier to administer. In the present study, sirolimus (SRL) was nanocrystallized, and the transport mechanism and efficacy of both formulations were compared in vitro and in vivo. The results showed that the 120 nm sirolimus nanocrystals (SRL NCs) had better ability to pass through the Caco-2 cell monolayer. SRL NCs were uptaken by Caco-2 cells via multiple endocytosis pathways, and the endoplasmic reticulum (ER), Golgi apparatus, and microtubules were identified as vital organelles for expelling SRL NCs out of the cells. SRL NCs decreased CD4+/CD8+ in normal mice after 14 days of daily gavage administration. Furthermore, SRL NCs enhanced the immune tolerance in an ovalbumin (OVA)-sensitized mouse model. SRL NCs significantly increased the percentage of Tregs (CD25+Foxp3+) among CD4+T cells. Collectively, these findings demonstrate that nanocrystallization of SRL enhances oral bioavailability, transcytosis, and prolongs drug residence time in vivo, while also enhancing SRL efficacy.

Can the same controlled attenuation parameter cut-offs be used for M and XL probes for diagnosing hepatic steatosis?

BACKGROUND AND AIM: There are limited studies on controlled attenuation parameter (CAP) using Fibroscan XL probe for the diagnosis of hepatic steatosis grade. The aim of this study was to determine whether previously defined optimal cut-offs for CAP using the M probe could be applied for the XL probe. METHODS: Adult patients with chronic liver disease who had a liver biopsy and examination with both the M and XL probes were included. Previously defined optimal cut-offs for CAP using the M probe were used for the diagnosis of steatosis grades ≥S1, ≥S2, and S3 (248, 268, and 280 dB/m, respectively). RESULTS: Data for 180 patients were analyzed (mean age 53.7 ± 10.8 years; central obesity 84.5%; non-alcoholic fatty liver disease 86.7%). The distribution of steatosis grades was S0, 9.4%; S1, 28.3%; S2, 43.9%, and S3, 18.3%. The sensitivity, specificity, positive predictive value, and negative predictive value of CAP using the M/XL probe for the diagnosis of steatosis grade ≥S1 was 93.9%/93.3%, 58.8%/58.8%, 95.6%/95.6%, and 50.0%/47.6%, respectively. These values were 94.6%/94.6%, 41.2%/44.1%, 72.6%/73.6%, and 82.4%/83.3%, respectively, for ≥S2, and 87.9%/87.9%, 27.2%/27.9%, 21.3%/21.5%, and 90.9%/91.1%, respectively, for S3. CONCLUSION: The same cut-off values for CAP may be used for the M and XL probes for the diagnosis of hepatic steatosis grade.

Ability of postoperative delirium to predict intermediate-term postoperative cognitive function in patients undergoing elective surgery at an academic medical centre: protocol for a prospective cohort study.

INTRODUCTION: Postoperative delirium (POD) is a common complication in elderly patients, characterised by a fluctuating course of altered consciousness, disordered thinking and inattention. Preliminary research has linked POD with persistent cognitive impairment and decreased quality of life. However, these findings maybe confounded by patient comorbidities, postoperative complications and frailty. Our objective is to determine whether POD is an independent risk factor for persistent impairments in attention and executive function after elective surgery. Our central hypothesis is that patients with POD are more likely to have declines in cognition and quality of life 1 year after surgery compared with patients without POD. We aim to clarify whether these associations are independent of potentially confounding factors. We will also explore the association between POD and incident dementia. METHODS AND ANALYSIS: This study will recruit 200 patients from the ongoing Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study. Patients who live ≤45 miles from the study centre or have a planned visit to the centre 10-16 months postoperatively will be eligible. Patients with POD, measured by the Confusion Assessment Method, will be compared with patients without delirium. The primary outcome of cognitive function and secondary outcomes of quality of life and incident dementia will be compared between cohorts. Cognition will be measured by Trails A and B and Stroop Color and Word Test, quality of life with Veteran's RAND 12-item Health Survey and incident dementia with the Short Blessed Test. Multivariable regression analyses and a Cox proportional hazards analysis will be performed. All results will be reported with 95% CIs and α=0.05. ETHICS AND DISSEMINATION: The study has been approved by the Washington University in St. Louis Institutional Review Board (IRB no 201601099). Plans for dissemination include scientific publications and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: NCT02241655.

Metabolic syndrome increases cardiovascular events but not hepatic events and death in patients with chronic hepatitis B.

Metabolic syndrome is an independent risk factor of liver cirrhosis in chronic hepatitis B (CHB). Whether metabolic syndrome affects the long-term prognosis of CHB patients in terms of hepatic events, cardiovascular events, and death remains unknown. We aimed to determine the incidences of hepatic events, cardiovascular events, and death in CHB patients with or without metabolic syndrome. From 2006 to 2008, we prospectively recruited 1,466 CHB patients for liver stiffness measurement (LSM) with transient elastography together with detailed metabolic profiling as baseline assessment. Patients were prospectively followed for any clinical events. The impact of LSM and metabolic syndrome on hepatic events, cardiovascular events, and death was evaluated. At baseline visit, the mean age was 46 ± 12 years, LSM value was 8.4 ± 6.3 kPa, and 188 patients (12.8%) had metabolic syndrome. At a mean follow-up of 88 ± 20 months, 93 and 44 patients developed hepatic and cardiovascular events, respectively; 70 patients died. Patients with baseline LSM >8.0 kPa had higher cumulative probability of hepatic events than those with LSM ≤8.0kPa at 8 years (12.3% versus 3.1%, P < 0.001). Patients with metabolic syndrome had higher cumulative probability of cardiovascular events than those without (8.0% versus 2.1%, P < 0.001). High LSM had no impact on cardiovascular events; neither did metabolic syndrome on hepatic events. LSM >8.0 kPa but not metabolic syndrome was an independent risk factor of death, with adjusted hazard ratios of 1.9 (95% confidence interval 1.1-3.2, P = 0.023) and 1.3 (95% confidence interval 0.8-2.4, P = 0.310), respectively. CONCLUSIONS: Metabolic syndrome increased the risk of cardiovascular events but not hepatic events and death; LSM was the important risk factor of hepatic events and death in CHB patients. (Hepatology 2016;64:1507-1517).

Next stop for the CRISPR revolution: RNA-guided epigenetic regulators.

Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific DNA targeting. The CRISPR-Cas system is naturally equipped for targeted DNA cutting through its native nuclease activity. As such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species. However, the biological code of life is not only encoded in genetics but also in epigenetics as well. While genetic sequence editing is a powerful ability, we must also be able to edit and regulate transcriptional and epigenetic code. Taking inspiration from work on earlier sequence-specific targeting technologies such as zinc fingers (ZFs) and transcription activator-like effectors (TALEs), researchers quickly expanded the CRISPR-Cas toolbox to include transcriptional activation, repression, and epigenetic modification. In this review, we highlight advances that extend the CRISPR-Cas toolkit for transcriptional and epigenetic regulation, as well as best practice guidelines for these tools, and a perspective on future applications.

Indoor air quality survey of nail salons in Boston.

Employees in nail salons, largely Vietnamese immigrant women in Boston, are exposed to a range of volatile organic chemicals from the products used in salons, including solvents, glues and polishes. Some of these chemicals have the potential to cause short and long-term adverse health effects. Only limited research has been performed on assessing occupational exposures. This project aimed to characterize total volatile organic compound (TVOC) and PM2.5 concentrations in nail salons as a function of ventilation, building characteristics, customer and employee occupancy, and type of services being performed. Students conducted sampling in 21 salons in Boston, MA from September to December, 2011. Study visits included: indoor environmental quality measurements (TVOCs, PM2.5 and carbon dioxide), site observations, and an interview. CO2 levels in 15 of 21 salons exceeded 800 ppm, suggesting that these salons may have insufficient ventilation. Higher TVOC and PM2.5 levels were found in salons with less ventilation (as estimated using CO2 concentrations). Contrary to our a priori hypothesis, average levels of TVOCs, CO2 and PM2.5 were consistent throughout salons, indicating that exposures may not be restricted to areas in the salon where work is being performed (e.g., at the manicure table). Higher TVOC concentrations were observed when tasks were being performed, yet were not dependent upon the number of tasks being performed. Improving ventilation conditions in salons to meet minimum outdoor air delivery requirements can reduce exposures to TVOCs.