Publications by authors named "Kerby Shedden"

130 Publications

Change in urban and non-urban pattern of ED use during the COVID-19 pandemic in 28 Michigan hospitals: an observational study.

BMJ Open 2021 02 5;11(2):e043024. Epub 2021 Feb 5.

Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Objective: To assess the trends in visits, overall and by age, to urban and non-urban emergency departments (EDs), and visits resulting in admission to hospital before and during the COVID-19 pandemic using a large regional database.

Setting: A large regional database of 28 EDs during the COVID-19 pandemic in Michigan, with an index case of 11 March 2020 and peak in the first week of April.

Participants: ED visits during the first 5 months of the calendar year were included and compared with the previous year. Facilities where these participants were seen were classified as urban or non-urban, with comparisons of total visits, COVID-like cases, paediatric and trauma.

Outcome Measures: Daily visits to EDs of patients presenting with COVID-like symptoms, trauma, age patterns and total cases, and stratified between urban and non-urban settings.

Results: There were 1 732 852 visits across the 2 years, 953 407 between study and comparison periods, and 457 130 visits defined as COVID-like (median age 44 years). Total ED visits decreased to 48% of the previous year, showing a delayed-inverse relationship with COVID-19. Trauma cases dropped but returned to the pre-COVID-19 rate by the end of May in Urban centres. Paediatric cases decreased to 20% of the previous year by the end of April. The oldest age groups showed the least change in ED visits in response to the pandemic.

Conclusions: This large US Midwestern state study describes a dramatic decrease in ED visits after the onset of the COVID-19 pandemic in Michigan, including stratification by varying ages and trauma, demonstrating the tangible impact of the COVID-19 pandemic on urban and non-urban EDs.
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http://dx.doi.org/10.1136/bmjopen-2020-043024DOI Listing
February 2021

Bariatric surgery and the risk of alcohol-related cirrhosis and alcohol misuse.

Liver Int 2021 Feb 2. Epub 2021 Feb 2.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.

Background & Aims: Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse.

Methods: Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender.

Results: A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P <.001; HR 0.43, P =.02) and alcohol misuse increased for Roux-en-Y and sleeve gastrectomy recipients (HR 1.86 and 1.35, P <.001, respectively). In those who had surgery before 2008, women had increased risk of AC and alcohol misuse compared to women without bariatric surgery (HR 2.1 [95% CI: 1.79-2.41] for AC; HR 1.98 [95% CI 1.93-2.04]).

Conclusions: Bariatric surgery is associated with a short-term decreased risk of AC but potential long-term increased risk of AC in women. Post-operative alcohol surveillance is necessary to reduce this risk.
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http://dx.doi.org/10.1111/liv.14805DOI Listing
February 2021

Quantitative morphometrics reveals glomerular changes in patients with infrequent segmentally sclerosed glomeruli.

J Clin Pathol 2021 Jan 11. Epub 2021 Jan 11.

Internal Medicine, University of Michigan Michigan Medicine, Ann Arbor, Michigan, USA

Aims: Detection of one segmentally sclerosed glomerulus (SSG) identifies patients with focal segmental glomerulosclerosis (FSGS) but rare SSGs may be missed in kidney biopsies. It is unknown whether alterations of unaffected glomeruli in patients with infrequent SSG can be detected by quantitative morphometrics.

Methods: We determined SSG frequency and obtained quantitative morphometrics in glomeruli without a pathologic phenotype in large kidney sections of non-involved kidney tissue from 137 patients undergoing total nephrectomy. We used multivariate modelling to identify morphometrics independently associated with increasing frequency of SSG and Receiver Operator Curve (ROC) analysis to determine the ability of quantitative morphometrics to identify patients with FSGS. We used the geometric distribution to estimate the sensitivity and specificity of a needle biopsy to identify patients with FSGS.

Results: In seventy-one patients (51.8%), at least one SSG was observed, and of those, 39 (54.9%) had an SSG lesion in less than 2% of all glomeruli (mean of 249 glomeruli per specimen). Increasing percent of SSG was independently associated with decreasing podocyte density and increasing mesangial index in multivariate modelling. For infrequent SSG lesions (<1% of glomeruli), kidney biopsy could miss FSGS diagnosis more than 74% of the time, and podocyte density had an area under the curve (AUC) of 0.77, and mesangial index, an AUC of 0.79 to identify patients with FSGS.

Conclusions: More than half of patients had FSGS, although 30% had infrequent SSG. Quantitative morphometrics in glomeruli without pathology, such as podocyte density and mesangial index, identified patients with infrequent SSG and may serve as clinical markers to identify patients with FSGS.
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http://dx.doi.org/10.1136/jclinpath-2020-207149DOI Listing
January 2021

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants.

PLoS One 2020 11;15(11):e0241441. Epub 2020 Nov 11.

Nottigham Digestive Diseases Centre and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom.

Objective: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method.

Material And Methods: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later.

Results: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence.

Conclusion: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes.

Clinical Trial: This trial was registered at ClinicalTrials.gov as NCT03191045.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657519PMC
December 2020

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

Nephrol Dial Transplant 2020 Oct 17. Epub 2020 Oct 17.

Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population.

Methods: Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort.

Results: Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 μg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts.

Conclusions: Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system.
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http://dx.doi.org/10.1093/ndt/gfaa208DOI Listing
October 2020

Critical Relevance of Stochastic Effects on Low-Bacterial-Biomass 16S rRNA Gene Analysis.

mBio 2020 06 9;11(3). Epub 2020 Jun 9.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

The bacterial microbiome of human body sites, previously considered sterile, remains highly controversial because it can be challenging to isolate signal from noise when low-biomass samples are being analyzed. We tested the hypothesis that stochastic sequencing noise, separable from reagent contamination, is generated during sequencing on the Illumina MiSeq platform when DNA input is below a critical threshold. We first purified DNA from serial dilutions of and from negative controls using three DNA purification kits, quantified input using droplet digital PCR, and then sequenced the 16S rRNA gene in four technical replicates. This process identified reproducible contaminant signal that was separable from an irreproducible stochastic noise, which occurred as bacterial biomass of samples decreased. This approach was then applied to authentic respiratory samples from healthy individuals ( = 22) that ranged from high to ultralow bacterial biomass. Using oral rinse, bronchoalveolar lavage (BAL) fluid, and exhaled breath condensate (EBC) samples and matched controls, we were able to demonstrate (i) that stochastic noise dominates sequencing in real-world low-bacterial-biomass samples that contain fewer than 10 copies of the 16S rRNA gene per sample, (ii) that critical examination of the community composition of technical replicates can be used to separate signal from noise, and (iii) that EBC is an irreproducible sampling modality for sampling the microbiome of the lower airways. We anticipate that these results combined with suggested methods for identifying and dealing with noisy communities will facilitate increased reproducibility while simultaneously permitting characterization of potentially important low-biomass communities. DNA contamination from external sources (reagents, environment, operator, etc.) has long been assumed to be the main cause of spurious signals that appear under low-bacterial-biomass conditions. Here, we demonstrate that contamination can be separated from another, random signal generated during low-biomass-sample sequencing. This stochastic noise is not reproduced between technical replicates; however, results for any one replicate taken alone could look like a microbial community different from the controls. Using this information, we investigated respiratory samples from healthy humans and determined the narrow range of bacterial biomass where samples transition from producing reproducible microbial sequences to ones dominated by noise. We present a rigorous approach to studies involving low-bacterial-biomass samples to detect this source of noise and provide a framework for deciding if a sample is likely to be dominated by noise. We anticipate that this work will facilitate increased reproducibility in the characterization of potentially important low-biomass communities.
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http://dx.doi.org/10.1128/mBio.00258-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373192PMC
June 2020

Toward a "treadmill test" for cognition: Improved prediction of general cognitive ability from the task activated brain.

Hum Brain Mapp 2020 Aug 4;41(12):3186-3197. Epub 2020 May 4.

Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA.

General cognitive ability (GCA) refers to a trait-like ability that contributes to performance across diverse cognitive tasks. Identifying brain-based markers of GCA has been a longstanding goal of cognitive and clinical neuroscience. Recently, predictive modeling methods have emerged that build whole-brain, distributed neural signatures for phenotypes of interest. In this study, we employ a predictive modeling approach to predict GCA based on fMRI task activation patterns during the N-back working memory task as well as six other tasks in the Human Connectome Project dataset (n = 967), encompassing 15 task contrasts in total. We found tasks are a highly effective basis for prediction of GCA: The 2-back versus 0-back contrast achieved a 0.50 correlation with GCA scores in 10-fold cross-validation, and 13 out of 15 task contrasts afforded statistically significant prediction of GCA. Additionally, we found that task contrasts that produce greater frontoparietal activation and default mode network deactivation-a brain activation pattern associated with executive processing and higher cognitive demand-are more effective in the prediction of GCA. These results suggest a picture analogous to treadmill testing for cardiac function: Placing the brain in a more cognitively demanding task state significantly improves brain-based prediction of GCA.
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http://dx.doi.org/10.1002/hbm.25007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375130PMC
August 2020

Designing and validating a low-cost real time locating system to continuously assess patient wait times.

J Biomed Inform 2020 06 24;106:103428. Epub 2020 Apr 24.

Department of Industrial and Operations Engineering, University of Michigan, Ann Arbor, MI, United States.

Objective: Outpatient clinics lack infrastructure to easily measure and understand patient wait times. Our objective was to design a low-cost, portable passive real time locating system within an outpatient clinic setting to measure patient wait times and patient-provider interactions.

Materials And Methods: Direct observation was used to determine workflow in an outpatient glaucoma clinic at the University of Michigan. We used off-the shelf, antenna-integrated ultra-high frequency (UHF) RFID readers (ThingMagic, Astra-Ex, Woburn, MA) and UHF re-useable passive RFID tags (Zebra Impinj Monza 4QT, Seattle, WA). We designed a custom RFID management application in the Java programming language that was equipped with 'live' device administration to collect time and location data from patients and providers. These hardware choices enabled low cost system installation. Hidden Markov Modeling (HMM) was used to smooth patient and provider location data. Location data were validated against direct observations and EHR evaluation.

Results: The HMM smoothed RFID system data accurately predicted patient location 80.6% of the time and provider location 79.1% of the time, compared to direct observation locations, an improvement over the raw RFID location data (65.0% and 77.9% accurate, respectively). Patient process time was on average 42.8 min (SD = 27.5) and wait time was 47.9 min (SD = 33.1). The installation and recurring capital costs of the system are approximately 10% of available commercially-supplied patient/provider tracking systems.

Discussion: Passive RFID time study systems can enable real-time localization of people in clinic, facilitating continuous capture of patient wait times and patient-provider interactions. The system must be tailored to the clinic to accurately reflect patient and provider movement.

Conclusions: Capturing wait time data continuously and passively can empower continuous clinical quality improvement initiatives to enhance the patient experience.
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http://dx.doi.org/10.1016/j.jbi.2020.103428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324007PMC
June 2020

A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP.

Pharmaceutics 2020 Jan 17;12(1). Epub 2020 Jan 17.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.

The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic data are desirable to judge the predicted outcomes. The aim of this study was to predict the systemic concentrations of ibuprofen after oral administration of an 800 mg immediate-release (IR) tablet to healthy subjects in fasted-state conditions. A mechanistic oral absorption model coupled with a two-compartmental pharmacokinetic (PK) model was built in Phoenix WinNonlinWinNonlin software and in the GastroPlus™ simulator. It should be noted that all simulations were performed in an ideal framework as we were in possession of a plethora of in vivo data (e.g., motility, pH, luminal and systemic concentrations) in order to evaluate and optimize these models. All this work refers to the fact that important, yet crucial, gastrointestinal (GI) variables should be integrated into biopredictive dissolution testing (low buffer capacity media, considering phosphate versus bicarbonate buffer, hydrodynamics) to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations can be performed and mechanistic insights can be gained from such simulations from current software, we need to move from correlations to predictions (IVIVC → IVIVP) and, moreover, we need to further determine the dynamics of the GI variables controlling the dosage form transit, disintegration, dissolution, absorption and metabolism along the human GI tract. Establishing the link between biopredictive in vitro dissolution testing and mechanistic oral absorption modeling (i.e., physiologically-based biopharmaceutics modeling (PBBM)) creates an opportunity to potentially request biowaivers in the near future for orally administered drug products, regardless of its classification according to the Biopharmaceutics Classification System (BCS).
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http://dx.doi.org/10.3390/pharmaceutics12010074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023481PMC
January 2020

Loss of Imprinting in Human Placentas Is Widespread, Coordinated, and Predicts Birth Phenotypes.

Mol Biol Evol 2020 02;37(2):429-441

Research Center for Group Dynamics, Institute for Social Research, University of Michigan, Ann Arbor, MI.

Genomic imprinting leads to mono-allelic expression of genes based on parent of origin. Therian mammals and angiosperms evolved this mechanism in nutritive tissues, the placenta, and endosperm, where maternal and paternal genomes are in conflict with respect to resource allocation. We used RNA-seq to analyze allelic bias in the expression of 91 known imprinted genes in term human placentas from a prospective cohort study in Mali. A large fraction of the imprinted exons (39%) deviated from mono-allelic expression. Loss of imprinting (LOI) occurred in genes with either maternal or paternal expression bias, albeit more frequently in the former. We characterized LOI using binomial generalized linear mixed models. Variation in LOI was predominantly at the gene as opposed to the exon level, consistent with a single promoter driving the expression of most exons in a gene. Some genes were less prone to LOI than others, particularly lncRNA genes were rarely expressed from the repressed allele. Further, some individuals had more LOI than others and, within a person, the expression bias of maternally and paternally imprinted genes was correlated. We hypothesize that trans-acting maternal effect genes mediate correlated LOI and provide the mother with an additional lever to control fetal growth by extending her influence to LOI of the paternally imprinted genes. Limited evidence exists to support associations between LOI and offspring phenotypes. We show that birth length and placental weight were associated with allelic bias, making this the first comprehensive report of an association between LOI and a birth phenotype.
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http://dx.doi.org/10.1093/molbev/msz226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993844PMC
February 2020

The respiratory microbiota: associations with influenza symptomatology and viral shedding.

Ann Epidemiol 2019 09 31;37:51-56.e6. Epub 2019 Jul 31.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor. Electronic address:

Purpose: Manifestations of infection and the degree of influenza virus vary. We hypothesized that the nose/throat microbiota modifies the duration of influenza symptoms and viral shedding. Exploring these relationships may help identify additional methods for reducing influenza severity and transmission.

Methods: Using a household transmission study in Nicaragua, we identified secondary cases of influenza virus infection, defined as contacts with detectable virus or a greater than 4-fold change in hemagglutinin inhibition antibody titer. We characterized the nose/throat microbiota of secondary cases before infection and explored whether the duration of symptoms and shedding differed by bacterial community characteristics.

Results: Among 124 secondary cases of influenza, higher bacterial community diversity before infection was associated with longer shedding duration (Shannon acceleration factor [AF]: 1.61, 95% confidence interval [CI]: 1.24, 2.10) and earlier time to infection (Shannon AF: 0.72, 95% CI: 0.53, 0.97; Chao1 AF: 0.992, 95% CI: 0.986, 0.998). Neisseria and multiple other oligotypes were significantly associated with symptom and shedding durations and time to infection.

Conclusions: The nose/throat microbiota before influenza virus infection was associated with influenza symptoms and shedding durations. Further studies are needed to determine if the nose/throat microbiota is a viable target for reducing influenza symptoms and transmission.
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http://dx.doi.org/10.1016/j.annepidem.2019.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755049PMC
September 2019

Measures of Cystic Fibrosis Airway Microbiota during Periods of Clinical Stability.

Ann Am Thorac Soc 2019 12;16(12):1534-1542

Department of Pediatrics, and.

Differences in cystic fibrosis (CF) airway microbiota between periods of clinical stability and exacerbation of respiratory symptoms have been investigated in efforts to better understand microbial triggers of CF exacerbations. Prior studies have often relied on a single sample or a limited number of samples to represent airway microbiota. However, the variability in airway microbiota during periods of clinical stability is not well known. To determine the temporal variability of measures of airway microbiota during periods of clinical stability, and to identify factors associated with this variability. Sputum samples ( = 527), obtained daily from six adults with CF during 10 periods of clinical stability, underwent sequencing of the V4 region of the bacterial 16S ribosomal RNA gene. The variability in airway microbiota among samples within each period of clinical stability was calculated as the average of the Bray-Curtis similarity measures of each sample to every other sample within the same period. Outlier samples were defined as samples outside 1.5 times the interquartile range within a baseline period with respect to the average Bray-Curtis similarity. Total bacterial load was measured with droplet digital polymerase chain reaction. The variation in Bray-Curtis similarity and total bacterial load among samples within the same baseline period was greater than the variation observed in technical replicate control samples. Overall, 6% of samples were identified as outliers. Within baseline periods, changes in bacterial community structure occurred coincident with changes in maintenance antibiotics ( < 0.05, analysis of molecular variance). Within subjects, bacterial community structure changed between baseline periods ( < 0.01, analysis of molecular variance). Sample-to-sample similarity within baseline periods was greater with fewer interval days between sampling. During periods of clinical stability, airway bacterial community structure and bacterial load vary among daily sputum samples from adults with CF. This day-to-day variation has bearing on study design and interpretation of results, particularly in analyses that rely on single samples to represent periods of interest (e.g., clinical stability vs. pulmonary exacerbation). These data also emphasize the importance of accounting for maintenance antibiotic use and granularity of sample collection in studies designed to assess the dynamics of CF airway microbiota relative to changes in clinical state.
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http://dx.doi.org/10.1513/AnnalsATS.201903-270OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956830PMC
December 2019

Distribution and outcomes of infection of Mycobacterium avium complex species in cystic fibrosis.

J Cyst Fibros 2020 03 6;19(2):232-235. Epub 2019 Aug 6.

Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Background: The majority of nontuberculous mycobacterial (NTM) pulmonary infections in people with cystic fibrosis (CF) are caused by Mycobacterium avium complex (MAC) species. Data on MAC species distribution and outcomes of infection in CF are lacking.

Methods: This was a single center, retrospective study. MAC isolates had species identification with MLSA of rpoB and the 16S23S ITS region. Clinical data were compared between species.

Results: Twenty-three people with CF and 57 MAC isolates were included. Infection with M. avium was the most common (65.2%). M. intracellulare was associated with higher rates of NTM disease, younger age, and steeper decline in lung function prior to infection.

Conclusions: We observed worse clinical outcomes in people with M. intracellulare infection relative to other MAC species. Further investigation of clinical outcomes of MAC infection among CF patients is warranted to better define the utility of species-level identification of MAC isolates in CF.
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http://dx.doi.org/10.1016/j.jcf.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002288PMC
March 2020

Multiple sclerosis relapse risk in the postoperative period: Effects of invasive surgery and anesthesia.

Mult Scler 2020 10 25;26(11):1437-1440. Epub 2019 Jun 25.

Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

Background: Postoperative multiple sclerosis (MS) relapses are a concern among patients and providers.

Objective: To determine whether MS relapse risk is higher postoperatively.

Methods: Data were extracted from medical records of MS patients undergoing surgery at a tertiary center (2000-2016). Conditional logistic regression estimated within-patient unadjusted and age-adjusted odds of postoperative versus preoperative relapse.

Results: Among 281 patients and 609 surgeries, 12 postoperative relapses were identified. The odds of postoperative versus preoperative relapse in unadjusted (odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.18-1.79;  = 0.33) or age-adjusted models (OR = 0.66, 95% CI = 0.20-2.16;  = 0.49) were not increased.

Conclusions: Surgery/anesthesia exposure did not increase postoperative relapse risk. These findings require confirmation in larger studies.
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http://dx.doi.org/10.1177/1352458519860304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930348PMC
October 2020

Inkjet-printed micro-calibration standards for ultraquantitative Raman spectral cytometry.

Analyst 2019 Jun 22;144(12):3790-3799. Epub 2019 May 22.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.

Herein we report the development of a cytometric analysis platform for measuring the contents of individual cells in absolute (picogram) scales; this study represents the first report of Raman-based quantitation of the absolute mass - or the total amount - of multiple endogenous biomolecules within single-cells. To enable ultraquantitative calibration, we engineered single-cell-sized micro-calibration standards of known composition by inkjet-printer deposition of biomolecular components in microarrays across the surface of silicon chips. We demonstrate clinical feasibility by characterizing the compositional phenotype of human skin fibroblast and porcine alveolar macrophage cell populations in the respective contexts of Niemann-Pick disease and drug-induced phospholipidosis: two types of lipid storage disorders. We envision this microanalytical platform as the foundation for many future biomedical applications, ranging from diagnostic assays to pathological analysis to advanced pharmaco/toxicokinetic research studies.
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http://dx.doi.org/10.1039/c9an00500eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711383PMC
June 2019

Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.

Alcohol Clin Exp Res 2019 02 22;43(2):334-341. Epub 2019 Jan 22.

Division of Gastroenterology and Hepatology , University of Michigan, Ann Arbor, Michigan.

Background: The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance.

Methods: We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment.

Results: A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either).

Conclusions: AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.
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http://dx.doi.org/10.1111/acer.13944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379081PMC
February 2019

Propagation Characteristics of Fasting Duodeno-Jejunal Contractions in Healthy Controls Measured by Clustered Closely-spaced Manometric Sensors.

J Neurogastroenterol Motil 2019 Jan;25(1):100-112

Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.

Background/aims: High-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings.

Methods: Ten fasting recordings were performed in 8 healthy controls using catheters with 3-4 gastrointestinal manometry clusters with 1-2 cm channel spacing. Migrating motor complex phase III characteristics were quantified. Spatial-temporal contour plots measured propagation direction and velocity of individual contractions. Coupling was defined by pressure peak continuity within clusters.

Results: Twenty-three phase III complexes (11 antral, 12 intestinal origin) with 157 (95% CI, 104-211) minute periodicities, 6.99 (6.25-7.74) minute durations, 10.92 (10.68-11.16) cycle/minute frequencies, 73.6 (67.7-79.5) mmHg maximal amplitudes, and 4.20 (3.18-5.22) cm/minute propagation velocities were recorded. Coupling of individual contractions was 39.1% (32.1-46.1); 63.0% (54.4-71.6) of contractions were antegrade and 32.8% (24.1-41.5) were retrograde. Individual phase III contractions propagated > 35 fold faster (2.48 cm/sec; 95% CI, 2.25-2.71) than complexes themselves. Phase III complexes beyond the proximal jejunum were longer in duration ( = 0.025) and had poorer contractile coupling ( = 0.025) than proximal complexes. Coupling was greater with 1 cm channel spacing vs 2 cm ( < 0.001).

Conclusions: Intestinal manometry using clustered closely-spaced pressure ports characterizes novel antegrade and retrograde propagation and coupling properties which degrade in more distal jejunal segments. Coupling is greater with more closely-spaced recordings. Applying similar methods to dysmotility syndromes will define the relevance of these methods.
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http://dx.doi.org/10.5056/jnm18112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326202PMC
January 2019

The respiratory microbiome and susceptibility to influenza virus infection.

PLoS One 2019 9;14(1):e0207898. Epub 2019 Jan 9.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.

Influenza is a major cause of morbidity and mortality worldwide. However, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- and middle-income countries. Supplementary methods of prevention should be explored to reduce the high burden of influenza. A potential target is the respiratory tract microbiome, complex microbial communities which envelop the respiratory epithelium and play an important role in shaping host immunity. Using a household transmission study, we examined whether the nose/throat microbiota was associated with influenza susceptibility among participants exposed to influenza virus in the household. Further, we characterized changes in the nose/throat microbiota to explore whether community stability was influenced by influenza virus infection. Using a generalized linear mixed effects model, we found a nasal/oropharyngeal community state type (CST) associated with decreased susceptibility to influenza. The CST was rare and transitory among young children but a prevalent and stable CST among adults. Using boosting and linear mixed effects models, we found associations between the nose/throat microbiota and influenza also existed at the taxa level, specifically with the relative abundance of Alloprevotella, Prevotella, and Bacteroides oligotypes. We found high rates of change between bacterial community states among both secondary cases and household contacts who were not infected during follow up. Further work is needed to separate the effect of influenza virus infection from the considerable short-term changes that occur even in the absence of virus. Lastly, age was strongly associated with susceptibility to influenza and the nose/throat bacterial community structure. Although additional studies are needed to determine causality, our results suggest the nose/throat microbiome may be a potential target for reducing the burden of influenza.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207898PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326417PMC
September 2019

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.

Mol Pharm 2018 12 12;15(12):5468-5478. Epub 2018 Nov 12.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109-1065 , United States.

Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma C variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00736DOI Listing
December 2018

An Expandable Mechanopharmaceutical Device (3): a Versatile Raman Spectral Cytometry Approach to Study the Drug Cargo Capacity of Individual Macrophages.

Pharm Res 2018 Nov 6;36(1). Epub 2018 Nov 6.

Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, 48109, USA.

Purpose: To improve cytometric phenotyping abilities and better understand cell populations with high interindividual variability, a novel Raman-based microanalysis was developed to characterize macrophages on the basis of chemical composition, specifically to measure and characterize intracellular drug distribution and phase separation in relation to endogenous cellular biomolecules.

Methods: The microanalysis was developed for the commercially-available WiTec alpha300R confocal Raman microscope. Alveolar macrophages were isolated and incubated in the presence of pharmaceutical compounds nilotinib, chloroquine, or etravirine. A Raman data processing algorithm was specifically developed to acquire the Raman signals emitted from single-cells and calculate the signal contributions from each of the major molecular components present in cell samples.

Results: Our methodology enabled analysis of the most abundant biochemicals present in typical eukaryotic cells and clearly identified "foamy" lipid-laden macrophages throughout cell populations, indicating feasibility for cellular lipid content analysis in the context of different diseases. Single-cell imaging revealed differences in intracellular distribution behavior for each drug; nilotinib underwent phase separation and self-aggregation while chloroquine and etravirine accumulated primarily via lipid partitioning.

Conclusions: This methodology establishes a versatile cytometric analysis of drug cargo loading in macrophages requiring small numbers of cells with foreseeable applications in toxicology, disease pathology, and drug discovery.
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http://dx.doi.org/10.1007/s11095-018-2540-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501567PMC
November 2018

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 1: Fasted State Conditions.

Mol Pharm 2018 12 12;15(12):5454-5467. Epub 2018 Nov 12.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109-1065 , United States.

The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract. Blood samples were taken to determine ibuprofen plasma levels. In this work, an in-depth statistical and pharmacokinetic analysis was performed to explain which underlying GI variables are determining the systemic concentrations of ibuprofen between (inter-) and within (intra-) subjects. In addition, the obtained plasma profiles were deconvoluted to link the fraction absorbed with the fraction dissolved. Multiple linear regressions were performed to explain and quantitatively express the impact of underlying GI physiology on systemic exposure of the drug (in terms of plasma C/AUC and plasma T). The exploratory analysis of the correlation between plasma C/AUC and the time to the first phase III contractions postdose (TMMC-III) explains ∼40% of the variability in plasma C for all fasted state subjects. We have experimentally shown that the in vivo intestinal dissolution of ibuprofen is dependent upon physiological variables like, in this case, pH and postdose phase III contractions. For the first time, this work presents a thorough statistical analysis explaining how the GI behavior of an ionized drug can explain the systemic exposure of the drug based on the individual profiles of participating subjects. This creates a scientifically based and rational framework that emphasizes the importance of including pH and motility in a predictive in vivo dissolution methodology to forecast the in vivo performance of a drug product. Moreover, as no extensive first-pass metabolism is considered for ibuprofen, this study demonstrates how intraluminal drug behavior is reflecting the systemic exposure of a drug.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00515DOI Listing
December 2018

Associations of snoring frequency and intensity in pregnancy with time-to-delivery.

Paediatr Perinat Epidemiol 2018 11 28;32(6):504-511. Epub 2018 Sep 28.

Department of Neurology, Sleep Disorders Center, University of Michigan, Ann Arbor, Michigan.

Background: Sleep-disordered breathing (SDB) is linked to adverse pregnancy outcomes. However, little is known about the association of SDB with timing of delivery. We examined the association of snoring frequency, a key SDB marker, and snoring intensity, a correlate of SDB severity, with time-to-delivery among a cohort of pregnant women.

Methods: In this prospective cohort study, 1483 third trimester pregnant women were recruited from the University of Michigan prenatal clinics. Women completed a questionnaire about their sleep, and demographic and pregnancy information was abstracted from medical charts. After exclusion of those with hypertension or diabetes, 954 women were classified into two groups by their snoring onset timing, chronic or pregnancy-onset. Within each of these groups, women were divided into four groups based on their snoring frequency and intensity: non-snorers; infrequent-quiet; frequent-quiet; or frequent-loud snorers. Cox proportional hazard regression models were used to investigate the association between snoring frequency and intensity and time-to-delivery, adjusting for maternal characteristics.

Results: Chronic snoring was reported by half of the pregnant women, and of those, 7% were frequent-loud snorers. Deliveries before 38 weeks' gestation are completed occurred among 25% of women with chronic, frequent-loud snoring. Compared with pre-pregnancy non-snorers, women with chronic frequent-loud snoring had an increased hazard ratio for delivery (adjusted hazard ratio 1.60, 95% confidence interval 1.04, 2.45).

Conclusions: Snoring frequency and intensity is associated with time-to-delivery in women absent of hypertension or diabetes. Frequent-loud snoring may have a clinical utility to identify otherwise low-risk women who are likely to deliver earlier.
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http://dx.doi.org/10.1111/ppe.12511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261672PMC
November 2018

Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project.

Int J Pharm 2018 Sep 23;548(1):120-127. Epub 2018 Jun 23.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA. Electronic address:

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.
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http://dx.doi.org/10.1016/j.ijpharm.2018.06.050DOI Listing
September 2018

Gastric emptying and intestinal appearance of nonabsorbable drugs phenol red and paromomycin in human subjects: A multi-compartment stomach approach.

Eur J Pharm Biopharm 2018 Aug 29;129:162-174. Epub 2018 May 29.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

The goal of this study was to create a mass transport model (MTM) model for gastric emptying and upper gastrointestinal (GI) appearance that can capture the in vivo concentration-time profiles of the nonabsorbable drug phenol red in solution in the stomach and upper small intestine by direct luminal measurement while simultaneously recording the contractile activity (motility) via manometry. We advanced from a one-compartmental design of the stomach to a much more appropriate, multi-compartmental 'mixing tank' gastric model that reflects drug distribution along the different regions of the stomach as a consequence of randomly dosing relative to the different contractile phases of the migrating motor complex (MMC). To capture the intraluminal phenol red concentrations in the different segments of the GI tract both in fasted and fed state conditions, it was essential to include a bypass flow compartment ('magenstrasse') to facilitate the transport of the phenol red solution directly to the duodenum (fasted state) or antrum (fed state). The fasted and fed state models were validated with external reference data from an independent aspiration study using another nonabsorbable marker (paromomycin). These results will be essential for the development and optimization of computational programs for GI simulation and absorption prediction, providing a realistic gastric physiologically-based pharmacokinetic (PBPK) model based on direct measurement of gastric concentrations of the drug in the stomach.
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http://dx.doi.org/10.1016/j.ejpb.2018.05.033DOI Listing
August 2018

Maternal Weight, Snoring, and Hypertension: Potential Pathways of Associations.

Am J Hypertens 2018 09;31(10):1133-1138

Sleep Disorders Center, Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

Background: Hypertensive disorders of pregnancy (HDP) are linked to excessive maternal weight and frequent snoring. However, pathways between maternal excessive weight, pregnancy-onset snoring, and HDP are only partially estimated. We examined and quantified the total and direct associations between excessive maternal weight and incident HDP and their indirect pathway through pregnancy-onset snoring.

Methods: Third trimester pregnant women enrolled from prenatal clinics of a large tertiary medical center. Sleep data were collected through a questionnaire. Demographic and pregnancy information and first trimester maternal weight were abstracted from medical charts. After exclusion of women with prepregnancy hypertension and/or chronic snoring, causal mediation analysis was used to estimate the total and direct association between maternal weight and incident HDP and their indirect association through pregnancy-onset snoring. The proportion of the mediated association through pregnancy-onset snoring from the total association of maternal weight and HDP was also quantified.

Results: After excluding those with chronic hypertension and/or snoring, the final sample included 1,333 pregnant women. In adjusted analysis, excessive maternal weight was directly associated with incident HDP; odds ratio (OR) = 1.87 (95% confidence interval (CI) 1.30, 2.70). Pregnancy-onset snoring significantly mediated the association between maternal weight and incident HDP; OR = 1.08 (95% CI 1.01, 1.17). The mediated pathway accounted for 15% of the total association between maternal weight and incident HDP.

Conclusions: Pregnancy-onset snoring mediates the association between maternal weight and incident HDP in women without prepregnancy snoring or hypertension. These findings demonstrate the relative contributions of excessive maternal weight and pregnancy-onset snoring to incident HDP.
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http://dx.doi.org/10.1093/ajh/hpy085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132116PMC
September 2018

The high burden of alcoholic cirrhosis in privately insured persons in the United States.

Hepatology 2018 09 20;68(3):872-882. Epub 2018 May 20.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.

Alcoholic cirrhosis (AC) is a major cause of liver-related morbidity and mortality in the United States. Rising rates of alcohol use disorders in the United States will likely result in more alcoholic liver disease. Our aim was to determine the prevalence, health care use, and costs of AC among privately insured persons in the United States. We collected data from persons aged 18-64 with AC (identified by codes from the International Classification of Diseases, Ninth and Tenth Revisions) enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009-2015). We determined yearly prevalence, weighted to the national employer-sponsored, privately insured population. Using competing risk analysis, we estimated event rates for portal hypertensive complications and estimated the association between AC and costs as well as admissions and readmissions. In 2015, 294,215 people had cirrhosis and 105,871 (36%) had AC. Mean age at AC diagnosis was 53.5 years, and 32% were women. Over the 7 years queried, estimated national cirrhosis prevalence rose from 0.19% to 0.27% (P < 0.001) and for AC from 0.07% to 0.10% (P < 0.001). Compared to non-AC, AC enrollees were significantly more likely to have portal hypertensive complications at diagnosis and higher yearly cirrhosis and alcohol-related admissions (25 excess cirrhosis admissions and 6.3 excess alcohol-related admissions per 100 enrollees) as well as all-cause readmissions. Per-person costs in the first year after diagnosis nearly doubled for AC versus non-AC persons (US$ 44,835 versus 23,319).

Conclusion: In a nationally representative cohort of privately insured persons, AC enrollees were disproportionately sicker at presentation, were admitted and readmitted more often, and incurred nearly double the per-person health care costs compared to those with non-AC. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29887DOI Listing
September 2018

Statistical Significance and the Dichotomization of Evidence: The Relevance of the for Statisticians.

J Am Stat Assoc 2017 30;112(519):902-904. Epub 2017 Oct 30.

Department of Statistics, University of Michigan.

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http://dx.doi.org/10.1080/01621459.2017.1311265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769160PMC
October 2017

Optimal group testing designs for estimating prevalence with uncertain testing errors.

J R Stat Soc Series B Stat Methodol 2017 Nov 19;79(5):1547-1563. Epub 2016 Dec 19.

University of California at Los Angeles, Los Angeles, U.S.A.

We construct optimal designs for group testing experiments where the goal is to estimate the prevalence of a trait using a test with uncertain sensitivity and specificity. Using optimal design theory for approximate designs, we show that the most efficient design for simultaneously estimating the prevalence, sensitivity, and specificity requires three different group sizes with equal frequencies. However, if estimating prevalence as accurately as possible is the only focus, the optimal strategy is to have three group sizes with unequal frequencies. Based on a Chlamydia study in the United States, we compare performances of competing designs and provide insights into how the unknown sensitivity and specificity of the test affect the performance of the prevalence estimator. We demonstrate that the proposed locally - and -optimal designs have high efficiencies even when the prespecified values of the parameters are moderately misspecified.
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http://dx.doi.org/10.1111/rssb.12223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726813PMC
November 2017

Clinical predictors of the medical interventions provided to patients with low back pain in the emergency department.

J Back Musculoskelet Rehabil 2018 Feb;31(1):197-204

Department of Physical Medicine and Rehabilitation, University of Michigan Health System, Ann Arbor, MI, USA.

Background: Low back pain is a common complaint in emergency departments (ED), where deviations from standard of care have been noted.

Objective: To relate the ordering of advanced imaging and opioid prescriptions with the presentation of low back pain in ED.

Methods: Six hundred adults with low back pain from three centers were prospectively analyzed for history, examination, diagnosis, and the ordering of tests and treatments.

Results: Of 559 cases the onset of pain was less than one week in 79.2%; however, most had prior low back pain, 63.5% having warning signs of a potential serious condition, and 83.9% had psychosocial risk factors. Computer tomography (CT) or magnetic resonance imaging (MRI) were ordered in 16.6%, opioids were prescribed in 52.6%, and hospital admission in 4.5%. A one-year follow-up of 158 patients found 40.8% received subsequent spine care and 5.1% had a medically serious condition. Caucasian race, age 50 years or older, warning signs, and radicular findings were associated with advanced imaging. Severe pain and psychosocial factors were associated with opioid prescribing.

Conclusions: Most patients present to the ED with acute exacerbations of chronic low back pain. Risk factors for a serious condition are common, but rarely do they develop. Racial disparities and psychosocial factors had concerning relationships with clinical decision-making.
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http://dx.doi.org/10.3233/BMR-170806DOI Listing
February 2018

Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs.

Mol Pharm 2017 12 4;14(12):4281-4294. Epub 2017 Aug 4.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00426DOI Listing
December 2017