Publications by authors named "David Schneider"

654 Publications

Increased Smoking Cessation among Veterans with Large Decreases in Posttraumatic Stress Disorder Severity.

Nicotine Tob Res 2021 Sep 3. Epub 2021 Sep 3.

Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis MO. 63104, United States.

Background: Improvement in posttraumatic stress disorder (PTSD) is associated with better health behavior such as better medication adherence and greater use of nutrition and weight loss programs. However, it is not known if reducing PTSD severity is associated with smoking cessation, a poor health behavior common in patients with PTSD.

Methods: Veterans Health Affairs (VHA) medical record data (2008 to 2015) were used to identify patients with PTSD diagnosed in specialty care. Clinically meaningful PTSD improvement, was defined as ≥20 point PTSD Checklist (PCL) decrease from the first PCL ≥ 50 and the last available PCL within 12 months and at least 8 weeks later. The association between clinically meaningful PTSD improvement and smoking cessation within 2-years after baseline among 449 smokers was estimated in Cox proportional hazard models. Entropy balancing controlled for confounding.

Results: On average, patients were 39.4 (SD=12.9) years of age, 86.6% were male and 71.5% were white. We observed clinically meaningful PTSD improvement in 19.8% of participants. Overall, 19.4% quit smoking in year 1 and 16.6% in year 2. More patients with vs. without clinically meaningful PTSD improvement stopped smoking (n=36, cumulative incidence=40.5% vs. 111, cumulative incidence=30.8%; respectively). After controlling for confounding, patients with vs. without clinically meaningful PTSD improvement were more likely to stop smoking within 2-years (HR=1.57; 95%CI:1.04-2.36).

Conclusions: Patients with clinically meaningful PTSD improvement were significantly more likely to stop smoking. Further research should determine if targeted interventions are needed or whether improvement in PTSD symptoms is sufficient to enable smoking cessation.

Implications: Patients with PTSD are more likely to develop chronic health conditions such as heart disease and diabetes. Poor health behaviors, including smoking, partly explain the risk for chronic disease in this patient population. Our results demonstrate that clinically meaningful PTSD improvement is followed by greater likelihood of smoking cessation. Thus, PTSD treatment may enable healthier behaviors and reduce risk for smoking related disease.
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http://dx.doi.org/10.1093/ntr/ntab179DOI Listing
September 2021

False Negative Rates in Benign Thyroid Nodule Diagnosis: Machine Learning for Detecting Malignancy.

J Surg Res 2021 Aug 28;268:562-569. Epub 2021 Aug 28.

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Background: Thyroid nodules are common; up to 67% of adults will show nodules on high-quality ultrasound, and 95% of these nodules are benign. FNA cytology is a crucial step in determining the risk of malignancy, and a false negative diagnosis at this stage delays cancer treatment. The purpose of this study is to develop a predictive model using machine learning which can identify false negative FNA results based on less-invasive clinical data.

Materials And Methods: We conducted a retrospective medical record review at one academic and one community center. Inclusion criteria were thyroid nodules evaluated by ultrasound and FNA with a Bethesda II (benign) result or malignancy detected on pathology or FNA. Linear, non-linear, and ensemble models were generated with scikit-learn using 10-fold cross validation with repetition and compared with AUROC. The classification task was the prediction of malignancy using information acquired from less-invasive ultrasound and FNA.

Results: A total of 604 subjects met inclusion criteria; 38 were diagnosed with malignancy. Of all algorithms tested, a Random Forest method achieved the best AUROC (0.64) in separating benign and malignant nodules, though the improvement over other tested algorithms was not statistically significant.

Conclusions: A Random Forest model performed better than random chance using readily available data obtained via standard evaluation of thyroid nodules. The diagnostic probability threshold of this model can be varied to minimize false positives at the cost of increasing the number of false negatives. Future studies will prospectively evaluate the model's performance.
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http://dx.doi.org/10.1016/j.jss.2021.06.076DOI Listing
August 2021

Assessing the Toxicity of 17α-Ethinylestradiol in Rainbow Trout Using a 4-Day Transcriptomics Benchmark Dose (BMD) Embryo Assay.

Environ Sci Technol 2021 08 22;55(15):10608-10618. Epub 2021 Jul 22.

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B3.

There is an urgent demand for more efficient and ethical approaches in ecological risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established an embryo benchmark dose (BMD) assay for rainbow trout (RBT; ) to derive transcriptomic points-of-departure (tPODs) as an alternative to live-animal tests. Embryos were exposed to graded concentrations of EE2 (measured: 0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects. In contrast, transcriptomics revealed responses that were in agreement with apical effects, including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L, the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the 10th percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive over-represented pathway, respectively) were within the same order of magnitude as empirically derived apical PODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving tPODs that are protective of chronic effects of EE2.
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http://dx.doi.org/10.1021/acs.est.1c02401DOI Listing
August 2021

Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment.

Cell Chem Biol 2021 Jun 12. Epub 2021 Jun 12.

GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain. Electronic address:

Guanine quadruplexes (G4s) are non-canonical nucleic acid structures commonly found in regulatory genomic regions. G4 targeting has emerged as a therapeutic approach in cancer. We have screened naphthalene-diimides (NDIs), a class of G4 ligands, in a cellular model of colorectal cancer (CRC). Here, we identify the leading compound T5 with a potent and selective inhibition of cell growth by high-affinity binding to G4s in ribosomal DNA, impairing RNA polymerase I (Pol I) elongation. Consequently, T5 induces a rapid inhibition of Pol I transcription, nucleolus disruption, proteasome-dependent Pol I catalytic subunit A degradation and autophagy. Moreover, we attribute the higher selectivity of carbohydrate-conjugated T5 for tumoral cells to its preferential uptake through the overexpressed glucose transporter 1. Finally, we succinctly demonstrate that T5 could be explored as a therapeutic agent in a patient cohort with CRC. Therefore, we report a mode of action for these NDIs involving ribosomal G4 targeting.
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http://dx.doi.org/10.1016/j.chembiol.2021.05.021DOI Listing
June 2021

Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrP.

Genet Sel Evol 2021 Jun 19;53(1):52. Epub 2021 Jun 19.

The Roslin Institute and R(D)SVS University of Edinburgh, Easter Bush, Midlothian, UK.

Expression of the cellular prion protein (PrP) is crucial for the development of prion diseases. Amino acid changes in PrP or a reduced amount of PrP may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrP, was previously found to be associated with a resistant PRNP genotype in sheep. Goats are another small ruminant where classical scrapie susceptibility is under strong genetic control. In this study, we assessed PrP in goats for the existence of similar associations between PrP fragments and genotype. Brain tissue homogenates from scrapie-free goats with wild type PRNP or polymorphisms (I142M, H143R, N146S, or Q222K) were deglycosylated prior to immunoblot for assessment of the relative abundance of the C1 fragment of PrP. The presence of K or S alleles demonstrated significantly different relative levels of C1 compared to that observed in wild type goats, which suggests that the genotype association with C1 is neither unique to sheep nor exclusive to the ovine Q171R dimorphism.
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http://dx.doi.org/10.1186/s12711-021-00646-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214774PMC
June 2021

Accuracy of computer-assisted, template-guided implant placement compared with conventional implant placement by hand-An in vitro study.

Clin Oral Implants Res 2021 Sep 28;32(9):1052-1060. Epub 2021 Jun 28.

Clinic of Reconstructive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.

Objectives: To compare free-hand to computer-assisted implant planning and placement (CAIPP) regarding planned to achieved implant position.

Material And Methods: Forty-eight cast/bone models were mounted in mannequin heads. On each side, a tooth gap of different sizes was created. In the test group (T), study implants were placed using a CAD-CAM guide based on virtual planning. In the control (C), free-hand implant placement was performed. After CBCT scanning, the implant position was compared with the planned position. Descriptive statistics were applied, and ANOVA was used to identify differences between groups and gaps. (p < .05).

Results: In C, mean lateral deviations at the implant base amounted to 0.7 mm (max. 1.8) (large gap) and 0.49 mm (1.22) (small gap). In T, 0.18 mm (0.49) and 0.24 mm (0.52) were recorded. At the apex, 0.77 mm (2.04) (large gap) and 0.51 mm (1.24) (small gap) were measured in C, and 0.31 mm (0.83)/0.34 mm (0.93) in T. Mean vertical deviations in C measured 0.46 mm (1.26) (large gap) and 0.45 mm (1.7) (small gap). In T, 0.14 mm (0.44) and 0.28 mm (0.78) were recorded. Mean angular deviations of 1.7° (3.2°) were observed in C (large gap) and 1.36° (2.1°) (small gap). In T, mean values were 1.57° (3.3°) and 1.32° (3.4°). Lateral and vertical deviations were significantly different between groups (not gaps), angular between gaps (not groups).

Conclusions: CAIPP protocols showed smaller deviations irrespective of the size of the tooth gap. In C, the gap size had an influence on the error in angulation only.
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http://dx.doi.org/10.1111/clr.13799DOI Listing
September 2021

Emergency department presentation of opioid use disorder and alcohol use disorder.

J Subst Abuse Treat 2021 08 3;127:108343. Epub 2021 Mar 3.

UT Southwestern Medical Center, Department of Family and Community Medicine, 5323 Harry Hines Blvd., K Building, 2nd Floor, Suite 400, Dallas, TX 75390-9194, USA. Electronic address:

Mixing alcohol and opioid prescription medications can have serious health consequences. This study examines demographic and geographic differences in opioid use disorders (OUD) and alcohol use disorders (AUD) in emergency department (ED) presentations in the state of Texas. Using all diagnosis codes, the study examined discharge records for ED visits related to AUD and OUD in Texas for 2017. The study classified visits into three mutually exclusive groups (AUD-only, OUD-only, and AUD/OUD) and reported the number of visits, fatalities, total charges, proportions, and rates per 100,000 population by patient demographic characteristics. Chi square statistics assessed the association between patient characteristics and ED visit type, and the study used analysis of variance to compare ED visit rates by patient demographics. The study also fitted a multinomial logistic regression w to predict ED visit type by patient demographic and geographic characteristics. There were 221,363 OUD and AUD ED visits from Texans in 2017. Among them, 3863 had both AUD and OUD. There were 2443 fatalities related to AUD-only ED visits, whereas this rate was 292 for OUD-only ED visits. The majority of these patients had Medicare and Medicaid. AUD-only ED visits were more prevalent (680.7 vs 112.5 per 100,000 population) and resulted in higher overall charges than OUD-only ED visits ($6.1 billion vs $1 billion in total charges). However, AUD/OUD ED visits resulted in higher total charges on average than either OUD-only or AUD-only ED visits. Compared to patients with outpatient discharge, patients with inpatient admissions were more likely to belong to the OUD-only visit group (OR = 1.20, 95% CI: 1.17-1.23) or the AUD/OUD visit group (OR = 2.44, 95% CI: 2.28-2.61) than to the AUD-only visit group. Compared to urban patients, rural patients were less likely to belong to OUD-related visit groups than the AUD-only visit group. In conclusions, AUD was more prevalent than OUD among ED visits and resulted in a higher number of fatalities and higher medical charges. Current health policy regarding substance use that is heavily tilted toward curbing the opioid crisis remains woefully tolerant to AUDs. While efforts to curb opioid misuse should continue, future efforts should raise awareness among ED providers of the disease burden of and social harms caused by alcoholism and alcohol addiction.
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http://dx.doi.org/10.1016/j.jsat.2021.108343DOI Listing
August 2021

Disparities in Telemedicine Access: A Cross-Sectional Study of a Newly Established Infrastructure during the COVID-19 Pandemic.

Appl Clin Inform 2021 05 9;12(3):445-458. Epub 2021 Jun 9.

University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, United States.

Background: The COVID-19 pandemic led to dramatic increases in telemedicine use to provide outpatient care without in-person contact risks. Telemedicine increases options for health care access, but a "digital divide" of disparate access may prevent certain populations from realizing the benefits of telemedicine.

Objectives: The study aimed to understand telemedicine utilization patterns after a widespread deployment to identify potential disparities exacerbated by expanded telemedicine usage.

Methods: We performed a cross-sectional retrospective analysis of adults who scheduled outpatient visits between June 1, 2020 and August 31, 2020 at a single-integrated academic health system encompassing a broad range of subspecialties and a large geographic region in the Upper Midwest, during a period of time after the initial surge of COVID-19 when most standard clinical services had resumed. At the beginning of this study period, approximately 72% of provider visits were telemedicine visits. The primary study outcome was whether a patient had one or more video-based visits, compared with audio-only (telephone) visits or in-person visits only. The secondary outcome was whether a patient had any telemedicine visits (video-based or audio-only), compared with in-person visits only.

Results: A total of 197,076 individuals were eligible (average age = 46 years, 56% females). Increasing age, rural status, Asian or Black/African American race, Hispanic ethnicity, and self-pay/uninsured status were significantly negatively associated with having a video visit. Digital literacy, measured by patient portal activation status, was significantly positively associated with having a video visit, as were Medicaid or Medicare as payer and American Indian/Alaskan Native race.

Conclusion: Our findings reinforce previous evidence that older age, rural status, lower socioeconomic status, Asian race, Black/African American race, and Hispanic/Latino ethnicity are associated with lower rates of video-based telemedicine use. Health systems and policies should seek to mitigate such barriers to telemedicine when possible, with efforts such as digital literacy outreach and equitable distribution of telemedicine infrastructure.
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http://dx.doi.org/10.1055/s-0041-1730026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189758PMC
May 2021

Recent Trends in Faculty Promotion in U.S. Medical Schools: Implications for Recruitment, Retention, and Diversity and Inclusion.

Acad Med 2021 Jun 1. Epub 2021 Jun 1.

I.M. Xierali is associate professor, Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; ORCID: https://orcid.org/0000-0002-3378-8063. M.A. Nivet is executive vice president, Institutional Advancement, University of Texas Southwestern Medical Center, Dallas, Texas. Z.A. Syed is associate professor and director, Family Medicine Residency Program, Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. A. Shakil is professor, Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. F.D. Schneider is professor and chair, Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Faculty promotion is important for retention and has implications for diversity. This study provides an update on recent trends in faculty promotion in U.S. medical schools.

Method: Using data from the Association of American Medical Colleges Faculty Roster, the authors examined trends in faculty promotion over ten years. Promotion status for full-time assistant and full-time associate professors who started between 2000 and 2009 inclusive was followed from January 1, 2010 to January 1, 2019. The authors used bivariate analyses to assess associations and promotion rates by sex, race/ethnicity, department, tenure status, and degree type.

Results: The promotion rate for assistant professors was 44.3% (2,330/5,263) in basic science departments, 37.1% (17,232/46,473) in clinical science departments, and 33.6% (131/390) in other departments. Among clinical departments, family medicine had the lowest rate of promoting assistant professors (24.4%; 484/1,982) and otolaryngology the highest rate (51.2%; 282/551). Faculty members who were male (38.9%; 11,687/30,017), White (40.0%; 12,635/31,596), tenured (58.7%; 98/167) or tenure-eligible (55.6%; 6,653/11,976), and holding MDs/PhDs (48.7%; 1,968/4,038) had higher promotion rates than, respectively, faculty who were female (36.3%; 7,975/21,998), minorities underrepresented in medicine (URM; 31.0%; 1,716/5,539), nontenured (32.5%; 12,174/37,433), and holding other/unknown degrees (20.6%; 195/948; all P < .001). These differences were less pronounced among associate professors; however, URM and nontenured faculty continued to have lower promotion rates compared to White, Asian, or tenured faculty at the associate professor level.

Conclusions: Promotion rates varied not only by faculty rank, but also by faculty sex, race/ethnicity, department, tenure status, and degree type. The differences were more pronounced for assistant professors than associate professors. URM faculty members, particularly assistant professors, were promoted at lower rates than their White and Asian peers. More research to understand the drivers of disparities in faculty promotion seems warranted.
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http://dx.doi.org/10.1097/ACM.0000000000004188DOI Listing
June 2021

Identifying and overcoming barriers to trauma screening in the primary care setting.

Fam Syst Health 2021 Jun 13;39(2):177-187. Epub 2021 May 13.

University of Texas Southwestern Medical Center.

Underrecognition of trauma exposure and PTSD has a significant impact on psychiatric health, physical health, and health behaviors. The purpose of this study is to explore barriers and opportunities for trauma screening in primary care. Primary care physicians (PCPs) and their patients were interviewed about the acceptability of trauma screening and brief treatment in primary care. Interview transcripts were coded and analyzed for themes using Atlas v. 7.0. Data showed PCPs informally screen for trauma but were hampered by organizational constraints including time, availability of behavioral health providers, and knowledge of trauma-informed-care practices. Most patients with trauma history met with behavioral health providers during their lifetimes, but still did not believe it was the PCPs' role to address trauma exposure, had fears of "appearing crazy," or were ambivalent about seeking treatment. Findings suggest an enormous complexity involved in screening for trauma in primary care service delivery. Trauma screening appears to work best within the course of relationship building where patients can begin to see that their physician is capable of playing an important role in managing trauma, depression, and PTSD symptoms. We address how trauma discussion can take place within existing trauma informed care guidelines. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/fsh0000593DOI Listing
June 2021

Implants sites with concomitant bone regeneration using a resorbable or non-resorbable membrane result in stable marginal bone levels and similar profilometric outcomes over 5 years.

Clin Oral Implants Res 2021 Aug 4;32(8):893-904. Epub 2021 Jun 4.

Clinic of Reconstructive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.

Objectives: To assess clinical and radiographic outcomes as well as the profilometric contour alterations of peri-implant hard and soft tissues around single implants treated with simultaneous guided bone regeneration (GBR) at 5 years.

Materials And Methods: Twenty-seven patients presenting with a single tooth gap in the esthetic zone received a two-piece implant. GBR was randomly performed using a resorbable (RES) or a non-resorbable membrane (N-RES) combined with a bone substitute material. Follow-up examinations were performed at baseline (BL = crown insertion), 1 year (FU-1), 3 years (FU-3), and at 5 years (FU-5) including clinical and radiographic parameters as well as profilometric changes. Statistics were performed by means of parametric and nonparametric tests.

Results: At 5 years, 20 out of 27 patients (9 RES, 11 N-RES) were re-examined. Median values for probing depth changed insignificantly between BL and FU-5 in both groups. The median marginal bone levels were located 0.23 mm (0.06; 0.46; RES) and 0.17 mm (0.13;0.28; N-RES) below the implant shoulder at FU-5 (changes over time p < .05). The calculated median profilometric change between BL and FU-5 was -0.28 mm (-0.53;-0.20; RES; p = .016) and -0.24 mm (-0.43;0.08; N-RES; p = .102; intergroup p = .380). The horizontal bone thickness decreased significantly between re-entry and FU-5 for group RES at all measured levels (p < .05) measuring 0.87 mm (0.0; 2.05) at the implant shoulder, whereas the decrease for group N-RES was insignificant (p = .031) with 0 mm (0; 0.84) at the implant shoulder at 5 years.

Conclusions: Implants sites with concomitant GBR using a resorbable or non-resorbable membrane revealed stable marginal bone levels and clinical outcomes. Profilometric changes were clinically negligible over 5 years. The observed change in hard tissue thickness was partially compensated by an increase in soft tissue thickness.
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http://dx.doi.org/10.1111/clr.13764DOI Listing
August 2021

Spt4 Promotes Pol I Processivity and Transcription Elongation.

Genes (Basel) 2021 03 12;12(3). Epub 2021 Mar 12.

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham 720 20th Street South, Birmingham, AL 35294, USA.

RNA polymerases (Pols) I, II, and III collectively synthesize most of the RNA in a eukaryotic cell. Transcription by Pols I, II, and III is regulated by hundreds of trans-acting factors. One such protein, Spt4, has been previously identified as a transcription factor that influences both Pols I and II. Spt4 forms a complex with Spt5, described as the Spt4/5 complex (or DSIF in mammalian cells). This complex has been shown previously to directly interact with Pol I and potentially affect transcription elongation. The previous literature identified defects in transcription by Pol I when was deleted, but the necessary tools to characterize the mechanism of this effect were not available at the time. Here, we use a technique called Native Elongating Transcript Sequencing (NET-seq) to probe for the global occupancy of Pol I in wild-type (WT) and (yeast) cells at single nucleotide resolution in vivo. Analysis of NET-seq data reveals that Spt4 promotes Pol I processivity and enhances transcription elongation through regions of the ribosomal DNA that are particularly G-rich. These data suggest that Spt4/5 may directly affect transcription elongation by Pol I in vivo.
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http://dx.doi.org/10.3390/genes12030413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000598PMC
March 2021

A Randomized Controlled Clinical Trial: No Clear Benefit to Prophylactic Central Neck Dissection in Patients With Clinically Node Negative Papillary Thyroid Cancer.

Ann Surg 2020 09;272(3):496-503

Division of Otolaryngology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Objective: The aim of this prospective randomized-controlled trial was to evaluate the risks/benefits of prophylactic central neck dissection (pCND) in patients with clinically node negative (cN0) papillary thyroid cancer (PTC).

Background: Microscopic lymph node involvement in patients with PTC is common, but the optimal management is unclear.

Methods: Sixty patients with cN0 PTC were randomized to a total thyroidectomy (TT) or a TT+ pCND. All patients received postoperative laryngoscopies and standardized radioiodine treatment. Thyroglobulin (Tg) levels and/or neck ultrasounds were performed at 6 weeks, 6 months, and 1 year.

Results: Tumors averaged 2.2 ± 0.2 cm and 11.9% had extra-thyroidal extension. Thirty patients underwent a pCND and 27.6% had positive nodes (all ≤6 mm). Rates of postoperative PTH < 10 (33.3% vs 24.1%, P = 0.57) and transient nerve dysfunction (13.3% vs 10.3%, P = 1.00) were not significantly different between groups. Six weeks after surgery, both TT and TT + pCND were equally likely to achieve a Tg < 0.2 (54.5% vs 66.7%, P = 0.54) and/or a stimulated Tg (sTg) <1 (59.3% vs 64.0%, P = 0.78). At 1 year, rates of Tg < 0.2 (88.9% vs 90.0%, P = 1.00) and sTg < 1 (93.8% vs 92.3%, P = 1.00) remained similar between groups. Neck ultrasounds at 1 year were equally likely to be read as normal (85.7% in TT vs 85.1% in pCND, P = 1.00).

Conclusions: cN0 PTC patients treated either with TT or TT + pCND had similar complication rates after surgery. Although microscopic nodes were discovered in 27.6% of pCND patients, oncologic outcomes were comparable at 1 year.
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http://dx.doi.org/10.1097/SLA.0000000000004345DOI Listing
September 2020

Development of a Comprehensive Toxicity Pathway Model for 17α-Ethinylestradiol in Early Life Stage Fathead Minnows ().

Environ Sci Technol 2021 04 23;55(8):5024-5036. Epub 2021 Mar 23.

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B3, Canada.

There is increasing pressure to develop alternative ecotoxicological risk assessment approaches that do not rely on expensive, time-consuming, and ethically questionable live animal testing. This study aimed to develop a comprehensive early life stage toxicity pathway model for the exposure of fish to estrogenic chemicals that is rooted in mechanistic toxicology. Embryo-larval fathead minnows (FHM; ) were exposed to graded concentrations of 17α-ethinylestradiol (water control, 0.01% DMSO, 4, 20, and 100 ng/L) for 32 days. Fish were assessed for transcriptomic and proteomic responses at 4 days post-hatch (dph), and for histological and apical end points at 28 dph. Molecular analyses revealed core responses that were indicative of observed apical outcomes, including biological processes resulting in overproduction of vitellogenin and impairment of visual development. Histological observations indicated accumulation of proteinaceous fluid in liver and kidney tissues, energy depletion, and delayed or suppressed gonad development. Additionally, fish in the 100 ng/L treatment group were smaller than controls. Integration of omics data improved the interpretation of perturbations in early life stage FHM, providing evidence of conservation of toxicity pathways across levels of biological organization. Overall, the mechanism-based embryo-larval FHM model showed promise as a replacement for standard adult live animal tests.
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http://dx.doi.org/10.1021/acs.est.0c05942DOI Listing
April 2021

The N-terminal domain of the A12.2 subunit stimulates RNA polymerase I transcription elongation.

Biophys J 2021 05 16;120(10):1883-1893. Epub 2021 Mar 16.

The Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address:

Eukaryotes express three DNA-dependent RNA polymerases (Pols) that are responsible for the entirety of cellular genomic expression. The three Pols have evolved to express specific cohorts of RNAs and thus have diverged both structurally and functionally to efficiently execute their specific transcriptional roles. One example of this divergence is Pol I's inclusion of a proofreading factor as a bona fide subunit, as opposed to Pol II, which recruits a transcription factor, TFIIS, for proofreading. The A12.2 (A12) subunit of Pol I shares homology with both the Rpb9 subunit of Pol II as well as the transcription factor TFIIS, which promotes RNA cleavage and proofreading by Pol II. In this study, the functional contribution of the TFIIS-like C-terminal domain and the Rpb9-like N-terminal domain of the A12 subunit are probed through mutational analysis. We found that a Pol I mutant lacking the C-terminal domain of the A12 subunit (ΔA12CTD Pol I) is slightly faster than wild-type Pol I in single-nucleotide addition, but ΔA12CTD Pol I lacks RNA cleavage activity. ΔA12CTD Pol I is likewise similar to wild-type Pol I in elongation complex stability, whereas removal of the entire A12 subunit (ΔA12 Pol I) was previously demonstrated to stabilize transcription elongation complexes. Furthermore, the ΔA12CTD Pol I is sensitive to downstream sequence context, as ΔA12CTD Pol I exposed to AT-rich downstream DNA is more arrest prone than ΔA12 Pol I. These data demonstrate that the N-terminal domain of A12 does not stimulate Pol I intrinsic RNA cleavage activity, but rather contributes to core transcription elongation properties of Pol I.
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http://dx.doi.org/10.1016/j.bpj.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204343PMC
May 2021

Endothelial Shear Stress and Platelet FcγRIIa Expression in Intracranial Atherosclerotic Disease.

Front Neurol 2021 25;12:646309. Epub 2021 Feb 25.

Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, VT, United States.

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD.
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http://dx.doi.org/10.3389/fneur.2021.646309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947292PMC
February 2021

Differential pulmonary immunopathology of domestic sheep (Ovis aries) and bighorn sheep (Ovis canadensis) with Mycoplasma ovipneumoniae infection: A retrospective study.

Comp Immunol Microbiol Infect Dis 2021 Jun 3;76:101641. Epub 2021 Mar 3.

Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA; United States Department of Agriculture, Agricultural Research Service, Animal Disease Research Unit, Pullman, WA, 99164, USA. Electronic address:

Mycoplasma ovipneumoniae is a respiratory pathogen that impacts domestic sheep (Ovis aries; DS) and bighorn sheep (Ovis canadensis; BHS). BHS are reported to be more susceptible than DS to developing polymicrobial pneumonia associated with M. ovipneumoniae infection. Using formalin-fixed paraffin-embedded tissues, we performed a retrospective study investigating the pulmonary immune response of DS and BHS to M. ovipneumoniae infection. M. ovipneumoniae infected DS exhibited a more robust and well-organized BALT formation as compared to BHS. Digital analysis of immunohistochemical chromogen deposition in lung tissue was used to quantitate T cell marker CD3, B cell markers CD20 and CD79a, macrophage markers CD163 and Iba1, and cytokine IL-17. A significant interaction of species and infection status was identified for CD3, CD163, and IL-17. BHS had a greater increase in bronchiolar CD3 and bronchiolar and alveolar CD163 with infection, as compared to DS. BHS had an increase in bronchiolar associated lymph tissue (BALT) and alveolar IL-17 with infection, while these remained similar in DS regardless of infection status. IL-17 in respiratory epithelium of bronchi and bronchioles comparatively decreased in DS and increased in BHS with infection. These data begin to define the interspecies differential immune response to pulmonary M. ovipneumoniae infection in DS and BHS and provide the first investigations of respiratory epithelium-associated IL-17 in ovine.
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http://dx.doi.org/10.1016/j.cimid.2021.101641DOI Listing
June 2021

Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer.

Cell Death Dis 2021 03 4;12(3):242. Epub 2021 Mar 4.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

Triple-negative breast cancer (TNBC) patients with upregulated Wnt/β-catenin signaling often have poor clinical prognoses. During pathological examinations of breast cancer sections stained for β-catenin, we made the serendipitous observation that relative to non-TNBC, specimens from TNBC patients have a greater abundance of nucleoli. There was a remarkable direct relationship between nuclear β-catenin and greater numbers of nucleoli in TNBC tissues. These surprising observations spurred our investigations to decipher the differential functional relevance of the nucleolus in TNBC versus non-TNBC cells. Comparative nucleolar proteomics revealed that the majority of the nucleolar proteins in TNBC cells were potential targets of β-catenin signaling. Next, we undertook an analysis of the nucleolar proteome in TNBC cells in response to β-catenin inhibition. This effort revealed that a vital component of pre-rRNA processing, LAS1 like ribosome biogenesis factor (LAS1L) was significantly decreased in the nucleoli of β-catenin inhibited TNBC cells. Here we demonstrate that LAS1L protein expression is significantly elevated in TNBC patients, and it functionally is important for mammary tumor growth in xenograft models and enables invasive attributes. Our observations highlight a novel function for β-catenin in orchestrating nucleolar activity in TNBCs.
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http://dx.doi.org/10.1038/s41419-021-03531-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933177PMC
March 2021

Influence of Lipid Excipients on Platelet Function and the Pharmacodynamic Effects of Aspirin.

J Cardiovasc Pharmacol 2021 Aug;78(2):297-301

Departments of Medicine, Cardiovascular Research Institute, the University of Vermont, Burlington, VT.

Abstract: The combination of pharmaceutical lipid excipients with aspirin in a novel liquid oral formulation (Vazalore) limits gastrointestinal toxicity of aspirin. This study was performed to determine whether the lipid excipients influence the pharmacodynamic effects of aspirin and whether the excipients directly affect platelet function. The pharmacodynamic effects of aspirin were assessed over a range of concentrations designed to exert limited to maximal inhibition of cyclooxygenase-1 (COX1) necessary for thromboxane A2 production. Platelet aggregation induced by arachidonic acid and assessed with the use of light transmission aggregometry was used as a direct measure of the inhibition of COX1 by aspirin. Flow cytometry was used to assess the direct effect of excipients on platelet function. Twice the ratio of lipid excipient to aspirin used in the formulation of the novel oral agent was used. Blood was taken from 20 healthy subjects and anticoagulated with trisodium citrate (3.2%, 1:10 vol/vol). Aspirin and excipients were added in vitro and incubated for 10 minutes before performance of light transmission aggregometry and flow cytometry. The excipients did not limit the pharmacodynamic effects of aspirin. When the extent of inhibition of platelet aggregation was limited, the excipients tended to enhance pharmacodynamic effects. The excipients did not activate platelets in the absence of agonist and did not alter activation of platelets in response to adenosine diphosphate, arachidonic acid, thrombin, or convulxin (a collagen mimetic). Lipid excipients used in an oral formulation of aspirin do not impair the pharmacodynamic effects of aspirin and do not alter platelet function.
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http://dx.doi.org/10.1097/FJC.0000000000000998DOI Listing
August 2021

Quorum sensing regulates rRNA synthesis in Saccharomyces cerevisiae.

Gene 2021 Apr 19;776:145442. Epub 2021 Jan 19.

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address:

Ribosome biogenesis requires the concerted activities of three nuclear RNA polymerases, (Pols) I, II, and III, to produce 25S, 18S and 5.8S ribosomal RNA (rRNA), messenger RNA (mRNA) encoding ribosomal proteins, and the 5S rRNA, respectively. The rRNA is processed and modified before being assembled with ribosomal proteins to produce a ribosome. Ribosome biogenesis requires extensive energetic investment by the cell, so it is critical that this process is tightly regulated in accord with cellular growth potential. Previous work revealed that rRNA synthesis in Saccharomyces cerevisiae is repressed prior to the cells shift from active growth (log phase) to limited/static growth (stationary phase). The mechanism(s) by which cells anticipate imminent stationary phase are unknown. In this study, we demonstrate that growing cells produce one or more compounds that accumulate in the growth medium, and that this compound induces repression of rRNA synthesis. When cells encounter this compound, rRNA synthesis is rapidly repressed. We further show that subunits of Pols I and II are degraded during the transition from log to stationary phase growth, but this degradation does not account for the observed repression of rRNA synthesis. Interestingly, repression of rRNA synthesis by spent media requires the nuclear exosome, implying that spent media stimulates rapid rRNA degradation. Together, these data suggest that yeast use quorum sensing to regulate rRNA synthesis in anticipation of high cell density in stationary phase.
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http://dx.doi.org/10.1016/j.gene.2021.145442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890424PMC
April 2021

Prescription opioid use duration and beliefs about pain and pain medication in primary care patients.

J Opioid Manag 2020 Nov-Dec;16(6):425-434

Research Director and Professor, Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, Missouri.

Background: Patient beliefs about pain and opioids have been reported from qualitative data. To overcome limitations of unstructured assessments and small sample sizes, we determined if pain and pain medication beliefs varied by chronic pain status and opioid analgesic use (OAU) duration in primary care patients.

Methods: Cross-sectional survey data obtained in 2017 and 2018 from 735 patients ≥ 18 years of age. The eight-item Barriers Questionnaire (BQ) measured beliefs about pain and pain medication. Patients reported OAU and use of other pain treatments. Multiple linear regression models estimated the association between never OAU, 1-90 day OAU and >90 day OAU and each BQ item.

Results: Overall, respondents were 49.1 (±15.4) years old, 38.7 percent white, 28.4 percent African-American, 23.5 percent Hispanic, and 68.6 percent female. About one-third never used opioids, 41.8 percent had 1-90 day OAU, and 21.6 percent had > 90 day OAU. Multiple linear regression analyses showed that compared to never OAU, > 90 day OAU had lower average agreement that analgesics are addictive (β = -0.50; 95 percent CI: -0.96, -0.03), and 1-90 day OAU (β = -0.53; 95 percent CI: -0.96, -0.10) and > 90 OAU (β = -0.55; 95 percent CI: -1.04, -0.06) had lower average agreement that analgesics make people do or say embarrassing things.

Conclusions: Patients with chronic OAU reported less concern about addiction and opioid-related behavior change. Never users were most likely to agree that opioids are addictive. There continues to be a need to educate patients about opioid risks. Assessing patients' beliefs may identify patients at risk for chronic OAU.
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http://dx.doi.org/10.5055/jom.2020.0600DOI Listing
January 2021

The Effect of Empagliflozin on Platelet Function Profiles in Patients with Stable Coronary Artery Disease in Trinidad: The EFFECT Pilot Study.

Cardiol Ther 2021 Jun 11;10(1):189-199. Epub 2020 Dec 11.

Cardiovascular Research Institute of Vermont, Colchester, VT, USA.

Introduction: This prospective pharmacodynamic (PD) study aimed to assess the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin on platelet reactivity.

Methods: Patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) (n = 20) who were actively treated with dual antiplatelet therapy (DAPT) of aspirin 81 mg daily and clopidogrel 75 mg daily were recruited. Platelet function was measured with the VerifyNow™ P2Y assay (Instrumentation Laboratory, Massachusetts, USA) and assessed before the initiation of and after 10 days of treatment with empagliflozin 25 mg once daily maintenance dose regimen. Results were compared with a paired t test.

Results: The mean P2Y reaction units (PRU) on empagliflozin was significantly less than without empagliflozin at baseline (187.35, 95% confidence interval (CI) 155.38-219.32 vs. 217.25, CI 180.60-253.90; p < 0.030). The mean difference in PRU was 29.90 (95% CI 3.17-56.63). No patients experienced any serious adverse events (SAEs).

Conclusions: Significantly attenuated platelet reactivity was observed on empagliflozin as compared to without empagliflozin. This dedicated pharmacodynamic study could be clinically pertinent for Trinidadian patients with stable CAD and T2DM on DAPT. Further studies are required to confirm these exploratory findings. (Funded by the University of the West Indies, St. Augustine; EFFECT).

Clinical Trial Registration: ClinicalTrials.gov number NCT04342819.
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http://dx.doi.org/10.1007/s40119-020-00208-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126525PMC
June 2021

Multigenerational experimental simulation of climate change on an economically important insect pest.

Ecol Evol 2020 Dec 27;10(23):12893-12909. Epub 2020 Oct 27.

Departamento de Ecología Evolutiva Instituto de Ecología Universidad Nacional Autónoma de México México Mexico.

Long-term multigenerational experimental simulations of climate change on insect pests of economically and socially important crops are crucial to anticipate challenges for feeding humanity in the not-so-far future. Mexican bean weevil , is a worldwide pest that attacks the common bean seeds, in crops and storage. We designed a long term (i.e., over 10 generations), experimental simulation of climate change by increasing temperature and CO air concentration in controlled conditions according to model predictions for 2100. Higher temperature and CO concentrations favored pest's egg-to-adult development survival, even at high female fecundity. It also induced a reduction of fat storage and increase of protein content but did not alter body size. After 10 generations of simulation, genetic adaptation was detected for total lipid content only, however, other traits showed signs of such process. Future experimental designs and methods similar to ours, are key for studying long-term effects of climate change through multigenerational experimental designs.
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http://dx.doi.org/10.1002/ece3.6847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713942PMC
December 2020

The association of opioid use duration and new depression episode among patients with and without insomnia.

J Opioid Manag 2020 Sep/Oct 2020;16(5):317-328

Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; The Bell Street Clinic, VA St. Louis Health Care System-John Cochran Division, St. Louis, Missouri.

Objective: Insomnia commonly co-occurs with depression, chronic pain, and opioid use. Both insomnia and chronic opioid analgesic use (OAU) are independent risk factors for a new depression episode (NDE). This study determined if the association between longer OAU duration and NDE was stronger in those with versus without insomnia.

Design: Retrospective cohort.

Setting: Veterans Health Administration electronic medical records (2000-2012).

Participants: New opioid users in follow-up (2002-2012), free of depression for two years prior to follow-up, and aged 18-80 (n = 70,997).

Methods: NDE was ≥ 2 ICD-9 codes in a 12-month period. Insomnia before OAU initiation was ≥1 ICD-9 code. Cox proportional hazard models stratified on insomnia assessed the relationship between initiating a 1-30, 31-90, or > 90 day period of OAU and NDE while controlling for confounders using inverse probability of treatment-weighted propensity scores (PS).

Results: Compared to 1-30 day OAU, 31-90 day was associated with NDE in those without (HR = 1.20; 95 percent CI: 1.12-1.28) but not with insomnia (HR = 1.06; 95 percent CI: 0.86-1.32). Results showed a stronger effect of chronic (>90) OAU in those with insomnia (HR = 1.59; 95 percent CI: 1.27-1.98) compared to those without (HR = 1.31; 95 percent CI: 1.21-1.42). However, all stratum-specific effects were not significantly different (p = 0.136).

Conclusions: Although stratum-specific risks were statistically similar, there was evidence for a trend that chronic OAU is a stronger risk factor for NDE in those with versus without insomnia. Providers are encouraged to monitor sleep impairment among patients on opioid therapy, as sleep may be associated with greater risk for NDE in patients with chronic OAU.
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http://dx.doi.org/10.5055/jom.2020.0587DOI Listing
December 2020

Defining the divergent enzymatic properties of RNA polymerases I and II.

J Biol Chem 2021 Jan-Jun;296:100051. Epub 2020 Nov 24.

Department of Biochemistry and Molecular Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address:

Eukaryotes express at least three nuclear DNA-dependent RNA polymerases (Pols) responsible for synthesizing all RNA required by the cell. Despite sharing structural homology, they have functionally diverged to suit their distinct cellular roles. Although the Pols have been studied extensively, direct comparison of their enzymatic properties is difficult because studies are often conducted under disparate experimental conditions and techniques. Here, we directly compare and reveal functional differences between Saccharomyces cerevisiae Pols I and II using a series of quantitative in vitro transcription assays. We find that Pol I single-nucleotide and multinucleotide addition rate constants are faster than those of Pol II. Pol I elongation complexes are less stable than Pol II elongation complexes, and Pol I is more error prone than Pol II. Collectively, these data show that the enzymatic properties of the Pols have diverged over the course of evolution, optimizing these enzymes for their unique cellular responsibilities.
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http://dx.doi.org/10.1074/jbc.RA120.015904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948988PMC
September 2021

Family medicine research capacity in the USA.

Fam Pract 2021 03;38(2):187-189

NorthShore University HealthSystem, Department of Family Medicine, University of Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.1093/fampra/cmaa119DOI Listing
March 2021

PTSD improvement and substance use disorder treatment utilization in veterans: Evidence from medical record data.

Drug Alcohol Depend 2021 01 18;218:108365. Epub 2020 Oct 18.

Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, United States; Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States.

Background: Clinical trials reveal posttraumatic stress disorder (PTSD) improvement leads to decreased substance use among patients with comorbid substance use disorder (SUD). Using administrative medical record data, we determined whether clinically meaningful PTSD Checklist (PCL) (≥20 points) score decreases were positively associated with SUD treatment utilization.

Methods: We used a retrospective cohort of Veterans Health Affairs (VHA) medical record data (2008-2015). PTSD Checklist (PCL) scores were used to categorize patients into those with a clinically meaningful PTSD improvement (≥20 point decrease) or not (<20 point decrease or increase). PTSD and SUD were measured by ICD-9 codes. Propensity score weighting controlled for confounding in logistic and negative binomial models that estimated the association between clinically meaningful PTSD improvement and use of SUD treatment and number of SUD clinic visits.

Results: The 699 eligible patients were, on average, 40.4 (±13.2) years old, 66.2% white and 33.1% were married. After controlling for confounding, there was a 56% increased odds of any SUD treatment utilization among those with a PCL decrease ≥20 vs < 20 (OR = 1.56; 95%CI = 1.04-2.33) but there was no association with number of SUD treatment visits.

Conclusions: Clinically meaningful reductions in PTSD symptoms were associated with any SUD treatment utilization but not amount of utilization. Improvement in PTSD symptoms, independent of the treatment modality, may enable SUD treatment seeking.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750304PMC
January 2021

Preoperative surgeon-performed ultrasound of massive thyroid goiter in rural Kenya.

Am J Surg 2021 05 3;221(5):925-926. Epub 2020 Oct 3.

Division of Endocrine Surgery, University of Wisconsin-Madison, USA.

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http://dx.doi.org/10.1016/j.amjsurg.2020.09.035DOI Listing
May 2021

Uncovering drivers of dose-dependence and individual variation in malaria infection outcomes.

PLoS Comput Biol 2020 10 8;16(10):e1008211. Epub 2020 Oct 8.

Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada.

To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impacts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acute Plasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.
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http://dx.doi.org/10.1371/journal.pcbi.1008211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544130PMC
October 2020
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