Incorporating sources of correlation between outcomes: An introduction to mixed models.

Animal research often involves measuring the outcomes of interest multiple times on the same animal, whether over time or for different exposures. These repeated outcomes measured on the same animal are correlated due to animal-specific characteristics. While this repeated measures data can address more complex research questions than single-outcome data, the statistical analysis must take into account the study design resulting in correlated outcomes, which violate the independence assumption of standard statistical methods (e.g. a two-sample t-test, linear regression). When standard statistical methods are incorrectly used to analyze correlated outcome data, the statistical inference (i.e. confidence intervals and p-values) will be incorrect, with some settings leading to null findings too often and others producing statistically significant findings despite no support for this in the data. Instead, researchers can leverage approaches designed specifically for correlated outcomes. In this article, we discuss common study designs that lead to correlated outcome data, motivate the intuition about the impact of improperly analyzing correlated outcomes using methods for independent data, and introduce approaches that properly leverage correlated outcome data.

Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time.

BACKGROUND: Breast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma. Estrogen is known for its cardiovascular (CV) protective properties through a variety of mechanisms including vasodilation of blood vessels and inhibition of vascular injury resulting in the prevention of atherosclerosis. In clinical trials and prospective cohorts, the long-term use of AIs can increase the risk for hypertension and hyperlipidemia. Studies demonstrate mixed results as to the impact of AIs on actual CV events and overall survival. METHODS: A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota (UMN). Subjects with a history of known tobacco use, hypertension, hyperlipidemia, and diabetes were excluded to eliminate potential confounding factors. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p = 0.045; Figure 1) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p = 0.91). There were no statistically significant changes in small or large arterial elasticity. CONCLUSIONS: We hypothesize that long-term use of AI can lead to persistent endothelial dysfunction, and further investigation is necessary. In our study, patients were on AI for approximately 5-10 years. As a result, we do not have data on whether these changes, such as EndoPAT® ratio and the elasticity of small and large arterial, are reversible with discontinuation of AI. These findings set the stage for a larger study to more conclusively determine the association between AI exposure and cardiovascular outcomes. Further studies should evaluate for multivariate associations withmodifiable risk factors for CV disease.

Linking genetic counseling communication skills to patient outcomes and experiences using a community-engagement and provider-engagement approach: research protocol for the GC-PRO mixed methods sequential explanatory study.

INTRODUCTION: In over 50 years since the genetic counseling (GC) profession began, a systematic study of GC communication skills and patient-reported outcomes in actual sessions across multiple clinical specialties has never been conducted. To optimize GC quality and improve efficiency of care, the field must first be able to comprehensively measure GC skills and determine which skills are most critical to achieving positive patient experiences and outcomes. This study aims to characterise GC communication skills using a novel and pragmatic measure and link variations in communication skills to patient-reported outcomes, across clinical specialties and with patients from diverse backgrounds in the USA. Our community-engagement and provider-engagement approach is crucial to develop recommendations for quality, culturally informed GC care, which are greatly needed to improve GC practice. METHODS AND ANALYSIS: A mixed methods, sequential explanatory design will be used to collect and analyze: audio-recorded GC sessions in cancer, cardiac, and prenatal/reproductive genetic indications; pre-visit and post-visit quantitative surveys capturing patient experiences and outcomes and post-visit qualitative interview data. A novel, practical checklist will measure GC communication skills. Coincidence analysis will identify patterns of GC skills that are consistent with high scores on patient-reported measures. Two-level, multilevel models will be used to evaluate how GC communication skills and other session/patient characteristics predict patient-reported outcomes. Four community advisory boards (CABs) and a genetic counselor advisory board will inform the study design and analysis. ETHICS AND DISSEMINATION: This study has been approved by the single Institutional Review Board of the University of Minnesota. This research poses no greater than minimal risk to participants. Results from this study will be shared through national and international conferences and through community-based dissemination as guided by the study's CABs. A lay summary will also be disseminated to all participants.

Chimeric Amphiphilic Disinfectants: Quaternary Ammonium/Quaternary Phosphonium Hybrid Structures.

Cationic biocides play a crucial role in the disinfection of domestic and healthcare surfaces. Due to the rise of bacterial resistance towards common cationic disinfectants like quaternary ammonium compounds (QACs), the development of novel actives is necessary for effective infection prevention and control. Toward this end, a series of 15 chimeric biscationic amphiphilic compounds, bearing both ammonium and phosphonium residues, were prepared to probe the structure and efficacy of mixed cationic ammonium-phosphonium structures. Compounds were obtained in two steps and good yields, with straightforward and chromatography-free purifications. Antibacterial activity evaluation of these compounds against a panel of seven bacterial strains, including two MRSA strains as well as opportunistic pathogen A. baumannii, were encouraging, as low micromolar inhibitory activity was observed for multiple structures. Alkyl chain length on the ammonium group was, as expected, a major determinant of bioactivity. In addition, high therapeutic indexes (up to 125-fold) for triphenyl phosphonium-bearing amphiphiles were observed when comparing antimicrobial activity to mammalian cell lysis activity.

Delay discounting demonstrates lower impulsivity linked to a higher likelihood of succeeding at smoking cessation.

Sixty-eight percent of smokers want to quit, but only one in 10 are successful at smoking cessation. Recently, impulsivity has been studied in relation to smoking cessation with measures like the delay discounting task (DDT). We aimed to build on the robust literature that has already revealed the association between impulsivity and smoking cessation, as well as look at the differences between sexes for which there is conflicting evidence. We hypothesized that lower impulsivity would be positively associated with cessation success. In the parent cessation trial, participants were randomized to 12 weeks of progesterone or placebo. Participants were asked to quit smoking, and their smoking status was monitored via expired carbon monoxide throughout the study. Participants completed a DDT at screening, week 4, and week 8 using the 27-item Monetary Choice Questionnaire, where participants decided between a small immediate reward or a larger delayed reward (LDR). The effective delay 50 (ED50), which is the delay at which the LDR loses half its value, was analyzed. To estimate the association between ED50 and cessation, a logistic mixed model with a participant random intercept was fit, controlling for study week, randomization, sex, and age. For the 181 participants, a doubling of the ED50 was associated with an 18% increase in the odds of tobacco cessation (95% confidence interval: 0.2-38% increase; p=0.05). In agreement with our hypothesis, lower impulsivity correlated to greater tobacco cessation success. Our study also showed no evidence of sex differences in the association between ED50 and smoking cessation.

Tobacco Free Nicotine Vaping Products: A Study of Health Halo Effects Among Middle School Youth.

Health halo effects are a form of biased processing, wherein a particular product claim bleeds over to other categories of analysis or to an overall healthier impression. This study tests whether the term tobacco-free nicotine triggers a health halo effect. Through an experiment with middle school youth (n = 599), we vary the flavor (tobacco vs. fruit) and nicotine source information (nicotine/tobacco-free nicotine/nicotine from tobacco) on the warning label of the vaping product participants viewed. We evaluate product measures (nicotine content beliefs, nicotine source beliefs, and risk perceptions) and comparative nicotine source misperceptions (addictiveness, safety, and risk). Findings show that the term tobacco-free nicotine triggers inaccurate nicotine content beliefs, nicotine source beliefs, and misperceptions associated with addictiveness, safety, and risk. We conclude with theoretical and regulatory implications.

Endothelial Dysfunction in Breast Cancer Survivors on Aromatase Inhibitors: Changes over Time.

Background: Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital. Methods: A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota. Subjects with a history of tobacco use, hypertension, or hyperlipidemia were excluded. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Pro ling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Results: After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p=0.045) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p=0.91). There were no statistically significant changes in small or large arterial elasticity. Conclusion: Endovascular dysfunction is an early sign for atherosclerosis and vascular impairment. This study suggests that postmenopausal breast cancer survivors on aromatase inhibitor therapy develop endothelial dysfunction as early as six months which is a predictor of adverse CV disease. We hypothesize that long-term use of AIs can lead to persistent endothelial dysfunction. It is unclear if these changes are reversible once AI use is discontinued and further investigation is necessary.

Characterizing cellular membrane partitioning of DMSO using low-temperature Raman spectroscopy.

Additives that help cells survive the stresses of freezing and thawing are known as cryoprotective agents (CPAs). Two different types of CPAs have been identified: penetrating and non-penetrating. Common penetrating CPAs include dimethylsulfoxide (DMSO) and glycerol. The location of a CPA (intracelluar or extracellular) is important for understanding the molecular mechanisms of action for the agent. Low-temperature Raman spectroscopy is a label-free method of detecting the location of CPAs at low temperature with high spatial resolution and chemical specificity. To this end, cells cryopreserved in DMSO using a variety of cooling rates and DMSO concentrations and imaged using Raman spectroscopy were analyzed using automated image analysis to determine the partitioning ratio (concentration of DMSO outside/concentration of DMSO inside the cell). The partitioning ratio was roughly 1 for Jurkat cells frozen at 1°C/min in varying concentrations of DMSO with the exception of 1% DMSO which had a partitioning ratio of 0.2. The partitioning ratio increased from 1 to 1.3 as the cooling rate increased from 1°C to 5°C/min. Different cell types, specifically sensory neurons cells and human induced pluripotent stem cells, exhibited differences in partitioning ratio when frozen in 10% DMSO and 1°C/min suggesting that differences in freezing response may result from differences in solute partitioning. The presence of intracellular ice changed the distribution of DMSO inside the cell and also the partitioning ratio.

Sensitivity and Specificity of MRI versus CBCT to Detect Vertical Root Fractures Using MicroCT as a Reference Standard.

INTRODUCTION: Vertical root fracture (VRF) in root-canal-treated teeth frequently results in tooth loss, partly because VRFs are difficult to diagnose and when detected the fracture is often beyond the point of preservation with surgical intervention. Nonionizing magnetic resonance imaging (MRI) has demonstrated the ability to detect small VRFs, but it is unknown how its diagnostic capabilities compare with the current imaging standard for VRF detection, cone-beam computed tomography (CBCT). This investigation aimed to compare the sensitivity and specificity between MRI and CBCT for detecting VRF, using micro-computed tomography (microCT) as a reference. METHODS: A total of 120 extracted human tooth roots were root canal treated using common techniques, and VRFs were mechanically induced in a proportion. Samples were imaged using MRI, CBCT, and microCT. Axial MRI and CBCT images were examined by 3 board-certified endodontists, who evaluated VRF status (yes/no) and gave a confidence assessment for that decision, from which a receiver operating characteristic curve was generated. Intra- and inter-rater reliability were calculated, sensitivity and specificity, and area under the curve. RESULTS: Intra-rater reliability was 0.29-0.48 for MRI and 0.30-0.44 for CBCT. Inter-rater reliability for MRI was 0.37 and for CBCT 0.49. Sensitivity was 0.66 (95% confidence interval [CI], 0.53-0.78) and 0.58 (95% CI, 0.45-0.70), and specificity 0.72 (95% CI, 0.58-0.83) and 0.87 (95% CI, 0.75-0.95) for MRI and CBCT, respectively. Area under the curve was 0.74 (95% CI, 0.65-0.83) for MRI and 0.75 (95% CI, 0.66-0.84) for CBCT. CONCLUSIONS: There was no significant difference in sensitivity or specificity between MRI and CBCT in detecting VRF, despite the early-stage development of MRI.

Atom Economical QPCs: Phenyl-Free Biscationic Quaternary Phosphonium Compounds as Potent Disinfectants.

Quaternary ammonium compounds (QACs) are vital disinfectants for the neutralization of pathogenic bacteria in clinical, domestic, and commercial settings. After decades of dependence on QACs, the emergence of antimicrobial resistance to this class of compounds threatens the ability of existing QAC products to effectively manage rising bacterial threats. The need for new disinfectants is therefore urgent, with quaternary phosphonium compounds (QPCs) emerging as a new class of promising antimicrobials that boast significant activity against highly resistant bacteria. Reported here is a series of twenty-one novel QPCs that replace phenyl substituents on the phosphorus center with alkyl groups yet allow for rapid synthetic routes in high yields. Within this series are structures containing methyl, ethyl, or cyclohexyl phosphonium substituents on bisphosphane scaffolds bearing ethyl linkers, affording atom economical structures and ones that represent exact analogs to nitrogenous amphiphiles. The resultant bisQPC structures display high antibacterial efficacy enjoyed by comparably constructed QACs, with three structures in the single-digit micromolar activity range despite structural simplification.

Developing wipe sampling strategy guidance for assessing environmental contamination of antineoplastic drugs.

Surveillance for environmental contamination of antineoplastic drugs has been recommended by authoritative bodies such as the United States Pharmacopeia and the National Association of Pharmacy Regulatory Authorities. Clear guidance is needed on how to develop sampling strategies that align with surveillance objectives efficiently and effectively. We conducted a series of simulations using previously collected surveillance data from nine cancer treatment centers to evaluate different sampling strategies. We evaluated the impact of sampling 2, 5, 10, or 20 surfaces, at monthly, quarterly, semi-annual, and annual frequencies, while employing either a random or sentinel surface selection strategy to assess contamination by a single antineoplastic drug (AD) or by a panel of three ADs. We applied two different benchmarks: a binary benchmark of above or below the limit of detection and AD-specific hygienic guidance values, based on 90th percentile values as quantitative benchmarks. The use of sentinel surfaces to evaluate a three-drug panel relative to 90th percentile hygienic guidance values (HGVs) resulted in the most efficient and effective surveillance strategy.

Vaping Flavors and Flavor Representation: A Test of Youth Risk Perceptions, Novelty Perceptions, and Susceptibility.

INTRODUCTION: Whether novelty-flavored vaping devices should be available in the marketplace has been a hotly contested debate. From one perspective, the variety of different flavors, such as fruit and mint, may help adult cigarette smokers who are seeking to switch to reduced-harm nicotine products. However, these flavors are also wildly popular among youth, creating concerns about new nicotine product use among minors. AIMS AND METHODS: This experiment (n = 176) tests whether vaping flavors (tobacco vs fruit) and flavor representations on packages (flavor color, flavor image) influence how middle school youth perceive vaping products. RESULTS: While results show no difference in risk perceptions based on condition, novelty perceptions (eg, how fun, interesting) and susceptibility to vaping are highest among those who view the fruit-flavored vaping product with flavor color and flavor image. Those who viewed this condition reported higher novelty perceptions and susceptibility than those who viewed the fruit-flavored vaping product with no flavor color and no flavor image. Additionally, they reported higher novelty perceptions than those who viewed the tobacco-flavored vaping product with flavor color and flavor image. A post-hoc analysis in supplemental data shows that youth who report lower risk perceptions and higher susceptibility have higher behavioral intentions to vape in the next year. CONCLUSION: Findings suggest that restricting flavor representation on packaging might reduce how fun and interesting youth perceive these products to be and how susceptible they are to using them.

Minimal Detectable Width of Tooth Fractures Using Magnetic Resonance Imaging and Method to Measure.

INTRODUCTION: Vertical root fracture (VRF) in root canal-treated (RCT) teeth is a common cause of pain, bone resorption, and tooth loss. VRF is also difficult to diagnose and measure. Magnetic resonance imaging (MRI) has the potential to identify VRF due to beneficial partial volume averaging, without using ionizing radiation. This investigation aimed to describe the narrowest VRFs detectable based on MRI, using micro-computed tomography (microCT) as the reference standard and proposes a method using profile integrals to measure the widths of small VRFs. METHODS: VRFs were induced in 62 RCT tooth root samples. All samples were imaged in a phantom using MRI and reference imaging was obtained using microCT. The stacks of 3-dimensional axial MRIs were assessed by 3 board-certified endodontists. Evaluators determined the most coronal slice within the stack that was discernible as the extent of the VRF. This slice was measured on correlated microCT sections to determine the minimum VRF width (µm) detectable using a profile integral-based method to measure small fractures and negate the effects of the point spread function. RESULTS: Using profile integrals to measure VRF width was repeatable and resulted in estimates that were on average 1 µm smaller than known reference widths. Adjusted median VRF width detected using MRI was 45 µm (first quartile: 26 µm, third quartile: 64 µm). CONCLUSION: Using profile integrals is a valid way to estimate small VRF width. The MRI approach demonstrated ability to repeatedly detect VRFs as small as 26 µm.

Development of a Multiprotein Classifier for the Detection of Early Stage Ovarian Cancer.

BACKGROUND: Individual serum biomarkers are neither adequately sensitive nor specific for use in screening the general population for ovarian cancer. The purpose of this study was to develop a multiprotein classifier to detect the early stages of ovarian cancer, when it is most treatable. METHODS: The Olink Proseek Multiplex Oncology II panel was used to simultaneously quantify the expression levels of 92 cancer-related proteins in sera. RESULTS: In the discovery phase, we generated a multiprotein classifier that included CA125, HE4, ITGAV, and SEZ6L, based on an analysis of sera from 116 women with early stage ovarian cancer and 336 age-matched healthy women. CA125 alone achieved a sensitivity of 87.9% at a specificity of 95%, while the multiprotein classifier resulted in an increased sensitivity of 91.4%, while holding the specificity fixed at 95%. The performance of the multiprotein classifier was validated in a second cohort comprised of 192 women with early stage ovarian cancer and 467 age-matched healthy women. The sensitivity at 95% specificity increased from 74.5% (CA125 alone) to 79.2% with the multiprotein classifier. In addition, the multiprotein classifier had a sensitivity of 95.1% at 98% specificity for late stage ovarian cancer samples and correctly classified 80.5% of the benign samples using the 98% specificity cutpoint. CONCLUSIONS: The inclusion of the proteins HE4, ITGAV, and SEZ6L improved the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer in serum samples. Furthermore, we identified several proteins that may be novel biomarkers of early stage ovarian cancer.

Prediction Model for Croup Admission Need.

OBJECTIVES: This study aims to generate a predictive model stratifying the probability of requiring hospitalization and inpatient respiratory intervention for croup patients presenting to the emergency department (ED), and secondarily to compare the model's performance with that of ED providers. METHODS: Retrospective data was collected on croup patients presenting to the EDs of 2 pediatric and 1 community hospital from 2019 to 2020, including demographics, preexisting conditions, and history of croup. The ED length of stay, previous dexamethasone administration, time to ED dexamethasone, number of ED racemic epinephrine doses, viral testing, and ED revisits were also recorded. Westley croup scores were derived at ED presentation and final disposition. For admitted patients, any respiratory interventions were recorded. Admission need was defined as either admitted and required an inpatient intervention or not admitted with ED revisit. A prediction model for admission need was fit using L1-penalized logistic regression. RESULTS: We included 2951 patients in the study, 68 (2.3%) of which needed admission. The model's predictors were disposition Westley croup scores, number of ED racemic epinephrine doses, previous dexamethasone administration, and history of intubation. The model's sensitivity was 66%, specificity was 91%, positive predictive value was 15%, and negative predictive value was 99%. ED providers' performance had a sensitivity of 72%, a specificity of 94%, a positive predictive value of 23%, and a negative predictive value of 99%. CONCLUSIONS: The croup admission need predictive model appears to support clinical decision making in the ED, with the potential to improve decision making when pediatric expertise is limited.

Quaternary Phosphonium Compounds: An Examination of Non-Nitrogenous Cationic Amphiphiles That Evade Disinfectant Resistance.

Quaternary ammonium compounds (QACs) serve as mainstays in the formulation of disinfectants and antiseptics. However, an over-reliance and misuse of our limited QAC arsenal has driven the development and spread of resistance to these compounds, as well as co-resistance to common antibiotics. Extensive use of these compounds throughout the COVID-19 pandemic thus raises concern for the accelerated proliferation of antimicrobial resistance and demands for next-generation antimicrobials with divergent architectures that may evade resistance. To this end, we endeavored to expand beyond canonical ammonium scaffolds and examine quaternary phosphonium compounds (QPCs). Accordingly, a synthetic and biological investigation into a library of novel QPCs unveiled biscationic QPCs to be effective antimicrobial scaffolds with improved broad-spectrum activities compared to commercial QACs. Notably, a subset of these compounds was found to be less effective against a known QAC-resistant strain of MRSA. Bioinformatic analysis revealed the unique presence of a family of small multiresistant transporter proteins, hypothesized to enable efflux-mediated resistance to QACs and QPCs. Further investigation of this resistance mechanism through efflux-pump inhibition and membrane depolarization assays illustrated the superior ability of P6P-10,10 to perturb the cell membrane and exert the observed broad-spectrum potency compared to its commercial counterparts. Collectively, this work highlights the promise of biscationic phosphonium compounds as next-generation disinfectant molecules with potent bioactivities, thereby laying the foundation for future studies into the synthesis and biological investigation of this nascent antimicrobial class.

Learning and Attention Deficit/Hyperactivity Disorders as Risk Factors for Prolonged Concussion Recovery in Children and Adolescents.

OBJECTIVE: Examine pre-existing learning disorders (LD) and attention deficit/hyperactivity disorders (ADHD) as risk factors for prolonged recovery and increased symptomology following pediatric mild traumatic brain injury (mTBI). METHODS: We conducted a retrospective cohort study of children/adolescents (5-17 years) with mTBI who presented to a Children's Minnesota Concussion Clinic between April 2018 and March 2019. Differences across strata of pre-existing conditions (present vs. absent) in time to recovery measures were estimated via Kaplan-Meier and Cox proportional hazards analyses and differences in symptom trajectories were examined via linear mixed-effects regression models. Regression models were adjusted for age, sex and other confounders. RESULTS: In our cohort of 680 mTBI patients, those with LD (n = 70) or ADHD (n = 107) experienced significantly longer median durations of symptoms (58 and 68 days, respectively) than those without (43 days). Accordingly, LD was significantly associated with delayed symptom recovery (adjusted hazard ratio (aHR) = 1.63, 95% CI: 1.16-2.29), return to school (1.47, 1.08-2.00), and return to physical activity (1.50, 1.10-2.04). Likewise, ADHD was associated with delayed recovery (1.69, 1.28-2.23), return to school (1.52, 1.17-1.97) and physical activity (1.55, 1.19-2.01). Further, patients with LD or ADHD reported, on average, significantly more concussion symptoms and higher vision symptom scores throughout recovery versus those without. There was no evidence that concussion or vision symptom recovery trajectories varied over time between those with/without LD or ADHD (joint P-interactions > 0.05). CONCLUSION: Pre-existing LD and ADHD are risk factors for prolonged and more symptomatic mTBI recovery in youth. These results can inform clinical concussion management and recovery expectations.

Differentiation of Human iPS Cells Into Sensory Neurons Exhibits Developmental Stage-Specific Cryopreservation Challenges.

Differentiation of human induced pluripotent stem cells (hiPSCs) generates cell phenotypes valuable for cell therapy and personalized medicine. Successful translation of these hiPSC-derived therapeutic products will rely upon effective cryopreservation at multiple stages of the manufacturing cycle. From the perspective of cryobiology, we attempted to understand how the challenge of cryopreservation evolves between cell phenotypes along an hiPSC-to-sensory neuron differentiation trajectory. Cells were cultivated at three different stages to represent intermediate, differentiated, and matured cell products. All cell stages remained ≥90% viable in a dimethyl sulfoxide (DMSO)-free formulation but suffered ≥50% loss in DMSO before freezing. Raman spectroscopy revealed higher sensitivity to undercooling in hiPSC-derived neuronal cells with lower membrane fluidity and higher sensitivity to suboptimal cooling rates in stem cell developmental stages with larger cell bodies. Highly viable and functional sensory neurons were obtained following DMSO-free cryopreservation. Our study also demonstrated that dissociating adherent cultures plays an important role in the ability of cells to survive and function after cryopreservation.

Spatial and Temporal Variability in Antineoplastic Drug Surface Contamination in Cancer Care Centers in Alberta and Minnesota.

The health risks of exposure to antineoplastic drugs (ADs) are well established, and healthcare professionals can be exposed while caring for cancer patients receiving AD therapy. Studies conducted worldwide over the past two decades indicate continuing widespread surface contamination by ADs. No occupational exposure limits have been established for ADs, but concerns over exposures have led to the development of guidelines, such as United States Pharmacopeia (USP) General Chapter <800> Hazardous Drugs-Handling in Healthcare. While recommending regular surveillance for surface contamination by ADs these guidelines do not provide guidance on sampling strategies. Better characterization of spatial and temporal variability of multidrug contamination would help to inform such strategies. We conducted surface-wipe monitoring of nine cancer care centers in Alberta, Canada and Minnesota, USA, with each center sampled eight times over a 12-month period. Twenty surfaces from within pharmacy and drug administration areas were sampled, and 11 drugs were analyzed from each wipe sample. Exposure data were highly left-censored which restricted data analysis; we examined prevalence of samples above limit of detection (LOD), and used the 90th percentile of the exposure distribution as a measure of level of contamination. We collected 1984 wipe samples over a total of 75 sampling days resulting in 21 824 observations. Forty-five percent of wipe samples detected at least one drug above the LOD, but only three of the drugs had more than 10% of observations above the LOD: gemcitabine (GEM) (24%), cyclophosphamide (CP) (16%), and paclitaxel (13%). Of 741 wipe samples with at least one drug above LOD, 60% had a single drug above LOD, 19% had two drugs, and 21% had three drugs or more; the maximum number of drugs found above LOD on one wipe was 8. Surfaces in the compounding area of the pharmacy and in the patient area showed the highest prevalence of samples above the LOD, including the compounding work surface, drug fridge handle, clean room cart, passthrough tray, and hazardous drug room temperature storage, the IV pump keypad, patient washroom toilet handle, patient washroom door handle, nurses' storage shelf/tray, and patient side table. Over the course of the study, both 90th percentiles and prevalence above LOD varied without clear temporal patterns, although some centers appeared to show decreasing levels with time. Within centers, the degree of variability was high, with some centers showing changes of two to three orders of magnitude in the 90th percentile of drug concentrations month to month. A clear difference was observed between the six centers located in Alberta and the three in Minnesota, with Minnesota centers having substantially higher percentages of samples above the LOD for CP and GEM. Other factors that were associated with significant variability in exposures were drug compounding volume, size of center, number of patients seen, and age of the center. We hope that demonstrating variability associated with drug, surface, clinic-factors, and time will aid in a better understanding of the nature of AD contamination, and inform improved sampling strategies.

Temporomandibular disorder-related characteristics and treatment outcomes in Oromandibular Dystonia patients in two different clinical settings: A cross-sectional study.

INTRODUCTION: Clinical presentation of oromandibular dystonia (OMD) is variable that can be further complicated by the presence of temporomandibular disorder (TMD) symptoms. We sought to evaluate variations in the clinical presentation of OMD patients, particularly TMD-related characteristics, in two clinical settings. METHODS: In a cross-sectional study design, a Web-based data collection survey was provided to eligible patients with OMD from movement disorder (MD) and oro-facial pain (OFP) clinics. The survey questionnaire was designed to collect information on demographic characteristics, clinical presentation particularly related to TMD, quality of life and treatment outcomes. Validated questionnaires were used when available such as the TMD Pain Screener, EuroQol 5-Dimensions 5-Levels (EQ-5D-5L), Jaw Functional Limitation Scale and Global Rating of Change Scale. RESULTS: Of 53 eligible patients, 31 responded to the survey for a 58% response rate. Forty-eight per cent of patients in the MD clinic and 60% of patients in the OFP clinic reported jaw pain along with involuntary movements. Of those, 90% from the MD group and 83% from the OFP group screened positive with the TMD Pain Screener at the onset of symptoms based on recall. Positive TMD Pain Screener response was observed in about 40% of patients in both clinics within 30 days of questionnaire response. No statistically significant differences were observed between two groups for any measured variables. CONCLUSION: Patients with OMD have features of TMD, irrespective of the clinical setting in which they seek and receive care. OMD patients from both clinics were similar in terms of clinical presentation, quality of life and treatment outcomes.