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In the design of buildings with minimal environmental impact, the incorporation of higher energy flexibility is becoming increasingly relevant. This approach is associated with dynamic modulations in setpoint temperatures. Until now, a link between indoor temperatures and cognitive performance of workers has been assumed, leading to high energy consumption and overcooling of office environments in summer conditions. However, research focusing on the relationship between thermal indoor environments and cognitive performance has rarely considered the influence of dynamic temperatures or temporal effects. This is the first experimental study aiming to understand the impact of temperature in relation to time of day on the subjective perception of cognitive load and performance under various thermal conditions in real-world office environments. The results indicated no observable relationship between temperature setpoints (25-30 °C) and cognitive performance. Instead, the temporal dynamics of cooling rather than fixed and static temperature setpoints appeared to have an impact., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Workers from various industries use personal protective equipment (PPE) including masks, respirators, and hearing protection to reduce their exposures to workplace hazards. Many studies have evaluated the physiological impacts of PPE use, but few have assessed the psychological impacts. The aim of the present study was to carry out a scoping review to compile existing evidence and determine the extent of knowledge on workplace mask, respirator or hearing protection use as a psychosocial hazard (stressor) that could result in a stress response and potentially lead to psychological injury., Methods: The scoping review followed recognized methods and was conducted using Ovid Emcare, PubMed, Sage Journals, ScienceDirect, Scopus, SpringerLink, Google Scholar and preprint databases (OSF Preprints and medRxiv). Articles on the stressors associated with the use of masks, respirators, and hearing protection were included. The extracted data included author(s) name, year of publication, title of article, study design, population data, stressors assessed, and key findings., Results: We retrieved 650 articles after removal of duplicates, of which 26 were deemed eligible for inclusion for review. Identified factors associated with PPE use that could potentially create a stress response were identified: communication impacts, physical impacts, psychological illness symptoms, cognitive impacts, and perceived PPE-related impacts. Evidence for respirators suggest that there may be psychological injury associated with their use. However, hearing protection appears to have a protective effect in reducing psychological symptoms such as anxiety, depression, and aggression., Conclusions: Mask or respirator use may lead to an increase in work-related stress. Whereas hearing protection may have protective effects against psychological symptoms and improves speech intelligibility. More research is needed to better understand potential psychosocial impacts of mask, respirator and/or hearing protection use., (© 2022. The Author(s).)

Introduction: Cardiac resynchronization therapy (CRT) improves outcomes in sinus rhythm, but the data in atrial fibrillation (AF) is limited. Atrio-ventricular junctional ablation (AVJA) has been proposed as a remedy. The objective was to test if AVJA results in LV end-systolic volume (ESV) reduction ≥ 15% from baseline to 6 months., Methods: The trial was a prospective multicenter randomized trial in 26 patients with permanent AF who were randomized 1:1 to CRT-D with or without AVJA., Results: LVESV improved similarly by at least 15% in 5/10 (50%) in the CRT-D-only arm and in 6/12 (50%) in the AVJA + CRT-D arm (OR = 1.00 [0.14, 7.21], p = 1.00). In the CRT-D-only arm, the median 6-month improvement in LVEF was 9.2%, not different from the AVJA + CRT-D arm, 8.2%. When both groups were combined, a significant increase in LVEF was observed (25.4% at baseline vs 36.2% at 6 months, p = 0.002). NYHA class from baseline to 6 months for all patients combined improved 1 class in 15 of 24 (62.5%), whereas 9 remained in the same class and 0 degraded to a worse class., Conclusion: In patients with permanent AF, reduced LVEF, and broad QRS who were eligible for CRT, there was insufficient evidence that AVJA improved echocardiographic or clinical outcomes; the results should be interpreted in light of a smaller than planned sample size. CRT, however, seemed to be effective in the combined study cohort overall, suggesting that CRT can be reasonably deployed in patients with AF., Trial Registration: ClinicalTrials.gov Identifier: NCT02946853., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This cross-sectional study explored the objectively measured Touchscreen Mobile Device (TSMD) use in free-living conditions. Data on TSMD use, gross body posture (lying, sitting, standing, stepping), and location of use (workplace, home, other) were collected over seven consecutive days from 54 adults (mean ± SD, 38 ± 10 years). The average duration of TSMD use was 152 ± 91 min/day, with a TSMD engagement of 51 ± 35 times/day. Participants under 30 years spent significantly more time on their TSMD, averaging 230 ± 108 min/day. By location, 54 ± 17% of use occurred at home and 24 ± 15% at work. The most common posture adopted during any TSMD use was sitting (77 ± 5 2 min/day), with participants also spending considerable time lying down in the home environment (39 ± 49 min/day). These findings provide valuable insights into how adults are using TSMDs, including the postures and locations of use. Further research is needed on the health and wellbeing implications of these usage patterns. Practitioner summary: This study explored Touchscreen Mobile Device (TSMD) use in free-living conditions among 54 adults (mean ± standard deviation, 38 ± 10 years). Participants under 30 years spent significantly more time on their devices. More than half of the time spent using TSMD occurred at home while sitting and lying down. Abbreviations: TSMD: touchscreen mobile device; SD: standard deviation; MSD: musculoskeletal disorder; HDR: higher degree by research; SEES: School of Earth and Environmental Sciences; UK: The United Kingdom; USA: United States of America; SAS: statistical analysis system; ANOVA: analysis of variance; SPSS: statistical package for the social sciences; h: hour; min/d: minutes per day; d: day; ICC: intraclass correlation; CI: confidence interval; min: minute; GPS: global positioning systemsHighlightsTouchscreen mobile device use and gross body posture were quantified objectively.The most common postures for touchscreen mobile device use were lying and sitting.Touchscreen mobile devices were used around twice as much at home than at work.Use at home, with a predominance of the lying posture, needs further investigation.

Importance: Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance., Objective: To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis., Design, Setting, and Participants: This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021., Main Outcomes and Measures: Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses., Results: Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years)., Conclusions and Relevance: In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Background: Docetaxel in combination with two HER2-directed therapies, trastuzumab and pertuzumab, is the current standard frontline therapy for patients with metastatic HER2-positive breast cancer. Ado-trastuzumab (T-DM1), an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule-inhibitory agent, emtansine, is approved in patients that have progressed with prior trastuzumab-based therapy. However, the benefit of T-DM1 in patients previously treated with pertuzumab therapy for metastatic breast cancer remains unclear., Methods: We identified thirty-three adults with metastatic HER2-positive breast cancer treated between March 2013 and July 2018 with T-DM1 either as subsequent therapy after progression on a pertuzumab-based regimen (i.e., "pertuzumab-pretreated") or without prior exposure to pertuzumab (i.e., "pertuzumab-naïve"). Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. For both cohorts receiving T-DM1, the primary endpoint was PFS and secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and T-DM1-related toxicity rate., Results: Pertuzumab-pretreated patients (n = 23, with 21 evaluable for T-DM1 efficacy) had a median PFS of 9.5 months (95% CI: 2.9-NA), 1-year OS rate of 67.4% (95% CI: 50.0-90.9%) with an unreached median, ORR of 14.3% (95% CI: 3.0-36.3%), and CBR of 52.4% (95% CI: 29.8-74.3%), with none of these measures being statistically different than those estimated for the pertuzumab-naïve group (n = 10). Treatment with T-DM1 after prior pertuzumab exposure (median T-DM1 duration 2.9 months) resulted in no grade ≥ 3 adverse events., Conclusions: In our cohort, prior exposure to pertuzumab did not significantly impact T-DM1's clinical efficacy or safety profile as second- or later-line therapy in patients with metastatic HER2-positive breast cancer., (© 2021. The Author(s).)

Our primary goal was to measure the NO (A) photoproduct appearance energy and ground-state dissociation energy of the N 2 -NO complex. We recorded velocity map ion images of NO photofragments resulting from the dissociation of the N 2 -NO complex excited between ∼225.8 and 224.0 nm, which ranged from the photodissociation threshold to about 342 cm -1 above the threshold. In the experiment, one photon dissociated the complex through the N 2 (X 1 Σ g + )-NO (A 2 Σ + ) ← N 2 (X 1 Σ g + )-NO (X 2 Π) transition, and a second photon nonresonantly ionized the NO (A) photoproduct. The lowest-energy photons near 225.8 nm did not have sufficient energy to photodissociate the lowest excited state of the complex; however, dissociation was observed with increasing photon energy. On the basis of the experiments, we determined the appearance energy for the NO (A) photoproduct to be 44 284.7 ± 2.8 cm -1 . From the appearance energy and the NO A ← X origin band transition, we determined a ground-state dissociation energy of 85.8 ± 2.8 cm -1 . As we increased the photon energy, the excess energy was partitioned into rotational modes of the diatomic products as well as product translational energy. We found good agreement between the average fraction of rotational energy and the predictions of a simple pseudo three atom impulsive model. Finally, at all photon energies, we observed some contribution from internally excited complexes in the resulting P (E T ). The maximum internal energy of these complexes was consistent with the ground-state dissociation energy.

Background: The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of patients with metastatic hormone receptor-positive breast cancer (mHRBC) who progress on nonsteroidal aromatase inhibitor (NSAI) therapy. However, none of the patients enrolled in the trial that led to this approval (BOLERO-2) had previously received CDK4/6 inhibitors (CDK4/6is), which have since become a frontline standard of care for mHRBC. As such, the clinical benefit of EVE plus EXE in patients who have previously received CDK4/6is remains unknown., Materials and Methods: Adult patients with mHRBC at our institution who progressed on an NSAI plus CDK4/6i or NSAI therapy alone and were treated with at least one cycle of EVE plus EXE between 2012 and 2018 were analyzed. Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. Primary objectives were to compare progression-free survival (PFS) and overall survival (OS) between patients who received prior NSAI plus CDK4/6i therapy versus an NSAI alone., Results: Among 43 patients, 17 had prior CDK4/6i exposure. With the exception of de novo metastatic disease, patient and disease characteristics were comparable across treatment cohorts. There was no significant difference in PFS (median, 3.6 vs. 4.2 months) or OS (median, 15.6 vs. 11.3 months) between patients who had received prior CDK4/6is and those who had not, respectively., Conclusion: Prior exposure to CDK4/6i therapy did not impact survival outcomes for patients with mHRBC taking EVE plus EXE. However, there was a trend toward improved OS in the CDK4/6i cohort that should be evaluated in larger cohorts., Implications for Practice: The use of CDK4/6 inhibitors in combination with a nonsteroidal aromatase inhibitor has become a standard frontline therapy in metastatic hormone receptor-positive breast cancer. An approved subsequent line of therapy is everolimus plus exemestane; however, the original data supporting this therapy predated approval of CDK4/6 inhibitors. As such, the clinical benefit of everolimus and exemestane in patients previously treated with a CDK4/6 inhibitor was unknown. This retrospective cohort study offers real-world data demonstrating prior CDK4/6 inhibitor exposure does not impact survival outcomes for everolimus plus exemestane., (© 2020 AlphaMed Press.)

Purpose: Conventionally fractionated, postoperative radiation therapy (cPORT; 50 Gy in 25 fractions) is considered for patients with Merkel cell carcinoma (MCC) to improve locoregional control. However, cPORT is associated with acute toxicity, especially in the head and neck (H&N) region, and requires daily treatments over several weeks. We previously reported high rates of durable local control with minimal toxicity using 8-Gy single-fraction radiation therapy (SFRT) in the metastatic setting. We report early results on a cohort of patients with localized H&N MCC who received postoperative SFRT if a cPORT regimen was not feasible., Methods and Materials: Twelve patients with localized MCC of the H&N (clinical/pathologic stages I-II) and no prior radiation therapy to the region were identified from an institutional review board-approved prospective registry who underwent surgical resection followed by postoperative SFRT. Time to event was calculated starting from the date of resection before SFRT. The cumulative incidence of in-field locoregional recurrences and out-of-field recurrences was estimated with death as a competing risk., Results: Twelve patients with H&N MCC were identified with clinical/pathologic stages I-II H&N MCC. Median age at diagnosis was 81 years (range, 58-96 years); 25% had immunosuppression. At a median follow-up of 19 months (range, 8-34), there were no in-field locoregional recurrences. A single out-of-field regional recurrence was observed, which was successfully salvaged. There were no MCC-specific deaths. No radiation-associated toxicities greater than grade 1 (Common Terminology Criteria for Adverse Events v5) were observed., Conclusions: Preliminary data suggest that SFRT could offer a potential alternative to cPORT to treat the primary site for localized H&N MCC, particularly in elderly or frail patients, with promising in-field local control and minimal toxicity. Further data with validation in larger cohorts are needed to confirm the sustained safety and efficacy of postoperative SFRT., (© 2020 The Authors.)

We used electronic medical record (EMR) data in the National Patient-Centered Clinical Research Network (PCORnet) to characterize "real-world" prescription patterns of Type 2 diabetes (T2D) medications. We identified a retrospective cohort of 613,203 adult patients with T2D from 33 datamarts (median patient number: 12,711) from 2012 through 2017 using a validated computable phenotype. We characterized outpatient T2D prescriptions for each patient in the 90 days before and after cohort entry, as well as demographics, comorbidities, non-T2D prescriptions, and clinical and laboratory variables in the 730 days prior to cohort entry. Approximately half of the individuals in the cohort were females and 20% Black. Hypertension (60.3%) and hyperlipidemia (50.5%) were highly prevalent. Most patients were prescribed either a single T2D drug class (42.2%) or had no evidence of a T2D prescription in the EMR (42.4%). A smaller percentage was prescribed multiple T2D drug types (15.4%). Among patients prescribed a single T2D drug type, metformin was the most common (42.6%), followed by insulin (18.2%) and sulfonylureas (13.9%). Newer classes represented approximately 13% of single T2D drug type prescriptions (dipeptidyl peptidase-4 inhibitors [6.6%], glucagon-like peptide-1 receptor agonists [2.5%], thiazolidinediones [2.0%], and sodium-glucose cotransporter-2 inhibitors [1.6%]). Among patients prescribed multiple T2D drug types, the most common combination was metformin and sulfonylureas (63.5%). Metformin-based regimens were highly prevalent in PCORnet's T2D population, whereas newer agents were prescribed less frequently. PCORnet is a novel source for the potential conduct of observational studies among patients with T2D., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Introduction: The purpose of this study was to compare bone mineral density (BMD) and bone turnover markers between combined oral contraceptive (COC) and non-COC users over 12 months., Materials and Methods: COC users (n = 34, age = 19.2 ± 0.5) and non-COC users (n = 28, age = 19.3 ± 0.6) provided serum at baseline, 6 months, and 12 months. C-terminal telopepetides (CTX) and pro-collagen type 1 N-terminal propeptides (P1NP) were determined using ELISA. BMD was measured at the three time points using dual-energy x-ray absorptiometry (DXA)., Results: COC users had greater CTX than non-COC users at baseline (18.6 ± 8.2 vs. 13.8 ± 5.3 ng/mL, P = 0.021) and 6 months (20.4 ± 10.3 vs. 14.2 ± 8.5 ng/mL, P = 0.018). Controlling for lean mass, groups were similar in BMD. Over 12 months, non-COC users maintained BMD at the spine, while the COC users declined 2.2% in lateral spine BMD (0.773 ± 0.014 to 0.756 ± 0.014 g/cm 2 , P = 0.03) and 0.7% in anterior-posterior spine BMD (1.005 ± 0.015 to 0.998 ± 0.015 g/cm 2 , P = 0.069). Non-COC users increased in BMD of the whole body over 12 months (P < 0.001) while COC users had no change. Women who began COCs within 4 years after menarche had lower BMD at the hip and whole body. Women taking very low dose COCs (20 mcg ethinyl estradiol, EE) significantly declined in CTX, P1NP, and lateral spine BMD in comparison to participants using low dose COCs (30/35 mcg EE)., Conclusion: College-aged women who did not use COCs increased BMD of the whole body, while COC users had elevated bone turnover, declines in spinal BMD, and lack of bone acquisition of the whole body over 12 months. Young females who initiate COC use early after menarche may experience skeletal detriments.

Intensive care unit (ICU) patients may experience ceftriaxone underexposure, but clinical outcomes data are lacking. The objective of this study was to determine the impact of ceftriaxone dosing on clinical outcomes among ICU patients without central nervous system (CNS) infection. A retrospective study of ICU patients receiving intravenous, empirical ceftriaxone for non-CNS infections was conducted. Patients ≥18 years of age who received ≤2 g of ceftriaxone daily for ≥72 h were included and categorized as receiving ceftriaxone 1 g or 2 g daily. The primary, composite outcome was treatment failure, defined as inpatient mortality and/or antibiotic escalation due to clinical worsening. Propensity score matching was performed based on the probability of receiving 2 g of ceftriaxone daily. Multivariable logistic regression determined the association between ceftriaxone dose and treatment failure in a propensity-matched cohort. A total of 212 patients were included in the propensity-matched cohort. The most common diagnoses (83.0%) were pneumonia and urinary tract infection. Treatment failure occurred in 17.0% and 5.7% of patients receiving 1 g and 2 g daily, respectively ( P =  0.0156). Overall inpatient mortality was 8.5%. Ceftriaxone 2 g dosing was associated with a reduced likelihood of treatment failure (adjusted odds ratio [aOR] = 0.190; 95% confidence interval [CI] = 0.059 to 0.607). Other independent predictors of treatment failure included sequential organ failure assessment score (aOR = 1.440; 95% CI = 1.254 to 1.653) and creatinine clearance at 72 h from ceftriaxone initiation (aOR = 0.980; 95% CI = 0.971 to 0.999). Therefore, ceftriaxone at 2 g daily, when used as appropriate antimicrobial coverage, may be appropriate for ICU patients with lower mortality risk., (Copyright © 2020 American Society for Microbiology.)

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8 + T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8 + T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8 + TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV + MCC had HLA alleles with the genetic potential that restrict CD8 + T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8 + TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity., (©2020 American Association for Cancer Research.)

Approximately one-third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing-risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non-regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I-III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin-only distant metastasis was associated with lower MCC-specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1-pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: PCORnet, the National Patient-Centered Clinical Research Network, represents an innovative system for the conduct of observational and pragmatic studies. We describe the identification and validation of a retrospective cohort of patients with type 2 diabetes (T2DM) from four PCORnet sites., Methods: We adapted existing computable phenotypes (CP) for the identification of patients with T2DM and evaluated their performance across four PCORnet sites (2012-2016). Patients entered the cohort on the earliest date they met one of three CP categories: (CP1) coded T2DM diagnosis (ICD-9/ICD-10) and an antidiabetic prescription, (CP2) diagnosis and glycosylated hemoglobin (HbA1c) ≥6.5%, or (CP3) an antidiabetic prescription and HbA1c ≥6.5%. We required evidence of health care utilization in each of the 2 prior years for each patient, as we also developed an incident T2DM CP to identify the subset of patients without documentation of T2DM in the 365 days before t 0 . Among a systematic sample of patients, we calculated the positive predictive value (PPV) for the T2DM CP and incident-T2DM CP using electronic health record (EHR) review as reference., Results: The CP identified 50 657 patients with T2DM. The PPV of patients randomly selected for validation was 96.2% (n = 1572; CI:95.1-97.0) and was consistently high across sites. The PPV for the incident-T2DM CP was 5.8% (CI:4.5-7.5)., Conclusions: The T2DM CP accurately and efficiently identified patients with T2DM across multiple sites that participate in PCORnet, although the incident T2DM CP requires further study. PCORnet is a valuable data source for future epidemiological and comparative effectiveness research among patients with T2DM., (© 2019 John Wiley & Sons, Ltd.)

Deletions and mutations involving the Retinoic Acid Induced 1 ( RAI1 ) gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo RAI1 gene mutation, c.3440G > A (p.R1147Q). We functionally characterized the RAI1 p.R1147Q mutant protein. The mutation, located near the nuclear localization signal, had no effect on the subcellular localization of the mutant protein. However, similar to previously reported RAI1 missense mutations in SMS patients, the RAI1 p.R1147Q mutant protein showed a significant deficiency in activating in vivo transcription of a reporter gene driven by a BDNF (brain-derived neurotrophic factor) intronic enhancer. In addition, expression of other genes associated with neurobehavioral abnormalities and/or neurodevelopmental disorders were found to be altered in this patient. These results suggest a likely contribution of RAI1, either alone or in combination of other factors, to social behavior and reinforce the RAI1 gene as a candidate gene in patients with autistic manifestations or social behavioral abnormalities.

To preserve environmental and human health, improved treatment processes are needed to reduce nutrients, microbes, and emerging chemical contaminants from domestic wastewater prior to discharge into the environment. Electrocoagulation (EC) treatment is increasingly used to treat industrial wastewater; however, this technology has not yet been thoroughly assessed for its potential to reduce concentrations of nutrients, a variety of microbial surrogates, and personal care products found in domestic wastewater. This investigation's objective was to determine the efficiency of a benchtop EC unit with aluminum sacrificial electrodes to reduce concentrations of the aforementioned biological and chemical pollutants from raw and tertiary-treated domestic wastewater. EC treatment resulted in significant reductions (p < 0.05, α = 0.05) in phosphate, all microbial surrogates, and several personal care products from raw and tertiary-treated domestic wastewater. When wastewater was augmented with microbial surrogates representing bacterial, viral, and protozoan pathogens to measure the extent of reduction, EC treatment resulted in up to 7-log10 reduction of microbial surrogates. Future pilot and full-scale investigations are needed to optimize EC treatment for the following: reducing nitrogen species, personal care products, and energy consumption; elucidating the mechanisms behind microbial reductions; and performing life cycle analyses to determine the appropriateness of implementation.

Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit., Objective: To examine whether CoQ10 could slow disease progression in early PD., Design, Setting, and Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation., Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E., Main Outcomes and Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo., Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo)., Conclusions and Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit., Trial Registration: clinicaltrials.gov Identifier: NCT00740714.

Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage(-) Sca-1(+) c-kit(+) (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice.

Hematopoietic stem cell (HSC) transplant is a well established curative therapy for some hematological malignancies. However, achieving adequate supply of HSC from some donor tissues can limit both its application and ultimate efficacy. The theory that this limitation could be overcome by expanding the HSC population before transplantation has motivated numerous laboratories to develop ex vivo expansion processes. Pioneering work in this field utilized stromal cells as support cells in cocultures with HSC to mimic the HSC niche. We hypothesized that through translation of this classic coculture system to a three-dimensional (3D) structure we could better replicate the niche environment and in turn enhance HSC expansion. Herein we describe a novel high-throughput 3D coculture system where murine-derived HSC can be cocultured with mesenchymal stem/stromal cells (MSC) in 3D microaggregates--which we term "micromarrows." Micromarrows were formed using surface modified microwells and their ability to support HSC expansion was compared to classic two-dimensional (2D) cocultures. While both 2D and 3D systems provide only a modest total cell expansion in the minimally supplemented medium, the micromarrow system supported the expansion of approximately twice as many HSC candidates as the 2D controls. Histology revealed that at day 7, the majority of bound hematopoietic cells reside in the outer layers of the aggregate. Quantitative polymerase chain reaction demonstrates that MSC maintained in 3D aggregates express significantly higher levels of key hematopoietic niche factors relative to their 2D equivalents. Thus, we propose that the micromarrow platform represents a promising first step toward a high-throughput HSC 3D coculture system that may enable in vitro HSC niche recapitulation and subsequent extensive in vitro HSC self-renewal.

Cardiovascular diseases, particularly acute myocardial infarction, are the leading causes of death worldwide. Important advances have been made in the secondary treatment for cardiovascular diseases such as heart transplantation and medical and surgical therapies. Although these therapies alleviate symptoms, and may even improve survival, none can reverse the disease process and directly repair the lasting damage. Thus, the cure of cardiovascular diseases remains a major unmet medical need. Recently, cellular therapy has been proposed as a candidate treatment for this. Many stem and progenitor cell populations have each been suggested as a potential basis for such therapy. This review assesses some of the more notable exogenous adult cell candidates and provides insights into the mechanisms by which they may mediate improvement in cardiac function following acute myocardial infarction. Research into the cellular therapy field is of great importance for the further planning of clinical trials for cardiac cellular myoplasty.

Mesenchymal stem cells or multipotent mesenchymal stromal cells (both referred to as MSC) have been shown in some studies to have a beneficial effect on myocardial recovery after infarct. Current strategies for MSC delivery to heart involve intravenous, intraarterial, and intramuscular delivery. Different routes of MSC delivery and a lack of knowledge of the mechanisms that MSC utilise to migrate in vivo has most likely led to the marked variations in results that have been found. This review aims to summarise the current knowledge of MSC migratory mechanisms and looks to future methods of MSC manipulation prior to delivery in order to enhance MSC migration and engraftment.

Previous studies have reported hyperphagia and obesity in female rats with bilateral lesions of the most posterodorsal part of the amygdala. In rats with unilateral posterodorsal amygdaloid lesions, a dense pattern of anterograde degeneration appears in the ipsilateral ventromedial hypothalamus, but not the contralateral nucleus. In the present study, female rats with unilateral ventromedial hypothalamic lesions or sham lesions were given either sham lesions or unilateral lesions of the posterodorsal amygdala (PDA) 20 days later. Unilateral lesions of the ventromedial hypothalamus resulted in hyperphagia and excessive weight gain. Subsequent amygdaloid lesions that were contralateral to the initial hypothalamic lesions resulted in hyperphagia and additional excessive weight gains, but amygdaloid lesions ipsilateral to the initial hypothalamic lesions did not. It is concluded that the effects of the two lesions on body weight are not additive and that the PDA and ventromedial hypothalamus are part of the same ipsilateral pathway regulating feeding behavior and body weight regulation.

The potential toxicity of ronidazole residues present in the tissues of food-producing animals was assessed using the Ames mutagenicity test. Since ronidazole is activated by reduction, reduced derivatives of ronidazole and metabolites formed by enzymatic reduction of ronidazole were tested for mutagenicity. When tested at levels several orders of magnitude higher than that at which ronidazole was mutagenic, 5-amino-4-S-cysteinyl-1,2- dimethylimidazole , a product of the dithionite reduction of ronidazole in the presence of cysteine, the 5-N-acetylamino derivative of ronidazole and 5-amino-1,2- dimethylimidazole all lacked mutagenic activity in Ames strain TA100. The metabolites of ronidazole formed by the incubation of ronidazole with microsomes under anaerobic conditions were also not mutagenic. These data demonstrate that although ronidazole is a potent mutagen, residues from it which may be present in the tissues of food-producing animals lack any mutagenic activity.