Search

Most of the available methods of settlement prediction for foundations on stone-column-reinforced grounds assume infinitely extended foundations on infinite grids of columns. Nevertheless, the real performance of a foundation with finite size is believed to differ from that of a corresponding foundation with infinite size. In the current paper, foundations with real sizes in the common engineering range are analysed. To cover various site conditions, both homogeneous and stratified weak soils are considered. In order to obtain reliable results, a well-tested advanced nonlinear finite element code is used in the modelling. Moreover, field load test results are utilised to calibrate the mathematical model. In the simulation, the post-installation in situ stress state is included in order to ensure that the mathematical model is capable of reproducing the field settlement records. It was shown that composite grounds with the same stone replacement ratio under structures with different sizes lead to different settlement improvement degrees. [ABSTRACT FROM AUTHOR]

An investigation was carried out to study the effect of the vibro-installation of stone columns on the soil state of stress. Post-installation soil parameters and load-settlement records were utilised to back-calculate the ratio of horizontal to vertical soil stress, K*. The load-settlement records were taken from a full-scale field load test, carried out on a single column within an extended group of stone columns. A coupled non-linear finite element formulation was utilised to simulate the test steps and the relevant settlement rate criterion. Post-installation soil parameters were adopted in the simulation in order to account for any vibration- and/or displacement-induced changes in the soil properties. The investigation revealed that the vibro-installation of stone columns significantly alters the soil state of stress. A practical range for the post-installation lateral earth pressure ratio, K*, in the analysed case was deduced. [ABSTRACT FROM AUTHOR]

Introduction: Leadership style and employee behavior has long been a topic of interest in organizational research., Objectives: To explore levels of despotic leadership, supervisor-employee value congruence, and organizational deviance among the studied nurses. Furthermore, to explore the connection between the three variables., Methods: The study employed a cross-sectional quantitative design. The researchers used three tools as follows: the despotic leadership survey, an organizational deviance scale, and a perceived supervisor-employee value congruence scale. The first of April 2023 to the first of July 2023 were the 3 months that were used to collect the data from 250 nurses. The data were analyzed using descriptive statistics, Spearman's correlation, Kruskal-Wallis test, and Mann-Whitney U test., Results: Nurses perceived a moderate level of despotic leadership as mean ±  SD , 16.80 ± 3.01, also a moderate level for organizational deviance (30.63 ± 4.65). The studied nurses perceived a moderate level of supervisor-employee value congruence (10.93 ± 1.32) Furthermore, there is a solid positive significant relationship between despotic leadership and organizational deviance where p  = .001. There is a negative significant relationship between despotic leadership and supervisor-employee value congruence where p  = .001. Also, there is a negative significant relationship between organizational deviance and supervisor-employee value congruence where p  = .001., Conclusion: Nurse managers need to retain leaders to inspire subordinates' uncluttered communication networks, stirring nurses' partaking in nursing committees' assemblies, and decision-making. Hospital administrators ought to focus more on the role that value congruence plays as a buffer for subordinates who exhibit organizational deviance and high levels of mistrust. Strategies should be employed to create and maintain value congruence and reinforce desired nondeviant behaviors to foster a positive work environment., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Study Design: Narrative review., Objectives: Artificial intelligence (AI) is being increasingly applied to the domain of spine surgery. We present a review of AI in spine surgery, including its use across all stages of the perioperative process and applications for research. We also provide commentary regarding future ethical considerations of AI use and how it may affect surgeon-industry relations., Methods: We conducted a comprehensive literature review of peer-reviewed articles that examined applications of AI during the pre-, intra-, or postoperative spine surgery process. We also discussed the relationship among AI, spine industry partners, and surgeons., Results: Preoperatively, AI has been mainly applied to image analysis, patient diagnosis and stratification, decision-making. Intraoperatively, AI has been used to aid image guidance and navigation. Postoperatively, AI has been used for outcomes prediction and analysis. AI can enable curation and analysis of huge datasets that can enhance research efforts. Large amounts of data are being accrued by industry sources for use by their AI platforms, though the inner workings of these datasets or algorithms are not well known., Conclusions: AI has found numerous uses in the pre-, intra-, or postoperative spine surgery process, and the applications of AI continue to grow. The clinical applications and benefits of AI will continue to be more fully realized, but so will certain ethical considerations. Making industry-sponsored databases open source, or at least somehow available to the public, will help alleviate potential biases and obscurities between surgeons and industry and will benefit patient care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Neurosurgeons and hospitals devote tremendous resources to improving recovery from lumbar spine surgery. Current efforts to predict surgical recovery rely on one-time patient report and health record information. However, longitudinal mobile health (mHealth) assessments integrating symptom dynamics from ecological momentary assessment (EMA) and wearable biometric data may capture important influences on recovery. Our objective was to evaluate whether a preoperative mHealth assessment integrating EMA with Fitbit monitoring improved predictions of spine surgery recovery., Methods: Patients age 21-85 years undergoing lumbar surgery for degenerative disease between 2021 and 2023 were recruited. For up to 3 weeks preoperatively, participants completed EMAs up to 5 times daily asking about momentary pain, disability, depression, and catastrophizing. At the same time, they were passively monitored using Fitbit trackers. Study outcomes were good/excellent recovery on the Quality of Recovery-15 (QOR-15) and a clinically important change in Patient-Reported Outcomes Measurement Information System Pain Interference 1 month postoperatively. After feature engineering, several machine learning prediction models were tested. Prediction performance was measured using the c-statistic., Results: A total of 133 participants were included, with a median (IQR) age of 62 (53, 68) years, and 56% were female. The median (IQR) number of preoperative EMAs completed was 78 (61, 95), and the median (IQR) number of days with usable Fitbit data was 17 (12, 21). 63 patients (48%) achieved a clinically meaningful improvement in Patient-Reported Outcomes Measurement Information System pain interference. Compared with traditional evaluations alone, mHealth evaluations led to a 34% improvement in predictions for pain interference (c = 0.82 vs c = 0.61). 49 patients (40%) had a good or excellent recovery based on the QOR-15. Including preoperative mHealth data led to a 30% improvement in predictions of QOR-15 (c = 0.70 vs c = 0.54)., Conclusion: Multimodal mHealth evaluations improve predictions of lumbar surgery outcomes. These methods may be useful for informing patient selection and perioperative recovery strategies., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Vitiligo, a common dermatological disorder in Saudi Arabia, is associated with significant psychological impacts. This study explores the relationship between vitiligo and the severity of major depressive disorder (MDD), highlighting the broader implications on mental health among affected individuals., Objective: We aim to assess the prevalence and predictors of depression among adult patients with vitiligo, and to examine the relationship between MDD severity and vitiligo., Methods: Using a cross-sectional design, the research used the vitiligo area severity index and the Patient Health Questionnaire-9 to measure the extent of vitiligo and depression severity, respectively. This study involved 340 diagnosed patients with vitiligo from various health care settings. Logistic and ordinal regression analysis were applied to evaluate the impact of sociodemographic variables and vitiligo types on MDD severity., Results: The prevalence of MDD was 58.8% (200/340) of participants. Depression severity varied notably: 18.2% (62/340) of patients experienced mild depression, 17.9% (61/340) moderate, 11.8% (40/340) moderately severe, and 10.9% (37/340) severe depression. Female patients had higher odds of severe depression than male patients (adjusted odds ratio [aOR] 3.14, 95% CI 1.93-5.1; P<.001). Age was inversely related to depression severity, with patients aged older than 60 years showing significantly lower odds (aOR 0.1, 95% CI 0.03-0.39; P<.001). Lower income was associated with higher depression severity (aOR 10.2, 95% CI 3.25-31.8; P<.001). Vitiligo types also influenced depression severity; vulgaris (aOR 5.3, 95% CI 2.6-10.9; P<.001) and acrofacial vitiligo (aOR 2.8, 95% CI 1.5-5.1; P<.001) were significantly associated with higher depression levels compared to focal vitiligo., Conclusions: The findings suggest that vitiligo contributes to an increased risk of severe depression, highlighting the need for integrated dermatological and psychological treatment approaches to address both the physical and mental health aspects of the disease., (©Amr Molla, Raed Jannadi, Hamza Alayoubi, Haya Altouri, Maryam Balkhair, Dareen Hafez. Originally published in JMIR Dermatology (http://derma.jmir.org), 12.07.2024.)

Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Stock and Employment from Foundation Medicine, Inc: D.R.Z., A.F., Y.H., C.G., M.C., C.X., D.J., B.W., P.P., W.C., P.H., J.H., L.D., A.Y. Stock and Employment from Natera: E.R., J.S., A.K., W.G., G.B., C.H., R.R., L.R., D.H., D.S., V.P., M.D., S.F. Stock and Employment from F. Hoffmann-La Roche: C.C., N.D., V.D., P.G., S.M. Honararia- Astellas, Pfizer, Seagen, BMS, Roche, Astra-Zeneca, MSD, Natera, Merck Serono, Johnson and Johnson - T.P. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Zollinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dyslexia-a learning disorder characterized by difficulty in word-level reading skills-can negatively impact nursing students' practice, which can, in turn, affect patient safety. Individuals with dyslexia are often stigmatized. There is a need to explore dyslexia awareness among nursing students and its relationship with stigma in Saudi Arabia., Objective: This study aimed to assess the dyslexia awareness levels among nursing students and its relation to stigma., Methods: A quantitative cross-sectional study was conducted on 154 nursing students at King Abdulaziz University, Saudi Arabia. Data were collected by asking the students to virtually complete the Knowledge and Beliefs about Developmental Dyslexia Scale (KBDDS) and the Consciousness Questionnaire-Learning Disabilities (SCQ-LD) from February to March 2021. Data were analyzed using chi-square tests to test significance and Cramer's V to determine the strength of the relationships among the categorical variables., Results: The overall dyslexia awareness level was moderate. Most participants believed that people had negative assumptions about individuals with dyslexia and that they judged and treated them differently. A moderately strong positive association was revealed between knowledge of the stigma surrounding dyslexia and knowledge of dyslexia itself ( p <0.001)., Conclusions: Increased dyslexia awareness is correlated with greater anticipation that dyslexic individuals will be stigmatized. Therefore, dyslexia awareness should be raised among nursing students. Students or nurses with dyslexia should also be encouraged to learn appropriate coping strategies to ensure patient safety., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2023.)

Objective: The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children., Methods: Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed., Results: A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications., Conclusions: SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

While young Saudi adults are reportedly prone to experiencing a variety of mental health problems, they tend to delay seeking mental health support. Therefore, this study aimed to explore the barriers and facilitators of seeking mental health support among young adults in Saudi Arabia. A qualitative research design was implemented using semi-structured interviews with 12 young adult participants in Saudi Arabia, recruited through social media platforms, and the interviews were then analyzed using thematic analysis. Two major themes emerged: barriers that impede the process of mental health help-seeking and facilitators that assist individuals in seeking mental health support. The barriers included public stigma and lack of awareness, unprofessional mental health practitioners, lack of accessibility to services and information, unsupportive families, intrapersonal dilemmas, and misconceptions based on religious beliefs. Facilitators of help-seeking included increasing societal and family awareness, promoting the accessibility of services, enhancing sources of external support, personal motivation to change, and online therapy. The findings of this study emphasize the importance of promoting mental health literacy among the Saudi public, particularly with regard to young adults and their unique mental health needs. Exploring facilitators and barriers may also assist mental health providers in developing tailored mental health campaigns and interventions directed at young adults.

Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates., Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples ( n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing., Results: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7-13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4-167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography., Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making. See related commentary by Morris and George, p. 438 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance., (© 2021. The Author(s).)

Importance: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC)., Objective: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance., Design, Setting, and Participants: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years., Main Outcomes and Measures: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival., Results: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients (88.5%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P < .001). Similarly, shortly after ACT ctDNA-positive patients were 17 times (HR, 17.5; 95% CI, 5.4-56.5; P < .001) more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 43.5; 95% CI, 9.8-193.5 P < .001). In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples., Conclusions and Relevance: Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer., Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples ( n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X)., Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling., Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention., (©2019 American Association for Cancer Research.)

Purpose: Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy., Patients and Methods: We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses., Results: Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence ( P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging ( P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods., Conclusion: ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

Background: Greater purpose in life is associated with lower rates of certain chronic diseases. Whether purpose in life can protect against development of prediabetes or type 2 diabetes is unknown., Purpose: To examine the association between purpose in life and blood glucose control among adults ≥50 years., Methods: We conducted a longitudinal cohort study of 3,907 participants of the Health and Retirement Study who at baseline did not have type 2 diabetes or prediabetes. Baseline purpose in life was measured using the Ryff and Keyes' Scales of Psychological Well-Being and grouped into tertiles (high, medium, and low). We used multivariable linear regression to examine the association between baseline purpose in life and HbA1c over 4 years. Multivariable logistic regression was used to examine the association between baseline purpose and incident prediabetes or type 2 diabetes over the same period., Results: After adjusting for sociodemographic factors, body mass index, physical activity, and physical and mental health factors, HbA1c was 0.07 percentage points lower among participants with high purpose than those with low purpose (95% confidence interval [CI] -0.12 to -0.02; p = .011). Participants with high purpose had lower odds of developing prediabetes or type 2 diabetes than those with low purpose (adjusted odds ratio 0.78; 95% CI 0.62 to 0.98; p = .037)., Conclusions: Among older adults, greater purpose in life is associated with a lower incidence of prediabetes or type 2 diabetes. Strategies to promote greater purpose in life should be tested as a part of type 2 diabetes prevention efforts.

Objectives: To characterize patterns of emergency department (ED) utilization for ambulatory care-sensitive conditions (ACSCs) among patients with established care within a patient-centered medical home., Study Design: Retrospective chart review using Michigan Medicine's (formerly University of Michigan Health System) electronic health record., Methods: Ten general medicine (GM) physicians reviewed 256 ambulatory care-sensitive ED encounters that occurred between January 1, 2014, and December 31, 2014, among patients of a GM medical home. Physician reviewers abstracted from the medical record the day and time of ED presentation and the source of ED referral (eg, patient self-referral vs physician referral). Physicians assessed the appropriateness of the care location (eg, ED vs primary care). Interrater reliability was assessed using the kappa statistic, and the χ2 test was used to assess differences in the appropriateness of the care location according to ED referral source., Results: Compared with all other days of the week, the fewest number of ED visits occurred on weekend days, and nearly half of patients (48%) presented to the ED after daytime hours, which were defined as 8 am to 3:59 pm. The majority (n = 185; 72%) of patients were self-referred to the ED. The ED was considered the appropriate care location in more than half (53%) of the reviewed cases. Among the 119 cases considered appropriate for GM management, the majority (86%) were self-referred to the ED., Conclusions: Patients with ACSCs often presented to the ED without contacting their medical home. Frequently, the ED is the most appropriate location given symptoms at presentation.

This corrects the article DOI: 10.1038/nature22364.

Precalcaneal congenital fibrolipomatous hamartoma is a benign condition of infancy that is sometimes misdiagnosed due to lack of reports in the literature. Lesions usually present with painless, non-pruritic, skin colored bilateral, solitary, symmetric nodules located in the middle of the heels. The lesions gradually increase in size and then regress by the age of 2 to3 years old.

Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.

Purpose of Review: The purpose of this paper was to review studies of behavioral economic interventions (financial incentives, choice architecture modifications, or commitment devices) to prevent type 2 diabetes mellitus (T2DM) among at-risk patients or improve self-management among patients with T2DM., Recent Findings: We found 15 studies that used varied study designs and outcomes to test behavioral economic interventions in clinical, workplace, or health plan settings. Of four studies that focused on prevention of T2DM, two found that financial incentives increased weight loss and completion of a fasting blood glucose test, and two choice architecture modifications had mixed effects in encouraging completion of tests to screen for T2DM. Of 11 studies that focused on improving self-management of T2DM, four of six tests of financial incentives demonstrated increased engagement in recommended care processes or improved biometric measures, and three of five tests of choice architecture modifications found improvements in self-management behaviors. Though few studies have tested behavioral economic interventions for prevention or treatment of T2DM, those that have suggested such approaches have the potential to improve patient behaviors and such approaches should be tested more broadly.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Background: Early diagnosis and treatment of prediabetes and type 2 diabetes mellitus (T2DM) can prevent future health problems, yet many individuals with these conditions are undiagnosed. This could be due, in part, to primary care physicians' (PCP) screening practices, about which little is known. The objectives of this study were to identify factors that influence PCPs' decisions to screen patients for T2DM and to characterize their interpretation and communication of screening test results to patients., Methods: We conducted semi-structured chart-stimulated recall interviews with 20 University of Michigan Health System (UMHS) primary care physicians. PCPs were asked about their recent decisions to screen or not screen 134 purposively sampled non-diabetic patients who met American Diabetes Association criteria for screening for T2DM. Interviews were audio-recorded, transcribed, and analyzed using qualitative directed content analysis. Data on patient demographic characteristics and comorbidities were abstracted from the electronic health record., Results: The most common reasons PCPs gave for not screening 63 patients for T2DM were knowledge of a previously normal screening test (49%) and a visit for reasons other than a health maintenance examination (48%). The most common reasons PCPs gave for screening 71 patients for T2DM were knowledge of a previously abnormal screening test (49%), and patients' weight (42%) and age (38%). PCPs correctly interpreted 89% of screening test results and communicated 95% of test results to patients. Among 24 patients found to have prediabetes, PCPs usually (58%) recommended weight loss and increased physical activity but never recommended participation in a Diabetes Prevention Program or use of metformin., Conclusions: Previous screening test results, visit types, and patients' weight and age influenced PCPs' decisions to screen for T2DM. When patients were screened, test results were generally correctly interpreted and consistently communicated. Recommendations to patients with prediabetes could better reflect evidence-based strategies to prevent T2DM.

Background: Lifestyle interventions targeting weight loss, such as those delivered through the Diabetes Prevention Program, reduce the risk of developing type 2 diabetes. Technology-mediated interventions may be an option to help overcome barriers to program delivery, and to disseminate diabetes prevention programs on a larger scale., Objective: We conducted a meta-analysis to evaluate the effect of such technology-mediated interventions on weight loss., Methods: In this meta-analysis, six databases were searched to identify studies reporting weight change that used technology to mediate diet and exercise interventions, and targeted individuals at high risk for developing type 2 diabetes. Studies published between January 1, 2002 and August 4, 2016 were included., Results: The search identified 1196 citations. Of those, 15 studies met the inclusion criteria and evaluated 18 technology-mediated intervention arms delivered to a total of 2774 participants. Study duration ranged from 12 weeks to 2 years. A random-effects meta-analysis showed a pooled weight loss effect of 3.76 kilograms (95% CI 2.8-4.7; P<.001) for the interventions. Several studies also reported improved glycemic control following the intervention. The small sample sizes and heterogeneity of the trials precluded an evaluation of which technology-mediated intervention method was most efficacious., Conclusions: Technology-mediated diabetes prevention programs can result in clinically significant amounts of weight loss, as well as improvements in glycaemia in patients with prediabetes. Due to their potential for large-scale implementation, these interventions will play an important role in the dissemination of diabetes prevention programs., (©Rachel R Bian, Gretchen A Piatt, Ananda Sen, Melissa A Plegue, Mariana L De Michele, Dina Hafez, Christina M Czuhajewski, Lorraine R Buis, Neal Kaufman, Caroline R Richardson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 27.03.2017.)

Purpose of Review: This study aims to summarize the recent peer-reviewed literature on workplace interventions for prevention of type 2 diabetes mellitus (T2DM), including studies that translate the Diabetes Prevention Program (DPP) curriculum to workplace settings (n = 10) and those that use different intervention approaches to achieve the specific objective of T2DM prevention among employees (n = 3)., Recent Findings: Weight reduction was achieved through workplace interventions to prevent T2DM, though such interventions varied substantially in their effectiveness. The greatest weight loss was reported among intensive lifestyle interventions (i.e., at least 4 months in duration) that implemented the structured DPP curriculum (n = 3). Weight reduction was minimal among less intensive interventions, including those that substantially modified the DPP curriculum (n = 2) and those that used non-DPP intervention approaches to prevent T2DM (n = 3). Most studies (n = 12) reported increased levels of physical activity following the intervention. Implementation of the DPP in workplaces may be an effective strategy to prevent T2DM among employees.

Background: Polyadenylation is a key regulatory step in eukaryotic gene expression and one of the major contributors of transcriptome diversity. Aberrant polyadenylation often associates with expression defects and leads to human diseases., Results: To better understand global polyadenylation regulation, we have developed a polyadenylation sequencing (PA-seq) approach. By profiling polyadenylation events in 13 human tissues, we found that alternative cleavage and polyadenylation (APA) is prevalent in both protein-coding and noncoding genes. In addition, APA usage, similar to gene expression profiling, exhibits tissue-specific signatures and is sufficient for determining tissue origin. A 3' untranslated region shortening index (USI) was further developed for genes with tandem APA sites. Strikingly, the results showed that different tissues exhibit distinct patterns of shortening and/or lengthening of 3' untranslated regions, suggesting the intimate involvement of APA in establishing tissue or cell identity., Conclusions: This study provides a comprehensive resource to uncover regulated polyadenylation events in human tissues and to characterize the underlying regulatory mechanism.

Alzheimer's disease (AD) is the most prevalent form of dementia affecting the elderly. Evidence has emerged signifying that stimulation of the reelin pathway should promote neural plasticity and suppress molecular changes associated with AD, suggesting a potential therapeutic application to the disease. This was explored through the use of lentiviral vector-mediated overexpression of the reelin homolog, F-spondin, which is an activator of the reelin pathway. Intrahippocampal gene transfer of F-spondin improved spatial learning/memory in the Morris Water Maze and increased exploration of the novel object in the Novel Object Recognition test in wild-type mice. F-spondin overexpression also suppressed endogenous levels of amyloid beta (Aβ(42)) in these mice and reduced Aβ plaque deposition while improving synaptophysin expression in transgenic mouse models of AD. These data demonstrate pathologic and cognitive improvements in mice through F-spondin overexpression., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Intranasal administration is emerging as a reliable and non-invasive method to bypass the blood-brain barrier and deliver drugs to the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. However, intranasal administration could also be used to create animal models of brain disease. Beta-amyloid peptide (Aβ) accumulation is a key feature of Alzheimer's disease (AD), and the most common models of AD are transgenic mice expressing mutant human genes linked to familial AD. An alternative model of amyloidosis utilizes intracerebroventricular infusion of thiorphan or phosphoramidon to block the activity of key Aβ degrading enzymes (NEP, NEP2) resulting in accumulation of Aβ. Here, we demonstrate that intranasal administration of phosphoramidon produces significantly elevated cerebral Aβ levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also showed increased levels of Aβ(40). These data show that intranasal delivery of drugs can be used to model AD and suggest that other phosphoramidon-sensitive peptidases are degrading Aβ in NEP/NEP2-deficient mice.

Proteases that degrade the amyloid-β peptide (Aβ) are important in protecting against Alzheimer's disease (AD), and understanding these proteases is critical to understanding AD pathology. Endopeptidases sensitive to inhibition by thiorphan and phosphoramidon are especially important, because these inhibitors induce dramatic Aβ accumulation (∼30- to 50-fold) and pathological deposition in rodents. The Aβ-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases (∼1.5- to 2-fold) in Aβ, indicating that other thiorphan/phosphoramidon-sensitive endopeptidases are at work. Of particular interest is the NEP homolog neprilysin 2 (NEP2), which is thiorphan/phosphoramidon-sensitive and degrades Aβ. We investigated the role of NEP2 in Aβ degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total Aβ species in the hippocampus and brainstem/diencephalon (∼1.5-fold). Increases in Aβ accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, Aβ levels were marginally increased (∼1.5- to 2-fold), compared with NEP(-/-)/NEP2(+/+) controls. Treatment of these double-knockout mice with phosphoramidon resulted in elevations of Aβ, suggesting that yet other NEP-like Aβ-degrading endopeptidases are contributing to Aβ catabolism., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)