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Introduction: Therapeutic drug monitoring (TDM) has proven to be a valuable strategy for optimizing biologic therapies, among which are anti-tumor necrosis factor (anti-TNF) treatments in inflammatory bowel disease (IBD). In particular, reactive TDM has been shown to manage treatment failures more cost-effectively than empirical dose adjustments for anti-TNF drugs. However, several challenges currently impede the widespread adoption of TDM in clinical practice, particularly addressing the delay between sample collection and result availability. To overcome this limitation, the use of point-of-care technology tests (POCTs) is a potential solution. Point-of-care technology tests are medical diagnostic tests performed at the site of patient care to provide immediate results, allowing for quicker decision-making and treatment. The current standard of care (SOC) for drug level measurement relies on the enzyme-linked immunosorbent assay (ELISA), a method that is time-consuming and requires specialized personnel. This study aims to evaluate a novel, user-friendly, and efficient POCT method (ProciseDx Inc.) and compare its performance with the SOC ELISA in assessing infliximab and adalimumab levels in blood samples from IBD patients. Methods: In this prospective, single-center study, we collected blood samples from IBD patients, both CD and UC, receiving infliximab (87 IBD patients; 50% UC and 50% CD) or adalimumab (60 patients; 14% UC and 48% CD) and we analyzed the blood's drugs levels using both the ProciseDx Analyzer POC and the SOC ELISA. We examined the correlation between the two methods using statistical analyses, including the Deming regression test. Additionally, we assessed the ease of use, turnaround time, and overall practicality of the POCT in a clinical setting. Results: The ProciseDx test demonstrated a strong correlation with the SOC ELISA for measuring both infliximab and adalimumab levels. In particular, the overall correlation between the ProciseDx POCT and the ELISA assessments showed an r coefficient of 0.83 with an R squared value of 0.691 (95% CI 0.717-0.902) for IFX measurements, and an r coefficient of 0.85 with an R squared value of 0.739 (95% CI 0.720-0.930). Conclusions: the ProciseDx POC test offers significantly faster turnaround times and is more straightforward to use, making it a viable alternative for routine clinical monitoring. Despite its promising potential, further refinement and validation of the ProciseDx test are necessary to ensure its effectiveness across diverse patient populations and clinical settings. Future research should focus on optimizing the POC tests' performance and evaluating its long-term impact on IBD management.

Background/objectives: Although there is a need for evidence-based physical activity programs in rural communities, evaluating such programs is often challenging due to access-related barriers and measurement tools that are not designed for rural contexts. This study aimed to explore and better understand the day-to-day experiences of rural-dwelling children using wrist-worn PA trackers as part of a study to develop a health promotion program., Methods: Ten caregivers and child dyads were enrolled ( n = 20). The children wore accelerometers pre- and post-intervention. Semi-structured interviews were completed post-intervention and were audio recorded, transcribed, and summary reports were generated based on recurring themes., Results: The children had a mean age of 8.7 (SD = 1.4) years and the majority were male (80%). The caregivers were female, white, and had a mean age of 43.6 (SD = 8.5) years, with an annual income of ≥USD 40,000. Factors contributing to device wear times included low caregiver burden, device functioning as a watch, and device interactivity. The children reported that the devices were acceptable, but may have changed their physical activity behaviors, with children regularly checking their step count. The caregivers preferred devices that monitored the children's activity levels without sharing location data., Conclusions: Identifying acceptable and feasible strategies to measure physical activity is vital to developing effective health promotion efforts. The lessons learned may help develop evaluation plans for implementing rural physical activity programming.

Objective: To identify differential trajectories of neurocognitive outcomes following pediatric concussion and investigate predictors associated with patterns of recovery up to 3 months., Methods: 74 participants aged 8-17 years completed attention/working memory, processing speed, and executive function measures at 2 weeks, 1 month, and 3 months post-injury. We used principal component analysis to generate a composite of information processing. Group-based trajectory modeling identified latent trajectories. Multinominal logistic regression was used to examine associations between risk factors and trajectory groups., Results: We identified three trajectories of neurocognitive outcomes. The medium (54.6%) and high improving groups (35.8%) showed ongoing increase in information processing, while the low persistent group showed limited change 3 months post-injury. This group recorded below average scores on Digit Span Forward and Backward at 3 months. History of pre-injury headache was significantly associated with the persistent low scoring group, relative to the medium improving ( p  = 0.03) but not the high improving group ( p  = 0.09)., Conclusions: This study indicates variability in neurocognitive outcomes according to three differential trajectories, with groups partially distinguished by preexisting child factors (history of frequent headaches). Modelling that accounts for heterogeneity in individual outcomes is essential to identify clinically meaningful indices that are indicative of children requiring intervention.

Background: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive modality that utilizes electrical currents to modulate pain in populations with acute and chronic pain. TENS has been demonstrated to produce hypoalgesic effects in postoperative pain, fibromyalgia, knee osteoarthritis, and healthy subjects. Transcutaneous auricular vagus nerve stimulation (TaVNS) is a non-invasive modality that modulates the vagus nerve by stimulating its auricular branches. The effects of the combination of TENS and TaVNS on producing an analgesic response have not been studied. Considering that TENS and TaVNS both stimulate similar analgesic pathways but through different means of activation, we can hypothesize that a combination of both methods can produce a more pronounced analgesic response. Therefore, the objective of this study is to assess the hypoalgesic effect of a combination of TENS and TaVNS in pain-free subjects., Methods/design: The study will be a simple crossover design conducted at the University of Hartford. Subjects will be recruited from the University of Hartford population via oral communication, digital flyers, and posters on campus. Thirty participants will undergo two sessions in a crossover manner with one week in between. During one session, the participants will receive TENS with active TaVNS and the other session will be a placebo procedure (TENS with placebo TaVNS). The order of these sessions will be randomized. Importantly, the pressure pain threshold (PPT) and heat pain threshold (HPT) assessors will be blinded to the treatment category. For active TaVNS, a frequency of 25 Hz will be applied with a pulse duration of 200 µs. For placebo TaVNS, the intensity will be increased to a sensory level and then decreased to 0 mA. High-frequency TENS of 100 Hz will be applied in both sessions, with a pulse duration of 200 µsec, asymmetrical biphasic square waveform, and intensity of maximal tolerance without pain. TENS and TaVNS will be turned on for 30 min after a baseline measurement of outcomes. TENS and TaVNS will then be turned off, but the electrodes will remain on until completion of post-treatment assessment. Pressure pain threshold, heat pain threshold, blood pressure, oxygen saturation, and heart rate will be tested 4 times: Once pre-intervention, once during intervention, once immediately after the intervention, and once 15 min post-intervention. Statistical analysis of the data obtained will consider a significance level of p < 0.05., Discussion: This study will provide evidence concerning the combined effects of TENS and TaVNS on pain threshold in pain-free participants. Based on the outcomes, a greater understanding of how TENS and TaVNS, when used in conjunction, can modulate pain pathways., Trial Registration: ClinicalTrials.gov NCT06361381. Registered on 09 April 2024., (© 2024. The Author(s).)

Introduction: Binge Eating Disorder (BED) has high lifetime prevalence rates, low treatment success rates, and high rates of treatment dissatisfaction, early discontinuation of care, and recurrence. Complementary and integrative health (CIH) interventions (non-mainstream practices used with conventional approaches for whole-person treatment) hold potential to overcome many treatment barriers and improve BED treatment outcomes. Some CIH interventions have empirical support for use in eating disorders. However, little is known about the current state of CIH use in BED., Methods: This mixed-methods cross-sectional study collected information from BED experts about CIH use in adult BED treatment. Fourteen expert BED researchers and clinicians were identified based on federal funding, PubMed-indexed publications, practice in the field, leadership in professional societies, and/or popular press distinction. Anonymously recorded semi-structured interviews were analyzed by ≥2 investigators using reflexive thematic analysis and quantification., Results: Expert opinions and experiences on/with CIH use were generally positive/supportive (64%) with mixed views (36%) varying by intervention and empirical support. The interventions most commonly described were mindfulness (71%), yoga (64%), and supplements/vitamins/pre-/probiotics/herbs (64%). Supplements/vitamins/pre-/probiotics/herbs had mixed views; all other interventions were generally viewed positively. The benefits most commonly associated with specific interventions (e.g., mindfulness, yoga, supplements) were: regulating/tolerating emotions/mood/stress/anxiety (50%); healing the relationship with the body/body image/movement/exercise-trauma (29%); biological/physiological benefits (29%); and directly supporting treatment ("space for self-separate from treatment," behavior change, "tolerating treatment") (29%). Intrinsic self-healing (e.g., patient-driven healing that comes from the patient's innate desire to heal based on the patient's lived experience(s)) and investigative research were also associated with CIH use broadly. Most experts (57%) expressed familiarity with existing literature/research for ≥1 CIH intervention; 50% identified a need for empirical testing. Half (50%) spontaneously described using ≥1 CIH intervention in their own clinical practice/center. The most used interventions were yoga (43%), meditation/mindfulness (29%), and acupuncture (21%). Eight experts (57%) endorsed the importance of correct implementation; 43% acknowledged CIH use in conventional treatments (2nd-wave CBT, 3rd-wave behavior therapies)., Discussion & Conclusions: CIH interventions can complement current BED treatments to improve clinical outcomes, particularly managing anxiety/stress/mood, healing the relationship with the body, addressing biological/physiological deficiencies, and tolerating treatment (thus reducing treatment dropout). Empirical testing is warranted with a particular need for randomized controlled trials and guidelines on implementation and use., Competing Interests: 6.Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Symptoms of hypocalcemia are reported in up to 50% of patients undergoing leukapheresis procedures. There is no set standard of practice for administering calcium supplementation in the prevention or treatment of hypocalcemia symptoms. The goal of this descriptive, retrospective study was to determine the prevalence of baseline hypocalcemia and symptomatic hypocalcemia during leukapheresis with acid citrate dextrose solution A and to identify patient characteristics associated with symptomatic hypocalcemia. Three percent of patients were found to have hypocalcemia before leukapheresis with 35% experiencing hypocalcemia symptoms during leukapheresis. Older age, higher albumin levels, and longer procedure time were associated with increased risk of hypocalcemia symptoms., (© 2023 Wiley Periodicals LLC.)

Background: Patients with rheumatoid arthritis (RA) have difficulties maintaining employment due to the impact of the disease on their work ability. This review aims to investigate the employment rates at different stages of disease and to identify predictors of employment among individuals with RA., Methods: The study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines focusing on studies reporting employment rate in adults with diagnosed RA. The literature review included cross-sectional and cohort studies published in the English language between January 1966 and January 2023 in the PubMed, Embase and Cochrane Library databases. Data encompassing employment rates, study demographics (age, gender, educational level), disease-related parameters (disease activity, disease duration, treatment), occupational factors, and comorbidities were extracted. Quality assessment was performed employing Newcastle-Ottawa Scale. Meta-analysis was conducted to ascertain predictors for employment with odds ratios and confidence intervals, and test for heterogeneity, using chi-square and I 2 -statistics were calculated. This review was registered with PROSPERO (CRD42020189057)., Results: Ninety-one studies, comprising of a total of 101,831 participants, were included in the analyses. The mean age of participants was 51 years and 75.9% were women. Disease duration varied between less than one year to more than 18 years on average. Employment rates were 78.8% (weighted mean, range 45.4-100) at disease onset; 47.0% (range 18.5-100) at study entry, and 40.0% (range 4-88.2) at follow-up. Employment rates showed limited variations across continents and over time. Predictors for sustained employment included younger age, male gender, higher education, low disease activity, shorter disease duration, absence of medical treatment, and the absence of comorbidities. Notably, only some of the studies in this review met the requirements for high quality studies. Both older and newer studies had methodological deficiencies in the study design, analysis, and results reporting., Conclusions: The findings in this review highlight the prevalence of low employment rates among patients with RA, which increases with prolonged disease duration and higher disease activity. A comprehensive approach combining clinical and social interventions is imperative, particularly in early stages of the disease, to facilitate sustained employment among this patient cohort., (© 2023. The Author(s).)

Objective: To evaluate changes in toothbrushing behaviour and plaque removal performance with usage of a next generation oscillating-rotating electric toothbrush (NG-OR)., Methods: This exploratory clinical study had a two-treatment, three-period, single-group, sequential design. Generally healthy adults with a screening whole mouth mean Turesky modified Quigley-Hein Plaque Index (TQHPI) score of at least 1.75 on a 0-5 scale and who were primarily OR brush users were enrolled. Participants used each OR toothbrush in A-B-B order, where a currently marketed OR brush with a traditional mechanical drive system (T-OR) was used in period A, and the NG-OR brush with a linear magnetic drive was used in period B. At Visit 1, qualifying participants brushed on-site with T-OR. After a 48 h washout, participants returned for Visit 2 and brushed on-site with NG-OR. Participants then used NG-OR for 1 week, twice daily, at home and returned for Visit 3 to brush on-site with NG-OR again. For all on-site brushings, participants were instructed to brush for 2 min without interactive features. Each toothbrush was tagged with a transmitter chip connected to a Motion Tracking System to record movements of the toothbrush and participant using infrared light transmission to determine Isochronicity (brushing time uniformly distributed across the dentition). Plaque was measured using TQHPI. Primary variables were Isochronicity and TQHPl whole mouth mean plaque reduction (pre-brushing minus post-brushing)., Results: Overall, 41 participants enrolled and received treatment; 40 completed the trial. NG-OR showed significantly greater Isochronicity after a single brushing (p = 0.043) and after a 1-week at-home use (p = 0.001) versus T-OR. NG-OR showed 41% greater whole mouth plaque removal than T-OR (p < 0.001) after a single brushing. Plaque reduction by region/surface was consistent with whole mouth results., Conclusion: The NG-OR brush showed greater brushing uniformity and plaque removal versus the T-OR brush., (© 2023 Procter & Gamble. International Journal of Dental Hygiene published by John Wiley & Sons Ltd.)

Introduction: Previous studies have shown that the population attributable risk of low forced expiratory volume in one second (FEV 1 ) for coronary artery disease (CAD) is substantial. FEV 1 can be low either because of airflow obstruction or ventilatory restriction. It is not known if low FEV 1 arising from spirometric obstruction or restriction are differently associated with CAD., Methods: We analyzed high resolution computed tomography (CT) scans acquired at full inspiration in lifetime non-smoker adults with no lung disease (controls) and those with chronic obstructive pulmonary disease enrolled in the Genetic Epidemiology of COPD (COPDGene) study. We also analyzed CT scans of adults with idiopathic pulmonary fibrosis (IPF) from a cohort of patients attending a quaternary referral clinic. Participants with IPF were matched 1:1 by FEV 1 %predicted to adults with COPD and 1:1 by age to lifetime non-smokers. Coronary artery calcium (CAC), a surrogate for CAD, was measured by visual quantification on CT using the Weston score. Significant CAC was defined as Weston score ≥7. Multivariable regression models were used to test the association of the presence of COPD or IPF with CAC, with adjustment for age, sex, body-mass-index, smoking status, hypertension, diabetes mellitus, and hyperlipidemia., Results: We included 732 subjects in the study; 244 with IPF, 244 with COPD, and 244 lifetime non-smokers. The mean (SD) age was 72.6 (8.1), 62.6 (7.4), and 67.3 (6.6) years, and median (IQR) CAC was 6 (6), 2 (6), and 1 (4), in IPF, COPD, and non-smokers, respectively. On multivariable analyses, the presence of COPD was associated with higher CAC compared to non-smokers (adjusted regression coefficient, β = 1.10 ± SE0.51; P = 0.031). The presence of IPF was also associated with higher CAC compared to non-smokers (β = 03.43 ± SE0.41; P < 0.001). The adjusted odds ratio for having significant CAC was 1.3, 95% CI 0.6 to 2.8; P = 0.53 in COPD and 5.6, 95% CI 2.9 to 10.9; P < 0.001 in IPF, compared to non-smokers. In sex stratified analyses, these associations were mainly noted in women., Conclusion: Adults with IPF displayed higher coronary artery calcium than those with COPD after accounting for age and lung function impairment., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Beginning January 26th, 2022, the National Board of Medical Examiners transitioned scoring of the United States Medical Licensing Examination (USMLE) Step 1 from a 3-digit score to pass/fail. In the past, the Step 1 score has been weighted heavily by program directors (PDs) as one of the most important metrics when assessing medical student's competitiveness., Objective: The objective of this study was to evaluate the perceptions of emergency medicine (EM) PDs on the transition to a pass/fail USMLE Step 1 exam, and to elicit the opinions of EM PDs on the USMLE examinations' ability to predict resident performance., Methods: A survey consisting of ranking and multiple-choice questions was sent to EM PDs. The multiple-choice questions were asked to determine EM PDs level of confidence in the ability of Step 1 and Step 2 Clinical Knowledge (CK) to predict a student's ability to succeed in residency. The ranking questions focused on assessing each program's current resident selection practices in comparison to expected selection criteria changes following a transition to pass/fail Step 1. R studio and MATLAB were used for statistical analysis, and a P value <0.05 was considered significant., Results: The survey was completed by 57 (20.21%) EM PDs. When asked if Step 1 and Step 2 CK are accurate predictors of a resident's ability to perform clinically within EM, only 10.5% of PDs answered 'yes' to Step 1 being predictive, compared to 31.6% for Step 2 CK. Regarding selection criteria, the top quartile of attributes (standardized letters of evaluation [1st], away rotations [2nd], clerkship grades [3rd] and Step 2 CK score [4th]) remained the same following the transition., Conclusion: Our results indicate that the top quartile of attributes might remain the same, despite most PDs agreeing that Step 2 CK is a better predictor of a resident's performance., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Bray et al.)

The negative impact of adverse experiences in childhood on neurodevelopment is well documented. Less attention however has been given to the impact of variations in "normative" parenting behaviors. The influence of these parenting behaviors is likely to be marked during periods of rapid brain reorganization, such as late childhood. The aim of the current study was to investigate associations between normative parenting behaviors and the development of structural brain networks across late childhood. Data were collected from a longitudinal sample of 114 mother-child dyads (54% female children, M age 8.41 years, SD = 0.32 years), recruited from low socioeconomic areas of Melbourne, Australia. At the first assessment parenting behaviors were coded from two lab-based interaction tasks and structural magnetic resonance imaging (MRI) scans of the children were performed. At the second assessment, approximately 18 months later ( M age 9.97 years, SD = 0.37 years) MRI scans were repeated. Cortical thickness (CT) was extracted from T1-weighted images using FreeSurfer. Structural covariance (SC) networks were constructed from partial correlations of CT estimates between brain regions and estimates of network efficiency and modularity were obtained for each time point. The change in these network measures, from Time 1 to Time 2, was also calculated. At Time 2, less positive maternal affective behavior was associated with higher modularity (more segregated networks), while negative maternal affective behavior was not related. No support was found for an association between local or global efficacy and maternal affective behaviors at Time 2. Similarly, no support was demonstrated for associations between maternal affective behaviors and change in network efficiency and modularity, from Time 1 to Time 2. These results indicate that normative variations in parenting may influence the development of structural brain networks in late childhood and extend current knowledge about environmental influences on structural connectivity in a developmental context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Richmond, Beare, Johnson, Bray, Pozzi, Allen, Seal and Whittle.)

Uterine rupture is a potentially life-threatening complication that is typically seen in pregnant females who have undergone prior uterine surgeries such as cesarean sections. This usually occurs when the uterine myometrium is weakened and thus is more prone to stress during labor. In an unscarred uterus, the incidence of uterine rupture is lower. Risk factors in the unscarred uterus include trauma, obstructed labor, high parity, placental abnormalities, operative deliveries, and imprudent use of uterotonic medications. This case report describes a situation in which uterine rupture occurred in the absence of the common risk factors. With prompt recognition of clinical signs, quick assembly of a team, and emergent interventions, this patient and her infant survived. The goal of this report is to educate clinicians on the occurrence of uterine rupture in an unscarred uterus and how to recognize and manage this complication., (Copyright© South Dakota State Medical Association.)

Toxic Epidermal Necrolysis (TEN), along with Stevens-Johnson Syndrome (SJS), are rare, life-threatening delayed type IV hypersensitivity mucocutaneous skin disorders that can often be precipitated by medications. The most common culprits are sulfonamide antibiotics and various antiseizure medications. We report a case of a 41-year-old Black female that initially presented with SJS, which then rapidly progressed to TEN, confirmed by hematoxylin and eosin stain skin biopsies. Approximately 80% of her body surface area had necrosis and epidermal detachment lesions. It was concluded that TEN was caused by the use of torsemide for treatment of her underlying diffuse anasarca attributable to alcoholic cirrhosis. During her one-month hospital stay, a multi-disciplinary team consisting of dermatology, gynecology, rheumatology, nephrology, and infectious disease evaluated and treated the patient. Interventions included various supportive care measures as well as intravenous steroids, cyclosporine, plasma exchange, and intravenous immunoglobulin. Given that the mortality rate for TEN is over 30%, and this patient had end-stage cirrhosis, her prognosis was extremely poor. Even though her TEN eventually healed slowly, the patient experienced complications. This case demonstrates the importance of cautiously using sulfonamide medications in patients with known hypersensitivity to sulfa drugs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Reddy et al.)

Objectives: Autologous chimeric antigen receptor (CAR) αβ T-cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T-cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood-derived CAR + Vδ1 γδ T cells expressing a second-generation CAR targeting the B-cell-restricted CD20 antigen., Methods: Donor-derived Vδ1 γδ T cells from peripheral blood were ex vivo -activated, expanded and engineered to express a novel anti-CD20 CAR. In vitro and in vivo assays were used to evaluate CAR-dependent and CAR-independent antitumor activities of CD20 CAR + Vδ1 γδ T cells against B-cell tumors., Results: Anti-CD20 CAR + Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B-cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR + Vδ1 γδ T cells did not induce xenogeneic graft-versus-host disease in immunodeficient mice., Conclusion: These preclinical data support the clinical evaluation of ADI-001, an allogeneic CD20 CAR + Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B-cell malignancies (NCT04735471)., Competing Interests: KPN, TB, AA, AM, JMR, LB, MMB, JK‐W, HS, SP, AD, CM, NTH, HT, VDR, AG‐R, M Hoopes, DS, RS, M Herrman, SEA, BTA, ZA, SP and SMH are, or were, employees of Adicet Bio, Inc., and FD, KS and KB are employees of Regeneron Pharmaceuticals, Inc., (© 2022 Adicet Bio Inc. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis., Methods: Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis., Discussion: The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936., (© 2021. The Author(s).)

T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies., (© 2021. The Author(s).)

This longitudinal study examined the neurodevelopmental correlates of aggression in children, focusing on structural brain properties. A community sample of 110 (60 females) children participated at age 8 years and again at age 10 years. Brain structure was assessed by using magnetic resonance imaging (MRI), and parents reported on child aggression using the Child Behavior Checklist. Analyses examined the relationship between aggression and development of volume of subcortical regions, cortical thickness, and subcortical-cortical structural coupling. Females with relatively high aggression exhibited reduced right hippocampal growth over time. Across males and females, aggression was associated with amygdala- and hippocampal-cortical developmental coupling, with findings for amygdala-cortical coupling potentially indicating reduced top-down prefrontal control of the amygdala in those with increasing aggression over time. Findings suggest that aggressive behaviors may be associated with alterations in normative brain development; however, results were not corrected for multiple comparisons and should be interpreted with caution.

CD3-engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells are potent therapeutic approaches for redirecting patient T cells to recognize and kill tumors. Here we describe a fully human bsAb (REGN5458) that binds to B-cell maturation antigen (BCMA) and CD3, and compare its antitumor activities vs those of anti-BCMA CAR T cells to identify differences in efficacy and mechanism of action. In vitro, BCMAxCD3 bsAb efficiently induced polyclonal T-cell killing of primary human plasma cells and multiple myeloma (MM) cell lines expressing a range of BCMA cell surface densities. In vivo, BCMAxCD3 bsAb suppressed the growth of human MM tumors in murine xenogeneic models and showed potent combinatorial efficacy with programmed cell death protein 1 blockade. BCMAxCD3 bsAb administration to cynomolgus monkeys was well tolerated, resulting in the depletion of BCMA+ cells and mild inflammatory responses characterized by transient increases in C-reactive protein and serum cytokines. The antitumor efficacy of BCMAxCD3 bsAb was compared with BCMA-specific CAR T cells containing a BCMA-binding single-chain variable fragment derived from REGN5458. Both BCMAxCD3 bsAb and anti-BCMA CAR T cells showed similar targeted cytotoxicity of MM cell lines and primary MM cells in vitro. In head-to-head in vivo studies, BCMAxCD3 bsAb rapidly cleared established systemic MM tumors, whereas CAR T cells cleared tumors with slower kinetics. Thus, using the same BCMA-binding domain, these results suggest that BCMAxCD3 bsAb rapidly exerts its therapeutic effects by engaging T cells already in place at the tumor site, whereas anti-BCMA CAR T cells require time to traffic to the tumor site, activate, and numerically expand before exerting antitumor effects., (© 2021 by The American Society of Hematology.)

The majority of studies using observational coding systems for family interaction data derive scales describing family members' behaviors based on rational/theoretical approaches. This study explored an empirical approach to identifying the component structure of parent-child observational data that incorporated the affective context of the interaction. Dyads of 155 typically developing 8-year-olds and their mothers completed questionnaires and two interaction tasks, one each designed to illicit positive and negative interactions. Behaviors were coded based on a modified version of the Family Interaction Macro-coding System. Multiple factor analysis identified four-component solutions for the maternal and child data. For both, two of the components included negative behaviors, one positive behavior, and one communicative behavior. Evidence for the validity of the maternal and child components was demonstrated by associations with child depression and anxiety symptoms and behavioral problems. Preliminary evidence supports an empirical approach to identify context-specific components in parent-child observational data.

Early Life Stress (ELS) is thought to influence Hypothalamic-Pituitary-Adrenal-Axis (HPAA) functioning, contributing to an increased risk for psychopathology through dysregulation of biological stress responses. Research exploring relationships between ELS and HPAA functioning has largely focused on its key hormonal output, cortisol. However, findings have been inconsistent, potentially due to cortisol's distinctive diurnal patterns and dynamic nature complicating its accurate measurement. Thus, this study explored the link between ELS and a more stable, structural component of the HPAA, specifically, anterior pituitary gland volume (PGV) in a community sample of children (N = 129, 68 female). PGV was traced from Magnetic Resonance Imaging brain scans across two time-points at ages 8 (baseline) and 10 years (follow-up). ELS exposure was assessed at baseline through parent-report questionnaires and maternal affective behavior observed in mother-child interaction tasks. ELS variables were reduced to a 5-factor structure using exploratory factor analysis - Uninvolved Parenting, Negative Affective Parenting, Neglect, Trauma, and Dysfunctional Discipline. Direct and sex-moderated associations between ELS and PGV were explored using regression and linear mixed models analyses. PGV-mediated associations between ELS and internalizing symptoms were also investigated. Childhood Neglect was significantly associated with greater baseline anterior PGV, that was stable over the follow-up period. This effect was found in the whole sample, and in males, specifically. No mediation effects were found. Results suggest that neglect may play a unique role in HPAA neurodevelopment; however, it is important that future research extends into adolescence to more clearly characterize these neurodevelopmental associations and any subsequent psychopathological outcomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well-described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient-reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non-EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE., Methods: We conducted a cross-sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi-square (categorical measures) and the Mann-Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation., Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non-EoE EGID), a higher proportion of those with a non-EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating (P < 0.01 for all). Participants with a non-EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain (P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5--4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2--3.3 for elemental formula)., Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non-EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.

Background: This was a retrospective chart review of procedural pain assessments and interventions during arterial catheter insertion in an adult neurological intensive care unit where patients with impaired consciousness are common. Overall, pain assessment was well documented (100%) by Registered Nurses, but not specific to arterial line insertion. Nurse practitioners commonly placed arterial lines and used local analgesia in over 75% of the documented procedures., Aims: The purpose of this study was to examine healthcare providers' pain-related practices documented during arterial catheter insertion, one of the most painful procedures in a neurological intensive care unit. Secondary purposes were determining whether patient characteristics, procedure-related factors, or provider licensure were associated with pain assessment or procedural pain interventions., Design: A retrospective records review design was used., Methods: 120 electronic patient medical records were reviewed during a one-year period., Results: 100 charts met inclusion criteria. Nurses assessed all pain within 4 hours following the procedure in all charts but procedure-specific pain assessments were documented in 4% of charts. Pain-related interventions for arterial line insertion were local analgesic (76% of charts) and other procedure-specific interventions (10%). Significant associations occurred between procedure specific pain assessments and decreased number of insertion attempts (p = .006) and between pain interventions and number of insertion attempts (p = .003). No provider documented procedural pain assessment regarding arterial line insertion. Associations between patient characteristics and pain interventions were significant for patient ethnicity (F = 8.967, p = .007)., Conclusions: Overall pain assessment was documented (100%) but not specific to arterial line insertion. Although arterial line insertion can be extremely painful, patients were rarely assessed for such pain by any clinician; 14% did not receive any preprocedural analgesia., Clinical Implications: The lack of procedural pain assessment in this vulnerable population indicates a need for increased pain management education for clinicians and further investigations to determine whether sufficient analgesia is provided to reduce procedural pain during arterial line insertion., (Published by Elsevier Inc.)

Objectives: Human papillomavirus (HPV) testing in cervical screening offers the potential for self-sampling to improve uptake among non-attenders. High-risk (HR) HPV detection in urine shows promise, but few studies have examined its sensitivity for cervical intraepithelial neoplasia (CIN2+) detection compared with standard cervical samples. The aims of this cross-sectional study were to optimise conditions for urine testing for HPV detection; to determine concordance for HR-HPV detection in matched urine, vaginal and cervical samples; to compare the sensitivity of HR-HPV testing for the detection of CIN2+ in matched samples; and to determine the acceptability of urine testing for cervical screening., Design: Cross-sectional study., Setting: Secondary care colposcopy clinic in North West England., Participants: Women aged 25 years of age or older, attending colposcopy clinic for management of abnormal cervical screening results or a suspicious-looking cervix. In total, 104 women took part in the study. Triple matched samples were available for 79 and 66 women using Abbott RealTi me (ART) and Roche Cobas 4800 (RC), respectively., Intervention: Self-collected urine and vaginal samples and practitioner-obtained cervical samples were tested for HR-HPV by ART and RC assays, including comparison of neat and preservative-fixed urine. Colposcopic opinion was recorded and directed cervical biopsies taken if clinically indicated. The acceptability of self-testing was evaluated by questionnaire., Primary Outcome Measure: The sensitivity of urine to detect underlying CIN2+., Secondary Outcome Measures: The comparative sensitivity of vaginal and cervical samples to detect CIN2+; the acceptability of urine sampling., Results: Preservative-fixed, but not neat urine, showed good concordance with vaginal samples for the detection of HR-HPV. The sensitivity for detecting CIN2+ was 15/18 (83%) for urine and 16/18 (89%) for cervical and vaginal samples by ART, and 15/17 (88%) for all samples by RC. Urine-based testing was broadly acceptable to women., Conclusions: Urinary HR-HPV detection offers an alternative strategy of cervical screening. Larger studies to determine its clinical utility are warranted., Competing Interests: Competing interests: HCK is Chair of the Advisory Committee for Cervical Screening (PHE), but the views expressed in this manuscript are those of the author and not Public Health England., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. Typically, National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to jfox46@jhu.edu .

Background: Sedentary behaviour and falls are important interrelated health issues in older people. One in three people aged 65 years and above fall at least once a year and sedentary behaviour has been identified as one of the risk factors for falls. Studies have shown that the duration of sedentary time increases with age. These dual problems need to be addressed effectively as the ageing population grows. Accelerometers enable accurate measurement of sedentary time. This study aims to establish the feasibility and effect of an individualized goal-setting health coaching intervention using feedback initially from an accelerometer and then pedometer over a period of 12 weeks (intervention) compared with providing a one-off advice through a brochure (control), on sedentary time in older people with a recent fall or at risk of one., Methods: A single-blinded randomized controlled feasibility trial involving 80 community-dwelling people aged 65 years and above will be conducted with 40 randomized to the intervention and another 40 to control. Primary outcomes will be the feasibility of the intervention and change in total sedentary time at 12 and 24 weeks. Secondary outcomes include a change in fear of falling based on the falls efficacy scale, gait speed, self-reported sedentary time, the proportion of fallers and number of falls. Four focus groups (two from each arm) will be conducted at the end of the study to evaluate the feasibility and effectiveness of this intervention. Feasibility findings will be primarily descriptive. Mean group differences will be examined using independent samples t test for normally distributed data and nonparametric tests (Kruskal-Wallis and Mann-Whitney U ) for non-normally distributed data. Differences in frequency of variables will be compared using chi-square test. Analysis of variance (ANOVA) will be used to test the post-intervention difference between the two groups at 12 and 24 weeks., Discussion: The trial will address a key gap in evidence about sedentary behaviour and falls amongst older people and will evaluate the feasibility of an intervention that could be implemented within the primary health care settings., Trial Registration: Australian New Zealand Clinical Trials Registry 12617001186347, Registered 11 August 2017., Competing Interests: All participants will give written informed consent before commencing their involvement in this study. Ethics approval for this research has been obtained from the University of Adelaide Human Research Ethics Committee and The Queen Elizabeth Hospital Human Research Ethics Committee (TQEH/LMH/MH) (HREC/17/TQEH/58).Not applicable.Professor Visvanathan has participated in international initiatives funded by educational grants from Nestle and has presented at symposiums funded by Nestle. She is on the Malnutrition in the Elderly Board with Nestle Australia. Associate Professor Chehade, Dr. Khow, Dr. Dollard, Ms. Bray, Ms. Smyth and Associate Professor Theou have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m 2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg -1 day -1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 μg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 μg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m 2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs., (© 2018 John Wiley & Sons Ltd.)

We report on the sizable production of fluorescent nanodiamonds (FNDs) containing a near infrared (NIR) color center - namely the silicon vacancy (SiV) defect, and their first demonstration inside cells for bio-imaging. We further demonstrate a concept of multi-color bio-imaging using FNDs to investigate intercellular processes using two types of FNDs. Due to their specific spectral properties, SiV FNDs can be distinguished from common nitrogen-vacancy (NV) FNDs and show a distinct initial spreading throughout the cell interior. The reported results are the first demonstration of multi-color labeling with FNDs that are especially interesting for in vivo bio-imaging due to their stable fluorescence.

Single crystal, nanoscale diamond membranes are highly sought after for a variety of applications including nanophotonics, nanoelectronics and quantum information science. However, so far, the availability of conductive diamond membranes has remained an unreachable goal. In this work we present a complete nanofabrication methodology for engineering high aspect ratio, electrically active single crystal diamond membranes. The membranes have large lateral directions, exceeding ∼500 × 500 μm 2 and are only several hundreds of nanometers thick. We further realize vertical single crystal p-n junctions made from the diamond membranes that exhibit onset voltages of ∼10 V and a current of several mA. Moreover, we deterministically introduce optically active color centers into the membranes, and demonstrate for the first time a single crystal nanoscale diamond LED. The robust and scalable approach to engineer the electrically active single crystal diamond membranes offers new pathways for advanced nanophotonic, nanoelectronic and optomechanical devices employing diamond.

Background: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old., Methods/design: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017., Discussion: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

Diamond nanocrystals that host room temperature narrowband single photon emitters are highly sought after for applications in nanophotonics and bioimaging. However, current understanding of the origin of these emitters is extremely limited. In this work, we demonstrate that the narrowband emitters are point defects localized at extended morphological defects in individual nanodiamonds. In particular, we show that nanocrystals with defects such as twin boundaries and secondary nucleation sites exhibit narrowband emission that is absent from pristine individual nanocrystals grown under the same conditions. Critically, we prove that the narrowband emission lines vanish when extended defects are removed deterministically using highly localized electron beam induced etching. Our results enhance the current understanding of single photon emitters in diamond and are directly relevant to fabrication of novel quantum optics devices and sensors.

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

Artificial atomic systems in solids are widely considered the leading physical system for a variety of quantum technologies, including quantum communications, computing and metrology. To date, however, room-temperature quantum emitters have only been observed in wide-bandgap semiconductors such as diamond and silicon carbide, nanocrystal quantum dots, and most recently in carbon nanotubes. Single-photon emission from two-dimensional materials has been reported, but only at cryogenic temperatures. Here, we demonstrate room-temperature, polarized and ultrabright single-photon emission from a colour centre in two-dimensional hexagonal boron nitride. Density functional theory calculations indicate that vacancy-related defects are a probable source of the emission. Our results demonstrate the unprecedented potential of van der Waals crystals for large-scale nanophotonics and quantum information processing.

Genetic and environmental factors influence complex disease in humans, such as metabolic syndrome, and Drosophila melanogaster serves as an excellent model in which to test these factors experimentally. Here we explore the modularity of endophenotypes with an in-depth reanalysis of a previous study by Reed et al. (2014), where we raised 20 wild-type genetic lines of Drosophila larvae on four diets and measured gross phenotypes of body weight, total sugar, and total triglycerides, as well as the endophenotypes of metabolomic and whole-genome expression profiles. We then perform new gene expression experiments to test for conservation of phenotype-expression correlations across different diets and populations. We find that transcript levels correlated with gross phenotypes were enriched for puparial adhesion, metamorphosis, and central energy metabolism functions. The specific metabolites L-DOPA and N-arachidonoyl dopamine make physiological links between the gross phenotypes across diets, whereas leucine and isoleucine thus exhibit genotype-by-diet interactions. Between diets, we find low conservation of the endophenotypes that correlate with the gross phenotypes. Through the follow-up expression study, we found that transcript-trait correlations are well conserved across populations raised on a familiar diet, but on a novel diet, the transcript-trait correlations are no longer conserved. Thus, physiological canalization of metabolic phenotypes breaks down in a novel environment exposing cryptic variation. We cannot predict the physiological basis of disease in a perturbing environment from profiles observed in the ancestral environment. This study demonstrates that variation for disease traits within a population is acquired through a multitude of physiological mechanisms, some of which transcend genetic and environmental influences, and others that are specific to an individual's genetic and environmental context., (Copyright © 2015 Williams et al.)

A facile and cost-effective self-assembly route to engineering of vital quantum plasmonic circuit components is reported. By modifying the surface energy of silver nanowires, the position and density of attached nanodiamonds can be maneuvered leading to silver nanowire/nanodiamond(s) hybrid nanostructures. These structures exhibit strong plasmonic coupling effects and thus hold promise to serve as quantum plasmonic components., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fluorescent nanodiamonds are attracting major attention in the field of bio-sensing and bio-labeling. In this work we demonstrate a robust approach to achieve an encapsulation of individual nanodiamonds with phenol-ionic complexes that enhance the photoluminescence from single nitrogen vacancy (NV) centers. We show that single NV centres in the coated nanodiamonds also exhibit shorter lifetimes, opening another channel for high resolution sensing. We propose that the nanodiamond encapsulation reduces the non-radiative decay pathways of the NV color centers. Our results provide a versatile and assessable way to enhance photoluminescence from nanodiamond defects that can be used in a variety of sensing and imaging applications.

Objective: The purpose of this study was to identify possible relationships between parent/guardian sociodemographics, intention, knowledge, and the oral health status of their child/ward. Intention includes three factors as defined in the Theory of Planned Behavior: attitudes, subjective norms and perceived control, and oral health status was measured by decayed, missing and filled teeth (dmft) scores., Methods: A convenience sample of parent/guardian with child/ward with age of three to five (n = 181 dyads) enrolled in a Head Start program in the state of Florida participated. A cross-sectional observational study comprised of two components, parent/guardian questionnaire and an oral health status form for recording dmft scores of participating child/ward was employed., Results: Parent/guardian race/ethnicity and years of education were significantly related to dmft of child/ward. The highest rates of severe early childhood caries (ECC) were found in child/ward whose parent/guardian is Hispanic and parent/guardian with less than a high school education. Multivariate regression analysis found that increased education level of parent/guardian was significantly associated with lower dmft in this population. No significant relationship was found between parent/guardian self-reported intention (attitudes, subjective norms and perceived control), knowledge and dmft scores of the child/ward., Conclusion: Researchers have called for greater attention to the impact of parental influences in the aetiology of ECC. Results from this study were consistent with current studies where parent/guardian race/ethnicity and educational level served as predictors of oral health status of children. In this study population, parent/guardian intention and knowledge were not shown to significantly impact the oral health status of their child/ward., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents.

Rho GTPases mediate stromal-epithelial interactions that are important for mammary epithelial cell (MEC) morphogenesis. Increased extracellular matrix (ECM) deposition and reorganization affect MEC morphogenesis in a Rho GTPase-dependent manner. Although the effects of altered ECM on MEC morphogenesis have been described, how MECs regulate stromal deposition is not well understood. Previously, we showed that p190B RhoGAP overexpression disrupts mammary gland morphogenesis by inducing hyperbranching in association with stromal alterations. We therefore hypothesized that MEC overexpression of p190B regulates paracrine interactions to impact fibroblast activation. Using a combination of in vivo morphometric and immunohistochemical analyses and primary cell culture assays, we found that p190B overexpression in MECs activates fibroblasts leading to increased collagen, fibronectin, and laminin production and elevated expression of the collagen crosslinking enzyme lysyl oxidase. Phosphorylation of the TGF-β effector SMAD2 and expression of the TGF-β target gene αSma were increased in p190B-associated fibroblasts, suggesting that elevated TGF-β signaling promoted fibroblast activation. Mechanical tension and TGF-β cooperate to activate fibroblasts. Interestingly, active TGF-β was elevated in conditioned medium from p190B overexpressing MECs compared to control MECs, and p190B overexpressing MECs exhibited increased contractility in a collagen gel contraction assay. These data suggest that paracrine signaling from the p190B overexpressing MECs may activate TGF-β signaling in adjacent fibroblasts. In support of this, transfer of conditioned medium from p190B overexpressing MECs onto wildtype fibroblasts or co-culture of p190B overexpressing MECs with wildtype fibroblasts increased SMAD2 phosphorylation and mRNA expression of ECM genes in the fibroblasts when compared to fibroblasts treated with control CM or co-cultured with control MECs. The increased ECM gene expression and SMAD2 phosphorylation were blocked by treatment with a TGF-β receptor inhibitor. Taken together, these data suggest that p190B overexpression in the mammary epithelium induces fibroblast activation via elevated TGF-β paracrine signaling.

Objectives: Patient engagement in effective oral hygiene following periodontal therapy is essential to long-term success. Motivational interviewing (MI) is a behavioural counselling approach documented to positively influence behaviour change related to smoking, diabetes control and medication adherence. Emerging evidence suggests utility of MI to improve oral health. The objective of this study was to evaluate whether the use of brief motivational interviewing (BMI) is effective in improving internal motivation for oral hygiene behaviour., Methods: A convenience sample of fifty-six previously treated periodontal patients who were in maintenance yet presented with signs of clinical inflammation were recruited to participate in this single blind, randomized controlled trial. Patients were randomly assigned to receive either BMI in conjunction with traditional oral health education (TOHE), (n = 29) or TOHE alone (n = 27). Bleeding on probing scores (BOP), plaque index (PI), pocket depths (PD), motivation (M), autonomous regulation (AR) controlled regulation (CR) and oral health knowledge (K) were assessed at baseline, 6 weeks and 12 weeks., Results: Statistically significant decreases were found over time for BOP (P = 0.001), PI (P = 0.001) and PD 4-6 mm (P = 0.001) for both groups. Differences in clinical parameters between groups were not evident at either 6 or 12 weeks., Conclusion: Results show that a one-time MI session is insufficient for improving oral hygiene in long-standing maintenance patients., (© 2012 John Wiley & Sons A/S.)

A fundamental imperative for mammalian cells is to coordinate cell metabolism and growth with environmentally induced stress. This review focuses on three highly integrated networks-the phosphoinositide 3-kinase (PI3K) signaling cascade, intermediate metabolism, and autophagy-that work together to maintain cellular homeostasis under basal conditions and to drive cell-mass accumulation and cell cycle progression in the presence of appropriate mitogenic stimuli. Dysfunction within any one of these networks results in compensatory responses from the other networks. These responses underpin several pathologies associated with major human diseases such as cancer. We discuss the PI3K, metabolism, and autophagy networks and provide selected insights into internetwork cross-talk mechanisms. In recognition of the extensive interactions observed in both healthy and diseased cells, we propose that the three networks be merged into a "metabolism-signaling supernetwork." A detailed understanding of this supernetwork will facilitate the development of novel therapies for cancer and other complex diseases.

Introduction: The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis., Methods: We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays., Results: Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes., Conclusions: These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis.

Aim: To evaluate the impact of a new model for the detection and management of deteriorating patients on knowledge and confidence of nursing staff in an acute hospital., Background: International evidence shows that clinical deterioration is not always recognized or acted on by nurses. The use of physiological track and trigger scoring systems accompanied by a graded response strategy has been recommended to monitor all adult patients in acute UK hospitals. However, little is known about the impact of these new systems in practice., Design: A single centre, mixed methods before-and-after study., Methods: A mixed methods before-and-after study, set in a district general hospital in England, in 2009, including a survey (n = 213) and qualitative interviews (n = 15) with nursing staff. The questionnaire examined knowledge and confidence in recognition and management of deteriorating patients 6 weeks before and after an intervention which included training, new observation charts and a new track and trigger system. Interviews further explored participants' perspectives. Comparisons were made between registered and unregistered nurses., Results: Following the intervention, knowledge, and confidence to recognize and manage deteriorating patients increased; the number of concerns were reduced. Scores were higher for registered than unregistered nurses before and after the intervention. Interviews confirmed these findings and provided detail on how nurses felt the new system had improved practice., Conclusion: The new model had a positive impact on the self-assessed knowledge and confidence of registered and unregistered nurses. Similar initiatives should take into account the clinical context and tailor training packages accordingly., (© 2012 Blackwell Publishing Ltd.)

Purpose: Targeting multiple anti-apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT-737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti-malarial drug that inhibits autophagy, will increase cytotoxicity of ABT-737., Experimental Design: Cytotoxicity of ABT-737 and HCQ was assessed in vitro in PC-3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry-Parkin reporter., Results: Induction of autophagy by ABT-737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT-737 both in vitro and in vivo. ABT-737 induced LC-3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT-737 and HCQ was a mechanism of cytotoxicity., Conclusions: We demonstrated that autophagy inhibition with HCQ enhances ABT-737 cytotoxicity in vitro and in vivo, that LC-3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies., (Copyright © 2012 Wiley Periodicals, Inc.)

mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.

Objectives: Novel treatment strategies are needed for treatment-experienced HIV-infected individuals. We retrospectively evaluated virologic outcomes on a dual-class, protease inhibitor (PI) plus raltegravir, antiretroviral (ARV) regimen., Methods: Virologic success was defined by a plasma HIV-RNA level ≤200 copies/mL. Adherence was measured using pharmacy refill data. The association between adherence and virologic failure was assessed using bivariate logistic regression., Results: In 39 individuals, median prior antiretroviral therapy (ART) exposure was 11 years. Of 39 individuals, 36 (92%) achieved an HIV-RNA ≤200 copies/mL. After a median follow-up of 328 days (interquartile range [IQR] 190-737 days), 74% maintained an HIV-RNA <200 copies/mL but only 44% had <50 copies/mL. Median adherence was 96.4% (IQR 83.3%-100%). For every 10% decrease in adherence, the odds of virologic failure increased by 90% (odds ratio [OR] = 1.9, 95% confidence interval [CI] 1.1-3.3). In all, 4 individuals had ≥2 preexisting major PI resistance mutations and all 4 had virologic failure., Conclusions: Most treatment-experienced individuals achieved virologic suppression on a dual-class regimen of a PI plus raltegravir. Success was limited by poor medication adherence and preexisting major PI resistance mutations.

Purpose: As more Americans use dietary supplements, the potential for increased adverse effects increases. The purpose of this study was to identify the current knowledge, attitudes and practice behaviors among California dental hygienists regarding herbal and dietary supplements (HDS)., Methods: A stratified random sample of 1,203 registered California hygienists were surveyed. The survey included items about personal characteristics as well as questions regarding knowledge, attitudes and beliefs and practice behavior about HDS. Three primary outcomes were analyzed: dental hygienists' knowledge about HDS, attitudes (confidence) about HDS and behavior practices (communication) regarding HDS. Confirmatory factor analysis was performed. Personal characteristics were assessed in stepwise multiple linear regression analysis for impact on knowledge scores., Results: The response rate was 21% (n=249). Dental hygienists have low levels of knowledge and confidence about HDS, as well as poor communication practices related to HDS. California dental hygienists scored a low mean of 38% on their knowledge of HDS. On the confidence scale (standardized range of 0 to 10 possible), hygienists scored 3.67±2.03. On the communication practices subscales (standardized range of 0 to 10 possible), hygienists scored 4.21±2.99 on general communication practices and 1.25±1.66 on specific communication practices. Dental hygienists who were members of the California Dental Hygienists' Association and attended a continuing education course on HDS within the last year or who personally used HDS scored significantly higher in knowledge, confidence and communication practices than their counter parts. These 3 attributes were identified as significant predicators for higher knowledge about HDS., Conclusion: There is a need to improve California dental hygienists' knowledge and involvement in the active management of patients who take HDS. Such actions can be expected to improve oral health outcomes. Focused training on HDS for hygienists should be designed to improve their knowledge and influence practice behaviors.