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Background: This study evaluates the effects of hydroxytyrosol (HT), a component of olive oil, on mammographic breast density reduction. We explored effects of HT on Wnt β -catenin and other pathways involved in cancer stem cell renewal, DNA repair, cell proliferation, and differentiation. Methods: Twenty-five milligrams per day oral dose of HT was given for 12 months in pre- and postmenopausal women at increased risk of breast cancer. Out of 51 patients enrolled, 41 completed the study. The annualized percent decrease in maximum mammographic volumetric breast density (max VBD%) between baseline (BL) and end of treatment (EOT) was analyzed. RNA sequencing (RNA-Seq) and multiplex analysis was performed on the breast biopsies to compare the BL with EOT samples. Results: Max VBD% showed a nonsignificant change; however, in women 60 years or older, the max VBD% decrease was significant (3.7%, p = 0.0391), especially in those with high BL mammographic density. Using RNA-Seq, 3330 unique transcripts were identified ( p < 0.05). Mitotic telophase/cytokinesis and DNA damage were upregulated, whereas Wnt, Notch, and oxidative stress-induced senescence pathways were downregulated ( p < 0.05). These pathways were confirmed by NanoString nCounter where significant decrease in proliferative genes (RELA and CDK4) and Wnt pathway (R-HSA-195721 and R-HAS-201681) was observed ( p < 0.05). Conclusions: HT reduced breast density only in women over 60 years, especially in those with high BL breast density. HT also reduced proliferation and affected the Wnt signaling pathway. This study lays the foundation for future larger studies in exploring a natural compound with well tolerability and overall nontoxic profile for chemoprevention of breast cancer. Trial Registration: ClinicalTrials.gov identifier: NCT02068092., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Akshjot Puri et al. International Journal of Breast Cancer published by John Wiley & Sons Ltd.)

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH 2 -terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC., Competing Interests: Competing interests: C. Yam reports grants from Conquer Cancer Foundation (Career Development Award supported by Fleur Fairman; the Gianni Bonadonna Breast Cancer Research Fellowship) and other support from MD Anderson Cancer Center (The University of Texas, Houston, TX) during the conduct of the study, as well as other support from Amgen, Merck, Genentech, and GSK outside the submitted work. S. Moulder also reports other support from Eli Lilly and Company and grants from ASCO Career Development Award Mentor outside the submitted work. J. Chang reports grants from the Cancer Prevention and Research Institute of Texas and from NIH during the conduct of the study. J.Chang is the sole inventor on patent application no. 10420838 entitled “Methods for treating cancer using iNOS-inhibitory compositions” held by Houston Methodist Hospital. C. Thomas reports support from NIH during this study. F. Meric-Bernstam reports grants and personal fees from F. Hoffmann-La Roche/Genentech during the conduct of the study, as well as personal fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, IBM Watson, Infinity Pharmaceuticals, The Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis and grants from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co. outside the submitted work. No disclosures were reported by other authors., (© 2024. The Author(s).)

(1) Background: Osteoarthritis is a degenerative joint disease that is commonly diagnosed in the aging population. Interestingly, the lower extremity joints have a higher published incidence of osteoarthritis than the upper extremity joints. Although much is known about the disease process, it remains unclear why some joints are more affected than others. (2) Methods: A comprehensive literature review was conducted utilizing the search engines PubMed, Google Scholar, and Elsevier from 2014 to 2024, directing our search to osteoarthritis of various joints, with the focus being on glenohumeral osteoarthritis. (3) Results and Discussion: The literature review revealed a publication difference, which may be explained by the inconsistency in classification systems utilized in the diagnosis of shoulder osteoarthritis. For instance, there are six classification systems employed in the diagnosis of glenohumeral osteoarthritis, making the true incidence and, therefore, the prevalence unobtainable. Furthermore, susceptibility to osteoarthritis in various joints is complicated by factors such as joint anatomy, weight-bearing status, and prior injuries to the joint. (4) Conclusions: This review reveals the lack of understanding of shoulder osteoarthritis's true incidence and prevalence while considering the anatomy and biomechanics of the glenohumeral joint. In addition, this is the first paper to suggest a single criterion for the diagnosis of glenohumeral osteoarthritis.

Objective: We aimed to investigate whether vedolizumab (VDZ) levels were associated with inflammatory markers or clinical or endoscopic scoring in inflammatory bowel disease (IBD)., Methods: Besides demographic data, clinical scoring, endoscopic data, and laboratory markers of IBD patients treated with VDZ from 2015 to 2020 who had trough levels drawn on maintenance therapy were collected at baseline and at follow-up (after at least 8 weeks on VDZ therapy or after change in dose frequency). Low drug levels were defined as VDZ trough <20 μg/mL., Results: We identified 89 patients with a mean age of 42.9 years. Of the 90 total trough levels drawn, 61.1% were low. Among patients on every 8 week (Q8 week) VDZ dosing, 81.5% had low troughs. After increasing dosing frequency to Q4 weeks, all patients showed improvement in VDZ levels, but 30.6% remained <20 μg/mL. Higher VDZ levels on Q8 week dosing were associated with higher albumin levels (P = 0.01). While higher VDZ levels on Q4 week dosing were associated with higher albumin (P = 0.02), lower erythrocyte sedimentation rate (P = 0.04) and higher likelihood of having mild disease or endoscopic remission (P = 0.01). No significant association was found between VDZ levels and clinical scoring, body mass index, hemoglobin, vitamin D or platelet levels on either Q8 or Q4 week dosing., Conclusions: Higher VDZ troughs were associated with higher albumin, mild endoscopic disease or endoscopic remission. Patients who continue to have low VDZ troughs despite Q4 week dosing may require a change in therapy., (© 2024 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

This study aims to test the psychometric properties of the Violent Risk Scale (VRS) in a sample of Portuguese remand prisoners. A total of 133 subjects participated in the present study. We carried out a Confirmatory Factor Analysis (CFA) to test the originally proposed two factor structure. Results showed evidence to support the VRS's psychometric qualities. The CFA tested the two-factor structure and showed evidence of the goodness of fit of the original two-factor model. Also, our findings indicated acceptable internal consistency for both subscales. The correlational analyses supported both convergent and discriminant validity of the VRS. Finally, this study also tested known-groups validity. The VRS score showed a satisfactory postdictive accuracy, which means that it is able to demonstrate distinctive scores for groups known to vary on the variables being measured. We consider this work represents an essential support for decision-makers to evaluate the appropriateness of different judicial measures., Competing Interests: Joana Andrade has declared no conflicts of interest. Hugo Gomes has declared no conflicts of interest. Rui Abrunhosa Gonçalves has declared no conflicts of interest. Stephen Wong has declared no conflicts of interest. Andreia de Castro Rodrigues has declared no conflicts of interest., (© 2023 The Australian and New Zealand Association of Psychiatry, Psychology and Law.)

Objective: This study proposes to identify and validate weighted sensor stream signatures that predict near-term risk of a major depressive episode and future mood among healthcare workers in Kenya., Approach: The study will deploy a mobile application (app) platform and use novel data science analytic approaches (Artificial Intelligence and Machine Learning) to identifying predictors of mental health disorders among 500 randomly sampled healthcare workers from five healthcare facilities in Nairobi, Kenya., Expectation: This study will lay the basis for creating agile and scalable systems for rapid diagnostics that could inform precise interventions for mitigating depression and ensure a healthy, resilient healthcare workforce to develop sustainable economic growth in Kenya, East Africa, and ultimately neighboring countries in sub-Saharan Africa. This protocol paper provides an opportunity to share the planned study implementation methods and approaches., Conclusion: A mobile technology platform that is scalable and can be used to understand and improve mental health outcomes is of critical importance., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We read with concern yet another communication from Dotan regarding the critical power (CP) concept which contains a litany of factual errors, false statements, and dated physiological interpretations. Space does not permit us to rebut every incorrect point made about our work (Wong et al., 2022) and the wider field in which it sits, but we will address what we consider to be some of the more egregious errors in his letter. We would first note, however, that our paper was not actually focused on the critical power concept.

High-dose intravenous methotrexate (HD-MTX) CNS prophylaxis in high-risk diffuse large B cell lymphoma (DLBCL) remains controversial. We describe real-world CNS relapse incidence following baseline cerebrospinal fluid (CSF) analysis to exclude asymptomatic leptomeningeal involvement in newly diagnosed high-risk DLBCL patients with versus without single-route HD-MTX CNS prophylaxis. Consecutively diagnosed high-risk systemic DLBCL patients without leptomeningeal involvement by CSF analysis (noCNS) were identified retrospectively. Five-year CNS relapse incidence and survival outcomes were examined, as stratified by receipt of HD-MTX prophylaxis. Secondary analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) by CSF analysis at diagnosis were compared with the noCNS group. No significant difference in 5-year CNS relapse incidence was observed following HD-MTX prophylaxis versus no prophylaxis (total n = 445) despite similar CNS-IPI risk; 6.2% versus 5.6%, adjusted HR 1.08 (95% CI 0.41-2.85), p = .88; nor in 5-year progression free survival (PFS) or overall survival (OS) risk. Of CNSinv patients, 93.3% had ≥1 extranodal site. Increased CNS relapse/progression risk (5-year risk; HR 10.7 [95% CI 5.35-21.37], p < .0001) and inferior PFS and OS were observed in CNSinv versus all noCNS patients. The CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse (HR 0.55, p = .052). HD-MTX prophylaxis does not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis. Asymptomatic patients with synchronous leptomeningeal involvement on baseline CSF examination are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement., (© 2023 Wiley Periodicals LLC.)

In the context of an emerging Japanese encephalitis outbreak within Australia, we describe a novel locally acquired case in New South Wales. A man in his 70s had rapidly progressive, fatal meningoencephalitis, diagnosed as caused by Japanese encephalitis virus by RNA-based metagenomic next-generation sequencing performed on postmortem brain tissue.

Objective: This study proposes to identify and validate weighted sensor stream signatures that predict near-term risk of a major depressive episode and future mood among healthcare workers in Kenya. Approach: The study will deploy a mobile app platform and use novel data science analytic approaches (Artificial Intelligence and Machine Learning) to identifying predictors of mental health disorders among 500 randomly sampled healthcare workers from five healthcare facilities in Nairobi, Kenya. Expectation: This study will lay the basis for creating agile and scalable systems for rapid diagnostics that could inform precise interventions for mitigating depression and ensure a healthy, resilient healthcare workforce to develop sustainable economic growth in Kenya, East Africa, and ultimately neighboring countries in sub-Saharan Africa. This protocol paper provides an opportunity to share the planned study implementation methods and approaches. Conclusion : A mobile technology platform that is scalable and can be used to understand and improve mental health outcomes is of critical importance.

Objective: Excessive daytime sleepiness (EDS) is common in patients with epilepsy (PWE). The Epworth Sleepiness Scale (ESS) is a self-reported measure of sleepiness in widespread use. The purpose of this study was to identify contributors to the ESS score in PWE and to identify variables associated with a high score indicative of EDS., Methods: A cross-sectional study was performed on 115 PWE presenting to the epilepsy clinic. Self-reported questionnaires were administered and demographic and clinical information was gathered from the electronic medical record. Regression analyses were performed., Results: A high ESS score was found in nearly 20% of the cohort. Obstructive sleep apnea (OSA) risk, standardized anti-seizure drug (ASD) dose, and female sex were associated with an increased likelihood of a high ESS score. Assessment of the ESS without the use of a cutpoint showed that standardized ASD dose and OSA risk were associated with the ESS in men, but standardized ASD dose was not associated with the ESS in women. Higher use of valproic acid and oxcarbazepine in men and higher use of lamotrigine in women may be contributing factors., Significance: Sex is likely to be a key factor in determining contributors to EDS in PWE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Functional Threshold Power (FTP) has been considered a valid alternative to other performance markers that represent the upper boundary of the heavy intensity domain. However, such a claim has not been empirically examined from a physiological perspective.This study examined the blood lactate and VO 2 response when exercising at and 15 W above the FTP (FTP +15W ). Thirteen cyclists participated in the study. The VO 2 was recorded continuously throughout FTP and FTP +15W , with blood lactate measured before the test, every 10 minutes and at task failure. Data were subsequently analysed using two-way ANOVA. The time to task failure at FTP and FTP +15W were 33.7 ± 7.6 and 22.0 ± 5.7 minutes (p < 0.001), respectively. The VO 2peak was not attained when exercising at FTP +15W (VO 2peak : 3.61 ± 0.81 vs FTP +15W 3.33 ± 0.68 L·min -1 , p < 0.001). The VO 2 stabilised during both intensities. However, the end test blood lactate corresponding to FTP and FTP +15W was significantly different (6.7 ± 2.1 mM vs 9.2 ± 2.9 mM; p < 0.05). The VO 2 response corresponding to FTP and FTP +15W suggests that FTP should not be considered a threshold marker between heavy and severe intensity.

Objective: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that is gaining recognition from clinicians and researchers. We aim to publish data from our cohort of patients with CNO living in the northwestern United States to increase the awareness of specific demographics, characteristics, and presentation of this rare disease., Methods: A retrospective chart review was performed of our electronic medical records. Patients with complete chart records who met criteria for a diagnosis of CNO from 2005 to 2019 were included. Extracted data including patient demographics, bone biopsy results, and lesion locations on advanced imaging were analyzed. King County census data were used to calculate the annual new case rate within our center., Results: A total of 215 CNO cases were diagnosed at our large tertiary pediatric hospital. The majority of cases were of White race residing in Washington's most populous county, King County. Most cases were diagnosed in 2016 to 2019, showing a significant increase in the annual case rate from 8 to 23 per million children in King County, though there did not appear to be a seasonal predilection. Biopsy rate decreased from 75% to 52%. One hundred fifty-two (71%) children had family history of autoimmunity. With increasing use of whole-body magnetic resonance imaging (WB-MRI), results showed 68% had multiple lesions., Conclusion: CNO has been diagnosed at an increased rate in recent years. WB-MRI may assist in identifying other lesions that may be asymptomatic on presentation. Bone biopsy is still required in some children at the time of diagnosis., (Copyright © 2022 by the Journal of Rheumatology.)

This paper presents a novel Lasso Logistic Regression model based on feature-based time series data to determine disease severity and when to administer drugs or escalate intervention procedures in patients with coronavirus disease 2019 (COVID-19). Advanced features were extracted from highly enriched and time series vital sign data of hospitalized COVID-19 patients, including oxygen saturation readings, and with a combination of patient demographic and comorbidity information, as inputs into the dynamic feature-based classification model. Such dynamic combinations brought deep insights to guide clinical decision-making of complex COVID-19 cases, including prognosis prediction, timing of drug administration, admission to intensive care units, and application of intervention procedures like ventilation and intubation. The COVID-19 patient classification model was developed utilizing 900 hospitalized COVID-19 patients in a leading multi-hospital system in Texas, United States. By providing mortality prediction based on time-series physiologic data, demographics, and clinical records of individual COVID-19 patients, the dynamic feature-based classification model can be used to improve efficacy of the COVID-19 patient treatment, prioritize medical resources, and reduce casualties. The uniqueness of our model is that it is based on just the first 24 hours of vital sign data such that clinical interventions can be decided early and applied effectively. Such a strategy could be extended to prioritize resource allocations and drug treatment for futurepandemic events.

Objectives: The aim of the current investigation is to estimate the incidence and risk for neurocognitive disorders (NCD) in a chronic kidney disease (CKD) cohort with diabetes, compared with an age and sex-matched control cohort., Design: Longitudinal follow-up., Setting: District general hospital North Wales, UK., Participants: Ninety-two patients with CKD and an age and gender-matched sample of 143 controls at baseline and at approximately 36 months., Interventions: Cognitive function was assessed in the patients with CKD (mean age 75.8±9.1; 49 men: 43 women) and the control cohort (mean age 74.4±6.2; 71 men: 72) at baseline and at approximately 36 months. An NCD diagnosis was based on patient, informant, case note review, neuropsychological assessment and application of Diagnostic and Statistical Manual of Mental disorders V.5 (DSM-5) for an NCD and Petersen's criteria for mild cognitive impairment., Results: Follow-up neuropsychological assessment and application of DSM-5 criteria of the cognitively normal patients and controls revealed, 25/92 (27%) of the CDK and 20/143 (13.9%) in the control cohort developed an NCD. The CKD cohort had a twofold increased risk for the development of an NCD compared with the controls, adjusted for age and sex. The incidence rate for an NCD in the CKD cohort was 10.5 and 5.1 in the controls, respectively. No association was observed with the stage of CKD and cognitive function., Conclusions: This longitudinal investigation found that patients with CKD have a twofold increased risk for the development of an NCD. The current investigation highlighted the need to recognise that NCD in patients with CKD is a common comorbidity and that they are at a much higher risk for the development of a significant neurodegenerative disorders. In view of these risks, neuropsychological screening and assessment should be incorporated into normal CKD clinical practice and management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)-resistant vs ASM-responsive outcome for patients with idiopathic generalized epilepsy (IGE)., Methods: This was a case-control study of ASM-resistant cases and ASM-responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM-resistant IGE., Results: We identified 118 ASM-resistant cases and 114 ASM-responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM-resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32-10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure-type combinations (absence, myoclonic, and generalized tonic-clonic seizures [OR 7.06, 95% CI 2.55-20.96]; absence and generalized tonic-clonic seizures [OR 4.45, 95% CI 1.84-11.34]), as well as EEG markers of increased generalized spike-wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12-11.36 for frequent and OR 7.21, 95% CI 1.50-54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27-38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver-operating characteristic curve, was 0.80., Significance: Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure-type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value., (© 2021 International League Against Epilepsy.)

Background: Prognostic cytological and molecular features of uveal melanoma have been well researched and are essential in management. Samples can be obtained in vivo through fine needle aspirate biopsy, vitrector cutter, forceps or post-enucleation for off-site testing. This study aims to examine cytological and chromosome microarray yields of these samples., Methods: A retrospective cohort analysis of 119 uveal melanoma biopsies submitted to our laboratory. Samples included those taken in vivo (n = 57) and post-enucleation (n = 62). Patient and tumour features were collected including age, sex, primary tumour location, basal diameter and tumour height. Prognostic outcomes measured include cell morphology, chromosomal status and immunohistochemistry., Results: Post-enucleation biopsies accounted for just over half of our samples (52%). Post-enucleation samples had a more successful genetic yield than in vivo biopsies (77% vs. 50%, p = 0.04) though there was no difference for cytological yields. There was no difference in cytological or microarray yields between instruments. The vitrector biopsy group had the smallest tumour thickness (5 mm vs. 10 mm [fine-needle aspirate biopsy], p = 0.003). There was a strong correlation between monosomy 3, BAP1 aberrancy and epithelioid cell type in post-enucleation samples (T b  = 0.742, p = 0.005). However, epithelioid morphology was not associated with either monosomy 3 (p = 0.07) or BAP1 aberrancy (p = 0.24) for in vivo biopsies., Conclusions: All three biopsy instruments provide similar cytological yields as post-enucleation sampling, although post-enucleation samples had a more successful chromosome microarray yield. Epithelioid cytomorphology alone is insufficient for prognostication in in vivo biopsies, immunohistochemistry would be a useful surrogate test., (© 2021 Royal Australian and New Zealand College of Ophthalmologists.)

Background: Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC). Resistance to platinum chemotherapy is common, and predictive biomarkers are needed to tailor treatment to patients likely to respond. In vitro evidence implicates the transforming growth factor-β (TGF-β) superfamily ligands activin-A and growth differentiation factor 11 (GDF-11) in innate platinum resistance. We performed a validation study to assess their utility as predictive biomarkers of platinum chemotherapy response in advanced NSCLC., Patients and Methods: Our study included 123 adult patients with advanced NSCLC without a driver mutation treated with platinum chemotherapy. 98 patients were from a retrospective cohort and 25 from a prospective cohort. We performed immunohistochemistry staining for Activin-A, GDF-11 and TGF-β on tumour samples for each patient and analysed IHC expression with objective radiological response and overall survival., Results: The overall median survival was 14.8 months. We performed statistical analysis around a cytoplasmic score of 8/18 for Activin-A and GDF-11 based on previously published work, and 110/30 for TGF-β based on a calculated cutpoint for significance. No survival difference was detected between these groups for Activin-A (p=0.35), GDF-11 (p=0.57) or TGF-β (p=0.34). There was no association between rates of progressive disease and high Activin-A expression (p=0.43), high GDF-11 expression (p=1.0) or high TGF-β expression p=0.89)., Conclusion: Within the confines of our study, Activin-A, GDF-11 and TGF-β expression was not a predictor of objective radiological response to chemotherapy or overall survival., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: In this study, the authors investigated the longitudinal effect of the recovery attributes of peer support workers (PSWs) on users of mental health services in Hong Kong over a 9-month period., Methods: Recovery attributes were measured among PSWs (N=26) employed by four local nongovernmental organizations before their commencement of service. The recovery-related outcomes of regular service users (N=181) were measured every 3 months for 9 months. Multilevel mixed-effects linear regression analyses with restricted maximum likelihood were used to analyze the possible association of PSWs' qualities on service users' recovery outcomes. The Holm-Bonferroni method was used to adjust for p values to account for multiple comparisons., Results: Results showed that levels of hope and self-esteem among PSWs were statistically significantly associated with improvements in hope and empowerment among service users over time., Conclusions: PSWs' recovery attributes may benefit service users' personal recovery. Future exploration on the specific pathways of recovery attributes of PSWs on service users' recovery is suggested.

Background: The strengths model of case management (SMCM), which was developed by Rapp and Goscha through collaborative efforts at the University of Kansas, assists individuals with mental illness in their recovery by mobilizing individual and environmental resources. Increasing evidence has shown that the utilization of the SMCM improves outcomes, including increased employment/educational attainment, reduced hospitalization rates, higher self-efficacy, and hope. However, little is known about the processes through which the SMCM improves outcomes for mental health service users. This study explores the views of case workers and service users on their experience of providing or receiving the SMCM intervention., Methods: A qualitative design was employed using individual interviews with service users and case workers drawn from two study conditions: the SMCM group and the control group (treatment as usual). For both study conditions, service users were recruited by either centres-in-charge or case workers from integrated community centres for mental wellness (ICCMWs) operated by three non-governmental organizations (NGOs) in different districts of Hong Kong. Through purposeful sampling, 24 service users and 14 case workers from the SMCM and control groups joined the study. We used an inductive approach to analyse the qualitative data., Results: We identified two overarching themes: service users' and case workers' (1) perceptions of the impacts of the interventions (SMCM and control group) and (2) experiences of the interventions, such as features of the interventions and the factors that facilitated the outcomes. The results showed that there were improvements in the functional recovery of the SMCM group in areas such as employment and family relationships, how self-identified goals were achieved, and how service users gained a better understanding of their own strengths and weaknesses. Regarding their experience of the interventions, participants in both the SMCM group and the control group reported that a good relationship between service users and case workers was vital. However, some concerns were raised about the use of SMCM tools, including the strengths assessment and the personal recovery plan (PRP) and the risk of case workers being subjective in the presentation of cases in group supervision sessions., Conclusion: The results were promising in terms of supporting the use of the SMCM, with some refinements, in mental health services for Chinese clients., Trial Registration: The Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617001435370 , registered on 10/10/2017., (© 2021. The Author(s).)

Patients with inflammatory bowel disease often present to the emergency department due to the chronic relapsing nature of the disease. Previous studies have shown younger patients to have an increased frequency of emergency department visits, resulting in repeated exposure to imaging studies and steroids, both of which are associated with risks. We performed a retrospective cohort analysis of inflammatory bowel disease patients seen at Houston Methodist Hospital's emergency department from January 2014 to December 2017 using ICD codes to identify patients with Crohn's disease, ulcerative colitis, or indeterminate colitis from the electronic medical record. Data were collected on demographics, medications, and imaging. Five hundred and fifty-nine patients were randomly selected for inclusion. Older age was associated with decreased risk of CT scan or steroid use. Patients with ulcerative colitis compared to Crohn's had decreased risk of CT scan, while there was an increased risk of CT in patients on a biologic, immunomodulator, or when steroids were given. Steroid use was also more common in those with inflammatory bowel disease as the primary reason for the visit. Patients in our study frequently received steroids and had CT scans performed. The increased risk of CT in those on a biologic, immunomodulator, or steroids suggests more severe disease may contribute. Guidelines are needed to reduce any unnecessary corticosteroid use and limit repeat CT scans in young inflammatory bowel disease patients to decrease the risk of radiation-associated malignancy over their lifetime.

Introduction: EEG monitoring is a critical tool for identifying cerebral ischemia during carotid endarterectomy (CEA). Quantitative EEG can be used to supplement visual EEG review, but which measures best predict post-clamp ischemia is unclear., Purpose: To determine which quantitative EEG parameters reliably detect intraoperative ischemia during CEA., Methods: The authors identified patients who underwent carotid endarterectomy at Columbia University Medical Center from 2007 to 2014 with intraoperative EEG monitoring. Two masked physicians reviewed these EEGs retrospectively and determined whether there was post-clamp ischemia, categorizing patients into (1) ischemic-change and (2) no-ischemic-change groups. The authors then studied the performance of a battery of quantitative EEG measures (alpha, beta, theta, and delta power bands, alpha-delta ratio, beta-delta ratio, amplitude-integrated EEG, and 90% spectral edge frequency) against physician review as the gold standard., Results: Of 118 patients, 15 were included in the ischemic-change group and 103 in the no-ischemic-change group. Ipsilateral post-clamp trough values of all the quantitative EEG measures assessed were significantly decreased for patients in the ischemic-change group. Decreases in alpha, beta, and theta power of 52.1%, 41.6%, and 36.4% or greater, respectively, were most predictive of post-clamp ischemia., Conclusions: Quantitative EEG monitoring during carotid endarterectomy, in addition to visual EEG monitoring, may improve the detection of cerebral ischemia and thus result in fewer perioperative strokes., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Background Despite recent advancements in the treatment of acute ischemic stroke (AIS) with large vessel occlusion (LVO), infarct progression over time and functional outcomes remain variable. This variation in outcomes may be partially attributed to an underlying state of chronic cerebral hypoperfusion and ischemia affecting small cerebral perforating arterioles, venules, and capillaries of the brain; broadly termed cerebral small vessel disease (CSVD). We investigated the association between CSVD burden and the degree of disability following successful recanalization with endovascular thrombectomy (EVT) in patients with AIS presenting with LVO. Methodology We conducted a single center retrospective analysis of all patients presenting with AIS LVO between May 2016 and May 2019. Patients who were premorbidly independent and presented within six hours from the last known well (LKW) with a proximal anterior circulation occlusion confirmed on computed tomography (CT) angiography of the head or neck were treated with EVT. Patients presenting after six hours and up to 24 hours from LKW with a target ischemic core to perfusion mismatch profile on CT or magnetic resonance (MR) perfusion, or a clinical imaging mismatch on MR diffusion-weighted imaging, were also treated. Patients with successful revascularization, defined as a thrombolysis in cerebral infarction score 2b or 3, were included and evaluated for CSVD burden. The presence of CSVD was quantified using the Fazekas scale (0-3). All patients were further evaluated for disability at 90 days using the modified Rankin Scale (mRS, range 0-6). An mRS score of ≤2 was defined as a good functional outcome. Results Of the 190 patients evaluated, absent (Fazekas grade 0), mild (Fazekas grade 1), moderate (Fazekas grade 2), and severe (Fazekas grade 3) CSVD was present in 33 (17.4%), 84 (44.2%), 35 (18.4%), and 38 (20.0%) patients, respectively. Patients with severe CSVD (Fazekas grade 3) were found to be older, had a higher presenting National Institute of Health Stroke Scale (NIHSS), and had greater proportions of preexisting atrial fibrillation and dementia compared to patients with no CSVD (Fazekas grade 0). Using a multivariate ordinal logistic regression model to adjust for age, presenting NIHSS, thrombus location, LKW to groin puncture time, use of tissue plasminogen activator, ischemic infarct volume, development of a symptomatic intracerebral hemorrhage, and treatment with hemicraniectomy, patients with Fazekas grade 3 were significantly more likely to have poor 90-day functional outcomes compared to patients with Fazekas grade 0 (odds ratio 10.25, 95% confidence interval [3.3-31.84]). Conclusions Based on our analytical cohort of AIS LVO patients treated with EVT, we found that patients with severe CSVD burden had worse functional outcomes at 90 days and increased mortality. These results provide evidence that the burden of CSVD may be considered an independent risk factor of poor clinical outcome and a predictor of mortality in patients with AIS presenting with LVO, despite successful radiographic recanalization with EVT., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Hooper et al.)

Background: Acute exacerbations of chronic hepatitis B virus (HBV) infections can occur in HBV-infected, hepatitis e antigen (HBeAg)-negative patients in the absence of recent withdrawal of antiviral or immunosuppressive therapies. Whether these spontaneous "flares" predict subsequent loss of hepatitis B surface antigen (HBsAg) has yet to be determined., Objectives: To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers., Methods: A retrospective review of an HBV database identified and followed HBeAg-negative patients for biochemical evidence of flares (ALT > 5× normal) and subsequent HBsAg status. Patients that subsequently cleared HBsAg were matched 1:1 with those who remained HBsAg positive., Results: Of 1299 HBeAg-negative patients followed for 10.2 ± 6.1 years, 88 (6.8%) developed spontaneous HBV flares. Flares occurred in 14/115 (12.2%) patients who subsequently cleared HBsAg and 4/111 (3.6%) matched patients who remained HBsAg positive (p = 0.025). The severity of flares was similar in the two study cohorts. Following multivariate analyses, only low HBV-DNA levels at baseline identified patients likely to subsequently clear HBsAg., Conclusions: Although more common in patients who subsequently clear HBsAg, spontaneous HBV flares do not predict subsequent HBsAg clearance.

Objective: Risk of early recurrent ischemic stroke in patients with atrial fibrillation may be high. ASA/AHA guidelines provide imprecise recommendations on the timing and anticoagulant choice for this indication. We assessed current opinions of stroke neurologists., Methods: Case scenarios describing patients with acute ischemic stroke (AIS) due to paroxysmal atrial fibrillation (AF) were presented to US board-certified stroke neurologists in an internet-based questionnaire. Questions assessed timing and choice of anticoagulation for secondary stroke prevention, factors prompting earlier anticoagulation, reasons for specific anticoagulant choice, and alternatives to anticoagulation in ineligible patients. Open-ended comments were also solicited., Results: Responses were available from 238/1239 stroke neurologists surveyed. In patients with small AIS without hemorrhagic transformation (HT), 51% elected to start anticoagulation within 96 hours. With increased stroke severity and asymptomatic HT, only 29% and 26% respectively chose to anticoagulate within 7 days. Few requested stability imaging before starting anticoagulation. With symptomatic HT the majority (79%) waited >14 days. 93% would anticoagulate earlier if left atrium/left atrial appendage or acute left ventricular thrombi, or mechanical heart valve were present. Direct oral anticoagulants (DOACs) were the preferred anticoagulation strategy (64%), and the remaining 38% preferred Warfarin. Aspirin was preferred by 57% in anticoagulation ineligible., Conclusion: Apart from AIS with symptomatic HT, there is a remarkable lack of consensus among stroke neurologists regarding the timing of anticoagulation for secondary stroke prevention in patients with AIS due to PAF. DOACs are the preferred anticoagulation strategy. More studies are required to clarify anticoagulant management in this patient population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Video-electroencephalogram (EEG) monitoring in the epilepsy monitoring unit (EMU) is essential for managing epilepsy and seizure mimics. Evaluation of care in the EMU would benefit from a validated code set capable of identifying EMU admissions from administrative databases comprised of large, diverse cohorts. We assessed the ability of code-based queries to parse EMU admissions from administrative billing records in a large academic medical center over a four-year period, 2016-2019. We applied prespecified queries for admissions coded as follows: 1) elective, 2) receiving video-EEG monitoring, and 3) including diagnoses typically required by major US healthcare payers for EMU admission. Sensitivity (Sn), specificity (Sp), and predictive value positive/negative (PVP, PVN) were determined. Two approaches were highly effective. Incorporating epilepsy, seizure, or seizure mimic codes as the admitting diagnosis (assigned at admission; Sn 96.3%, Sp 100.0%, PVP 98.3%, and PVN 100.0%) or the principal diagnosis (assigned after discharge; Sn 94.9%, Sp 100.0%, PVP 98.8%, and PVN 100.0%) identified elective adult EMU admissions with comparable reliability (p = 0.096). The addition of surgical procedure codes further separated EMU admissions for intracranial EEG monitoring. When applied to larger, more comprehensive datasets, these code-based queries should enhance our understanding of EMU utilization and access to care on a scalable basis., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Obstructive sleep apnea (OSA) is common in patients with epilepsy (PWE), and treatment may improve seizure control. However, OSA is often undiagnosed in PWE, and understanding of the risk profile for OSA is important. In this study, we sought to determine if OSA risk is similar in patients with generalized versus focal epilepsy., Methods: We recruited 115 patients presenting to the Rutgers-Robert Wood Johnson Epilepsy Clinic with focal or generalized epilepsy. Obstructive sleep apnea risk was assessed using the Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ). Sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Demographic and clinical information was gathered from the electronic medical record. Unadjusted and adjusted analyses were carried out to assess differences in the SA-SDQ between patients with generalized versus focal epilepsy. Further analyses were done to assess the relationship between seizure frequency, epilepsy type, and the SA-SDQ., Results: Unadjusted mean SA-SDQ scores, as well as scores high enough to represent likely OSA, were similar in patients with generalized versus focal epilepsy. However, in adjusted analyses, patients with generalized epilepsy had a significantly higher mean SA-SDQ score. Older age, higher body mass index (BMI), and a history of hypertension (HTN) were also associated with higher SA-SDQ scores. Sleep Apnea Scale of the Sleep Disorders Questionnaire scores were not significantly affected by the presence of a seizure within the prior one month or six months. Average ESS scores and the percentage of scores consistent with an abnormal degree of sleepiness were statistically similar in patients with generalized versus focal epilepsy., Significance: Our study suggests that patients with generalized epilepsy have a higher risk of OSA. Further studies measuring OSA directly as well as assessing potential benefits of treatment are needed., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fifty-five year-old female presented with five weeks of progressively worsening headaches precipitated by a sudden neck movement. The headaches were exacerbated by sitting up or standing. There was associated diplopia and facial pain. Investigations were consistent with intracranial hypotension with a possible spontaneous spinal cerebrospinal fluid leak. Symptoms improved dramatically after an epidural blood patch., Competing Interests: Nil.

Population studies indicate women have higher prevalences of depression and anxiety than men. Interferon (IFN) is a biologic agent that can induce or exacerbate depression and/or anxiety. Whether women are more likely to experience these side effects of IFN during treatment remains to be determined. The aim of this study was to document levels of depression and anxiety in female and male patients before and during IFN-based treatment. This was a prospective open-label study in which depression was measured by Beck Depression Inventory (BDI) and anxiety by Hospital Anxiety and Depression Scale (HADS). Before treatment, the prevalence of depression was higher in females (3/13 [23%]) than males (1/25 [4%]), but the difference did not reach statistical significance ( P  = 0.12). Initial BDI scores were also higher in females but not significantly ( P  = 0.07). During treatment, BDI scores increased to a similar extent in both genders. A similar percentage of nondepressed patients at baseline developed depression (females: 50% versus males: 35%, P  = 0.45). Before treatment, anxiety was significantly more common in females (7/13 [54%]) than males (3/25 [12%]) ( P  = 0.016) and median HADS scores were higher in females ( P  = 0.03). During treatment, increases in HADS scores were similar in the 2 genders. A similar percentage of patients without anxiety at baseline developed anxiety on treatment (females: 50% versus males: 23%, P  = 0.31). The frequency and extent of IFN-induced/exacerbated depression and anxiety are not gender dependent.

Purpose: To investigate the performance of seizure detection methods and nursing staff response in our epilepsy monitoring unit (EMU)., Methods: We retrospectively reviewed 38 EMU patient admissions over a 1-year period capturing 133 epileptic and non-epileptic seizures with associated video-EEG data. We recorded detailed seizure event characteristics for further analysis., Results: Rates of seizure detection, alarm usage, and time to nursing response varied by seizure type. Patients self-activated the push button (PB) alarm for 31.1% of all seizures, but only 8.9% of focal impaired awareness (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS). In comparison, the Persyst automated seizure alarm reliably detected both electrographic seizures (76.2% of electrographic seizures) and FIAS/FBTCS (87.2% of FIAS/FBTCS), with a false positive alarm rate (FAR) of 0.14/hour, or every 7.3 h. 11.4% of all seizures went unrecognized by nursing staff, of which the majority (80.0%) were FIAS. The PB alarm was of higher yield for alerting nurses to focal aware seizures (FAS) and psychogenic non-epileptic seizures (PNES) versus FIAS and FBTCS (p < 0.001). In contrast, nurses relied more on the automated Persyst software alarm to detect FIAS (p < 0.001). Time to nursing response was no different following audible alarm onset for the PB compared to the Persyst alarms (p = 0.14)., Conclusion: Automated seizure detection software plays an important role in our EMU in seizure recognition, particularly for alerting nurses to FIAS. More rigorous studies are needed to determine the best utilization of various monitoring techniques and to promote high quality standards and patient safety in the EMU., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) rates have been increasing worldwide and contribute to a growing "global health security threat" as reported by the WHO. Our group previously reported an overall rate of 7% in CA-MRSA upper extremity infections between 2004-2009 at the Auckland Regional Hand Unit. This fell below the Center for Disease Control (CDC) recommendation for empiric antimicrobial cover once local rates exceed 10-15%. We examined prevalence and characteristics of CA-MRSA upper extremity infections in our region over a subsequent 5-year period. Methods: One thousand two hundred and fifty-two patients with upper extremity infections requiring operative management between 2011 and 2015 inclusive were included in this study. Associated clinical characteristics were recorded including ethnicity, cultured organisms, antibiotic sensitivities, infection rate, and treatment practice. Results: One hundred and fifty (12%) of patients had culture positive CA-MRSA upper extremity infections. There was an increasing annual trend. Of note, rates of CA-MRSA in the Maori and Pacific Island ethnic subpopulations exceeded 15% in 2014 and 2015. Susceptibilities, associated factors and patient demographics are reported. Conclusions: Our unit enjoys significantly lower rates of CA-MRSA upper extremity infections than has been reported internationally. However, trends are increasing relative to our prior 6-year report, and the threshold for empiric treatment has been met within the Maori and Pacific Island ethnic subpopulations. This evolving threat is also highlighted by increasing cases of multi-drug resistant CA-MRSA. Evolving regional guidelines for empiric coverage of CA-MRSA among high-risk ethnic subpopulations identified by this study are underway.

The purpose of this study was to examine the physical activity (PA) of children with physical disabilities (PD) and its associated environmental and behavioral factors at home and at school. One hundred and forty-seven Hong Kong children (mean age = 13.5 ± 2.5 years) with PD from three special schools participated. We used BEACHES (Behaviors of Eating and Activity for Children's Health: Evaluation System) to assess their PA and associated variables at home (before dinner) and during four school settings (before classes, recess, lunch breaks, after classes) on four school days. Overall, the children were typically inactive and spent little time in moderate-to-vigorous physical activity (MVPA), range = 6.3% to 17.0% across settings. At home, children were more active when fathers were present ( p < 0.001). At school, prompts to be active contributed to their MVPA% before classes ( p < 0.01) and during recess and lunch breaks (both p < 0.001). The presence of a child's mother was positively associated with MVPA% before classes ( p < 0.001) and the presence of other children was associated with MVPA% during recess and lunch breaks (both p < 0.05). With children with PD accruing small amounts of MVPA in both home and school settings, multifaceted interventions reflecting both contextual and personal factors should be considered in order to increase the health-enhancing PA of this population.

Implantable neural stimulators represent an advanced treatment adjunct to medication for pharmacoresistant epilepsy and alternative for patients that are not good candidates for resective surgery. Three treatment modalities are currently FDA-approved: vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation. These devices were originally trialed in very similar patient populations with focal epilepsy, but head-to-head comparison trials have not been performed. As such, device selection may be challenging due to large overlaps in clinical indications and efficacy. Here we will review the data reported in the original pivotal clinical trials as well as long-term experience with these technologies. We will highlight differences in their features and mechanisms of action which may help optimize device selection on a case-by-case basis.

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To review the performance and utility of the International Academy of Cytology (IAC) Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy (FNAB) Cytology five category stratification and evaluate the impact of rapid onsite evaluation (ROSE)., Method: A retrospective analysis of breast FNAB cytology cases with matched histopathological results at a single institution over a 32 months period using a structured reporting system with 5 diagnostic categories ("inadequate/insufficient," "benign," "atypical," "suspicious of malignancy" and "malignant") closely paralleling the proposed IAC System., Results: Of 2,696 breast FNAB cases, there were 579 with matched histopathology and 456 of these had ROSE. ROSE decreased the number in the "insufficient" category (17.1% without ROSE to 4.0% with ROSE) and increased the number in the "malignant" (17.9 to 39.0%) with a lesser impact on the "atypical," "benign" and "suspicious of malignancy" categories. The performance data showed a positive predictive value of 96.4%, negative predictive value of 97.6%, and a risk of malignancy of a FNAB categorized as "insufficient" to be 2.6%, "benign" 1.7%, "atypical" 15.7%, "suspicious of malignancy" 84.6%, and "malignant" 99.5%., Conclusion: Breast FNAB is an accurate test enabling effective diagnosis of breast lesions. ROSE improved the performance by decreasing the proportion of "insufficient" and "atypical" and increasing the "suspicious of malignancy" and "malignant" diagnoses and enabling immediate triage for further biopsy where necessary., (© 2019 S. Karger AG, Basel.)

Background: Long-term physical conditions affect 10% to 12% of children and adolescents worldwide. These individuals are at greater risk of developing psychological problems, particularly anxiety and depression, sometimes directly related to their illness or medical care (e.g. health-related anxiety). There is limited evidence regarding the effectiveness of psychological therapies for treating anxiety and depression in this population. Therapies designed for children and adolescents without medical issues may or may not be appropriate for use with those who have long-term physical conditions., Objectives: This review was undertaken to assess the effectiveness and acceptability of psychological therapies in comparison with controls (treatment-as-usual, waiting list, attention placebo, psychological placebo, or non-psychological treatment) for treating anxiety and depression in children and adolescents with long-term physical conditions., Search Methods: We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 27 September 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to May 2016). In addition we searched the Web of Science (Core Collection) (12 October 2018) and conducted a cited reference search for reports of all included trials. We handsearched relevant conference proceedings, reference lists of included articles, and grey literature., Selection Criteria: Randomised controlled trials (RCTs), cluster-randomised trials and cross-over trials of psychological therapies for treating anxiety or depression in children with long-term physical conditions were included., Data Collection and Analysis: Abstracts and complete articles were independently reviewed by two authors. Discrepancies were addressed by a third author. Odds ratio (OR) was used for comparing dichotomous data and standardised mean differences (SMD) for comparing continuous data. Meta-analysis was undertaken when treatments, participants, and the underlying clinical question were similar. Otherwise, narrative analysis of data was undertaken., Main Results: Twenty-eight RCTs and one cross-over trial with 1349 participants were included in the review. Most participants were recruited from community settings and hospital clinics in high-income countries. For the primary outcome of treatment efficacy, short-term depression (versus any control), there was low-quality evidence from 16 trials involving 1121 participants suggesting that psychological therapies may be more effective than control therapies (SMD -0.31, 95% CI -0.59 to -0.03; I 2 = 79%). For the primary outcome of treatment efficacy, short-term anxiety (versus any control), there was inadequate evidence of moderate-quality from 13 studies involving 578 participants to determine whether psychological therapies were more effective than control conditions (SMD -0.26, CI -0.59 to 0.07, I 2 = 72%). Planned sensitivity analyses could not be undertaken for risk of bias due to the small number of trials that rated high for each domain. Additional sensitivity analysis demonstrated that psychological interventions specifically designed to reduce anxiety or depression were more effective than psychological therapies designed to improve other symptoms or general coping. There was some suggestion from subgroup analyses that they type of intervention (Chi² = 14.75, df = 5 (P = 0.01), I² = 66.1%), the severity of depression (Chi² = 23.29, df = 4 (P = 0.0001), I² = 82.8%) and the type of long-term physical condition (Chi² = 10.55, df = 4 (P = 0.03), I² = 62.1%) may have an impact on the overall treatment effect.There was qualitative (reported), but not quantitative evidence confirming the acceptability of selected psychological therapies for anxiety and depression. There was low-quality evidence that psychological therapies were more effective than control conditions in improving quality of life (SMD 1.13, CI 0.44 to 1.82, I 2 = 89%) and symptoms of long-term physical conditions (SMD -0.34, CI -0.6 to -0.06, I 2 = 70%), but only in the short term. There was inadequate low-quality evidence to determine whether psychological therapies were more effective than control conditions at improving functioning in either the short term or long term. No trials of therapies for addressing health-related anxiety were identified and only two trials reported adverse effects; these were unrelated to psychological therapies. Overall, the evidence was of low to moderate quality, results were heterogeneous, and only one trial had an available protocol., Authors' Conclusions: A limited number of trials of variable quality have been undertaken to assess whether psychological therapies are effective for treating anxiety and depression in children and adolescents with long-term physical conditions. According to the available evidence, therapies specifically designed to treat anxiety or depression (especially those based on principles of cognitive behaviour therapy (CBT)) may be more likely to work in children and adolescents who have mild to moderate levels of symptoms of these disorders, at least in the short term. There is a dearth of therapies specifically designed to treat health-related anxiety in this age group.

Objective: Chronic kidney disease (CKD) affects nearly 9% of global populations and is strongly associated with older age. Neurocognitive disorders (NCDs), which include mild cognitive impairment and dementia, are rising as a result of ageing populations throughout the world. This investigation's aim is to report the frequency of mild to major NCD in a clinical cohort of adults with mild to moderate CKD and diabetes., Setting: Glan Clwyd District general Hospital, North Wales, UK., Participants: We enrolled 178 patients with CKD and diabetes, aged 55 years and over with an estimated glomerular filtration rate <60 >15 mL/min/1.73 m 2 , attending a specialist renal and diabetic outpatient clinic., Outcome Measures: Frequency of mild and major NCD and the association with the stage of CKD was assessed in all patients attending the specialist clinic. The diagnosis of NCD was based on patient and informant interview, case note review, neuropsychological assessment and application of Diagnostic and Statistical Manual of Mental Disorders version 5., Results: This investigation found 86/178 (48%) of the cohort with an NCD ranging from mild (n=49) to major symptoms (n=37). No association was found with NCD and the stage of CKD. Mild and major NCD was associated poorer outcomes in several cognitive domains, including, language, executive, memory, fluency and attention function (p<0.05)., Conclusions: This is the first UK investigation to report that cognitive changes occur in a significant number of older adults with CKD and diabetes. The unexpected finding was that prior to cognitive assessment, not any of the cohort had a pre-existing diagnosis of cognitive impairment, suggesting that the current prevalence and incidence rates of NCD in the general population are possibly significantly underestimated. Our findings also suggest that the cognitive function of patients with CKD should be screened and monitored routinely as part of their overall care management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Recent studies indicated that dysregulation of noncoding RNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design: We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results: In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K , which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3'-untranslated region of eEF2K and FOXM1 mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1 , the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis. Conclusions: Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC. Clin Cancer Res; 24(17); 4225-41. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Long-term physical conditions affect 10% to 12% of children and adolescents worldwide; these individuals are at greater risk of developing psychological problems, particularly anxiety and depression. Access to face-to-face treatment for such problems is often limited, and available interventions usually have not been tested with this population. As technology improves, e-health interventions (delivered via digital means, such as computers and smart phones and ranging from simple text-based programmes through to multimedia and interactive programmes, serious games, virtual reality and biofeedback programmes) offer a potential solution to address the psychological needs of this group of young people., Objectives: To assess the effectiveness of e-health interventions in comparison with attention placebos, psychological placebos, treatment as usual, waiting-list controls, or non-psychological treatments for treating anxiety and depression in children and adolescents with long-term physical conditions., Search Methods: We searched the Cochrane Common Mental Disorders Group's Controlled Trials Register (CCMDTR to May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2017), Web of Science (1900 - 18 August 2016, updated 31 August 2017) and Ovid MEDLINE, Embase, PsycINFO (cross-search 2016 to 18 Aug 2017). We hand-searched relevant conference proceedings, reference lists of included articles, and the grey literature to May 2016. We also searched international trial registries to identify unpublished or ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs), cluster-randomised trials, and cross-over trials of e-health interventions for treating any type of long-term physical condition in children and adolescents (aged 0 to 18 years), and that measured changes in symptoms or diagnoses of anxiety, depression, or subthreshold depression. We defined long-term physical conditions as those that were more than three-months' duration. We assessed symptoms of anxiety and depression using patient- or clinician-administered validated rating scales based on DSM III, IV or 5 (American Psychological Association 2013), or ICD 9 or 10 criteria (World Health Organization 1992). Formal depressive and anxiety disorders were diagnosed using structured clinical interviews. Attention placebo, treatment as usual, waiting list, psychological placebo, and other non-psychological therapies were eligible comparators., Data Collection and Analysis: Two review authors independently reviewed titles, abstracts, and full-text articles; discrepancies were resolved through discussion or addressed by a third author. When available, we used odds ratio (OR) to compare dichotomous data and standardised mean differences (SMD) to analyse continuous data, both with 95% confidence intervals (CI). We undertook meta-analysis when treatments, participants, and the underlying clinical question were adequately similar. Otherwise, we undertook a narrative analysis., Main Results: We included five trials of three interventions (Breathe Easier Online, Web-MAP, and multimodal cognitive behavioural therapy (CBT)), which included 463 participants aged 10 to 18 years. Each trial contributed to at least one meta-analysis. Trials involved children and adolescents with long-term physical conditions, such as chronic headache (migraine, tension headache, and others), chronic pain conditions (abdominal, musculoskeletal, and others), chronic respiratory illness (asthma, cystic fibrosis, and others), and symptoms of anxiety or depression. Participants were recruited from community settings and hospital clinics in high income countries.For the primary outcome of change in depression symptoms versus any control, there was very low-quality evidence meaning that it could not be determined whether e-health interventions were clearly better than any comparator (SMD -0.06, 95% CI -0.35 to 0.23; five RCTs, 441 participants). For the primary outcome of change in anxiety symptoms versus any comparator, there was very low-quality evidence meaning that it could not be determined whether e-health interventions were clearly better than any comparator (SMD -0.07, 95% CI -0.29 to 0.14; two RCTs, 324 participants). For the primary outcome of treatment acceptability, there was very low-quality evidence that e-health interventions were less acceptable than any comparator (SMD 0.46, 95% CI 0.23 to 0.69; two RCTs, 304 participants).For the secondary outcome of quality of life, there was very low-quality evidence meaning that it could not be determined whether e-health interventions were clearly better than any comparator (SMD -0.83, 95% CI -1.53 to -0.12; one RCT, 34 participants). For the secondary outcome of functioning, there was very low-quality evidence meaning that it could not be determined whether e-health interventions were clearly better than any comparator (SMD -0.08, 95% CI -0.33 to 0.18; three RCTs, 368 participants). For the secondary outcome of status of long-term physical condition, there was very low-quality evidence meaning that it could not be determined whether e-health interventions were clearly better than any comparator (SMD 0.06, 95% CI -0.12 to 0.24; five RCTs, 463 participants).The risk of selection bias was considered low in most trials. However, the risk of bias due to inadequate blinding of participants or outcome assessors was considered unclear or high in all trials. Only one study had a published protocol; two trials had incomplete outcome data. All trials were conducted by the intervention developers, introducing another possible bias. No adverse effects were reported by any authors., Authors' Conclusions: At present, the field of e-health interventions for the treatment of anxiety or depression in children and adolescents with long-term physical conditions is limited to five low quality trials. The very low-quality of the evidence means the effects of e-health interventions are uncertain at this time, especially in children aged under 10 years.Although it is too early to recommend e-health interventions for this clinical population, given their growing number, and the global improvement in access to technology, there appears to be room for the development and evaluation of acceptable and effective technologically-based treatments to suit children and adolescents with long-term physical conditions.

TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial-to-mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self-renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss-of-function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW-associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Here, we show that HEMATOLOGICAL AND NEUROLOGICAL EXPRESSED 1-LIKE (HN1L) is a targetable breast cancer stem cell (BCSC) gene that is altered in 25% of whole breast cancer and significantly correlated with shorter overall or relapse-free survival in triple-negative breast cancer (TNBC) patients. HN1L silencing reduced the population of BCSCs, inhibited tumor initiation, resensitized chemoresistant tumors to docetaxel, and hindered cancer progression in multiple TNBC cell line-derived xenografts. Additionally, gene signatures associated with HN1L correlated with shorter disease-free survival of TNBC patients. We defined HN1L as a BCSC transcription regulator for genes involved in the LEPR-STAT3 signaling axis as HN1L binds to a putative consensus upstream sequence of STAT3, LEPTIN RECEPTOR, and MIR-150. Our data reveal that BCSCs in TNBC depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter ( d max ) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a d max of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR ., (©2017 American Association for Cancer Research.)

This study explored the changing views of key stakeholders (peer support workers, their co-workers, and service users) about peer support services in a non-Western community, using a longitudinal qualitative approach. Five trainee peer support workers (PSWs), 15 service users, and 14 co-workers were interviewed over a 12-month period, under the auspices of the Peer Support Workers Project (also known as the Mindset project) in Hong Kong. A total of 77 interviews were transcribed and thematic analyses were conducted across the participant groups at three different time points (training, work placements, and employment). During the initial implementation of the services, uncertainty about the role of the PSWs were reported. However, trusting and beneficial relationships with service users were gradually built, showing growing resilience and confidence over time. The participants realized that PSWs' experiences of mental illnesses were a unique asset that could help service users to alleviate their own somatic symptoms and improve their connections with others. Our findings highlight that the perceptions of peer support services changed from confusion to viewing PSWs as an asset, to an awareness of the importance of family support, and to the belief that implementing such a program will benefit both service users and PSWs., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Therapeutic treatment for persons with epilepsy (PWE) should address seizure control and the broad spectrum of associated comorbidities. Since both epilepsy and antiepileptic drugs (AEDs) can induce decreased libido, sexual health assessment is an important aspect of quality care in PWE as well as other patients receiving AEDs. This paper presents findings from a pilot quality initiative conducted in the ambulatory care epilepsy, pain management, and psychiatric services (N=15 clinicians) which addressed two themes: 1) whether libido is routinely questioned with/without the electronic medical record (EMR) and 2) clinicians' knowledge that both epilepsy and AEDs can induce decreased libido. All clinicians used the EMR, 40% used the GU-ROS section, but only 1 clinician (6.67%) questioned patients regarding libido. Of the clinicians, 26.7% demonstrated knowledge that both AEDs and epilepsy can cause decreased libido. Our results suggest that a treatment gap for epilepsy-induced and AED-induced decreased libido may be related to systems issues (duration of clinical visit, billing codes, EMR template) and physician barriers including decreased knowledge. Further research in this field and replication of this pilot quality initiative are indicated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A truly practical lab-on-a-chip (LOC) system for point-of-care testing (POCT) hepatotoxicity assessment necessitates the embodiment of full-automation, ease-of-use and "sample-in-answer-out" diagnostic capabilities. To date, the reported microfluidic devices for POCT hepatotoxicity assessment remain rudimentary as they largely embody only semi-quantitative or single sample/gene detection capabilities. In this paper, we describe, for the first time, an integrated LOC system that is somewhat close to a practical POCT hepatotoxicity assessment device - it embodies both tissue sample preparation and multiplex real-time RT-PCR. It features semi-automation, is relatively easy to use, and has "sample-in-answer-out" capabilities for multiplex gene expression analysis. Our tissue sample preparation module incorporating both a microhomogenizer and surface-treated paramagnetic microbeads yielded high purity mRNA extracts, considerably better than manual means of extraction. A primer preloading surface treatment procedure and the single-loading inlet on our multiplex real-time RT-PCR module simplify off-chip handling procedures for ease-of-use. To demonstrate the efficacy of our LOC system for POCT hepatotoxicity assessment, we perform a preclinical animal study with the administration of cyclophosphamide, followed by gene expression analysis of two critical protein biomarkers for liver function tests, aspartate transaminase (AST) and alanine transaminase (ALT). Our experimental results depict normalized fold changes of 1.62 and 1.31 for AST and ALT, respectively, illustrating up-regulations in their expression levels and hence validating their selection as critical genes of interest. In short, we illustrate the feasibility of multiplex gene expression analysis in an integrated LOC system as a viable POCT means for hepatotoxicity assessment.

Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression.