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This article explores the impact of diagnostic/psychiatric labelling on the attitudes and behavioural intentions of school-aged children towards a hypothetical peer presented with symptoms of attention deficit hyperactivity disorder (ADHD). A sample of 120 children aged 11—12 years read one of three vignettes describing the behaviour of a gender-neutral, same-age peer presenting with symptoms of ADHD. The participants completed self-report measures of attitudes and behavioural intentions after reading the respective vignettes. The majority of participants perceived the vignette character as being male and the attitude held towards him was predominately negative. Significant positive relationships were found between attitudes and children's willingness to engage in social, academic and physical activities. Diagnostic/psychiatric labelling had no additional influence upon attitudes or behavioural intentions. Children's negative attitude towards peers with symptoms of ADHD, given its association with friendship choice, is an important target for change in reducing stigma. [ABSTRACT FROM AUTHOR]

Considerable variation is observed in the near-edge X-ray absorption fine structure (NEXAFS) spectra of amino acids. To unambiguously characterize the chemical origin of this variation, we have acquired the nitrogen 1s NEXAFS spectra of several amino acids and other model compounds and complemented these experimental measurements with ab initio calculations of isolated molecules and molecular clusters. The systematic differences observed between the zwitterionic and un-ionized forms of amino acids arise directly from the structural difference (-NH2vs -NH3), which leads to a change in the degree of Rydberg-valence mixing. Further change arises from quenching of this Rydberg character in the spectra of condensed amino acids. Ab initio calculations are used to explore the degree of Rydberg-valence mixing in the solid state. [ABSTRACT FROM AUTHOR]

The nature of the linear dichroism in the near-edge X-ray absorption fine structure (NEXAFS) spectra of linear n-alkanes is a matter of long-standing controversy. Linear dichroism in the carbon 1s → σ*C-C transition has been interpreted within a building block model and a molecular orbital model, leading to two different descriptions for the angular dependence of this feature. When used for measurement of molecular orientation, the application of these two different models will lead to different results. We have explored the linear dichroism in the carbon 1s NEXAFS spectra of single crystals of the linear n-alkane hexacontane (n. 60H122). An analysis of the angular dependence in this spectrum shows that the transition dipole moment associated with the carbon 1s → σ*C-C transition is oriented along the macromolecular chain axis, contradicting the predictions of the building block model. However, other transitions are observed in the σ*C-H and the σ*C-C bands that are orthogonal to the dominant transitions for each band. We also observe that radiation damage can be manifest in the form of molecular reorientation in highly ordered organic thin films. [ABSTRACT FROM AUTHOR]

For many years, viscosity has been the primary method used by researchers in rheumatology to assess the physiochemical properties of synovial fluid in both normal and osteoarthritic patients. However, progress has been limited by the lack of methods that provide multiple layers of information, use small sample volumes, and are rapid. Raman spectroscopy was used to assess the biochemical composition of synovial fluid collected from 40 patients with clinical evidence of knee osteoarthritis (OA) at the time of elective surgical treatment. Severity of knee osteoarthritis was assessed by a radiologist using Kellgren/Lawrence (K/L) scores from knee joint x rays, while light microscopy and Raman spectroscopy were used to examine synovial fluid (SF) aspirates (2 to 10 L), deposited on fused silica slides. We show that Raman bands used to describe protein secondary structure and content can be used to detect changes in synovial fluid from osteoarthritic patients. Several Raman band intensity ratios increased significantly in spectra collected from synovial fluid in patients with radiological evidence of moderate-to-severe osteoarthritis damage. These ratios can be used to provide a “yes/no” damage assessment. These studies provide evidence that Raman spectroscopy would be a suitable candidate in the evaluation of joint damage in knee osteoarthritis patients. [ABSTRACT FROM AUTHOR]

Background: The adolescent borderline personality disorder (BPD) diagnosis has been widely debated for many years. Strikingly, young people's experiences of both receiving a diagnosis of BPD, and of living with BPD, are largely under-explored. The current study seeks to address these gaps in the literature in a multi-perspectival design utilising young people-parent dyads., Methods: Young people (aged 16-18 years) with a diagnosis of BPD (n = 5) and their mothers (n = 5) were recruited from two NHS Community Mental Health Services in the West Midlands and participated in semi-structured interviews. Data were analysed using interpretative phenomenological analysis [IPA]., Findings: Analysis identified two superordinate themes with five subthemes: (1) The "ugly" reality of living with BPD (providing a stark insight into what it is like to live with the unpredictable nature of experiences labelled as BPD), and (2) The diagnosis that dare not speak its name (highlighting the complexities of how the diagnosis itself is experienced by participants as a symbol of personal and permanent defectiveness and danger)., Discussion: Findings highlight a clear commonality of experience centred around the intensity of the young people's emotional distress and the accompanying pressure on parents to keep young people safe, both of which services must strive to do more to contain. Ultimately, the costs of receiving a BPD diagnosis appear to outweigh the benefits, and this paper adds support to calls for change in respect to how we conceptualise difficulties labelled as BPD and how we communicate about these difficulties, in order to avoid causing harm., (© 2024 The Author(s). Psychology and Psychotherapy: Theory, Research and Practice published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Introduction: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice., Materials & Methods: Pan-Scotland study between August 2018-August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS., Results: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis., Conclusions: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland. It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate., Competing Interests: Declaration of competing interest Dr Adam L Peters has received a travel grant to attend the Royal College of Radiology Clinical Oncology academic training day from the Beatson Cancer Charity. Miss Beatrix Elsberger has had an advisor role with Exact Sciences, and has received a travel grant to attend a meeting in London. The funds received were put back into the departmental pot to help fund a research nurse., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss-of-function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found that deletion of CDKL5 or expression of a clinically relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. Cdkl5-knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.

Background: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin., Methods: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31 P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy., Results: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m 2 , and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P =0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P =0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes ( P =0.009 and P =0.008, respectively), T1 and T2 mapping ( P =0.001 and P =0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation ( P =0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls ( P =0.013)., Conclusions: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31 P-metabolism alongside structural skeletal muscle changes., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04467411., Competing Interests: Disclosures None.

Background: Major health inequalities exist surrounding the utilisation of cervical cancer screening services globally. Jordan, a low- and middle-income country, has poor screening rates (15.8%), with barriers to accessing services, including lack of education. Emerging studies demonstrate that intimate partner violence (IPV) impacts reproductive health decisions. As a large proportion of Jordanian women have reported experiencing IPV, this study examines the association between IPV and cervical cancer screening in Jordan, the first of its kind using national-level data., Methods: Using Jordan's Demographic Health Survey 2017-18, cervical cancer screening awareness and self-reported screening were estimated in participants who answered questions on IPV (n = 6679). After applying sample weights, Heckman's two-stage probit model determined the association of awareness and utilisation of cervical cancer screening with experience of IPV, adjusting for the socio-economic factors., Results: Of the women with privacy to answer the IPV module, 180 (3.4%) were found to be victims of sexual violence, 691 of physical violence (12.6%) and 935 (16.2%) of emotional violence. Women subjected to sexual violence were less likely to admit to having awareness of a Pap smear test; however, this did not impact screening rates. Victims of emotional violence were more likely to be screened than non-victims. No association between physical violence and cervical cancer screening was found., Conclusions: A significant association between cervical screening awareness and IPV demonstrates that cancer screening policies must consider IPV among women to improve screening awareness. The paper further sheds light on the paradoxical association between emotional violence and screening. It is acknowledged this situation may be far worse than reported, as women without autonomy were unlikely to answer IPV questions that may endanger them-targeted surveys on cervical cancer screening warrant further investigation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Urquhart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3',5'-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5'-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling.

Drug overdose remains a leading cause of death in the US, and the majority of opioid overdose fatalities involve fentanyl. This study aims to measure the degree of concordance between self-reported and biologically tested exposure to fentanyl. We conducted a cross-sectional analysis using survey and urinalysis data collected between 2019 and 2020 from Anne Arundel County, Maryland. Among urinalysis participants (n =113), 30% reported daily fentanyl use, and among this group, only 54% had a fentanyl-positive result. Cohen Kappa between self-reported and biologically detected fentanyl use was 0.26, indicating minimal agreement between the 2 markers. Limitations to interpreting self-reported and urinalysis data are discussed in this report., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all breast cancers and male malignancies. Despite recognised clinico-pathological and molecular differences to female breast cancer (FBC), the clinical management of MBC follows established FBC treatment strategies. Loss of function mutations in the DNA damage response genes BRCA1 and BRCA2 , have been strongly implicated in the pathogenesis of MBC. While there have been extensive clinical advancements in other BRCA -related malignancies, including FBC, improvements in MBC remain stagnant. Here we present a review that highlights the lack of treatment evidence for BRCA -related MBC and the required national and global collaborative effort to address this unmet need. In doing so, we summarise the transformative clinical advancements with poly(ADP-ribose) polymerase (PARP) inhibitors in other BRCA -related cancers namely, FBC and prostate cancer.

Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.

Drug overdose remains a leading cause of death in the US, with growing rates attributable to illicit fentanyl use. Recent HIV outbreaks among people who inject drugs (PWID) and service disruptions from COVID-19 have renewed concerns on HIV resurgence. We examined the relationship between fentanyl use and three injection-related HIV risk behaviors among PWID in Baltimore City (BC) and Anne Arundel Country (AAC), Maryland. PWID (N = 283) were recruited to the study through targeted sampling at street-based locations in BC and AAC from July 2018 to March 2020. Receptive syringe sharing (RSS) [adjusted odds ratio (AOR): 2.8, 95% confidence interval (CI): 1.2-6.3] and daily injecting (AOR: 1.9, 95% CI: 1.0-3.6) were associated with injecting fentanyl and cocaine together. Fentanyl availability and COVID-19 bring new HIV prevention challenges, particularly among those who inject fentanyl with cocaine, highlighting the importance to expand and sustain harm reduction, prevention, and treatment services for PWID to reduce HIV and overdose burden., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

HER2-positive breast cancers, representing up to 20% of all breast cancers, are more aggressive and have poorer outcomes. Systemic therapy has been proven to prevent disease recurrence and improve survival. Existing literature provides only limited evidence to support this in smaller HER2-positive tumors. The study aimed to evaluate HER-2 positive breast cancer management and treatment of all T1N0 tumors in the North of Scotland, diagnosed 2012-2019. Clinical-pathological details, comorbidities, treatments and clinical events were retrieved from the Scottish North Cancer Alliance audit database and analyzed using univariate and multivariate analysis including cox-regression and log-rank testing (SPSSv23).Overall, 299 patients (41% screen detected/ 56.9% symptomatic /2.1% other), median age 63 years and median tumor size 13 mm, were included. Most cancers were grade 2/3 (43.1%/ 55.5%). Most patients (59.5%) received treatment with trastuzumab (tT); 40.8% concurrent with chemotherapy and endocrine therapy. 7.7% of patients received neo adjuvant chemotherapy. Median follow-up time was 2.6 years, with recurrence on average occurring 2.9 years after diagnosis. Patients receiving trastuzumab were younger, had a higher grade and larger size tumor. 78.5% of patients in the untreated group (non-tT) were ER positive compared to 65.2% in the treated group (tT). Trastuzumab significantly lowered breast cancer recurrence (Tt=3.4% versus non-Tt=8.3%, p = 0.022 HR= 0.096, 95% CI 0.025-0.361). In conclusion, receiving anti-HER2 treatment significantly improved clinical outcome in this T1N0 patient group. Consideration, at the very least informed discussions with patients, should be undertaken to treat these early stage HER2-positive breast cancers., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Regional variation in clinical practice may identify differences in care, reveal inequity in access, and explain inequality in outcomes. The study aim was to measure geographical variation in Scotland for adjuvant chemotherapy use and mortality in early-stage breast cancer., Patients and Methods: In this retrospective cohort study using population cancer registry-based data linkage, patients with surgically treated early breast cancer between 2001 and 2018 were identified from the Scottish Cancer Registry. Geographical regions considered were based on NHS Scotland organisational structure including 14 territorial Health Boards as well as three regional Cancer Networks. Regional variation in the proportion receiving chemotherapy, breast cancer mortality and all-cause mortality was investigated. Inter-regional comparisons of chemotherapy use were adjusted for differences in case mix using logistic regression. Comparison of breast cancer-specific mortality and all-cause mortality used regression with a parametric survival model. Time trends were assessed using moving average plots., Results: Chemotherapy use ranged from 35% to 46% of patients across Health Boards without adjustment. Variation reduced between 2001 and 2018. Following adjustment for clinical case mix, variation between cancer networks was within 3 percentage points, but up to 10 percentage points from the national average in some Health Boards. Differences in breast cancer mortality and all-cause mortality between cancer networks were modest, with hazard ratios of between 0.933 (95% confidence interval 0.893-0.975) and 1.041 (1.002-1.082) compared with the national average. Survival improved over the time period studied., Conclusion: With adequate case mix adjustment, variation in adjuvant chemotherapy use for early breast cancer in Scotland is small, with a trend towards greater convergence in practice and improved mortality outcomes in more recent cohorts. This suggests very limited regional inequity in access and convergence of clinical practice towards risk-stratified treatment recommendations. Outliers require assessment to understand the reasons for variance., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To evaluate the efficacy of UPA in women with fibroid induced menorrhagia., Methods: Embase, MEDLINE, CAB Abstracts, Cochrane Central Register of Controlled Trials, PsychInfo were searched up to 18th May 2020 and updated on 7th February 2021. Randomised controlled trials evaluating the efficacy of UPA in women with fibroid induced menorrhagia were included in the study., Results: Two authors independently reviewed and extracted the study data. Statistical heterogeneity was quantified using I 2 statistics. Publication bias and data asymmetry was assessed by funnel plots. A meta-analysis was conducted where appropriate. Six studies were eligible for inclusion. UPA (5 mg and 10 mg) achieved statistically significant amenorrhoeic outcome when compared to placebo (p<0.00001). Increased adverse events (AE) profile was observed in the higher UPA dose, however, did not reach statistical significance., Conclusions: This review demonstrates the efficacy of UPA in achieving amenorrhoea in women with fibroid induced menorrhagia. However, the favourable dose of UPA remains inconclusive when AE profile is taken into account. Evidence remains obscure regarding liver damage and further research is warranted to attain a conclusive outcome., Competing Interests: Declaration of Competing Interest Authors have no competing interests to disclose., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Considering most people who inject drugs (PWID) received help with the first injection, understanding the perspective of potential 'initiators' is a priority to inform harm reduction interventions. This paper examines how PWID narrate their experiences with injection initiation and assistance from the lens of their lived experience and perceptions of harm reduction., Methods: In-depth interviews were conducted with individuals who reported injection drug use and recent (past 30 days) opioid use in Baltimore ( N  = 19) and Anne Arundel County ( N  = 4), Maryland and analyzed using a narrative approach., Results: Respondents cast initiation events as meaningful transitions to a life characterized by predictable harms, including homelessness, infections, and social stigma. Respondents used examples from their personal experience to explain experiences with initiation and assistance by strategically attributing personal agency and predicting specific injection-related harms for initiates. In their narratives, respondents balanced notions of individual agency with harm reduction intentions by distinguishing between two forms of harm: perceived inevitable distal harm caused by long-term injection (e.g. socioeconomic decline) and potentially avoidable proximal harm caused by risky injection practices (e.g. overdose, HIV)., Conclusions: These findings highlight opportunities for interventions targeting injection initiation events and support the implementation of safer injection training in interventions. This identity of the 'responsible drug user' could be leveraged to support employing peers to help mitigate harm among inexperienced PWID either through peer outreach or formal venues, such as overdose prevention sites.

The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term "microbiome" is used to describe the diverse community of micro-organisms existing within the gastrointestinal tract. The gut microbiome plays an important role in oestrogen metabolism through its ability to deconjugate oestrogens within the gut resulting in their reabsorption. Therefore, it is not unsurprising that "dysbiosis", the disruption of normal gut microbiota composition, is now thought to play a role in the development of the disease, as women with breast cancer have been shown to have altered gut microbiota and this has been correlated with tumour characteristics. There is emerging evidence to suggest that the gut microbiota may also impact on breast cancer treatment, by mediating both drug efficacy and toxicity. The present review will discuss the influence of the gut microbiota on systemic treatments for breast cancer, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, endocrine therapy and immunotherapy as well as other targeted treatments., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2021.)

Background: In Baltimore, the emergence of fentanyl and its analogues exacerbated an existing heroin crisis and increased uncertainty about drug composition and potency. In an effort to reduce overdoses, harm reduction organizations and health departments across the U.S. began distributing fentanyl test strips, a low barrier, inexpensive drug checking strategy. Studies show that people who use drugs (PWUD) frequently suspect that their drugs contain fentanyl and are interested in using fentanyl test strips to check their drugs; however, some people question their usefulness in regions where fentanyl presence is assumed. Understanding the utility of fentanyl test strips in fentanyl-saturated markets is a priority to best tailor interventions., Methods: In-depth interviews (N = 20) were conducted with individuals who reported recent (past 30 days) opioid use in Baltimore, MD., Results: Fentanyl was viewed as pervasive, dangerous, and difficult to avoid in the local drug supply. This dominant narrative characterized PWUD as disempowered by the heightened unpredictability of the drug market. While several strategies are used to navigate the drug market, respondents wanted more information about their drugs. In this context, fentanyl test strips were used in unique and unexpected ways to empower PWUD to be savvier market consumers, including avoiding fentanyl when there could be negative social or legal consequences, negotiating with dealers, and helping others in their social network navigate the opaque drug market., Conclusion: These findings add nuance and place fentanyl preference and use in the context of the drug market. When fentanyl presence is assumed, people used fentanyl test strips in unexpected ways to gain some control over their drug use. Novel uses for fentanyl test strips strengthen existing strategies used to navigate the drug market and mitigate overdose risk, and highlight their potential to quickly disseminate valuable information about the local drug supply., Competing Interests: Declaration of Competing Interests SGS is an expert witness for plaintiffs in opioid litigation. Remaining authors report no conflict of interest nor financial disclosures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The aims of the study were to identify factors related to (1) adolescents and young adults (AYA) desire to discuss health topics; (2) whether discussions occurred at their last medical visit; and (3) the gap (unmet need) between desire and actual discussion., Methods: We used data from a nationally representative, cross-sectional online survey of AYA aged 13-26 years (n = 1,509) who had had a visit in the past 2 years. Bivariate analyses examined 11 topics. Multivariable regression identified health care factors and demographic factors related to unmet need across four salient topics (HIV/sexually transmitted infections, alcohol and drug use, tobacco, and contraception)., Results: Across 11 topics, unmet need averaged 28% and ranged as high as 60%; unmet need generally increased with AYA age. In multivariable analyses, ever having discussed confidentiality with a health care provider was associated with greater desire to discuss three of four salient topics, increased discussions (four of four topics), and reduced unmet need (two topics). Patient use of a clinical checklist/questionnaire at the last medical visit was associated with an increase in discussions (four topics) and reduced unmet need (four topics). Longer office visits were associated with an increase in discussions (three topics) and reduced unmet need (two topics). Older and minority youth had greater desire for discussions and unmet need., Conclusions: A considerable gap exists between young people's desire to discuss health topics with their health care providers and actual practice., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

This paper explores how a peer-and street-based naloxone distribution program (Bmore POWER) reshapes narratives and practices around drug use and harm reduction in an urban context with an enduring opioid epidemic. Data collection included observations of Bmore POWER outreach events and interviews with peers. Bmore POWER members create a sense of community responsibility around overdose prevention and reconfigure overdose hotspots from places of ambivalence to places of grassroots action. It expands a harm reduction approach to Black communities that have not traditionally embraced it and that have been underserved by drug treatment programs. Policy makers should consider ways to use peers grounded in specific communities to expand other aspects of harm reduction, such as syringe and support services., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Empirical evidence suggests that the Solihull Approach parenting group, 'Understanding Your Child's Behaviour' (UYCB), can improve child behaviour and parental well-being. However, little is known about parents' in-depth experience of participating in the UYCB programme. This study provides an in-depth qualitative evaluation of UYCB, focussing on possible moderating factors and mechanisms of change that may inform programme development., Method: Ten parents (eight mothers and two fathers), recruited from seven UYCB groups across two locations, were interviewed within 7 weeks of completing the group and again 10 months later. Data were analysed using interpretative phenomenological analysis., Results: Four themes were identified: 'Two Tiers of Satisfaction', 'Development as a Parent', 'Improved Self-belief' and 'The "Matthew Effect"'. In summary, the majority of parents were immensely satisfied at both completion and follow-up: they valued an experience of containment and social support and perceived improvement in specific child difficulties, their experience of parenting, their confidence and their coping. Most parents appeared to have developed more reflective and empathic parenting styles, with self-reported improved behaviour management. Theoretical material was well received, although some struggled with technical language. Positive outcomes appeared to be maintained, even reinforced, at follow-up, and were associated with having few initial child difficulties, perceiving improvement at completion and persevering with the recommendations. Two participants, whose children had the most severe difficulties, perceived deterioration and felt that the group was insufficient for their level of difficulties., Conclusion: Through in-depth analysis of parental experiences, UYCB appears to achieve its aims and communicate well its theoretical principles, although change may also occur through processes common to other group programmes (e.g. social support). Recommendations, stemming from the experiences of these parents, include simplified language, separate groups for parents with complex needs, greater emphasis on the importance of perseverance, and additional support for parents who appear to be struggling to make changes., (© 2015 John Wiley & Sons Ltd.)

Background: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer., Methods: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients., Results: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines., Conclusion: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

Homozygous recessive mutations in either EFEMP2 (encoding fibulin-4) or FBLN5 (encoding fibulin-5), critical genes for elastogenesis, lead to autosomal recessive cutis laxa types 1B and 1A, respectively. Previously, fibulin-4 was shown to bind lysyl oxidase (LOX), an elastin/collagen cross-linking enzyme, in vitro. Consistently, reported defects in humans with EFEMP2 mutations are more severe and broad in range than those due to FBLN5 mutations and encompass both elastin-rich and collagen-rich tissues. However, the underlying disease mechanism in EFEMP2 mutations has not been fully addressed. Here, we show that fibulin-4 is important for the integrity of aortic collagen in addition to elastin. Smooth muscle-specific Efemp2 loss in mouse (termed SMKO) resulted in altered fibrillar collagen localization with larger, poorly organized fibrils. LOX activity was decreased in Efemp2-null cells, and collagen cross-linking was diminished in SMKO aortas; however, elastin cross-linking was unaffected and the level of mature LOX was maintained to that of wild-type aortas. Proteomic screening identified multiple proteins involved in procollagen processing and maturation as potential fibulin-4-binding partners. We showed that fibulin-4 binds procollagen C-endopeptidase enhancer 1 (Pcolce), which enhances proteolytic cleavage of the procollagen C-terminal propeptide during procollagen processing. Interestingly, however, procollagen cleavage was not affected by the presence or absence of fibulin-4 in vitro. Thus, our data indicate that fibulin-4 serves as a potential scaffolding protein during collagen maturation in the extracellular space. Analysis of collagen in other tissues affected by fibulin-4 loss should further increase our understanding of underlying pathologic mechanisms in patients with EFEMP2 mutations., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy., Methods: Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations., Results: We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin., Conclusions: In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

Introduction: In a previous biomarker discovery project using gene-expression profiling we identified Serpin B3 (SB3) as a predictor of resistance to platinum doublet chemotherapy (PtC) in non-small-cell lung cancer (NSCLC). This independent prospective study was designed to confirm the predictive utility of SB3., Methods: SB3 immunohistochemistry was scored by previously validated criteria (score 0 = negative, score 1 = 1%-10% tumor cells positive, score 2 = 11%-50% tumor cells positive, and score 3 = >50% tumor cell positive) in 197 patients with stage IV NSCLC treated with PtC. This provided 80% power to detect a median survival increase from 150 days in patients with an SB3 immunohistochemistry score of 2 or more to 300 days in those with an SB3 score of 0 or 1., Results: Thirty-six percent of NSCLCs stained positive for SB3. Median survival for SB3 negative/score 0 was 332 days, SB3 positive/score 1 was 268 days, and SB3 positive/score 2 or 3 was 120 days (p = 0.004). Cox proportional hazards analysis demonstrated that SB3 positivity is an independent predictor of survival (hazard ratio = 1.87; 95% confidence interval, 1.29-2.71; p = 0.001).The disease control rate in SB3 score 0, 1 = 65%, and score of 2 or more = 20 % (p = 0.002), with median survival 306 days (score 0, 1) versus 120 days (score ≥ 2, hazard ratio= 1.71; 95% confidence interval. 1.14-3.10; p = 0.002)., Conclusions: SB3-positive immunohistochemistry score of 2 or more (>10% tumor cells positive) identifies a subgroup of patients with stage IV NSCLC who have a poor survival (median 120 days) when treated with PtC, similar to that estimated for untreated or chemo-refractory stage IV NSCLC. Further prospective qualification using biospecimens from randomized studies is needed, but SB3 seems to be a useful biomarker that identifies a highly resistant subgroup in whom PtC should be avoided.

Endovascular repair of abdominal aortic aneurysm is a common procedure and not without complications. The aim of this study was to evaluate the early results of the Anaconda endograft (Vascutek Ltd., Inchinnan, Scotland, UK) in 106 patients in three hospitals in the west of Scotland. A prospective registry of 106 consecutive patients undergoing endoluminal repair of their abdominal aortic aneurysms using the Anaconda device was set up to record the clinical outcomes, with a mean follow-up of two years. There was no 30-day perioperative mortality in the 106 patients. Only type II endoleaks were detected on serial computed tomography scanning at follow-up. Technical success was achieved in 99% (105/106) in this study; one patient was converted to open surgical repair. Two cases of proximal device migration (>1 cm) were detected at one month and 19 months, respectively, with no associated endoleak or sac enlargement. Five cases of endograft limb thrombosis were noted in this study. Our early clinical experience with the Anaconda endograft compares favourably with other commercially available endografts in the treatment of abdominal aortic aneurysms. The main advantages of this device are that it is re-deployable and that it has a magnetic wire system which makes it easy to implant.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) arises in up to 10% of organ transplant recipients and is fatal in ∼50% of cases. PTLD can be modeled in SCID mice using EBV+ve human B lymphoblastoid cell lines (BLCLs), and the current study investigated intraperitoneal (ip) inoculation of such animals in experiments which assessed the effect of EBV-specific cytotoxic T lymphocytes (CTLs) and cytokines on PTLD growth. Ip transfer of one dose of autologous CTLs, or CD8-enriched T cells, into ip BLCL-inoculated animals significantly delayed tumor development (P = 0.001) and prevented tumor formation in a significant proportion (40%) of mice (P = 0.001). A combination of interleukin (IL)2, 7, and 15 conditioning of CTLs prior to ip injection significantly delayed ip BLCL-derived tumor formation in vivo when compared to CTLs expanded in vitro using only IL2 (P = 0.04) and prevented tumor outgrowth in a significant proportion (60%) of mice (P = 0.02). Daily ip IL2 dosing of ip CTL-inoculated mice significantly delayed tumor development in vivo (P = 0.004) and prevented tumor outgrowth in a significant proportion (78%) of mice (P = 0.02) when compared to animals dosed with vehicle only. In SCID mice, autologous CTLs, and CD8-enriched T cells, have significant capacity to hinder development of PTLD-like tumors. Whilst studies are needed to delineate the role of cytokine conditioning and CD4-enriched T cells, the results suggest that IL2 plays a key role in supporting CTL funtion in vivo., (Copyright © 2011 Wiley-Liss, Inc.)

This cross-sectional study examined the joint effects of self-efficacy and illness representations on dietary self-care and diabetes distress in adolescents with type 1 diabetes by comparing two theoretical models: the Self-regulation Model (Leventhal, H., Meyer, D., & Nerenz, D. (1980). The common-sense representations of illness danger. In S. Rachman (Ed.), Medical Psychology (Vol. 2, pp. 7-30). New York: Pergamon.) and Social Cognitive Theory (Bandura, A. (1997). Self efficacy: The exercise of control. New York: W.H. Freeman.). One hundred and fifty-one adolescents with type 1 diabetes completed self-report measures of dietary self-efficacy, illness representations, dietary self-care and diabetes distress. Data were analysed using structural equation modelling. The model best supported by the data (Leventhal's Self-regulation Model) showed that dietary self-efficacy, perceived consequences and treatment effectiveness had direct and independent effects on both dietary self-care and diabetes distress. Together with dietary self-efficacy, perceived short-term treatment effectiveness was a significant predictor of dietary self-care. Age was found to be a negative predictor of short-term treatment effectiveness beliefs. Diabetes distress was best predicted by self-efficacy and perceived consequences. It can be concluded that to target effectively dietary self-care and distress, clinicians should focus on key illness representation variables (perceived short-term treatment effectiveness and perceived consequences) in conjunction with self-efficacy.

In a recent phase II clinical trial using banked allogeneic CTL lines to treat EBV-associated posttransplant lymphoproliferative disease, a response rate of 52% was recorded 6 mo posttreatment. Tumor response was associated with an increase in both CTL/recipient HLA matches and CD4(+) T cells within the infused CTL lines. The present study was undertaken to correlate tumor response with CTL specificity. The majority of CTL lines infused recognized EBV-encoded nuclear Ag-3 proteins, but CTL protein specificity itself did not correlate with tumor response. Specificity in conjunction with donor/recipient functional HLA matching as opposed to HLA matching alone, however, was important for tumor response. CTL receptor TCR beta-chain variable gene subfamilies were polyclonal, with no preferential use of a particular family. However, tumor response was improved in those receiving CTL lines with polyclonal vs clonal distribution for subfamilies 2, 3, and 9. Interestingly, in five of six tumors (five Hodgkin's-like and one Burkitt's-like posttransplant lymphoproliferative disease) with restricted viral gene expression a complete response was recorded, although in some cases the tumor cells did not express the proteins recognized by the infused CTL. Thus CTL were advantageous when functionally HLA matched but for certain tumor types complete responses occurred in the absence of detectable specific CTL/tumor recognition. We suggest that either the allogenic CTL contained small, undetectable, EBV-specific, HLA-matched T cell populations or perhaps they stimulated nonspecific inflammatory responses in vivo, which were beneficial for tumor regression. These observations should be considered when designing and implementing CTL therapies.

Unlabelled: Experiencing invasive medical procedures can be a devastating experience for some children and their parents. The potential impact on staff who perform the procedure and who may have to restrain the child who is unwilling to have an essential procedure is a neglected area of research. Children's distress and their coping are affected by those around them so it is important to understand how nurses react in these situations., Aim: To explore the experiences of nursing staff involved in facilitating invasive procedures for children who do not want them., Method: Participants were selected at random from staff lists of one hospital in the West Midlands. Data collection was undertaken using unstructured qualitative interviews with ten paediatric nurses and in two focus groups. Theories generated from each interview were tested and validated with participants in subsequent interviews and then in the focus groups., Findings: The most common experiences reported by the participants were 'getting upset' and 'getting stressed' by some aspect of the medical procedure, either because the child or parents became upset or the procedure had gone wrong in some way. Procedural protocols that exist to protect children, for example, by limiting the number of unsuccessful attempts to undertake the procedure, also protect staff by providing a framework to manage emotions during the procedure. Being able to explain the process and need for the procedure to the child and parents, obtaining consent where possible for the use of certain techniques, such as restraint, and having the time to adequately prepare a child for a procedure, all helped minimise the likelihood of an unsuccessful procedure, thereby reducing the risk of the nurse being emotionally affected by a distressed child., Conclusion: Nurses working with children who are unwilling to undergo invasive procedures experience negative emotions but these are short lived due to a combination of protective factors and coping strategies. Further research is needed to understand the experiences of medical staff and of nurses working outside paediatric environments who may not experience the same support and protection as those in paediatric settings.

A variety of cardiac tumors have been acknowledged in the literature since the 16th century as rare forms of cardiac disease. Of the primary tumors, myxomas account for at least 30% to 50% of benign tumors. Despite significant advances in cardiac diagnostics leading to early recognition of myxomas, the potential for deleterious effects secondary to embolic complications remains high. The purpose of this paper is to provide nurses with an understanding of the epidemiology, pathology, clinical presentation, and assessment of individuals with cardiac myxomas. A case presentation is used to illustrate how the misdiagnosis of cardiac myxoma led to a delay in patient treatment. Prompt recognition, diagnosis, and treatment are important in improving patient outcomes and quality of life. Due to the infrequency of cardiac myxomas, ensuring appropriate preoperative and postoperative nursing care to the patient with a cardiac myxoma is essential.

We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV-positive posttransplantation lymphoproliferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects of CTL infusions were observed and the response rate (complete or partial) in 33 patients was 64% at 5 weeks and 52% at 6 months. Fourteen patients achieved a complete remission, 3 showed a partial response, and 16 had no response at 6 months (5 died before completing treatment). At 5 weeks, there was a significant trend toward better responses with higher numbers of CD4(+) cells in infused CTL lines (P = .001) that were maintained at 6 months (P = .001). Patients receiving CTLs with closer HLA matching responded better at 6 months (P = .048). Female patients responded better than male patients, but the differences were not statistically significant. Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for individual patients. The response rate in this poor prognosis patient group is encouraging.

Aims: The aims of the study were (i) to examine whether an empirical psychosocial taxonomy, based on key diabetes-related variables, is independent of type of diabetes and treatment, and (ii) to further establish the external validation of the taxonomy., Methods: In a cross-sectional study, 82 patients with Type 1 and 86 patients with Type 2 diabetes mellitus were assigned to one of three psychosocial patient profiles based on their Multidimensional Diabetes Questionnaire (MDQ) scores. General psychological and diabetes-specific measures were obtained through self-report and HbA(1c) was measured., Results: Equal proportions of Type 1 and Type 2 patients, and of patients using insulin and oral medication/diet only were classified within each of the three psychosocial profiles. External validation confirmed the validity and distinctiveness of the patients' profiles. The patient profiles were independent of demographic variables, body mass index, duration of diabetes, complexity of treatment, number of complications, social desirability, and major stress levels., Conclusions: The Psychosocial Taxonomy for Patients with Diabetes provides a new way to categorize individuals who may have more in common than just their type of diabetes and/or its treatment and can help target interventions to individual patients' needs.