The Spectrum of Dysregulated Aldosterone Production: An International Human Physiology Study.

CONTEXT: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. OBJECTIVE: To investigate the contributions of renin-independent aldosteronism, and ACTH-mediated aldosteronism, in individuals with a low-renin phenotype representing the entire continuum of blood pressure. . DESIGN/PARTICIPANTS: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. SETTING: 4 international centers. . INTERVENTIONS/MAIN OUTCOME MEASURES: Saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. RESULTS: There was a continuum of non-suppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < 0.0001) and non-suppressible aldosterone production post-dexamethasone (r = 0.40, P < 0.0001). Beyond participants who met criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of non-suppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy, and the remainder were treated with mineralocorticoid receptor antagonists. CONCLUSIONS: In the context of a low-renin phenotype, there is a continuum of dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low-renin have dysregulated aldosterone production and may benefit from aldosterone-directed therapy.

Remote consultations in community mental health: A qualitative study of clinical teams.

WHAT IS KNOWN ON THE SUBJECT?: Mental health care can be delivered remotely through video and telephone consultations. Remote consultations may be cheaper and more efficient than in person consultations. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: Accessing community mental health care through remote consultations is perceived as not possible or beneficial for all service users. Delivering remote consultations may not be practical or appropriate for all clinicians or community mental health teams. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Remote consultation cannot be a 'one-size-fits-all' model of community mental health care. A flexible approach is needed to offering remote consultation that considers its suitability for the service-user, service and clinician. ABSTRACT: INTRODUCTION: Responding to COVID-19, community mental health teams in the UK NHS abruptly adopted remote consultations. Whilst they have demonstrable effectiveness, efficiency, and economic benefits, questions remain around the acceptability, feasibility and medicolegal implications of delivering community mental health care remotely. AIM: To explore perceived advantages, challenges, and practice adaptations of delivering community mental health care remotely. METHODS: Ten community mental health teams in an NHS trust participated in a service evaluation about remote consultation. Fifty team discussions about remote consultation were recorded April-December 2020. Data analysis used a framework approach with themes being coded within a matrix. RESULTS: Three major horizontal themes of operations and team functioning, clinical pathways, and impact on staff were generated, with vertical themes of advantages, challenges, equity and adaptations. DISCUSSION: Remote consultation is an attractive model of community mental healthcare. Clinical staff note benefits at individual (staff and service-user), team, and service levels. However, it is not perceived as a universally beneficial or practical approach, and there are concerns relating to access equality. IMPLICATIONS FOR PRACTICE: The suitability of remote consultation needs to be considered for each service-user, clinical population and clinical role. This requires a flexible and hybrid approach, attuned to safeguarding equality.

Imaging of Endometriotic Lesions Using cRGD-MN Probe in a Mouse Model of Endometriosis.

Approximately 10% of women suffer from endometriosis during their reproductive years. This disease is a chronic debilitating condition whose etiology for lesion implantation and survival heavily relies on adhesion and angiogenic factors. Currently, there are no clinically approved agents for its detection. In this study, we evaluated cRGD-peptide-conjugated nanoparticles (RGD-Cy5.5-MN) to detect lesions using magnetic resonance imaging (MRI) in a mouse model of endometriosis. We utilized a luciferase-expressing murine suture model of endometriosis. Imaging was performed before and after 24 h following the intravenous injection of RGD-Cy5.5-MN or control nanoparticles (Cy5.5-MN). Next, we performed biodistribution of RGD-Cy5.5-MN and correlative fluorescence microscopy of lesions stained for CD34. Tissue iron content was determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Our results demonstrated that targeting endometriotic lesions with RGD-Cy5.5-MN resulted in a significantly higher delta T2* upon its accumulation compared to Cy5.5-MN. ICP-OES showed significantly higher iron content in the lesions of the animals in the experimental group compared to the lesions of the animals in the control group. Histology showed colocalization of Cy5.5 signal from RGD-Cy5.5-MN with CD34 in the lesions pointing to the targeted nature of the probe. This work offers initial proof-of-concept for targeting angiogenesis in endometriosis which can be useful for potential clinical diagnostic and therapeutic approaches for treating this disease.

Co-administration of temozolomide (TMZ) and the experimental therapeutic targeting miR-10b, profoundly affects the tumorigenic phenotype of human glioblastoma cells.

Introduction: Recent studies have shown that miRNA-10b is highly expressed in high-grade glioblastoma multiforme (GBM), and its inhibition leads to deregulation of multiple pathways in tumorigenesis, resulting in repression of tumor growth and increased apoptosis. Thus, we hypothesized that suppressing miR-10b could enhance the cytotoxicity of conventional GBM chemotherapy with temozolomide (TMZ). Methods: Inhibition of miR-10b in glioblastoma cells was achieved using an experimental therapeutic consisting of anti-miR10b antagomirs conjugated to iron oxide nanoparticles (termed MN-anti-miR10b). The nanoparticles serve as delivery vehicles for the antagomirs as well as imaging reporters guiding the delivery in future animal studies. Results: Treatment of U251 and LN229 human glioblastoma cells with MN-anti-miR10b led to inhibition of miR-10b accompanied by repression of growth and increase in apoptosis. We next explored whether MN-anti-miR10b could enhance the cytotoxic effect of TMZ. During these studies, we unexpectedly found that TMZ monotherapy increased miR-10b expression and changed the expression of corresponding miR-10b targets. This discovery led to the design of a sequence-dependent combination treatment, in which miR-10b inhibition and induction of apoptosis by MN-anti-miR10b was followed by a sub-therapeutic dose of TMZ, which caused cell cycle arrest and ultimately cell death. This combination was highly successful in significant enhancement of apoptosis and decrease in cell migration and invasiveness. Discussion: Considering the unexpected effects of TMZ on miR-10b expression and possible implications on its clinical application, we reasoned that comprehensive in vitro studies were warranted before embarking on studies in animals. These intriguing findings serve as a solid foundation for future in vivo studies and offer promise for the successful treatment of GBM.

Deep learning-enabled quantification of simultaneous PET/MRI for cell transplantation monitoring.

Current methods of in vivo imaging islet cell transplants for diabetes using magnetic resonance imaging (MRI) are limited by their low sensitivity. Simultaneous positron emission tomography (PET)/MRI has greater sensitivity and ability to visualize cell metabolism. However, this dual-modality tool currently faces two major challenges for monitoring cells. Primarily, the dynamic conditions of PET such as signal decay and spatiotemporal change in radioactivity prevent accurate quantification of the transplanted cell number. In addition, selection bias from different radiologists renders human error in segmentation. This calls for the development of artificial intelligence algorithms for the automated analysis of PET/MRI of cell transplantations. Here, we combined K-means++ for segmentation with a convolutional neural network to predict radioactivity in cell-transplanted mouse models. This study provides a tool combining machine learning with a deep learning algorithm for monitoring islet cell transplantation through PET/MRI. It also unlocks a dynamic approach to automated segmentation and quantification of radioactivity in PET/MRI.

Detection of Endometriosis Lesions Using Gd-Based Collagen I Targeting Probe in Murine Models of Endometriosis.

PURPOSE: Endometriosis is a chronic condition characterized by high fibrotic content and affecting about 10% of women during their reproductive years. Yet, no clinically approved agents are available for non-invasive endometriosis detection. The purpose of this study was to investigate the utility of a gadolinium-based collagen type I targeting probe (EP-3533) to non-invasively detect endometriotic lesions using magnetic resonance imaging (MRI). Previously, this probe has been used for detection and staging of fibrotic lesions in the liver, lung, heart, and cancer. In this study we evaluate the potential of EP-3533 for detecting endometriosis in two murine models and compare it with a non-binding isomer (EP-3612). PROCEDURES: For imaging, we utilized two GFP-expressing murine models of endometriosis (suture model and injection model) injected intravenously with EP3533 or EP-33612. Mice were imaged before and after bolus injection of the probes. The dynamic signal enhancement of MR T1 FLASH images was analyzed, normalized, and quantified, and the relative location of lesions was validated through ex vivo fluorescence imaging. Subsequently, the harvested lesions were stained for collagen, and their gadolinium content was quantified by inductively coupled plasma optical emission spectrometry (ICP-OES). RESULTS: We showed that EP-3533 probe increased the signal intensity in T1-weighted images of endometriotic lesions in both models of endometriosis. Such enhancement was not detected in the muscles of the same groups or in endometriotic lesions of mice injected with EP-3612 probe. Consequentially, control tissues had significantly lower gadolinium content, compared to the lesions in experimental groups. Probe accumulation was similar in endometriotic lesions of either model. CONCLUSIONS: This study provides evidence for feasibility of targeting collagen type I in the endometriotic lesions using EP3533 probe. Our future work includes investigation of the utility of this probe for therapeutic delivery in endometriosis to inhibit signaling pathways that cause the disease.

A Book Review of 'Basics of Child Neuropsychology: A Primer for Educators and Clinicians' by Stephen R Hooper.

A Book Review of 'Basics of Child Neuropsychology: A Primer for Educators and Clinicians' by Stephen R. Hooper.

The protein corona from nanomedicine to environmental science.

The protein corona spontaneously develops and evolves on the surface of nanoscale materials when they are exposed to biological environments, altering their physiochemical properties and affecting their subsequent interactions with biosystems. In this Review, we provide an overview of the current state of protein corona research in nanomedicine. We next discuss remaining challenges in the research methodology and characterization of the protein corona that slow the development of nanoparticle therapeutics and diagnostics, and we address how artificial intelligence can advance protein corona research as a complement to experimental research efforts. We then review emerging opportunities provided by the protein corona to address major issues in healthcare and environmental sciences. This Review details how mechanistic insights into nanoparticle protein corona formation can broadly address unmet clinical and environmental needs, as well as enhance the safety and efficacy of nanobiotechnology products.

Comparison of PD-L1 expression and MMR status between primary and matched metastatic lesions in patients with cervical cancer.

PURPOSE: Programmed death-ligand 1 (PD-L1) and DNA mismatch repair (MMR) are considered predictive biomarkers for immunotherapy in cervical cancer. However, their expression in primary tumors and metastases does not always match affecting the course of treatment. We investigated the consistency of their expression in primary and matched recurrent/metastatic lesions from patients with cervical cancer. METHODS: Primary and matched recurrent/metastatic specimens from patients with recurrent cervical cancer (n = 194) were stained for PD-L1 and MMR (MLHI, MSH6, MSH2, and PMS2) using immunohistochemistry. The degree of consistency of PD-L1 and MMR expression in these lesions was analyzed. RESULTS: The inconsistency rate of PD-L1 expression in primary and recurrent/metastatic lesions was 33.0%, and it varied between the recurrence sites. Positive PD-L1 rate in primary lesions was lower (15.4%) than that in recurrent/metastatic lesions (30.4%). The discordance rate of MMR expression between primary and recurrent/metastatic lesions was 4.1%. CONCLUSION: We conclude that to use PD-L1 as a predictive biomarker for immunotherapy, analysis of both metastatic and primary lesions may be required. High consistency rate of MMR expression between primary and metastatic lesions suggests that testing primary lesions alone can be sufficient for guiding the course of therapy, thereby solving the difficulty of obtaining recurrent/metastatic specimens in clinic.

De-identified Bayesian personal identity matching for privacy-preserving record linkage despite errors: development and validation.

BACKGROUND: Epidemiological research may require linkage of information from multiple organizations. This can bring two problems: (1) the information governance desirability of linkage without sharing direct identifiers, and (2) a requirement to link databases without a common person-unique identifier. METHODS: We develop a Bayesian matching technique to solve both. We provide an open-source software implementation capable of de-identified probabilistic matching despite discrepancies, via fuzzy representations and complete mismatches, plus de-identified deterministic matching if required. We validate the technique by testing linkage between multiple medical records systems in a UK National Health Service Trust, examining the effects of decision thresholds on linkage accuracy. We report demographic factors associated with correct linkage. RESULTS: The system supports dates of birth (DOBs), forenames, surnames, three-state gender, and UK postcodes. Fuzzy representations are supported for all except gender, and there is support for additional transformations, such as accent misrepresentation, variation for multi-part surnames, and name re-ordering. Calculated log odds predicted a proband's presence in the sample database with an area under the receiver operating curve of 0.997-0.999 for non-self database comparisons. Log odds were converted to a decision via a consideration threshold θ and a leader advantage threshold δ. Defaults were chosen to penalize misidentification 20-fold versus linkage failure. By default, complete DOB mismatches were disallowed for computational efficiency. At these settings, for non-self database comparisons, the mean probability of a proband being correctly declared to be in the sample was 0.965 (range 0.931-0.994), and the misidentification rate was 0.00249 (range 0.00123-0.00429). Correct linkage was positively associated with male gender, Black or mixed ethnicity, and the presence of diagnostic codes for severe mental illnesses or other mental disorders, and negatively associated with birth year, unknown ethnicity, residential area deprivation, and presence of a pseudopostcode (e.g. indicating homelessness). Accuracy rates would be improved further if person-unique identifiers were also used, as supported by the software. Our two largest databases were linked in 44 min via an interpreted programming language. CONCLUSIONS: Fully de-identified matching with high accuracy is feasible without a person-unique identifier and appropriate software is freely available.

Promoting mental health and well-being in schools: examining mindfulness, relaxation and strategies for safety and well-being in English primary and secondary schools-study protocol for a multi-school, cluster randomised controlled trial (INSPIRE).

There are increasing rates of internalising difficulties, particularly anxiety and depression, being reported in children and young people in England. School-based universal prevention programmes are thought to be one way of helping tackle such difficulties. This paper describes an update to a four-arm cluster randomised controlled trial ( http://www.isrctn.com/ISRCTN16386254 ), investigating the effectiveness of three different interventions when compared to usual provision, in English primary and secondary pupils. Due to the COVID-19 pandemic, the trial was put on hold and subsequently prolonged. Data collection will now run until 2024. The key changes to the trial outlined here include clarification of the inclusion and exclusion criteria, an amended timeline reflecting changes to the recruitment period of the trial due to the COVID-19 pandemic and clarification of the data that will be included in the statistical analysis, since the second wave of the trial was disrupted due to COVID-19.Trial registration ISRCTN Registry ISRCTN16386254. Registered on 30 August 2018.

The impact of universal, school based, interventions on help seeking in children and young people: a systematic literature review.

Reviews into universal interventions to improve help seeking in young people focus on specific concepts, such as behaviour, do not differentiate between interpersonal and intrapersonal help seeking, and often report on statistical significance, rather than effect size. The aim of this review was to address the gaps highlighted above, to investigate the impact of universal, school-based interventions on help-seeking in children and young people, as well as to explore longer term impact. Four databases were searched. Data were extracted on country of origin, design, participant, school, and intervention characteristics, the help-seeking concept measured (e.g. knowledge, attitude/intention, behaviour), the duration between baseline and each follow-up (if applicable) and effect sizes at each follow-up. Quality assessment of the studies was undertaken using the Effective Public Health Practice Project (EPHPP) quality assessment tool. Overall, 14 different interventions met inclusion criteria. The majority of the studies were rated low in the quality assessment. Three constructs were most frequently reported a) intrapersonal attitudes towards help-seeking, b) interpersonal attitudes towards help-seeking and c) intrapersonal intended help-seeking. Findings around intervention effect were mixed. There was tentative evidence that interventions impacting interpersonal attitudes produced small effect sizes when measured between 3 and 6 months post intervention and that when effect sizes were initially observed intrapersonal attitudes, this remained at 3-6 month follow-up. Further work should pay attention to implementation factors, understanding the core ingredients needed to deliver effective interventions and whether embedding mental health education could help sustain or top up effect sizes from help-seeking interventions.

Synthesis of siRNA-Conjugated Dextran-Coated Iron Oxide Nanoparticles for Islet Protection During Transplantation and Noninvasive Imaging.

Pancreatic islet transplantation (Tx) has a lifesaving potential for type 1 diabetes (T1D) patients. Islet damage during and after transplantation is one of the major reasons hampering its wide clinical application. Inability to monitor transplanted islets also severely limits our understanding of mechanisms regarding declining graft function after transplantation. Our team has proposed to use magnetic nanoparticles conjugated to siRNA (MN-siRNA) to label islets prior to transplantation with two goals in mind: to protect them from damage by silencing harmful genes and to monitor them after transplantation using noninvasive magnetic resonance imaging (MRI). This manuscript provides a step-by-step protocol for the synthesis and characterization of MN-siRNA probes.

Magnetic Particle Imaging of Transplanted Human Islets Using a Machine Learning Algorithm.

Human islet transplantation is a promising therapy to restore normoglycemia for type 1 diabetes (T1D). Despite recent advances, human islet transplantation remains suboptimal due to significant islet graft loss after transplantation. Various immunological and nonimmunological factors contribute to this loss therefore signifying a need for strategies and approaches for visualizing and monitoring transplanted human islet grafts. One such imaging approach is magnetic particle imaging (MPI), an emerging imaging modality that detects the magnetization of iron oxide nanoparticles. MPI is known for its specificity due to its high image contrast and sensitivity. MPI through its noninvasive nature provides the means for monitoring transplanted human islets in real time. Here we summarize an approach to track transplanted human islets using MPI. We label human islet from donors with dextran-coated ferucarbotran iron oxide nanoparticles, transplant the labeled human islet into under the left kidney capsule, and image graft cells using an MPI scanner. We engineer a K-means++, clustering-based unsupervised machine learning algorithm for standardized image segmentation and iron quantification of the MPI, which solves problems with selection bias and indiscriminate signal boundary that accompanies this newer imaging modality. In this chapter, we summarize the methods of this emerging imaging modality of MPI in conjunction with unsupervised machine learning to monitor and visualize islets after transplantation.

miRNA Theranostic Nanoparticles Promote Pancreatic Beta Cell Proliferation in Type 1 Diabetes Model.

Type 1 diabetes (T1D) is a chronic autoimmune disorder which affects the insulin-producing beta cells in the pancreas. A variety of strategies, namely, insulin replacement therapy, engineered vaccines, immunomodulators, etc., have been explored to correct this condition. Recent studies have attributed the development of T1D to the anomalous expression of microRNAs in the pancreatic islets. Here, we describe the protocol for the development of a theranostic approach to modify the expression of aberrant miRNAs. The MRI-based nanodrug consists of superparamagnetic iron oxide nanoparticles conjugated to microRNA-targeting oligonucleotides that can promote proliferation of pancreatic beta cells in a mouse model of T1D. This theranostic approach can successfully serve as a potential therapeutic approach for the targeted treatment of T1D with minimal side effects.

Vascularized Islet Transplantation as Composite Islet-Kidney Grafts with Nanoparticle-Labeled Islets in Large Animal Preclinical Transplant Models.

Although there are many patients with diabetes and end-stage renal failure (DM/ESRD) who would benefit from a transplantation strategy that addresses both their ESRD and its underlying cause, current methods of islet and kidney transplantation using live donors have had only limited success. The first major obstacle is that the number of islets obtained from a live donor partial pancreatectomy is generally insufficient to cure diabetes in recipients, as large numbers of intraportally administered islets are lost due to ischemia before they are engrafted and vascularized in the recipient liver. To overcome this hurdle, we have developed a strategy to transplant islets as a vascularized graft. Autologous prevascularization of donor islets under the donor's own renal capsule prior to transplantation preserves islets and thus achieves normal glycemic control in diabetic recipients in our preclinical transplant models with a limited donor pancreas resection. In addition, from an immunological perspective, the innate tolerogenic qualities of the kidney provide immunoprotection for the engrafted, vascularized islets when they are transplanted as part of the composite islet-kidney (I-K) grafts. This "Trojan Horse" approach of transplanting a composite I-K eliminates the lengthy time which is otherwise required for vascularization of intraportally administered free islets, minimizing loss of islets to ischemic damage and facilitating the induction of tolerance. We have also recently developed a strategy to further minimize the required size of resected donor pancreas to prepare composite I-K graft using a novel, synthesized, small interfering RNA (siRNA)-nanoparticle probe. In this chapter, we introduce our living donor transplantation strategy to cure diabetic nephropathy using composite I-K graft.

Leveraging Administrative Data to Better Understand and Address Child Maltreatment: A Scoping Review of Data Linkage Studies.

BACKGROUND: This scoping review aimed to overview studies that used administrative data linkage in the context of child maltreatment to improve our understanding of the value that data linkage may confer for policy, practice, and research. METHODS: We searched MEDLINE, Embase, PsycINFO, CINAHL, and ERIC electronic databases in June 2019 and May 2020 for studies that linked two or more datasets (at least one of which was administrative in nature) to study child maltreatment. We report findings with numerical and narrative summary. RESULTS: We included 121 studies, mainly from the United States or Australia and published in the past decade. Data came primarily from social services and health sectors, and linkage processes and data quality were often not described in sufficient detail to align with current reporting guidelines. Most studies were descriptive in nature and research questions addressed fell under eight themes: descriptive epidemiology, risk factors, outcomes, intergenerational transmission, predictive modelling, intervention/service evaluation, multi-sector involvement, and methodological considerations/advancements. CONCLUSIONS: Included studies demonstrated the wide variety of ways in which data linkage can contribute to the public health response to child maltreatment. However, how research using linked data can be translated into effective service development and monitoring, or targeting of interventions, is underexplored in terms of privacy protection, ethics and governance, data quality, and evidence of effectiveness.

Omniparticle Contrast Agent for Multimodal Imaging: Synthesis and Characterization in an Animal Model.

PURPOSE: Individual imaging modalities have certain advantages, but each suffers from drawbacks that other modalities may overcome. The goal of this study was to create a novel contrast agent suitable for various imaging modalities that after a single administration can bridge and strengthen the collaboration between the research fields as well as enrich the information obtained from any one modality. PROCEDURES: The contrast agent platform is based on dextran-coated iron oxide nanoparticles (for MRI and MPI) and synthesized using a modified co-precipitation method, followed by a series of conjugation steps with a fluorophore (for fluorescence and photoacoustic imaging), thyroxine (for CT imaging), and chelators for radioisotope labeling (for PET imaging). The fully conjugated agent was then tested in vitro in cell uptake, viability, and phantom studies and in vivo in a model of intraductal injection and in a tumor model. RESULTS: The agent was synthesized, characterized, and tested in vitro where it showed the ability to produce a signal on MRI/MPI/FL/PA/CT and PET images. Studies in cells showed the expected concentration-dependent uptake of the agent without noticeable toxicity. In vivo studies demonstrated localization of the agent to the ductal tree in mice after intraductal injection with different degrees of resolution, with CT being the best for this particular application. In a model of injected labeled tumor cells, the agent produced a signal with all modalities and showed persistence in tumor cells confirmed by histology. CONCLUSIONS: A fully functional omniparticle contrast agent was synthesized and tested in vitro and in vivo in two animal models. Results shown here point to the generation of a potent signal in all modalities tested without detrimental toxicity. Future use of this agent includes its exploration in various models of human disease including image-guided diagnostic and therapeutic applications.