Comparing Research Priority-Setting Partnerships for Older Adults Across International Health Care Systems: A Systematic Review.

OBJECTIVES: Priority setting partnerships (PSPs) attempt to shape the research agenda to address the needs of local populations of interest. We reviewed the PSPs for older adults, with a focus on exemplar health care systems: United Kingdom (UK; publicly funded), United States (private health insurance-based), South Korea (national health insurance-based), and Africa (out-of-pocket). DESIGN: Systematic review. SETTING AND PARTICIPANTS: We searched databases and sources (January 2011-October 202l; updated in February 2023) for PSPs of older adults' health care. METHODS: Based on the British geriatric medicine curriculum, we extracted and categorized the PSP topics by areas and the research priorities by themes, and generated evidence maps depicting and comparing the research gaps across the systems. We evaluated PSP quality using the Nine Common Themes of Good Clinical Practice. RESULTS: We included 32 PSPs (United Kingdom: n = 25; United States: n = 7; South Korea and Africa: n = 0) and identified priorities regarding 27 conditions or service arrangements in the United Kingdom and 9 in the United States (predominantly in neurology/psychiatry). The UK priorities focused on treatments and interventions whereas the US on prognostic/predictive factors. There were notable research gaps within the existing PSPs, including common geriatric conditions like continence and frailty. The PSP quality evaluation revealed issues around lacking inclusion of ethnic minorities. CONCLUSIONS AND IMPLICATIONS: Research priorities for older adult health care vary internationally, but certain health care systems/countries have no available PSPs. Where PSPs are available, fundamental aspects of geriatric medicine have not been included. Future researchers should conduct prioritizations in different countries, focus on core geriatric syndromes, and ensure the inclusion of all relevant stakeholder groups.

International research priority setting exercises in stroke: A systematic review.

BACKGROUND: Agreeing on priority topics for stroke research can help make best use of limited funding, people, and time. Formal priority-setting exercises collate stakeholders' opinions to reach consensus on the most important research questions. Several stroke research priority setting exercises have been published. Exploring commonalities and differences between these exercises could bring a better understanding of priority research topics. AIM: We collated and compared published stroke research priority setting exercises across international healthcare systems. SUMMARY OF REVIEW: Multidisciplinary, electronic literature databases were searched from 2000 to 2021, using a validated search syntax. Inclusion criteria were: full article; stroke focus (any subtype); prioritization method described; and lists priorities for research. Priorities were extracted, coded, and assigned to categories using thematic analysis. The Nine Common Themes of Good Practice and the Reporting guideline for priority setting of health research checklists were used to assess methodological and reporting quality respectively. From 623 titles assessed, 14 studies were eligible for inclusion, including 2410 participants and describing 165 priorities. The majority of priority setting exercises were conducted in high-income countries (86%, n = 12 articles), published between 2011 and 2021 (64%, n = 9), and included views of healthcare professionals (57%, n = 8), and stroke survivors (50%, n = 7). Caregivers (n = 3, 21%) were under-represented. The James Lind Alliance priority setting method was most commonly used (50%, n = 7). Priorities were grouped into 10 thematic categories. Rehabilitation and follow-up was the most common priority theme (15%, n = 25 priorities), followed by psychological recovery (14%, n = 23), pathology (14%, n = 23), and caregivers and support (14%, n = 23). Priorities differed by year and case-mix (stakeholder group and demographics) of respondents. No article was judged high quality for all aspects of method or reporting. Common limitations were around inclusiveness and evaluation of the exercise. CONCLUSION: Stroke research priorities are dynamic and context-specific. However, there was a common theme of prioritizing research that considered life after stroke. Future priority settings should consider the inclusion of nonindustrialized countries and stroke survivors with a range of impairments.

Comparing international dementia research priorities-Systematic review.

OBJECTIVES: Research priority setting aims to collate stakeholder opinion to determine the most pressing research questions. Priority setting exercises influence decisions around research funding, development and policy. We compared published dementia research priority setting exercises from international healthcare systems. METHODS: Four multidisciplinary, international, electronic databases were searched for relevant studies (2010 until 2021). Priorities were extracted, coded and assigned to categories using thematic analysis. The Nine Common Themes of Good Practice (9CTGP) and the Reporting guideline for priority setting of health research (REPRISE) checklists were used to assess methodological and reporting quality respectively. RESULTS: From 265 titles, 10 priority setting exercises (1179 participants, 147 priorities) were included. Studies spanned four continents and the majority included people living with dementia and their care-givers in the priority setting process (68%). Only one paper met all the best practice indicators. Issues around inclusiveness, implementation and evaluation of the priorities were apparent in nine papers. We categorised priorities under eight themes: caregivers (25%, n = 37), support (24%, n = 35), awareness and education (16%, n = 24), drugs and interventions (14%, n = 21), diagnosis (8%, n = 12), pathology (6%, n = 9), research design (5%, n = 7), and prevention (1%, n = 2). Priorities varied by geographical region, with awareness and education of higher priority in low-middle income countries, compared to caregivers and support in high income countries. CONCLUSIONS: Key priorities were identified with some commonality around themes considered of greatest importance. There is scope to improve the process and reporting of priority setting. Priorities differed according to contextual factors and so, priorities specific to one healthcare setting may not be applicable to others.

A Case Report of Cerebral Venous Thrombosis as a Complication of Coronavirus Disease 2019 in a Well-appearing Patient.

INTRODUCTION: While thrombotic complications of severe coronavirus disease 2019 (COVID-19) have been documented, the overall risk in non-critically ill cases of COVID-19 remains unknown. CASE REPORT: We report a case of a previously healthy male patient who presented to the emergency department with headache and extremity paresthesia. The patient was diagnosed with cerebral venous thrombosis (CVT) and found to have a positive COVID-19 test. Inpatient anticoagulation was initiated, and symptoms had largely resolved at discharge. CONCLUSION: This case demonstrates the importance of considering thrombotic complications, such as CVT, even in well-appearing COVID-19 patients with no other risk factors for thromboembolic disease.

Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies.

microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important networks involved in cancer initiation and progression open up significant innovative areas for therapy and diagnosis that have been sadly lacking for deadly female reproductive tract cancers. This review will highlight the recent advances in the field of miRNAs in epithelial ovarian cancer, endometrioid endometrial cancer and squamous-cell cervical carcinoma focusing on studies associated with actual clinical information in humans. Importantly, recent miRNA profiling studies have included well-characterized clinical specimens of female reproductive tract cancers, allowing for studies correlating miRNA expression with clinical outcomes. This review will summarize the current thoughts on the role of miRNA processing in unique miRNA species present in these cancers. In addition, this review will focus on current data regarding miRNA molecules as unique biomarkers associated with clinically significant outcomes such as overall survival and chemotherapy resistance. We will also discuss why specific miRNA molecules are not recapitulated across multiple studies of the same cancer type. Although the mechanistic contributions of miRNA molecules to these clinical phenomena have been confirmed using in vitro and pre-clinical mouse model systems, these studies are truly only the beginning of our understanding of the roles miRNAs play in cancers of the female reproductive tract. This review will also highlight useful areas for future research regarding miRNAs as therapeutic targets in cancers of the female reproductive tract.

RAMP1 is a direct NKX3.1 target gene up-regulated in prostate cancer that promotes tumorigenesis.

The homeodomain-containing transcription factor, NKX3.1, plays an important role in the suppression of prostate tumorigenesis. Herein, we identify the receptor activity-modifying protein 1 (RAMP1) as a direct NKX3.1 target gene through analysis of chromatin immunoprecipitation coupled to massively parallel sequencing and gene expression data. RAMP1 is a coreceptor for certain G-protein-coupled receptors, such as the calcitonin gene-related peptide receptor, to the plasma membrane. We found that RAMP1 expression is specifically elevated in human prostate cancer relative to other tumor types. Furthermore, RAMP1 mRNA and protein levels are significantly higher in human prostate cancer compared with benign glands. We identified multiple NKX3.1 binding sites in the RAMP1 locus in human prostate cancer cells and in the normal mouse prostate. Analyses of Nkx3.1 knockout mice and human prostate cancer cell lines indicate that NKX3.1 represses RAMP1 expression. Knockdown of RAMP1 by shRNA decreased prostate cancer cell proliferation and tumorigenicity in vitro and in vivo. By using gene expression profiling and pathway analyses, we identified several cancer-related pathways that are significantly altered in RAMP1 knockdown cells, including the mitogen-activated protein kinase signaling pathway. Further experiments confirmed a reduction in MAP2KI (MEK1) expression and phosphorylated-extracellular signal-regulated kinase 1/2 levels in RAMP1 knockdown cells. These data provide novel insights into the role of RAMP1 in promoting prostate tumorigenesis and support the potential of RAMP1 as a novel biomarker and possible therapeutic target in prostate cancer.

Antioxidant treatment promotes prostate epithelial proliferation in Nkx3.1 mutant mice.

Discordant results in preclinical and clinical trials have raised questions over the effectiveness of antioxidants in prostate cancer chemoprevention. Results from the large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that antioxidants failed to prevent, and in some cases promoted, prostate cancer formation in men without a history of the disease. One possible explanation for these alarming results is the notion that the effects of antioxidant treatment on the prostate are modified by specific, intrinsic genetic risk factors, causing some men to respond negatively to antioxidant treatment. Loss of expression of the homeobox transcription factor NKX3.1 in the prostate is frequently associated with human prostate cancer. Nkx3.1 mutant mice display prostatic hyperplasia and dysplasia and are used as a model of the early stages of prostate cancer initiation. While the mechanisms by which Nkx3.1 loss promotes prostate tumorigenicity are not completely understood, published data have suggested that elevated reactive oxygen species (ROS) associated with Nkx3.1 loss may be a causative factor. Here we have tested this hypothesis by treating Nkx3.1 mutant mice with the antioxidant N-acetylcysteine (NAC) for 13 weeks post-weaning. Surprisingly, while NAC treatment decreased ROS levels in Nkx3.1 mutant mouse prostates, it failed to reduce prostatic epithelial hyperplasia/dysplasia. Rather, NAC treatment increased epithelial cell proliferation and promoted the expression of a pro-proliferative gene signature. These results show that ROS do not promote proliferation in the Nkx3.1-null prostate, but instead inhibit proliferation, suggesting that antioxidant treatment may encourage prostate epithelial cell proliferation early in prostate tumorigenesis. Our findings provide new insight that may help explain the increased prostate cancer risk observed with vitamin E treatment in the SELECT trial and emphasize the need for preclinical studies using accurate models of cancer.

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis.

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.