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Genetic testing has the potential to revolutionize primary care, but few health systems have developed the infrastructure to support precision population medicine applications or attempted to evaluate its impact on patient and provider outcomes. In 2018, Sanford Health, the nation’s largest rural nonprofit health care system, began offering genetic testing to its primary care patients. To date, more than 11,000 patients have participated in the Sanford Chip Program, over 90% of whom have been identified with at least one informative pharmacogenomic variant, and about 1.5% of whom have been identified with a medically actionable predisposition for disease. This manuscript describes the rationale for offering the Sanford Chip, the programs and infrastructure implemented to support it, and evolving plans for research to evaluate its real-world impact.

Objective: To identify LGBTQ+ diversity, equity, and inclusion (DEI) publications and contextualize the current frequency of the literature across subspecialty surgical fields., Methods: A PRISMA systematic review using PubMed, MEDLINE, and Web of Science was conducted in April 2024. The main inclusion criterion was intrafield DEI content for defined subspecialties; exclusion criteria were foreign language, poor methodology, and duplicates. The primary endpoint was the number of publications across subspecialties. Secondary endpoints included publication dates, study design, and sample size., Results: Of the 702 articles identified, 27 were included in the analysis. Neurologic surgery had 2 studies; plastic surgery, 11 studies; orthopedic surgery, 7 studies; otolaryngology, 5 studies; and thoracic surgery, 2 studies. There was a statistically significant different frequency of publications across subspecialties (P = 0.031). Post hoc residual analysis indicated that neurosurgery and thoracic surgery had statistically fewer publications, while plastic surgery had statistically more publications (P = 0.04, 0.002, 0.21, 0.42, and 0.04 for neurologic surgery, plastic surgery, orthopedic surgery, otolaryngology, and thoracic surgery, respectively). Secondary outcomes found a majority of publications between 2022 and 2024. Study methodologies involved cross-sectional studies, editorials, and retrospective reviews (14, 11, and 3 respectively) and had a median sample size of 248.5., Conclusions: This systematic review provides objective data to contextualize DEI literature across surgical subspecialties. Overall, this review highlights the lack of LGBTQ+ DEI literature in neurosurgery and advocates for correcting this gap for the benefit of both surgeons and patients. Understanding the current numbers and evaluating progress in other surgical fields might provide solutions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Vaginal self collection (SC) is safe and effective for human papillomavirus (HPV) testing and can increase cervical cancer screening coverage for underserved women. To better understand the impact of SC methodology on HPV test outcomes, empirical testing was conducted using different swab collection workflows. Deposition of the collection swab into resuspension buffer resulted in a 2.4-cycle reduction in threshold detection of human beta-hemoglobin during PCR when compared to "swirl-and-toss". In addition, reducing the swab resuspension volume from 10 mL to 3 mL resulted in a 2.6-cycle reduction in threshold detection of human beta-globin. A systematic literature search (01/01/2020 to 08/02/2023) of Ovid Medline and Embase, followed by data extraction and analysis, was conducted to further assess the impact of resuspension volume on performance following SC. HPV test performance for SC, relative to clinician collection (CC), was calculated for detection of cervical pre-cancer. Data were stratified by the resuspension volume ratio of SC to CC being either ≥ 1.0 or < 1.0. SC with a volume ratio of ≥ 1.0 and < 1.0 had a relative ≥ CIN2 sensitivity of 92.0 % (95 % CI: 88.0, 96.0) and 97.0 % (95 % CI: 94.0, 100), respectively. Taken together, these results suggest that SC conditions can be modified to optimize sample recovery and performance, as part of cervical cancer screening., (© 2024 The Authors. Published by Elsevier Inc.)

Introduction: Radiotherapy (RT) stands as one of the main cancer treatments. The impact of RT and cancer treatment can have a physical and psychological impact on patients and their carers. To gain patient's trust, and ensure they feel valued, information should be provided before, during, and after RT. Patient and public involvement (PPI) has been lacking, and increased engagement with PPI groups could improve this. This rapid review aims to analyse the literature, and describe and report patient perception, experience, and satisfaction regarding the information received concerning their course of RT., Methods: To allow the synthesis of results, a pragmatic decision was made to use a rapid review approach to analyse the literature, providing more timely information to inform future work. This rapid review utilised systematic review methods and was conducted according to a pre-defined protocol including clear inclusion criteria (PROSPERO registration: CRD42023415916).Electronic databases CINAHL, AMED, Pubmed/MEDLINE, EMBASE, and PsycINFO were searched using a comprehensive search for published studies from January 2012 to November 2023. Two independent reviewers applied the eligibility criteria. Evidence from literature was extracted and transcribed into qualitative data and Braun and Clarke's six-step thematic analysis (TA) was employed to determine themes by one reviewer and checked by a second [26]. Due to the heterogeneity of the included literature, the analysis of this review is presented primarily through narrative synthesis., Results: Sixty eight articles met the inclusion criteria for this review. Emerging themes included; a desire for information based on patient characteristics, information format, patient preparedness, timing e.g. timing of information and changing priorities over time, health care professional (HCP) involvement, barriers to information, and motivators for better information delivery., Conclusions: Several factors can influence a patient's desire for information, from whom and when they receive it, to what format they would prefer to receive it. There is benefit to be gained in employing PPI and patient advocacy to inform future studies that aim to further understand the themes that emerged from this review. Such studies can therefore inform HCPs in providing patient-specific information and support by utilising multiple teaching strategies available to them., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of European Society for Radiotherapy & Oncology.)

Background: A robust evidence base is required to assist healthcare commissioners and providers in selecting effective and sustainable approaches to improve cancer diagnosis and treatment. Such evidence can be difficult to build, given the fast-paced and highly pressured nature of healthcare delivery, the absence of incentives, and the presence of barriers in conducting pragmatic yet robust research evaluations. Cancer Research UK (CRUK) has played an active part in building the evidence base through its funding of programmes to identify, evaluate and scale-up innovative approaches across the UK. The aim of this paper is to describe and explain the research design and intended approach and activities for two cancer services improvement projects in Scotland funded by CRUK., Methods: A hybrid effectiveness-implementation study design will assess both the efficiency of the new pathways and their implementation strategies, with the aim of generating knowledge for scale-up. A range of implementation, service and clinical outcomes will be assessed as determined by the projects' Theories of Change (ToCs). A naturalistic case study approach will enable in-depth exploration of context and process, and the collection and synthesis of data from multiple sources including routine datasets, patient and staff surveys, in-depth interviews and observational and other data. The evaluations are informed throughout by a patient/public representatives' group, and by small group discussions with volunteer cancer patients., Discussion: Our approach has been designed to provide a holistic understanding of how (well) the improvement projects work (in relation to their anticipated outcomes), and how they interact with their wider contexts. The evaluations will help identify barriers, facilitators, and unanticipated consequences that can impact scalability, sustainability and spread. By opting for a pragmatic, participatory evaluation research design, we hope to inform strategies for scaling up successful innovations while addressing challenges in a targeted manner., (© 2023. The Author(s).)

Background: Prostate cancer is the most common cancer in men in the developed world, with most deaths caused by advanced and metastatic disease which has no curative options. Here, we identified Mbtps2 alteration to be associated with metastatic disease in an unbiased in vivo screen and demonstrated its regulation of fatty acid and cholesterol metabolism., Methods: The Sleeping Beauty transposon system was used to randomly alter gene expression in the Pten Null murine prostate. MBTPS2 was knocked down by siRNA in LNCaP, DU145 and PC3 cell lines, which were then phenotypically investigated. RNA-Seq was performed on LNCaP cells lacking MBTPS2, and pathways validated by qPCR. Cholesterol metabolism was investigated by Filipin III staining., Results: Mbtps2 was identified in our transposon-mediated in vivo screen to be associated with metastatic prostate cancer. Silencing of MBTPS2 expression in LNCaP, DU145 and PC3 human prostate cancer cells reduced proliferation and colony forming growth in vitro. Knockdown of MBTPS2 expression in LNCaP cells impaired cholesterol synthesis and uptake along with reduced expression of key regulators of fatty acid synthesis, namely FASN and ACACA., Conclusion: MBTPS2 is implicated in progressive prostate cancer and may mechanistically involve its effects on fatty acid and cholesterol metabolism., (© 2023. The Author(s).)

ARF GTPases are central regulators of membrane trafficking that control local membrane identity and remodeling facilitating vesicle formation. Unraveling their function is complicated by the overlapping association of ARFs with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and numerous interactors. Through a functional genomic screen of three-dimensional (3D) prostate cancer cell behavior, we explore the contribution of ARF GTPases, GEFs, GAPs, and interactors to collective invasion. This revealed that ARF3 GTPase regulates the modality of invasion, acting as a switch between leader cell-led chains of invasion or collective sheet movement. Functionally, the ability of ARF3 to control invasion modality is dependent on association and subsequent control of turnover of N-cadherin. In vivo, ARF3 levels acted as a rheostat for metastasis from intraprostatic tumor transplants and ARF3/N-cadherin expression can be used to identify prostate cancer patients with metastatic, poor-outcome disease. Our analysis defines a unique function for the ARF3 GTPase in controlling how cells collectively organize during invasion and metastasis., (© 2023 Sandilands et al.)

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.

Drosophila larval crawling is easily-observable and relatively stereotyped. Crawling consists of linear locomotion interrupted by periods when the larvae pause, swing their heads, and change direction (a 'search'). Here we identify Numb, a peripheral membrane adaptor protein, as an important regulator of searching behavior. When Numb RNAi transgenes were expressed in all neurons, searching frequency increased while linear movement appeared normal. Numb's role in suppressing searching behavior was verified by rescuing this phenotype with a Numb homologue from mice. Such behavioral specificity suggests that further analysis of searching might help identify additional, evolutionarily-conserved interactors of the Numb protein., (Copyright: © 2021 by the authors.)

Introduction: Behavioral sleep disorders, including chronic insomnia (CI), are generally assessed by subjective parent interview. However, evidence suggests that parental report of children's overnight behaviors is unreliable, perhaps due to recall bias or confusion due to sleep deprivation. Video technology has been used clinically to capture complex behavioral disorders in children during the day. However, there is no standardized means of analyzing child and parent behavior at bedtime or during the night. We aimed to create an algorithm for this purpose. Methods: Child brain tumor survivors (a population previously shown to have a high prevalence of CI) were screened for difficulties initiating and maintaining sleep using sub-scales from the Sleep Disturbance Scale for Children. Those who screened positive (n = 3) then completed a detailed parent interview to confirm a clinical diagnosis of CI. One night of home video footage was obtained from initial settling period to morning waking (SOMNOmedics camera). Footage was imported into BORIS © software and a coding system for parent and child behavior was developed over multiple iterations until agreeable inter-rater reliability (>70%) was achieved between two independent coders. Results: The final coding categories were: 1) time domains, 2) physical environment, 3) child global status, 4) location, 5) activity, and 6) physical interaction. This achieved 74% inter-reliability in its last iteration. Discussion: A statistically acceptable behavior scoring algorithm was achieved. With further development, this tool could be applied clinically to investigate behavioral insomnia and in research to provide more objective outcome measurement., (Copyright © 2019 Galbraith, Bull and Hill.)

The link between prostate cancer (PC) development and lipid metabolism is well established, with AR intimately involved in a number of lipogenic processes involving SREBP1, PPARG, FASN, ACC, ACLY and SCD1. Recently, there is growing evidence implicating the role of obesity and peri-prostatic adipose tissue (PPAT) in PC aggressiveness and related mortality, suggesting the importance of lipid pathways in both localised and disseminated disease. A number of promising agents are in development to target the lipogenic axis in PC, and the likelihood is that these agents will form part of combination drug strategies, with targeting of multiple metabolic pathways (e.g. FASN and CPT1), or in combination with AR pathway inhibitors (SCD1 and AR)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Primary care providers manage the majority of patients with chronic kidney disease (CKD), although the most effective chronic disease management (CDM) strategies for these patients are unknown. We assessed the efficacy of CDM interventions used by primary care providers managing patients with CKD., Methods: The Medline, Embase and Cochrane Central databases were systematically searched (inception to November 2014) for randomized controlled trials (RCTs) assessing education-based and computer-assisted CDM interventions targeting primary care providers managing patients with CKD in the community. The efficacy of CDM interventions was assessed using quality indicators [use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), proteinuria measurement and achievement of blood pressure (BP) targets] and clinical outcomes (change in BP and glomerular filtration rate). Two independent reviewers evaluated studies for inclusion, quality and extracted data. Random effects models were used to estimate pooled odds ratios (ORs) and weighted mean differences for outcomes of interest., Results: Five studies (188 clinics; 494 physicians; 42 852 patients with CKD) were included. Two studies compared computer-assisted intervention strategies with usual care, two studies compared education-based intervention strategies with computer-assisted intervention strategies and one study compared both these intervention strategies with usual care. Compared with usual care, computer-assisted CDM interventions did not increase the likelihood of ACEI/ARB use among patients with CKD {pooled OR 1.00 [95% confidence interval (CI) 0.83-1.21]; I2 = 0.0%}. Similarly, education-related CDM interventions did not increase the likelihood of ACEI/ARB use compared with computer-assisted CDM interventions [pooled OR 1.12 (95% CI 0.77-1.64); I2 = 0.0%]. Inconsistencies in reporting methods limited further pooling of data., Conclusions: To date, there have been very few randomized trials testing CDM interventions targeting primary care providers with the goal of improving care of people with CKD. Those conducted to date have shown minimal impact, suggesting that other strategies, or multifaceted interventions, may be required to enhance care for patients with CKD in the community., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Health behaviour change is an important component of management for patients with chronic kidney disease (CKD); however, the optimal method to promote health behaviour change for self-management of CKD is unknown. The See Kidney Disease (SeeKD) targeted screening programme screened Canadians at risk for CKD and promoted health behaviour change through individual counselling and goal setting., Objectives: The objectives of this study are to determine the effectiveness of individual counselling sessions for eliciting behaviour change and to describe participant characteristics associated with behaviour change., Design: This is a cross-sectional, descriptive study., Setting: The study setting is the National SeeKD targeted screening programme., Patients: The participants are all 'at risk' patients who were screened for CKD and returned a follow-up health behaviour survey (n = 1129)., Measurements: Health behaviour change was defined as a self-reported change in lifestyle, including dietary changes or medication adherence., Methods: An individual counselling session was provided to participants by allied healthcare professionals to promote health behaviour change. A survey was mailed to all participants at risk of CKD within 2-4 weeks following the screening event to determine if behaviour changes had been initiated. Descriptive statistics were used to describe respondent characteristics and self-reported behaviour change following screening events. Results were stratified by estimated glomerular filtration rate (eGFR) (< 60 and ≥ 60 mL/min/1.73 m(2)). Log binomial regression analysis was used to determine the predictors of behaviour change., Results: Of the 1129 respondents, the majority (89.8 %) reported making a health behaviour change after the screening event. Respondents who were overweight (body mass index [BMI] 25-29.9 kg/m(2)) or obese (BMI ≥ 30.0 kg/m(2)) were more likely to report a behaviour change (prevalence rate ratio (PRR) 0.66, 95 % confidence interval (CI) 0.44-0.99 and PRR 0.49, 95 % CI 0.30-0.80, respectively). Further, participants with a prior intent to change their behaviour were more likely to make a behaviour change (PRR 0.58, 95 % CI 0.35-0.96). Results did not vary by eGFR category., Limitations: We are unable to determine the effectiveness of the behaviour change intervention given the lack of a control group. Potential response bias and social desirability bias must also be considered when interpreting the study findings., Conclusions: Individual counselling and goal setting provided at screening events may stimulate behaviour change amongst individuals at risk for CKD. However, further research is required to determine if this behaviour change is sustained and the impact on CKD progression and outcomes.

Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

The large-scale production of vast numbers of suitable salt nuclei and their upward launch is one of the main technological barriers to the experimental testing of marine cloud brightening (MCB). Very promising, though not definitive, results have been obtained using an adapted version of effervescent spray atomization. The process is simple, robust and inexpensive. This form of effervescent spraying uses only pressurized water and air sprayed from small nozzles to obtain very fine distributions. While it is far from optimized, and may not be the best method if full deployment is ever desired, we believe that even in its present form the process would lend itself well to preliminary field test investigations of MCB. Measurements obtained using standard aerosol instrumentation show approximately lognormal distributions of salt nuclei with median diameters of approximately 65 nm and geometric standard deviations slightly less than 2. However, these measurements are not in agreement with those based on scanning electron microscopy imaging of collected particles, an observation that has not yet been explained. Assuming the above distribution, 10(15) particles per second could be made with 21 kW of spray power, using approximately 200 nozzles. It is envisioned that existing snow making equipment can be adapted to launch the nuclei 60-100 m into the air, requiring approximately 20 kW of additional power.