Impact on costs and outcomes of multi-gene panel testing for advanced solid malignancies: a cost-consequence analysis using linked administrative data.

Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference <0.10). There were higher mean health-care costs with OCTANE ($79,702 vs. $59,550), mainly due to outpatient and specialist visits. Publicly funded drug costs were less with OCTANE ($20,015 vs. $24,465). OCTANE enrollment was not associated with improved OS (restricted mean survival time [standard error]: 1.50 (±0.03) vs. 1.44 (±0.03) years, log-rank p = 0.153), varying by tumor type. In five tumor types with ≥35 OCTANE patients, OS was similar in three (breast, colon, uterus, all p > 0.40), and greater in two (ovary, biliary, both p < 0.05). OCTANE was associated with greater clinical trial enrollment (25.4% vs. 9.5%, p < 0.001) and better end-of-life quality due to less death in hospital (10.2% vs. 16.4%, p = 0.003). Results were robust in sensitivity analysis. Interpretation: We found an increase in healthcare costs associated with multi-gene panel testing for advanced cancer treatment. The impact on OS was not significant, but varied across tumor types. OCTANE was associated with greater trial enrollment, lower publicly funded drug costs and fewer in-hospital deaths suggesting important considerations in determining the value of NGS panel testing for advanced cancers. Funding: T.P H holds a research grant provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario (#IA-035 and P.HSR.158) and through funding of the Canadian Network for Learning Healthcare Systems and Cost-Effective 'Omics Innovation (CLEO) via Genome Canada (G05CHS).

Testing the 'Faith Moves Mountains model' to increase Alzheimer's disease awareness, detection, and diagnosis among rural, racially, and ethnically diverse older adults.

OBJECTIVES: Racially and ethnically diverse populations have recently contributed to the majority of rural and small-town growth. Consequently, the disproportionately high risk and prevalence of Alzheimer's disease and related dementias (ADRD) among rural and minoritized older residents will likely increase. To address this threat, we tested the hypotheses that (1) a faith-based, resident-led approach would increase basic ADRD knowledge and diagnosis, and (2) older age, female gender, lower educational levels, and more years lived rural would predict number of referrals, new dementia diagnoses, and treatment. METHODS: An adaptation of Schoenberg's Faith Moves Mountains model, previously successful in detection and management of other chronic illnesses in rural settings, guided this community-based participatory research. Local faith community members were trained as research assistants to recruit, administer surveys, conduct brief memory assessments, teach brain health strategies, and follow-up with residents. Outreaches were offered virtually during the pandemic, then in-person monthly at rotating church sites, and repeated ∼1 year later. RESULTS: This rural sample was racially and ethnically diverse (74.5% non-White), with 28% reporting eight or less years of formal education. Findings included that referrals and years lived rural were significant and positive predictors of new ADRD treatments [(b = 3.74, χ2(1, n = 235) = 13.01, p < 0.001); (b = 0.02, χ2(1, n = 235 = 3.93, p = 0.048)], respectively, regardless of participant characteristics. CONCLUSION: Resident-led action research in rural, diverse, faith communities is a successful approach to increasing ADRD disease knowledge, detection, diagnosis, and treatment.

High incidence of catheter-associated urinary tract infections and related antibiotic resistance in two hospitals of different geographic regions of Sierra Leone: a prospective cohort study.

OBJECTIVE: Catheter-associated urinary tract infections (CAUTI) are common worldwide, but due to limited resources, its actual burden in low-income countries is unknown. Currently, there are gaps in knowledge about CAUTI due to lack of surveillance activities in Sierra Leone. In this prospective cohort study, we aimed to determine the incidence of CAUTI and associated antibiotic resistance in two tertiary hospitals in different regions of Sierra Leone. RESULTS: The mean age of the 459 recruited patients was 48.8 years. The majority were females (236, 51.3%). Amongst the 196 (42.6%) catheterized patients, 29 (14.8%) developed CAUTI. Bacterial growth was reported in 32 (84%) patients. Escherichia coli (14, 23.7%), Klebsiella pneumoniae (10, 17.0%), and Klebsiella oxytoca (8, 13.6%) were the most common isolates. Most isolates were ESBL-producing Enterobacteriaceae (33, 56%) and WHO Priority 1 (Critical) pathogens (38, 71%). Resistance of K. pneumoniae, K. oxytoca, E. coli, and Proteus mirabilis was higher with the third-generation cephalosporins and penicillins but lower with carbapenems, piperacillin-tazobactam and amikacin. To reduce the high incidence of CAUTI and multi-drug resistance organisms, urgent action is needed to strengthen the microbiology diagnostic services and develop and implement catheter bundles that provide clear guidance for catheter insertion, care and removal.

Future Role of Health Technology Assessment for Genomic Medicine in Oncology: A Canadian Laboratory Perspective.

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

Antibiotic use and consumption among medical patients of two hospitals in Sierra Leone: a descriptive report.

BACKGROUND: Although one of the main drivers of antimicrobial resistance is inappropriate antibiotic prescribing, there are limited resources to support the surveillance of antibiotic consumption in low-income countries. In this study, we aimed to assess antibiotic use and consumption among medical patients of two hospitals in different geographic regions of Sierra Leone. METHODS: This is a cross-sectional study of adult (18 years or older) patients receiving medical care at two hospitals (34 Military Hospital-MH and Makeni Government Hospital-MGH) between March 2021 and October 2021. After admission to the medical or intensive care unit, patients were sequentially recruited by a nurse from each hospital. Demographic and clinical characteristics and information on the dose of antibiotics, their routes, and frequency of administration and duration were collected using a questionnaire adapted from previous studies and encrypted in EpiCollect software (Epic, Verona WI). A physician reviews and verifies each completed questionnaire. Data analysis was done using STATA version 16. RESULTS: The mean age of the 468 patients evaluated in this study was 48.6 years. The majority were women (241, 51.7%) and treated at MGH (245, 52.0%). Clinical diagnosis of bacterial infection was made in only 180 (38.5%) patients. Regardless of the diagnosis, most (442, 94.9%) patients received at least one antibiotic. Of a total 813 doses of antibiotics prescribed by the two hospitals, 424 (52.2%) were administered in MH. Overall, antibiotic consumption was 66.9 defined daily doses (DDDs) per 100 bed-days, with ceftriaxone being the most commonly used antibiotic (277, 34.1%). The ACCESS and WATCH antibiotics accounted for 18.9 DDDs per 100 bed-days (28.2%) and 48.0 DDDs per 100 bed-days (71.7%), respectively. None of the patients were prescribed a RESERVE antibiotics. The antibiotic consumption was lower in MH (61.3 DDDs per 100 bed-days) than MGH (76.5 DDDs per 100 bed-days). CONCLUSION: Antibiotic consumption was highest with ceftriaxone, followed by levofloxacin and metronidazole. Given the high rate of consumption of antibiotics in the WATCH category of the AWaRe classification, there is a need to initiate surveillance of antibiotic consumption and establish hospital-based antibiotic stewardship in these settings.

MicroRNA-375 Is Induced during Astrocyte-to-Neuron Reprogramming and Promotes Survival of Reprogrammed Neurons when Overexpressed.

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs' expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming.

Evaluating the effects of age on the long-term functional outcomes following anatomic total shoulder arthroplasty.

BACKGROUND: In the past decade, the number of anatomic total shoulder arthroplasty (aTSA) procedures has steadily increased. Patients over 65 years of age comprise the vast majority of recipients, and outcomes have been well documented; however, patients are opting for definitive surgical treatment at younger ages.We aim to report on the effects of age on the long-term clinical outcomes following aTSA. METHODS: Among the patients who underwent TSA, 119 shoulders were retrospectively analyzed. Preoperative and postoperative clinical outcome data were collected. Linear regression analysis (univariate and multivariate) was conducted to evaluate the associations of clinical outcomes with age. Kaplan-Meier curves and Cox regression analyses were performed to evaluate implant survival. RESULTS: At final follow-up, patients of all ages undergoing aTSA experienced significant and sustained improvements in all primary outcome measures compared with preoperative values. Based on multivariate analysis, age at the time of surgery was a significant predictor of postoperative outcomes. Excellent implant survival was observed over the course of this study, and Cox regression survival analysis indicated age and sex to not be associated with an increased risk of implant failure. CONCLUSIONS: When controlling for sex and follow-up duration, older age was associated with significantly better patient-reported outcome measures. Despite this difference, we noted no significant effects on range of motion or implant survival. Level of evidence: IV.

MicroRNA-375 is induced during astrocyte-to-neuron reprogramming and promotes survival of reprogrammed neurons when overexpressed.

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. MicroRNAs (miRNAs), as post-transcriptional regulators of gene expression, play crucial roles during development and under various pathological conditions. To understand the function of miRNAs during AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activates essential neuronal genes to initiate reprogramming process but also induces miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes ( nELAVLs ), which encode a family of RNA-binding proteins and are also upregulated by NeuroD1. We further showed that manipulating miR-375 level regulates nELAVLs expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/ nELAVLs are also induced by reprogramming factors Neurog2 and ASCL1 in HA suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improves NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA even in cultures treated with the chemotherapy drug Cisplatin. Moreover, miR-375 overexpression doesn't appear to compromise maturation of the reprogrammed neurons in long term HA cultures. Lastly, overexpression of miR-375-refractory ELAVL4 induces apoptosis and reverses the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrate a neuro-protective role of miR-375 during NeuroD1-mediated AtN reprogramming and suggest a strategy of combinatory overexpression of NeuroD1 and miR-375 for improving neuronal reprogramming efficiency.

Global rural health disparities in Alzheimer's disease and related dementias: State of the science.

INTRODUCTION: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators. METHODS: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: "What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?" In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings. RESULTS: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions. DISCUSSION: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities. HIGHLIGHTS: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel "location dynamics" model guides assessment of rural-specific ADRD issues.

Stroke in Sierra Leone: Case fatality rate and functional outcome after stroke in Freetown.

BACKGROUND: There is limited information on long-term outcomes after stroke in sub-Saharan Africa (SSA). Current estimates of case fatality rate (CFR) in SSA are based on small sample sizes with varying study design and report heterogeneous results. AIMS: We report CFR and functional outcomes from a large, prospective, longitudinal cohort of stroke patients in Sierra Leone and describe factors associated with mortality and functional outcome. METHODS: A prospective longitudinal stroke register was established at both adult tertiary government hospitals in Freetown, Sierra Leone. It recruited all patients ⩾ 18 years with stroke, using the World Health Organization definition, from May 2019 until October 2021. To reduce selection bias onto the register, all investigations were paid by the funder and outreach conducted to raise awareness of the study. Sociodemographic data, National Institute of Health Stroke Scale (NIHSS), and Barthel Index (BI) were collected on all patients on admission, at 7 days, 90 days, 1 year, and 2 years post stroke. Cox proportional hazards models were constructed to identify factors associated with all-cause mortality. A binomial logistic regression model reports odds ratio (OR) for functional independence at 1 year. RESULTS: A total of 986 patients with stroke were included, of which 857 (87%) received neuroimaging. Follow-up rate was 82% at 1 year, missing item data were <1% for most variables. Stroke cases were equally split by sex and mean age was 58.9 (SD: 14.0) years. About 625 (63%) were ischemic, 206 (21%) primary intracerebral hemorrhage, 25 (3%) subarachnoid hemorrhage, and 130 (13%) were of undetermined stroke type. Median NIHSS was 16 (9-24). CFR at 30 days, 90 days, 1 year, and 2 years was 37%, 44%, 49%, and 53%, respectively. Factors associated with increased fatality at any timepoint were male sex (hazard ratio (HR): 1.28 (1.05-1.56)), previous stroke (HR: 1.34 (1.04-1.71)), atrial fibrillation (HR: 1.58(1.06-2.34)), subarachnoid hemorrhage (HR: 2.31 (1.40-3.81)), undetermined stroke type (HR: 3.18 (2.44-4.14)), and in-hospital complications (HR: 1.65 (1.36-1.98)). About 93% of patients were completely independent prior to their stroke, declining to 19% at 1 year after stroke. Functional improvement was most likely to occur between 7 and 90 days post stroke with 35% patients improving, and 13% improving between 90 days to 1 year. Increasing age (OR: 0.97 (0.95-0.99)), previous stroke (OR: 0.50 (0.26-0.98)), NIHSS (OR: 0.89 (0.86-0.91)), undetermined stroke type (OR: 0.18 (0.05-0.62)), and ⩾1 in-hospital complication (OR: 0.52 (0.34-0.80)) were associated with lower OR of functional independence at 1 year. Hypertension (OR: 1.98 (1.14-3.44)) and being the primary breadwinner of the household (OR: 1.59 (1.01-2.49)) were associated with functional independence at 1 year. CONCLUSION: Stroke affected younger people and resulted in high rates of fatality and functional impairment relative to global averages. Key clinical priorities for reducing fatality include preventing stroke-related complications through evidence-based stroke care, improved detection and management of atrial fibrillation, and increasing coverage of secondary prevention. Further research into care pathways and interventions to encourage care seeking for less severe strokes should be prioritized, including reducing the cost barrier for stroke investigations and care.

Sensory sensitivity, intolerance of uncertainty and sex differences predicting anxiety in emerging adults.

As multiple vulnerability factors have been defined for anxiety disorders, it is important to investigate the interactions among these factors to understand why and how some individuals develop anxiety. Sensory Sensitivity (SS) and Intolerance of Uncertainty (IU) are independent vulnerability factors of anxiety, but their unique relationship in predicting anxiety has rarely been studied in non-clinical populations. The objective of this investigation was to examine the combined effects of SS and IU on self-reported anxiety in a sample of university students. In addition, with the frequently reported sex bias in anxiety literature, we expected that the combined effects of vulnerability factors would be different for females and males. A convenience sample of 313 university students, ages 17-26 years was recruited. The participants completed the Intolerance of Uncertainty Scale (IUS-12), the Adult/Adolescent Sensory Profile (AASP), and the Beck Anxiety Inventory (BAI). Results of moderated mediation analyses demonstrated a strong partial mediation between SS and anxiety through IU, providing evidence that IU, a cognitive bias against the unknown, was one mechanism that explained how SS was related to anxiety. Further, the effect of IU on anxiety was approximately twice as strong in females. Our results highlight the importance of studying the unique relationships among multiple vulnerability factors to better understand anxiety susceptibility in emerging adults.

Nature of the evidence base and strengths, challenges and recommendations in the area of nutrition and health claims: a position paper from the Academy of Nutrition Sciences.

The regulation of health claims for foods by the Nutrition and Health Claims Regulation is intended, primarily, to protect consumers from unscrupulous claims by ensuring claims are accurate and substantiated with high quality scientific evidence. In this position paper, the Academy of Nutrition Sciences uniquely recognises the strengths of the transparent, rigorous scientific assessment by independent scientists of the evidence underpinning claims in Europe, an approach now independently adopted in UK. Further strengths are the separation of risk assessment from risk management, and the extensive guidance for those submitting claims. Nevertheless, four main challenges in assessing the scientific evidence and context remain: (i) defining a healthy population, (ii) undertaking efficacy trials for foods, (iii) developing clearly defined biomarkers for some trial outcomes and (iv) ensuring the composition of a food bearing a health claim is consistent with generally accepted nutrition principles. Although the Regulation aims to protect the consumer from harm, we identify some challenges from consumer research: (i) making the wording of some health claims more easily understood and (ii) understanding the implications of the misperceptions around products bearing nutrition or health claims. Recommendations are made to overcome these challenges. Further, the Academy recommends that a dialogue is developed with the relevant national bodies about Article 12(c) in the Regulation. This should further clarify the GB Guidance to avoid the current non-level playing field between health professionals and untrained 'influencers' who are not covered by this Article about the communication of authorised claims within commercial communications.

Mechanistic evidence underpinning dietary policy: bringing the jigsaw pieces together?

Observational research, mainly prospective cohort studies (PCS), has represented a long-standing challenge for those attempting to draw up consistent policy recommendations in the area of diet and health. This has been due to the inherent limitations in ascribing causality from observed associations due to problems of confounding of the findings and publication and citation bias. Developments in nutritional epidemiology research over the past 20-30 years have enabled causal criteria to be derived from observational studies and the totality of the primary literature to be reviewed objectively, reducing previous focus on narrative accounts of individual studies. The gold standard approach to assessing causal relationships is via randomised controlled trials (RCT), but neither RCT nor PCS provide direct evidence for biological plausibility, which is a key criterion for assessing causality. Although extensive mechanistic data are available in the literature, a systematic approach to select and assess quality and relevance of published studies has not been available. This limits their use in the development of diet and health policy. Recent studies have investigated a proposed two-step framework and novel methodologies for integrating heterogeneous data from cell, animal and human studies. Pilot and feasibility studies have shown this to be a useful novel approach to studies of diet and cancer, but further refinements are required, including development of appropriate quality criteria which are less dependent on RCT designs. Future studies are needed to fully verify the approach and its potential for use in other diet-disease relationships.

Community-Based Strategies to Reduce Alzheimer's Disease and Related Dementia Incidence Among Rural, Racially/Ethnically Diverse Older Adults.

Purpose of Review: The purpose of this paper was to address the research question "What recent advances in Alzheimer's Disease and Related Dementias (ADRD) risk reduction strategies can be tailored for rural, racially/ethnically diverse populations?" A rural resident's life story that grounded the work is shared. Next, a brief description is provided regarding ADRD risk factors of importance in rural, multicultural settings. Gaps in U.S.-based research are highlighted. Policy actions and interventions that may make a difference in alleviating rural, ADRD-related disparities are offered. Recent Findings: More than a dozen factors, including lack of built environment, periodontitis, poor air quality, and sensory loss, were identified that are of particular relevance to rural groups. Evidence of importance to underserved residents has also emerged regarding the harmful effects of ultra-processed foods on brain health, benefits of even minimal physical activity, and importance of social engagement, on brain health. Summary: Resident-led initiatives will be key to creating change at the community level. Health providers are also called to assist in identifying and adapting culturally specific upstream approaches, in partnership with community stakeholders. These mechanisms are vital for decreasing ADRD burdens in underserved communities facing the largest disparities in preventive care.

High levels of surgical antibiotic prophylaxis: Implications for hospital-based antibiotic stewardship in Sierra Leone.

Objective: Despite the impact of inappropriate prescribing on antibiotic resistance, data on surgical antibiotic prophylaxis in sub-Saharan Africa are limited. In this study, we evaluated antibiotic use and consumption in surgical prophylaxis in 4 hospitals located in 2 geographic regions of Sierra Leone. Methods: We used a prospective cohort design to collect data from surgical patients aged 18 years or older between February and October 2021. Data were analyzed using Stata version 16 software. Results: Of the 753 surgical patients, 439 (58.3%) were females, and 723 (96%) had received at least 1 dose of antibiotics. Only 410 (54.4%) patients had indications for surgical antibiotic prophylaxis consistent with local guidelines. Factors associated with preoperative antibiotic prophylaxis were the type of surgery, wound class, and consistency of surgical antibiotic prophylaxis with local guidelines. Postoperatively, type of surgery, wound class, and consistency of antibiotic use with local guidelines were important factors associated with antibiotic use. Of the 2,482 doses administered, 1,410 (56.8%) were given postoperatively. Preoperative and intraoperative antibiotic use was reported in 645 (26%) and 427 (17.2%) cases, respectively. The most commonly used antibiotic was ceftriaxone 949 (38.2%) with a consumption of 41.6 defined daily doses (DDD) per 100 bed days. Overall, antibiotic consumption was 117.9 DDD per 100 bed days. The Access antibiotics had 72.7 DDD per 100 bed days (61.7%). Conclusions: We report a high rate of antibiotic consumption for surgical prophylaxis, most of which was not based on local guidelines. To address this growing threat, urgent action is needed to reduce irrational antibiotic prescribing for surgical prophylaxis.