Publications by authors named "J William L Brown"

17,291 Publications

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Interspecies chimeric conditions affect the developmental rate of human pluripotent stem cells.

PLoS Comput Biol 2021 Mar 1;17(3):e1008778. Epub 2021 Mar 1.

Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Wisconsin, United States of America.

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.
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http://dx.doi.org/10.1371/journal.pcbi.1008778DOI Listing
March 2021

Yarning as an Interview Method for Non-Indigenous Clinicians and Health Researchers.

Qual Health Res 2021 Feb 28:1049732321995802. Epub 2021 Feb 28.

CQUniversity Brisbane, Brisbane, Queensland, Australia.

In this article, we discuss the origins, epistemology, and forms of Yarning as derived from the literature, and its use in research and clinical contexts. Drawing on three Yarns, the article addresses the extent to which non-Indigenous researchers and clinicians rightfully use and adapt this information-gathering method, or alternatively, may engage in yet another form of what can be described as post-colonialist behavior. Furthermore, we argue that while non-Indigenous researchers can use Yarning as an interview technique, this does not necessarily mean they engage in Indigenous methodologies. As we note, respectfully interviewing Aboriginal and Torres Strait Islander peoples can be a challenge for non-Indigenous researchers. The difficulties go beyond differences in language to reveal radically different expectations about how relationships shape information giving. Yarning as a method for addressing cross-cultural clinical and research differences goes some way to ameliorating these barriers, but also highlights the post-colonial tensions.
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http://dx.doi.org/10.1177/1049732321995802DOI Listing
February 2021

Mild Motor Signs Matter in Typical Brain Aging: The Value of the UPDRS Score Within a Functionally Intact Cohort of Older Adults.

Front Aging Neurosci 2021 11;13:594637. Epub 2021 Feb 11.

Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.

To characterize the clinical correlates of subclinical Parkinsonian signs, including longitudinal cognitive and neural (via functional connectivity) outcomes, among functionally normal older adults. Participants included 737 functionally intact community-dwelling older adults who performed prospective comprehensive evaluations at ~15-months intervals for an average of 4.8 years (standard deviation 3.2 years). As part of these evaluations, participants completed the Unified Parkinson's Disease Rating Scale (UPDRS) longitudinally and measures of processing speed, executive functioning and verbal episodic memory. T1-weighted structural scans and task-free functional MRI scans were acquired on 330 participants. We conducted linear mixed-effects models to determine the relationship between changes in UPDRS with cognitive and neural changes, using age, sex, and education as covariates. Cognitive outcomes were processing speed, executive functioning, and episodic memory. Greater within-person increases in UPDRS were associated with more cognitive slowing over time. Although higher average UPDRS scores were significantly associated with overall poorer executive functions, there was no association between UPDRS and executive functioning longitudinally. UPDRS scores did not significantly relate to longitudinal memory performances. Regarding neural correlates, greater increases in UPDRS scores were associated with reduced intra-subcortical network connectivity over time. There were no relationships with intra-frontoparietal or inter-subcortical-frontoparietal connectivity. Our findings add to the aging literature by indicating that mild motor changes are negatively associated with cognition and network connectivity in functionally intact adults.
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http://dx.doi.org/10.3389/fnagi.2021.594637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904682PMC
February 2021

The impact of pulmonary artery catheter use in cardiac surgery.

J Thorac Cardiovasc Surg 2021 Feb 2. Epub 2021 Feb 2.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pa. Electronic address:

Objective: Pulmonary artery catheterization provides continuous monitoring of hemodynamic parameters that may aid in the perioperative management of patients undergoing cardiac surgery. However, prior data suggest that pulmonary artery catheterization has limited benefit in intensive care and surgical settings. Thus, this study sought to determine the impact of pulmonary artery catheter insertion on short-term postoperative outcomes in a large, contemporaneous cohort of patients undergoing open cardiac surgery compared with standard central venous pressure monitoring.

Methods: This was an observational study of open cardiac surgeries from 2010 to 2018. Patients with pulmonary artery catheter insertion were identified and matched against patients without pulmonary artery catheter insertion via 1:1 nearest neighbor propensity matching. Multivariable analysis was performed to assess the impact of pulmonary artery catheterization on operative mortality in the overall cohort, as well as recent heart failure, mitral valve disease, and tricuspid insufficiency subgroups.

Results: Of the 11,820 patients undergoing (Society of Thoracic Surgeons indexed) coronary or valvular surgery, 4605 (39.0%) had pulmonary artery catheter insertion. Propensity score matching yielded 3519 evenly balanced pairs. Compared with central venous pressure monitoring, pulmonary artery catheter use was not associated with improved operative mortality in the overall cohort or in the recent heart failure, mitral valve disease, or tricuspid insufficiency subgroups. Intensive care unit length of stay was longer (P < .001), and there were more packed red blood cell transfusions in the pulmonary artery catheterization group (P < .001); however, postoperative outcomes were otherwise similar, including stroke, sepsis, and new renal failure (P > .05).

Conclusions: These findings suggest that pulmonary artery catheterization may have limited benefit in cardiac surgery.
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http://dx.doi.org/10.1016/j.jtcvs.2021.01.086DOI Listing
February 2021

Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine.

Lancet 2021 Feb 25. Epub 2021 Feb 25.

Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK; Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.

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http://dx.doi.org/10.1016/S0140-6736(21)00502-XDOI Listing
February 2021

Health outcomes coding trends in the US Food and Drug Administration's Sentinel System during transition to International Classification of Diseases-10 coding system: a brief review.

Pharmacoepidemiol Drug Saf 2021 Feb 27. Epub 2021 Feb 27.

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Background And Purpose: The transition from International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) to ICD-10-CM poses a challenge to epidemiologic studies that use diagnostic codes to identify health outcomes and covariates. We evaluated coding trends in health outcomes in the US Food and Drug Administration's Sentinel System during the transition.

Methods: We reviewed all health outcomes coding trends reports on the Sentinel website through November 30, 2019 and analyzed trends in incidence and prevalence across the ICD-9-CM and ICD-10-CM eras by visual inspection.

Results: We identified 78 unique health outcomes (22 acute, 32 chronic, and 24 acute or chronic) and 140 time-series graphs of incidence and prevalence. The reports also included code lists and code mapping methods used. Of the 140 graphs reviewed, 81 (57.9%) showed consistent trends across the ICD-9-CM and ICD-10-CM eras, while 51 (36.4%) and 8 (5.7%) graphs showed inconsistent and uncertain trends, respectively. Chronic HOIs and acute/chronic HOIs had higher proportions of consistent trends in prevalence definitions (83.9% and 78.3%, respectively) than acute HOIs (28.6%). For incidence, 55.6% of acute HOIs showed consistent trends, while 41.2% of chronic HOIs and 39.3% of acute/chronic HOIs showed consistency.

Conclusions: Researchers using ICD-10-CM algorithms obtained by standardized mappings from ICD-9-CM algorithms should assess the mapping performance before use. The Sentinel reports provide a valuable resource for researchers who need to develop and assess mapping strategies. The reports could benefit from additional information about the algorithm selection process and additional details on monthly incidence and prevalence rates.
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http://dx.doi.org/10.1002/pds.5216DOI Listing
February 2021

The current and potential role of community pharmacy in asset-based approaches to health and wellbeing: a qualitative study.

Int J Clin Pharm 2021 Feb 26. Epub 2021 Feb 26.

Health Education England, Manchester, UK.

Background Asset-based approaches seek to positively mobilise the strengths, capabilities, and resources of individuals and communities. To date, limited consideration has been given to the potential value of this approach in relation to community pharmacy practice, yet this is important and timely given community pharmacy's expanding role and contribution to public health initiatives. Objectives This qualitative study aimed to explore the current and potential role of community pharmacy in asset-based approaches. Methods Fifteen semi-structured telephone interviews were undertaken with community pharmacists and project leads, and public health policy and strategic leads in the UK. Transcripts were analysed using simultaneous inductive open and deductive coding using an applied Theory of Change as an illustrative lens. Results The shift towards patient-facing roles in community pharmacy was felt to offer expanded relational opportunities to engage and collaborate with individuals, communities, and other stakeholders. However, only a small number of respondents described examples of systemic asset-based working within the pharmacy sector. The adoption of asset-based approaches was challenged or enabled by several factors including the availability of protected time/resources, workplace and organisational culture/values, strategic leadership, commissioning, and funding arrangements. Conclusions The study provides valuable insights into the potential for community pharmacy, a previously unconsidered sector, to further adopt and contribute to asset-based approaches and play a more central role in the improvement of public health and reduction of health inequalities.
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http://dx.doi.org/10.1007/s11096-021-01244-zDOI Listing
February 2021

Characteristics to consider when selecting a positive control material for an in vitro assay.

ALTEX 2021 Feb 24. Epub 2021 Feb 24.

Empa, Swiss Federal Laboratories for Material Testing and Research, Particles-Biology Interactions Laboratory, St. Gallen, Switzerland.

The use of in vitro assays to inform decision-making requires robust and reproducible results across studies, laboratories, and time. Experiments using positive control materials are an integral component of an assay procedure to demonstrate the extent to which the measurement system is performing as expected. This paper reviews ten characteristics that should be considered when selecting a positive control material for an in vitro assay: 1) the biological mechanism of action, 2) ease of preparation, 3) chemical purity, 4) verifiable physical properties, 5) stability, 6) ability to generate responses spanning the dynamic range of the assay, 7) technical or biological interference, 8) commercial availability, 9) user toxicity, and 10) disposability. Examples and a case study of the monocyte activation test are provided to demonstrate the application of these characteristics for identification and selection of potential positive control materials. Because specific positive control materials are often written into testing standards for in vitro assays, selection of the positive control material based on these characteristics can aid in ensuring the long-term relevance and usability of these standards.
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http://dx.doi.org/10.14573/altex.2102111DOI Listing
February 2021

Applications of Artificial Intelligence for Retinopathy of Prematurity Screening.

Pediatrics 2021 Feb 26. Epub 2021 Feb 26.

Athinoula A. Martinos Center for Biomedical Imaging and Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts.

Objectives: Childhood blindness from retinopathy of prematurity (ROP) is increasing as a result of improvements in neonatal care worldwide. We evaluate the effectiveness of artificial intelligence (AI)-based screening in an Indian ROP telemedicine program and whether differences in ROP severity between neonatal care units (NCUs) identified by using AI are related to differences in oxygen-titrating capability.

Methods: External validation study of an existing AI-based quantitative severity scale for ROP on a data set of images from the Retinopathy of Prematurity Eradication Save Our Sight ROP telemedicine program in India. All images were assigned an ROP severity score (1-9) by using the Imaging and Informatics in Retinopathy of Prematurity Deep Learning system. We calculated the area under the receiver operating characteristic curve and sensitivity and specificity for treatment-requiring retinopathy of prematurity. Using multivariable linear regression, we evaluated the mean and median ROP severity in each NCU as a function of mean birth weight, gestational age, and the presence of oxygen blenders and pulse oxygenation monitors.

Results: The area under the receiver operating characteristic curve for detection of treatment-requiring retinopathy of prematurity was 0.98, with 100% sensitivity and 78% specificity. We found higher median (interquartile range) ROP severity in NCUs without oxygen blenders and pulse oxygenation monitors, most apparent in bigger infants (>1500 g and 31 weeks' gestation: 2.7 [2.5-3.0] vs 3.1 [2.4-3.8]; = .007, with adjustment for birth weight and gestational age).

Conclusions: Integration of AI into ROP screening programs may lead to improved access to care for secondary prevention of ROP and may facilitate assessment of disease epidemiology and NCU resources.
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http://dx.doi.org/10.1542/peds.2020-016618DOI Listing
February 2021

Fragility fracture identifies patients at imminent risk for subsequent fracture: real-world retrospective database study in Ontario, Canada.

BMC Musculoskelet Disord 2021 Feb 26;22(1):224. Epub 2021 Feb 26.

Amgen Canada Inc., Mississauga, ON, Canada.

Background: The secondary fracture prevention gap in the osteoporosis field has been previously described as a 'crisis'. Closing this gap is increasingly important in the context of accumulating evidence showing that an incident fragility fracture is associated with an increased risk of subsequent fracture within 1-2 years, known as imminent fracture risk. The objective of this study was to use health services data to characterize the time between index fragility fractures occurring at different osteoporotic sites and subsequent fractures.

Methods: This retrospective observational study used de-identified health services data from the publicly funded healthcare system in Ontario, the largest province of Canada. Patients aged > 65 with an index fragility fracture occurring between 2011 and 2015 were identified from the ICES Data Repository using International Classification of Diseases (ICD)-10 codes. We examined median time to subsequent fragility fractures for osteoporotic fracture sites until the end of follow-up (2017). BMD assessment and use of osteoporosis therapies following index fracture were also characterized.

Results: Among 115,776 patients with an index fragility fracture, 17.8% incurred a second fragility fracture. Median time between index and second fracture occurring at any site was 555 days (interquartile range: 236-955). For each index fracture site examined, median time from index to second fracture was < 2 years. The proportion of patients with BMD assessment was 10.3% ≤1 year prior to and 16.4% ≤1 year post index fracture. The proportion of patients receiving osteoporosis therapy was 29.8% ≤1 year prior, 34.6% ≤1 year post, and 25.9% > 3 years post index fracture.

Conclusions: This cohort of Canadian patients aged > 65 years who experienced a fragility fracture at any site are at imminent risk of experiencing subsequent fracture within the next 2 years and should be proactively assessed and treated.
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http://dx.doi.org/10.1186/s12891-021-04051-9DOI Listing
February 2021

WEST NILE VIRUS INFECTION IN RUFFED GROUSE (BONASA UMBELLUS) IN PENNSYLVANIA, USA: A MULTI-YEAR COMPARISON OF STATEWIDE SEROSURVEYS AND VECTOR INDICES.

J Wildl Dis 2021 Jan;57(1):51-59

Bureau of Wildlife Management, Pennsylvania Game Commission, 2001 Elmerton Avenue, Harrisburg, Pennsylvania 17110, USA.

Eastern populations of Ruffed Grouse (Bonasa umbellus) have been in a decades-long decline across the mid-Atlantic and southern Appalachian Mountains of the US. West Nile virus (WNV), which first arrived in the US in 1999, is suspected to have contributed to these declines based on decreased population indices since the arrival of WNV in Pennsylvania as well as on high, experimentally induced WNV-associated morbidity rates. A 3-yr statewide survey was conducted across Pennsylvania to measure flavivirus (i.e., WNV) seroprevalence among hunter-harvested grouse. The overall seroprevalence from 2015-17 was 14.4% (81/563); annual seroprevalence ranged from 2.8% (4/145) in the 2017 hunt year to 22.6% (52/230) in 2016-17. We analyzed the effects of numerous variables (i.e., Ruffed Grouse age and sex, hunt year, WNV vector index [VI], and region of Pennsylvania) on WNV serostatus by logistic regression. While there was no significant difference in WNV seroprevalence between sex and age group, there was significant variation in seroprevalence between geographic regions of Pennsylvania and across hunt years. Additionally, there was a negative correlation between WNV seroprevalence and VI. Low seroprevalence rates among Ruffed Grouse corresponded to years with a high VI, supporting experimental findings that Ruffed Grouse may be highly susceptible to WNV-associated disease. Additional strategic research efforts are essential to more effectively measure the effects of WNV on Ruffed Grouse and other vulnerable avian species.
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http://dx.doi.org/10.7589/JWD-D-19-00016DOI Listing
January 2021

Baseline modified Glasgow prognostic score associated with survival in metastatic urothelial cell carcinoma treated with immune checkpoint inhibitors.

Oncologist 2021 Feb 25. Epub 2021 Feb 25.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.

Background: The modified Glasgow Prognostic Score (mGPS), a clinical tool that incorporates albumin and C-reactive protein, has proven useful in the prognostication of multiple cancers. Several immune checkpoint inhibitors (ICI) have been approved for the treatment of metastatic urothelial cell carcinoma (mUC) but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in mUC patients receiving ICI.

Methods: We retrospectively reviewed mUC patients treated with ICI (PD-1 or PD-L1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographic progression, respectively. mGPS was defined as a summary score with one point given for CRP > 10 mg/L and/or albumin < 3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model. These outcomes were also assessed by Kaplan-Meier analysis.

Results: A total of 53 patients were included with a median follow up 27.1 months. The median age was 70 years with 84.9% male and 20.8% black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. Increased mGPS at the time of ICI initiation was associated with poorer OS and PFS in UVA, MVA and K-M analyses.

Conclusions: The mGPS may be a useful prognostic tool in mUC patients when treatment with ICI is under consideration. These results warrant a larger study for validation.

Implications For Practice: The ideal prognostic tool for use in a busy clinical practice is easy-to-use, cost-effective, and capable of accurately predicting clinical outcomes. There is currently no universally accepted risk score in metastatic urothelial cell carcinoma (mUC), particularly in the immunotherapy era. The modified Glasgow prognostic score (mGPS) incorporates albumin and C-reactive protein and may reflect underlying chronic inflammation, a known risk factor for resistance to immune checkpoint inhibitors (ICI). We found that baseline mGPS is associated with survival outcomes in patients with mUC treated with ICI and may help clinicians to prognosticate for their patients beginning immunotherapy.
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http://dx.doi.org/10.1002/onco.13727DOI Listing
February 2021

Age of thawed plasma does not affect clinical outcomes or biomarker expression in patients receiving prehospital thawed plasma: a PAMPer secondary analysis.

Trauma Surg Acute Care Open 2021 11;6(1):e000648. Epub 2021 Feb 11.

Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Prehospital plasma administration during air medical transport reduces the endotheliopathy of trauma, circulating pro-inflammatory cytokines, and 30-day mortality among traumatically injured patients at risk of hemorrhagic shock. No clinical data currently exists evaluating the age of thawed plasma and its association with clinical outcomes and biomarker expression post-injury.

Methods: We performed a secondary analysis from the prehospital plasma administration randomized controlled trial, PAMPer. We dichotomized the age of thawed plasma creating three groups: standard-care, YOUNG (day 0-1) plasma, and OLD (day 2-5) plasma. We generated HRs and 95% CIs for mortality. Among all patients randomized to plasma, we compared predicted biomarker values at hospital admission (T0) and 24 hours later (T24) controlling for key difference between groups with a multivariable linear regression. Analyses were repeated in a severely injured subgroup.

Results: Two hundred and seventy-one patients were randomized to standard-care and 230 to plasma (40% YOUNG, 60% OLD). There were no clinically or statistically significant differences in demographics, injury, admission vital signs, or laboratory values including thromboelastography between YOUNG and OLD. Compared with standard-care, YOUNG (HR 0.66 (95% CI 0.41 to 1.07), p=0.09) and OLD (HR 0.64 (95% CI 0.42 to 0.96), p=0.03) plasma demonstrated reduced 30-day mortality. Among those randomized to plasma, plasma age did not affect mortality (HR 1.04 (95% CI 0.60 to 1.82), p=0.90) and/or adjusted serum markers by plasma age at T0 or T24 (p>0.05). However, among the severely injured subgroup, OLD plasma was significantly associated with increased adjusted inflammatory and decreased adjusted endothelial biomarkers at T0.

Discussion: Age of thawed plasma does not result in clinical outcome or biomarker expression differences in the overall PAMPer study cohort. There were biomarker expression differences in those patients with severe injury. Definitive investigation is needed to determine if the age of thawed plasma is associated with biomarker expression and outcome differences following traumatic injury.

Level Of Evidence: II.
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http://dx.doi.org/10.1136/tsaco-2020-000648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880105PMC
February 2021

Alert Cards to improve awareness of an otological emergency.

BMJ Open Qual 2021 Feb;10(1)

Neurofibromatosis 2 Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

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http://dx.doi.org/10.1136/bmjoq-2019-000906DOI Listing
February 2021

Associations between vaping and Covid-19: Cross-sectional findings from the HEBECO study.

Drug Alcohol Depend 2021 Feb 13;221:108590. Epub 2021 Feb 13.

Department of Behavioural Science and Health, University College London, UK.

Aims: To explore i) associations between vaping and self-reported diagnosed/suspected Covid-19; ii) changes in vaping since Covid-19 and factors associated with these changes; iii) whether Covid-19 motivated current or recent ex-vapers to quit.

Methods: Cross-sectional online survey of 2791 UK adults recruited 30/04/2020-14/06/2020. Participants self-reported data on sociodemographic characteristics, diagnosed/suspected Covid-19, vaping status, changes in vaping and motivation to quit vaping since Covid-19.

Results: There were no differences in diagnosed/suspected Covid-19 between never, current and ex-vapers. Bayes factors indicated there was sufficient evidence to rule out small negative (protective) associations between vaping status and diagnosed/suspected Covid-19. Among current vapers (n = 397), 9.7 % (95 % CI 6.8-12.6 %) self-reported vaping less than usual since Covid-19, 42.0 % (37.2-46.9 %) self-reported vaping more, and 48.3 % (43.4-53.2 %) self-reported no change. In adjusted analyses, vaping less was associated with being female (aOR = 3.40, 95 % CI 1.73-6.71), not living with children (aOR = 4.93, 1.15-21.08) and concurrent smoking (aOR = 8.77, 3.04-25.64), while vaping more was associated with being younger (aOR = 5.26, 1.37-20.0), living alone (aOR = 2.08, 1.14-3.85), and diagnosed/suspected Covid-19 (aOR = 4.72, 2.60-8.62). Of current vapers, 32.2 % (95 % CI 27.5-36.8 %) were motivated to quit vaping since Covid-19, partly motivated by Covid-19, and 21.0 %, (10.5-31.4 %) of recent ex-vapers quit vaping due to Covid-19.

Conclusions: Among UK adults, self-reported diagnosed/suspected Covid-19 was not associated with vaping status. Half of current vapers changed their vaping consumption since Covid-19, with the majority reporting an increase, and a minority was motivated to quit due to Covid-19.

Registration: The analysis plan was pre-registered, and it is available at https://osf.io/6j8z3/.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881695PMC
February 2021

E-liquid purchase as a function of workplace restriction in the experimental tobacco marketplace.

Exp Clin Psychopharmacol 2021 Feb 25. Epub 2021 Feb 25.

Fralin Biomedical Research Institute at Virginia Tech Carilion.

E-cigarette use is prohibited in most smoke-free environments. The effect of this policy on tobacco consumption could be examined using the Experimental Tobacco Marketplace (ETM). The ETM allows observation of policy on smokers' purchasing behavior under conditions that simulate "real-world" circumstances. A within-subject design was used to evaluate the effect of workplace policy (Vaping Allowed vs. Not Allowed) and nicotine concentration (24 mg/mL vs. 0 mg/mL) on tobacco product consumption. Participants (n = 31) completed one sampling and two ETM/workplace sessions per week for 2 weeks. During the sampling session, participants were given an e-cigarette with a 2-day supply of a commercially available e-liquid of their preferred flavor. Before purchasing, participants were informed whether e-cigarette use was permitted. During the four ETM sessions, participants purchased for the following 24 hr, including the 4-hr work shift that started immediately after buying products in the ETM. The workplace session consisted of data entry tasks in a mock office environment. Participants could use any purchased tobacco products during two 15-min breaks. Condition order was counterbalanced. The results show that permitting E-cigarette use in the workplace increased e-liquid purchase on average, but nicotine concentration had no effect on e-liquid demand. Cigarette demand was unaltered across conditions. The present study suggests that allowing e-cigarette use in the workplace would increase demand for e-liquid regardless of nicotine strength. However, it would not change conventional cigarette demand. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pha0000444DOI Listing
February 2021

The FDA MyStudies app: a reusable platform for distributed clinical trials and real-world evidence studies.

JAMIA Open 2020 Dec 11;3(4):500-505. Epub 2020 Dec 11.

Moderna, Inc, Cambridge, Massachusetts, USA.

We developed a mobile application and secure patient data storage platform, FDA MyStudies, to address privacy, engagement, and extensibility challenges in mobile clinical research. The system extends the capabilities of the mobile frameworks Apple ResearchKit and ResearchStack through an intuitive front-end application and secure storage environment that can support health research studies. The platform supports single or multisite studies via role-based access and can be implemented within highly secure data environments. As a proof-of-concept, pregnant women participated in a descriptive study via the app in which data not routinely captured in electronic health records (EHR) were collected and linked with existing patient data to provide a more wholistic view of the patient and illustrate how patient data combined with EHR data could be used to support public health research.
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http://dx.doi.org/10.1093/jamiaopen/ooaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886578PMC
December 2020

Human sensory cortical contribution to the long-term storage of aversive conditioning.

J Neurosci 2021 Feb 22. Epub 2021 Feb 22.

Department of Psychology, Florida State University, Tallahassee, Florida

Growing animal data evince a critical role of the sensory cortex in the long-term storage of aversive conditioning, following acquisition and consolidation in the amygdala. Whether and how this function is conserved in the human sensory cortex is nonetheless unclear. We interrogated this question in a human aversive conditioning study employing multidimensional assessments of conditioning and long-term (15 days) retention. Conditioned stimuli (CS; Gabor patches) were calibrated to differentially activate the parvocellular (P) and magnocellular (M) visual pathways, further elucidating cortical versus subcortical mechanisms. Full-blown conditioning and long-term retention emerged for M-biased CS (vs. limited effects for P-biased CS), especially among anxious individuals, in all four dimensions assessed: threat appraisal (threat ratings), physiological arousal (skin conductance response), perceptual learning (discrimination sensitivity, ', and response speed), and cortical plasticity (visual evoked potentials/VEPs and cortical current density). Interestingly, while behavioral, physiological, and VEP effects were comparable at immediate and delayed assessments, the cortical substrates evolved markedly over time, transferring from high-order cortices (inferotemporal/fusiform cortex and orbitofrontal cortex/OFC) immediately to the primary/secondary (V1/V2) visual cortex after the delay. In sum, the contrast between P- and M-biased conditioning confirms privileged conditioning acquisition via the subcortical pathway while the immediate cortical plasticity lends credence to the triadic amygdala-OFC-fusiform network thought to underlie threat processing. Importantly, long-term retention of conditioning in the basic sensory cortices supports the conserved role of the human sensory cortex in the long-term storage of aversive conditioning.A growing network of neural substrates has been identified in threat learning and memory. The sensory cortex plays a key role in long-term threat memory in animals, but such a function in humans remains unclear. To explore this problem, we conducted multidimensional assessments of immediate and delayed (15-day) effects of human aversive conditioning. Behavioral, physiological, and scalp electrophysiological data demonstrated conditioning effects and long-term retention. High-density EEG (hdEEG) intracranial source analysis further revealed the cortical underpinnings, implicating high-order cortices immediately and primary/secondary visual cortices (V1/V2) after the long delay. Therefore, while high-order cortices support aversive conditioning acquisition (i.e., threat learning), the human sensory cortex (akin to the animal homologue) underpins long-term storage of conditioning (i.e., long-term threat memory).
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http://dx.doi.org/10.1523/JNEUROSCI.2325-20.2021DOI Listing
February 2021

Managing Opioids and Mitigating Risk: A Survey of Attitudes, Confidence and Practices of Oncology Health Care Professionals.

Curr Oncol 2021 Feb 12;28(1):873-878. Epub 2021 Feb 12.

Department of Supportive Care, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.

In response to Canada's opioid crisis, national strategies and guidelines have been developed but primarily focus on opioid use for chronic noncancer pain. Despite the well-established utility of opioids in cancer care, and the growing emphasis on early palliative care, little attention has been paid to opioid risk in this population, where evidence increasingly shows a higher risk of opioid-related harms than was previously thought. The primary objective of this study was to assess oncology clinicians' attitudes, confidence, and practices in managing opioids in outpatients with cancer. This was explored using pilot-tested, profession-specific surveys for physicians/nurse practitioners, nurses and pharmacists. Descriptive analyses were conducted in aggregate and separately based on discipline. Univariate and multiple linear regression analyses were performed to explore relationships between confidence and practices within and across disciplines. The survey was distributed to approximately 400 clinicians in January 2019. Sixty-five responses (27 physicians/nurse practitioners, 31 nurses, 7 pharmacists) were received. Participants endorsed low confidence, differing attitudes, and limited and varied practice in managing and mitigating opioid risks in the cancer population. This study provides valuable insights into knowledge gaps and clinical practices of oncology healthcare professionals in managing opioids and mitigating associated risks for patients with cancer.
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http://dx.doi.org/10.3390/curroncol28010086DOI Listing
February 2021

Obesity-Associated Myeloid Immunosuppressive Cells, Key Players in Cancer Risk and Response to Immunotherapy.

Obesity (Silver Spring) 2021 Feb 22. Epub 2021 Feb 22.

Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana, USA.

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.
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http://dx.doi.org/10.1002/oby.23108DOI Listing
February 2021

Assessment of Commercial SARS-CoV-2 Antibody Assays, Jamaica.

Int J Infect Dis 2021 Feb 18. Epub 2021 Feb 18.

The University of the West Indies, Department of Microbiology, Kingston, Jamaica, West Indies; Global Virus Network, Baltimore, MD, United States of America. Electronic address:

Background: The performance of the Roche Elecsys® Anti-SARS-CoV-2, Abbott Architect SARS-CoV-2 IgM and IgG, Euroimmun SARS-CoV-2 IgA, Euroimmun SARS-CoV-2 IgG ELISA, and Trillium IgG/IgM rapid assays was evaluated in Jamaica.

Methods: Diagnostic sensitivities of the assays were assessed by testing serum samples from SARS-CoV-2 PCR-confirmed persons and diagnostic specificity was assessed by testing serum samples collected during 2018-2019 from healthy persons and from persons with antibodies to a wide range of viral infections.

Results: Serum samples collected ≥14 days after onset of symptoms, or an initial SARS-CoV-2 RT-PCR positive test for asymptomatics, showed diagnostic sensitivities ranging from 67.9-75.0% when including all possible disease severities and increased to 90.0-95.0% when examining those with moderate to critical disease. Grouping moderate to critical disease showed a significant association with a SARS-CoV-2 antibody positive result for all assays. Diagnostic specificity ranged from 96.7-100.0%. For all assays examined, SARS-CoV-2 real-time PCR cycle threshold (Ct) values of the initial nasopharyngeal swab sample testing positive were significantly different for samples testing antibody positive versus negative.

Conclusions: These data from a predominantly African descent Caribbean population shows comparable diagnostic sensitivities and specificities for all testing platforms assessed and limited utility of these tests for persons with asymptomatic and mild infections.
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http://dx.doi.org/10.1016/j.ijid.2021.02.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891043PMC
February 2021

Commentary: Reoperative cardiac surgery: The importance of surgeon judgment.

J Thorac Cardiovasc Surg 2021 Jan 20. Epub 2021 Jan 20.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pa. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.017DOI Listing
January 2021

In Regard to Nam et al.

Authors:
J Martin Brown

Int J Radiat Oncol Biol Phys 2021 Mar;109(4):1124

Department of Neurology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1016/j.ijrobp.2020.11.028DOI Listing
March 2021

Impact of Thoracic Radiation on Patients Undergoing Cardiac Surgery.

Semin Thorac Cardiovasc Surg 2021 Feb 17. Epub 2021 Feb 17.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh; Heart and Vascular Institute, University of Pittsburgh Medical Center. Electronic address:

Prior thoracic radiation has been associated with worse outcomes after cardiac surgery. This study sought to report long-term outcomes in patients undergoing surgery for radiation-associated heart disease. This was an observational study of open cardiac surgeries from 2011 and 2018. Patients with a history of malignancy that required thoracic radiation were identified, and this cohort was matched against a non-irradiated comparison group via Mahalanobis distance matching. Kaplan-Meier survival estimation and multivariable Cox regression analysis were performed to assess the long-term impact of thoracic radiation in patients undergoing cardiac surgery. Of the 15,284 patients receiving cardiac surgery in this time-frame, 269 were identified with a history of thoracic radiation for prior malignancy. Patients with prior radiation had increased 1-year and 5-year mortality (p<0.001), despite no difference for 30-day mortality (p=0.719), compared to non-irradiated patients. Mahalanobis distance matching yielded 269 equitably matched pairs. On multivariable analysis, patients with prior radiation demonstrated significantly increased hazard of death, as compared to the non-irradiated group (HR 1.40, 95% CI: 1.02, 1.94, p=0.038). Patients with radiation for breast cancer demonstrated a non-significant trend towards reduced hazard of death, as compared to patients with more extensive radiation exposure. There was an increase in long-term mortality in patients with prior radiation undergoing cardiac surgery, however open cardiac surgery can safely be performed in these patients with similar operative mortality. These findings may serve as a useful adjunct in shared decision-making for patients and surgeons alike.
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http://dx.doi.org/10.1053/j.semtcvs.2021.01.008DOI Listing
February 2021

Geospatial assessment of helicopter emergency medical service overtriage.

J Trauma Acute Care Surg 2021 Feb 17. Epub 2021 Feb 17.

Division of Trauma and General Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.

Background: Despite evidence of benefit after injury, helicopter emergency medical services (HEMS) overtriage (OT) remains high. Scene and transfer OT are distinct processes. Our objectives were to identify geographic variation in overtriage, patient-level predictors, and determine if overtriage impacts population-level outcomes.

Methods: Patients ≥16 undergoing scene or interfacility HEMS in the Pennsylvania Trauma Outcomes Study were included. Overtriage was defined as discharge within 24hr of arrival. Patients were mapped to zip code and rates of OT were calculated. Hot spot analysis identified regions of high and low OT. Mixed effects logistic regression determined patient predictors of OT. High and low OT regions were compared for population-level injury fatality rates. Analyses were performed for scene and transfer patients separately.

Results: 85,572 patients were included (37.4% transfers). OT was 5.5% among scene and 11.8% among transfer HEMS (p<0.01). Hot spot analysis demonstrated geographic variation in high and low OT for scene and transfer patients. For scene patients, OT was associated with distance (OR 1.03; 95%CI 1.01-1.06 per 10mi, p=0.04), neck injury (OR 1.27; 95%CI 1.01-1.60, p=0.04), and single-system injury (OR 1.37; 95%CI 1.15-1.64, p<0.01). For transfer patients, OT was associated with rurality (OR 1.64; 95%CI 1.22-2.21, p<0.01), facial injury (OR 1.22; 95%CI 1.03-1.44, p=0.02), and single-system injury (OR 1.35; 95%CI 1.18-2.19, p<0.01). For scene patients, high OT was associated with higher injury fatality rate (coeff 1.72; 95%CI 1.68, 1.76, p<0.01); low OT was associated with lower injury fatality rate (coeff -0.73; 95%CI -0.78, -0.68, p<0.01). For transfer patients, high OT was not associated with injury fatality rate (p=0.53); low OT was associated with lower injury fatality rate (coeff -2.87; 95%CI -4.59, -1.16, p<0.01).

Conclusions: Geographic OT rates vary significantly for scene and transfer HEMS and are associated with population-level outcomes. These findings can help guide targeted performance improvement initiatives to reduce HEMS overtriage.

Level Of Evidence: Epidemiological, Level IV.
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http://dx.doi.org/10.1097/TA.0000000000003122DOI Listing
February 2021

Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.

Blood Cancer Discov 2021 Jan 3;2(1):54-69. Epub 2020 Dec 3.

Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and post-therapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state, and a distinct expression profile together with MBL cells compared to normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically-driven growth dynamics and together with its persistent presence suggests a central role in the normal-to-cancer transition.
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http://dx.doi.org/10.1158/2643-3230.BCD-19-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888194PMC
January 2021

Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1.

ACS Med Chem Lett 2021 Feb 28;12(2):288-294. Epub 2021 Jan 28.

Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Rd, Lawrence Township, New Jersey 08648, United States.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both potency and pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883469PMC
February 2021

Association of step count with PROMIS® pediatric health-related quality of life measures in children and adolescents with persistent asthma.

J Allergy Clin Immunol Pract 2021 Feb 15. Epub 2021 Feb 15.

Department of Population Health Sciences, Duke University School of Medicine, Durham, NC; Department of Pediatrics, Duke University School of Medicine, Durham, NC.

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http://dx.doi.org/10.1016/j.jaip.2021.01.046DOI Listing
February 2021

Thirty-day hospital readmissions following cardiac surgery are associated with mortality and subsequent readmission.

Semin Thorac Cardiovasc Surg 2021 Feb 15. Epub 2021 Feb 15.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh; Heart and Vascular Institute, University of Pittsburgh Medical Center. Electronic address:

To assess the impact of hospital readmission within 30-days of discharge, on long-term postoperative outcomes. All patients who underwent cardiac surgery from 2011 - 2018 were included. Patients who had transcatheter procedures, VAD, and transplant were excluded. Inverse probability of treatment weighting (IPTW) propensity scoring was used for population risk adjustment. Multivariable analysis was performed to identify association with long-term mortality and readmission. The total risk adjusted (propensity scoring with IPTW) patient population consisted of 14,538 patients divided into those who were not readmitted in 30-days (non-readmitted) (n=12,627) and patients who were readmitted within 30-days (30-day readmitted) (n=1911). Following IPTW, all baseline characteristics and postoperative complications were equivalent between cohorts (SMD <0.10). Patients who required intraoperative [OR 1.178 (1.05, 1.32); p=0.006] and postoperative [1.32 (1.18, 1.48); p<0.001] blood transfusions were at greater risk for 30-day readmission. Median follow-up period was 4.19 years (2.45 - 6.10). The 30-day readmission cohort had a significantly higher mortality risk during early (6 months) follow-up [HR 2.49 (2.01-3.10); p<0.001] and late (60 months) follow-up [HR 1.30 (1.16-1.47); p<0.001]. After risk adjustment, the 30-day readmission cohort was significantly associated with increased mortality over the study follow-up period [HR 1.62 (1.48, 1.78); p<0.001]. 30-day readmissions were an independent predictor of subsequent long-term hospital readmission [HR 1.61 (1.50, 1.73); p<0.001]. Patients who require 30-day readmissions following cardiac surgery are at increased risk of long-term mortality and repeat readmissions. Early postoperative hospital readmission may be a marker for worse long-term outcomes in cardiac surgery.
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http://dx.doi.org/10.1053/j.semtcvs.2020.12.015DOI Listing
February 2021

Incremental costs of fragility fractures: a population-based matched -cohort study from Ontario, Canada.

Osteoporos Int 2021 Feb 18. Epub 2021 Feb 18.

Amgen Canada Inc, Mississauga, Ontario, Canada.

Using a matched cohort design, the 1-year excess cost of incident fragility fractures at any site was $26,341 per patient, with 43% of total excess costs attributed to hospitalization. The high economic burden of fractures in Ontario underscores the urgency of closing the secondary fracture prevention gap.

Introduction: This retrospective real-world observational study was conducted to document the incremental costs associated with fragility fractures in Ontario, Canada.

Methods: Patients aged >65 years with an index fragility fracture occurring between January 2011 and March 2015 were identified from administrative databases and matched 1:1 to a cohort of similar patients without a fracture. Healthcare resource utilization data were extracted from healthcare records and associated costs were calculated on a per-patient level and for the province of Ontario. Costs were presented as 2017 Canadian dollars.

Results: The eligible cohort included 115,776 patients with a fragility fracture. Of these, 101,773 patients were successfully matched 1:1 to a non-fracture cohort. Overall, hip fractures (n = 31,613) were the most common, whereas femur fractures (n = 3002) were the least common type. Hospitalization and continuing care/home care/long-term care accounted for more than 60% of 1-year direct costs, whereas 5% was attributed to medication costs. First-year costs per patient in the fracture cohort were approximately threefold higher versus the non-fracture cohort (mean $37,362 versus $11,020, respectively). The incremental first-year direct healthcare costs of fragility fractures for the province of Ontario were calculated at $724 million per year.

Conclusions: Fragility fractures were associated with a threefold increase in overall mean healthcare costs per patient compared to patients without fractures. With an aging population, there is an urgent need for improved prevention strategies for patients at high-risk of fracture to decrease the economic burden of fragility fractures on the Canadian healthcare system.
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http://dx.doi.org/10.1007/s00198-021-05877-8DOI Listing
February 2021