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Complete raw and unedited blots assembly used to determine PPARα expression. | (1) original and (2) inverted files of the full raw unedited alpha tubulin blot. (3) original and (4) inverted files of the full raw unedited PPAR alpha blot. (5) The uncropped blots with the relevant bands are clearly labeled.Exposing primary cells infected with the alpha variant of SARS-CoV-2 to therapeutic concentrations (CSince the online deposition of these initial findings (To demonstrate the role of PPARα-induced fatty acid oxidation in our mechanism, we used etomoxir an irreversible inhibitor of CPT1A a rate-limiting enzyme in the pathway ( | PMC9937660 | ||
Metabolic regulators affect COVID-19 severity and progression | To assess the clinical relevance of these findings we collected a total of 3233 cases of confirmed COVID-19 patients admitted to Hadassah and Ichilov Medical Centers between March 2020 to February 2021. A total of 1156 of these patients (35.8%) were registered with in-hospital use of different metabolic regulators ( | PMC9937660 | ||
The host-immune response in hospitalized COVID-19 patients in different metabolic interventions. | INFLAMMATION, DISEASE PROGRESSION | (Reports suggest that severe COVID-19 is characterized by early inflammation, marked by elevated C-reactive protein (CRP) To track disease progression, we followed changes in CRP during the first 21 days of hospitalization. Data were fitted using locally weighted scatterplot smoothing (Lowess) comparing each drug group to all other high-risk patients that did not take metabolic regulators (n=648; Analysis of an additional observational cohort of 2123 patients examined in the Outpatient Lipid Clinics of the University of Bologna and the Niguarda Hospital in Milan during the last 12 months and on adequately dosed statins, fenofibrate, or both for at least 3 months ( | PMC9937660 | |
Pilot study of prospective administration of nanocrystallized fenofibrate in humans with COVID-19 treated with standard-of-care | respiratory deterioration, pneumonia | PNEUMONIA | To further assess the clinical relevance of our findings, we performed an interventional single-arm clinical study in severe, hospitalized COVID-19 patients, who exhibited respiratory deterioration and severe pneumonia (NCT04661930; | PMC9937660 |
Analysis of variant emergence dynamics and distribution during the study period in participants and other hospitalized patients. | VIRUS, DISEASE, DELETION | (Enrolled participants exhibited a higher prevalence of chronic medical conditions compared to other hospitalized patients admitted with severe COVID-19 during the same period and treated under the same standard-of-care, who were used as historical controls (Dynamic changes in serum levels of CRP and NLR, which mark the immunoinflammatory progression of the disease, also demonstrated favorable trends (Patients treated with nanocrystallized fenofibrate also exhibited lower mortality, lower respiratory intervention rates, and significantly increased withdrawal rate from supplemental oxygen by day 7 (weighed difference of 26.1 percentage points; 95% CI, 7.0–45.2; p=0.003; Novaplex SARS-CoV-2 variant analysis showed a dominant presence of 69/70 deletion and N501Y substitution mutation correlating to the B.1.1.7 (UK) variant of the virus in the patient population ( | PMC9937660 | |
Discussion | inflammation | INFLAMMATION, VIRUS | Viruses are dependent on host metabolism to obtain macromolecules essential for their lifecycle. While metabolic interventions of host pathways offer promise, the current reliance on animal models and cell lines limits our ability to identify targets for intervention due to critical metabolic and genetic differences between animal models, cell lines, and patients. In this work, we utilized primary human cells and clinical samples to chart SARS-CoV-2 metabolic response, to identify metabolic targets that could rapidly translate to the treatment of severe COVID-19.Glycolysis is often upregulated to supply nucleotides for virus replication (Our study demonstrates coordinated changes in lipid metabolism, such as the upregulation of palmitoylation and cholesterol synthesis (Fibrates are a family of amphipathic carboxylic acids that are ligands of PPARα, known to up-regulate lipid oxidation and lower serum triglycerides (Our work shows that several structurally different ligands of PPARα have a similar anti-viral effect (One challenge in the investigation of host metabolic pathways in vitro is the difficulty to study lipid metabolism in proliferating cell lines and stem-cell-derived models (One challenge in the validation of our findings is that hamster models are unresponsive to fibrates (The clinical importance of understanding the role of lipid metabolism in COVID-19 is further emphasized by the negative response induced by thiazolidinediones (TZD) in our study. Thiazolidinediones are ligands of PPARγ that upregulate lipogenesis in certain tissues (To validate our findings, we carried out a prospective non-randomized interventional study of 15 severe hospitalized COVID-19 patients (NCT04661930). Severe COVID-19 patients treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care showed dramatic improvement in inflammation and faster recovery compared to patients admitted during the same period in neighboring hospitals and treated with the same standard of care ( | PMC9937660 |
Clinical limitations | comorbidity | PATHOLOGY, SARS-COV-2 INFECTION, STILL | While our clinical results are highly encouraging, baseline differences between the groups and lack of randomization must be noted. Therefore, confounding and/or random error cannot be excluded. For instance, the higher comorbidity burden in the fenofibrate group may have conditioned a lower threshold for the initial hospital admission, with consequent favorable differences in outcomes relative to controls.In addition, it must be noted that the study controls were assigned from neighboring clinical centers serving the same diverse and mixed ethnic population, as clinical outcomes of non-consenting patients at the Barzilai Medical Center were significantly worse than the treatment group as these patients often refused or had difficulties in adhering to treatment. Thus, the best control that replicated the clinical characteristics of the patients and course of treatment, were patients that were qualified for the study but were not included simply because they were in another local hospital. Standard of care during this time period was identical for all clinical centers in Israel.Our work demonstrates the importance of weaving primary human cells, with clinical samples, and observational data for the rapid clinical translation of new metabolic interventions. Additional work is needed to confirm the specific activation of biochemical pathways and validate our findings in pathology samples. Still, this mechanistic understanding allowed us to design an ad hoc preliminary prospective clinical study and showed significant differences from the control group despite the small number of patients.Our work charts the metabolic response of human lung epithelium to SARS-CoV-2 infection. Our data suggest that the up-regulation of lipid oxidation might be an effective therapeutic target in the treatment of COVID-19. A definitive answer regarding the efficacy of fenofibrate for the treatment of COVID-19 will require the execution of large randomized controlled clinical trials with meaningful clinical outcomes. Two randomized placebo-controlled trials are ongoing, including a large international trial in the US, Mexico, Greece, and several South American countries (FERMIN trial; NCT04517396), and a clinical trial in Israel (FENOC trial; NCT04661930). | PMC9937660 |
Acknowledgements | Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. The authors would like to thank Prof. Benjamin R tenOever and his team at the Icahn School of Medicine for providing viral load quantifications ( | PMC9937660 | ||
Additional information | PMC9937660 | |||
Competing interests | Heart Failure, heart failure, NDD | PCT, HEART FAILURE, HEART FAILURE, HEART, EDWARDS | is registered as an investor in a PCT regarding the use of metabolic regulators for COVID. The author has a patent on the use of PPAR agonists to treat COVID. The author has no other competing interests to declare.No competing interests declared.No competing interests declared.has received personal honoraria for statistical consultation from Recipharm, and personal honoraria for manuscript writing from both Sharper Srl and Fidia Pharmaceuticals. The author has no other competing interests to declare.is President of Fondazione (totally supported by family). The author has no other competing interests to declare.received funding from National Institutes of Health (1R01HL157108-01A1,1R01AG074989-01) . The author has no other competing interests to declare.has received consulting honoraria from Sanifit, Bristol Myers Squibb, Merck, Edwards Lifesciences, Bayer, JNJ, Fukuda-Denshi, NGM Bio, Mayo institute of technology and the University of Delaware, and research grants from the National Institutes of Health, Abbott, Microsoft, Fukuda-Denshi and Bristol Myers Squibb. He has received compensation from the American Heart Association and the American College of Cardiology for editorial roles, and visiting speaker honoraria from Washington University, Emory University, University of Utah, the Japanese Association for Cardiovascular Nursing and the Korean Society of Cardiology. The author is named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of Heart Failure and Preserved Ejection Fraction and for the use of biomarkers in heart failure with preserved ejection fraction. The author has participated on the Advisory board for Bristol-Myers Squibb Data safety monitoring board for studies by the University of Delaware and UT Southwestern, and is Vice President of North American Artery Society. The author has received research device loans from Atcor Medical, Fukuda-Denshi, Unex, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. The author has no other competing interests to declare.is affiliated with BioStats Statistical Consulting Ltd where they work as a Biostatistician. The authors has received payment for statistical work for the manuscript and consulting fees from Tissue Dynamics Ltd. The author has no other competing interests to declare.has received consulting honoraria from Sanofi, Roche and Neopharm, and lectures honoraria from Roche . He is the chairmen of the Israel Association for the study of the liver. The author has no other competing interests to declare.is registered as an investor in a PCT regarding the use of metabolic regulators for COVID and has a patent on the use of PPAR agonists to treat COVID. The author has no other competing interests to declare. | PMC9937660 |
Author contributions | Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing.Data curation, Validation, Investigation, Methodology.Investigation.Investigation.Validation, Investigation, Visualization.Resources, Validation, Investigation.Validation, Investigation.Resources, Validation, Investigation, Methodology.Conceptualization, Software, Validation, Investigation, Methodology.Validation, Investigation.Data curation, Investigation.Resources, Data curation, Investigation.Resources, Data curation, Investigation.Resources, Data curation, Writing – review and editing.Resources, Data curation, Investigation, Writing – review and editing.Resources, Data curation, Investigation, Methodology, Writing – review and editing.Software, Formal analysis, Validation, Visualization, Methodology.Formal analysis, Validation, Investigation.Project administration.Resources, Methodology.Conceptualization, Resources.Resources, Methodology.Conceptualization, Supervision, Validation, Investigation, Methodology.Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing. | PMC9937660 | ||
Ethics | -20 | Clinical trial registration NCT04661930.Human subjects: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. In the observational studies - the Israeli study was approved by the local institutional review board of the Hadassah Medical Center (IRB approval number no. HMO 0247-20) and the local institutional review board of the Ichilov Medical Center (IRB approval number no. 0282-20-TLV). The Italian study was reviewed by the local ethical board (AVEC) of the IRCSS S.Orsola-Malpighi University Hospital (approval number no. code LLD-RP2018). The American study was reviewed by the local institutional review board of the Corporal Michael J. Crescenz VA Medical Center (IRB approval number 01654). The interventional study was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation E6 and the principles of the Declaration of Helsinki or local regulations, whichever afforded greater patient protection. The study was reviewed and approved by the Barzilai Medical Center Research Ethics Committee (0105-20-BRZ). Statistical analysis of the Israeli studies was done by BioStats Statistical Consulting Ltd. (Maccabim, Israel), funded by the sponsor. Data management is performed in compliance with GCP and 21 CFR part 1. Statistical analyses and reporting are performed in compliance with E6 GCP, E9, and ISO 14155. Independently validated by the author. Statistical analysis of the Italian study was done by Prof. Arrigo Cicero and Dr. Chiara Pavanello. Statistical analysis of the US study was done by Prof. Jordana Cohen. | PMC9937660 | |
Additional files | PMC9937660 | |||
Differentially expressed genes (DEG) analysis in SARS-CoV-2 infected human lung epithelium. | LUNG | (Tab 2) Normal bronchial epithelial cells (Tab 3) Lung Biopsies (Tab 4) Small airway (Tab 5-6) Epithelial cells in bronchial alveolar lavage fluid. (Tab 7) Primer list used for qPCR gene expression validations. | PMC9937660 | |
Observational study descriptive statistics. | COPD | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, -11 | (Tab 1-8) Characteristics of COVID-19 patients in the cohort. SBP, systolic blood pressure; DBP, diastolic blood pressure; COPD, chronic obstructive pulmonary disease; SpO2, oxygen saturation; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range. Continuous variables were compared with a two-sample t-test and categorical variables with Fisher’s exact test. (Tab 9-11) Observational comparison between unique patients' visits to Hadassah Medical Center taking metabolic regulators and unique patients in various hospitalization conditions in patients with COVID-19 taking metabolic regulators in different periods. Patients taking thiazolidinediones (n=37; | PMC9937660 |
International comparative validation cohorts descriptive statistics. | (Tab 1) Comparative Cohort of the Outpatient Lipid Clinics of the University of Bologna and of the Niguarda Hospital in Milan. (A) Characteristics of included patients stratified by lipid-lowering treatment. A cohort of 2,123 patients (M: 48.1%, F: 51.9%) on statins (1,791, mean age 59.2±15.2 years), fenofibrate (220, mean age 60.7±15.4 years) or both (112, mean age 62.9±16.3 years) were interviewed. Patients on statins were significantly younger than those on both drugs ( | PMC9937660 | ||
Interventional study descriptive statistics. | obesity, DM, chronic kidney disease, fever, cough, asthma, low immunoinflammatory stress, dyslipidemia, COPD, diabetes | OBESITY, CORONARY HEART DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, ASTHMA, DYSLIPIDEMIA, REGRESSION, HYPERTENSION, CEREBROVASCULAR DISEASE, CHRONIC LIVER DISEASE, DIABETES | (Tab 1) Characteristics of patients compared in the patients in the interventional study 15 Participants who met the inclusion criteria were assigned to intervention with nanocrystallized fenofibrate (TriCor, AbbVie Inc, North Chicago, IL USA) at a dose of 145 mg (1 tablet) once per day. Standard care for severe-hospitalize COVID-19 patients was provided according to local practice: antiviral treatment, vitamin D3, low-dose glucocorticoids, convalescent plasma, and supportive care as well as antipyretic for symptoms of fever (products containing paracetamol, or non-steroidal anti-inflammatories such as aspirin and ibuprofen) and dextromethorphan for symptoms of cough. Standard chronic treatments were continued unless COVID-19, clinical status, or fenofibrate treatment was a counterindication for the treatment. Control patients were collected from the observational study’s database and filtered to patients that meet the inclusion criteria, were admitted with low immunoinflammatory stress (NLR <10 at admission), and were treated according to the standard care used in the interventional study. SBP, systolic blood pressure; DBP, diastolic blood pressure; COPD, chronic obstructive pulmonary disease; SpO2, oxygen saturation; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range. Continuous variables were expressed as median [IQR] and were compared with a Mann-Whitney U test. Categorical variables were expressed as a count and percentage (%) and compared with a chi-squared test or Fisher’s exact test. The sample size is detailed in each display item. (Tab 2) Cox regression model of 28-days mortality in the treatment group versus control. Adjusted HR and p-values were calculated based using an unadjusted Cox regression model, a Cox regression model adjusting for age, gender, and pre-existing comorbidities (smoking, asthma, COPD, DM, hypertension, diabetes, coronary heart disease, obesity, dyslipidemia, cerebrovascular disease, chronic liver disease, and chronic kidney disease) or a Cox regression model adjusting for significantly different patient characteristics, obesity, chronic kidney disease, and SpO2. ( | PMC9937660 |
Strengthening the reporting of observational studies in epidemiology (STROBE) reporting standards used in the observetional studies. | PMC9937660 | |||
Consolidated Standards of Reporting Trials (CONSORT) reporting standards used in the interventional studies. | PMC9937660 | |||
Data availability | Software resources: Our custom Cell Analysis CellProfiler Pipeline is available on The following previously published datasets were used:
| PMC9937660 | ||
References | SARS-CoV-2 infection, toxicity, inflammation, primary lung bronchiole, deaths | VIRUS, SARS-COV-2 INFECTION, INFLAMMATION, DISEASE, VIRAL INFECTION, PATHOGENESIS | In this study, a metabolism-related drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both α and δ variants. Patients taking fibrates displayed significantly lower markers of inflammation and experienced faster recovery from disease. The data offer significant support for the concept that PPARα should be considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete studies of fenofibrate in large randomized controlled clinical trials.In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.
Thank you for submitting your article "Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1) Please articulate if there was a "reagent control" for the PPARalpha KO experiments, and provide such control data if available.2) Please provide information available relating to mechanisms that are at play in how the virus is mediating the metabolic effects or the proteins involved in this process.
The authors performed RNA-Seq on primary bronchial and small airway epithelial cells that had been challenged in the lab with SARS-CoV-2, as well as lung biopsies and bronchoalveolar lavage from COVID-19 patients. All four groups showed enrichment for genes in lipid and carbohydrate metabolism, with increases in expression of genes encoding rate-limiting enzymes in glycolysis and the synthesis of fatty acids and cholesterol, increase in ER stress, and decreased expression of lipid catabolism genes. Based on these findings the authors hypothesized that interventions which decrease ER stress or increase lipid catabolism would inhibit SARS-CoV-2 replication. The authors then examined the effect of five drugs that block lipid metabolism and found that fenofibrate significantly decreased viral load without obvious toxicity. Since fenofibrate is a PPARa agonist, and it has been reported to block SARS-CoV-2 via direct effects on Spike and ACE2, other PPARa agonists were tested and also shown to inhibit SARS-CoV-2. The mechanistic importance of PPARa was supported by the finding that PPARa knockout, and Etoxomir, a drug which blocks a downstream target of PPARa, both blocked the antiviral effect of fenofibrate.To follow up their lab observations, hospital records for people with COVID-19 were examined for association of clinical outcomes with the use of fibrates and other drugs including metformin, SGLT2 inhibitors, thiazolidinediones, statins, and IRE1a inhibitor. COVID-19 patients taking fibrates were underrepresented among hospitalizations, ICU admissions, and deaths. Among people hospitalized with COVID-10, CRP and neutrophil:lymphocyte ratio normalized faster and survival probability was far better with fibrates than with any other of the drugs. This study was done in Israel and complementary observational data was obtained at sites in Italy and in the US.Finally, in a small clinical trial, fenofibrate was given to 15 patients admitted to hospital with severe COVID-19 and outcomes were compared to historical controls. Patients treated with fenofibrate had shorter hospitalization, were more likely to be discharged within 28 days, had lower rate of ICU admission, and CRP and neutrophil:lymphocyte ratio were significantly improved. While this was a small trial, and it was not a randomized trial, these preliminary results are exciting and provide optimism that the larger clinical trials currently in place will confirm the findings here.This very interesting paper presents a well-designed set of experiments that convincingly show the importance of PPARalpha for SARS-CoV-2 replication and pathogenesis, and for the utility of currently approved PPARalpha agonists in the treatment of severe COVID-19.
In this work, the authors use multiple tools to evaluate their hypothesis, which includes in vitro studies of primary lung bronchiole and small airway epithelial cells, observational studies of more than 3,000 patients, comparative epidemiological analysis from cohorts in Italy and the Veterans Health Administration in the United States, and prospective non-randomized interventional open-label study.The work follows the hypothesis that the metabolic pathway has a significant role in the SARS-CoV-2 viral infection. The authors did extensive work to validate their hypothesis, which resulted in a clinical trial, which seems to be successful and reduces significantly the severity of SARS-CoV-2 infection.This is a very important study, as it is: 1. Tackle a significant clinical issue (Covid-19) and offer a potential treatment to reduce its severity. 2. Demonstrate an example of a scientific process that starts as an in vitro study, goes throw an observational one, and ends in a clinical trial. 3. Offers a potential mechanism of action for the SARS-CoV-2.Overall, I think that this is a very strong study with significant relevance, and I would strongly recommend accepting it.There are some points that I think could strengthen the work (although it is very extensive):1. As the paper focus on the metabolic effect of SARS-CoV-2, it could be a nice addition if the authors could pinpoint how the virus (or which set of proteins) is modulating the metabolic effect.2. In the observational data (Figure 3) the authors show that thiazolidinedione (TZD) produces a negative effect. It would be nice to elaborate on this point, as the action mechanism if this drug is related to the activation of PPARgama, which is related to similar metabolic pathways that were mentioned in this study.Reviewer #1 (Recommendations for the authors):The authors performed RNA-Seq on primary bronchial and small airway epithelial cells that had been challenged in the lab with SARS-CoV-2, as well as lung biopsies and bronchoalveolar lavage from COVID-19 patients. All four groups showed enrichment for genes in lipid and carbohydrate metabolism, with increases in expression of genes encoding rate-limiting enzymes in glycolysis and the synthesis of fatty acids and cholesterol, increase in ER stress, and decreased expression of lipid catabolism genes. Based on these findings the authors hypothesized that interventions which decrease ER stress or increase lipid catabolism would inhibit SARS-CoV-2 replication. The authors then examined the effect of five drugs that block lipid metabolism and found that fenofibrate significantly decreased viral load without obvious toxicity. Since fenofibrate is a PPARa agonist, and it has been reported to block SARS-CoV-2 via direct effects on Spike and ACE2, other PPARa agonists were tested and also shown to inhibit SARS-CoV-2. The mechanistic importance of PPARa was supported by the finding that PPARa knockout, and Etoxomir, a drug which blocks a downstream target of PPARa, both blocked the antiviral effect of fenofibrate.To follow up their lab observations, hospital records for people with COVID-19 were examined for association of clinical outcomes with the use of fibrates and other drugs including metformin, SGLT2 inhibitors, thiazolidinediones, statins, and IRE1a inhibitor. COVID-19 patients taking fibrates were underrepresented among hospitalizations, ICU admissions, and deaths. Among people hospitalized with COVID-10, CRP and neutrophil:lymphocyte ratio normalized faster and survival probability was far better with fibrates than with any other of the drugs. This study was done in Israel and complementary observational data was obtained at sites in Italy and in the US.Finally, in a small clinical trial, fenofibrate was given to 15 patients admitted to hospital with severe COVID-19 and outcomes were compared to historical controls. Patients treated with fenofibrate had shorter hospitalization, were more likely to be discharged within 28 days, had lower rate of ICU admission, and CRP and neutrophil:lymphocyte ratio were significantly improved. While this was a small trial, and it was not a randomized trial, these preliminary results are exciting and provide optimism that the larger clinical trials currently in place will confirm the findings here.Thank you. The reviewer’s remarks are much appreciated.Reviewer #2 (Recommendations for the authors):In this work, the authors use multiple tools to evaluate their hypothesis, which includes in vitro studies of primary lung bronchiole and small airway epithelial cells, observational studies of more than 3,000 patients, comparative epidemiological analysis from cohorts in Italy and the Veterans Health Administration in the United States, and prospective non-randomized interventional open-label study.The work follows the hypothesis that the metabolic pathway has a significant role in the SARS-CoV-2 viral infection. The authors did extensive work to validate their hypothesis, which resulted in a clinical trial, which seems to be successful and reduces significantly the severity of SARS-CoV-2 infection.Thank you. The reviewer’s remarks are much appreciated.This is a very important study, as it is: 1. Tackle a significant clinical issue (Covid-19) and offer a potential treatment to reduce its severity. 2. Demonstrate an example of a scientific process that starts as an in vitro study, goes throw an observational one, and ends in a clinical trial. 3. Offers a potential mechanism of action for the SARS-CoV-2.Overall, I think that this is a very strong study with significant relevance, and I would strongly recommend accepting it.There are some points that I think could strengthen the work (although it is very extensive):1. As the paper focus on the metabolic effect of SARS-CoV-2, it could be a nice addition if the authors could pinpoint how the virus (or which set of proteins) is modulating the metabolic effect.We thank the reviewer for their comments. We now include a wide metabolic analysis displaying the metabolic outcome of different viral proteins expression in primary cells. We show that a subset of viral proteins cause lipid accumulation (Figure 2H), inhibits PPARα activity (Supp. Figure S2) and lipid oxidation (Figure 2G) and upregulates SARS-CoV-2 related immunoinflammatory markers (Figure 2I, Supp. Figure S2).2. In the observational data (Figure 3) the authors show that thiazolidinedione (TZD) produces a negative effect. It would be nice to elaborate on this point, as the action mechanism if this drug is related to the activation of PPARgama, which is related to similar metabolic pathways that were mentioned in this study.We thank the reviewer for their comments. We show lipid accumulation induced by PPARγ agonist rosiglitazone, increases immunoinflammatory markers in primary lung epithelial cells (Supp. Figure S7). | PMC9937660 |
Background | T2D, type 2 diabetes | TYPE 2 DIABETES | The objective was to test the efficacy of a scalable, virtually delivered, diabetes-tailored weight management program on glycemic control in adults with type 2 diabetes (T2D). | PMC10079927 |
Methods | This was a single arm, three-site clinical trial. Participants had baseline HbA1c between 7–11% and BMI between 27–50 kg/m | PMC10079927 | ||
Results | Participants ( | PMC10079927 | ||
Conclusions | The scalable, virtually delivered T2D-tailored weight management program had favorable and clinically meaningful effects on glycemic control, body weight, and psychosocial outcomes. | PMC10079927 | ||
Subject terms | PMC10079927 | |||
Introduction | T2D, Diabetes | DISEASE, TYPE 2 DIABETES, DIABETES | Diabetes is a debilitating, deadly, and costly disease [The American Diabetes Association (ADA) Standards of Care underscore the multiple benefits of weight management in the effective management of type 2 diabetes (T2D) [While clinic-based lifestyle interventions that reduce both weight and HbA1c are the most studied [ | PMC10079927 |
Methods | T2D | This single-arm, three-site trial included Pennington Biomedical Research Center in Baton Rouge, LA, University of Florida in Gainesville, FL, and Virginia Commonwealth University in Richmond, VA. All participants were given verbal and written explanations about the study, provided written informed consent, and received incentives for data collection visits ($50 at 0 and 12 weeks, $125 at 24 weeks). Participants were recruited in cohorts, ranging from 7 to 31 participants (mean Participants had a reported diagnosis of T2D, were 18–70 y, objectively measured HbA1c between 7–11% and Body Mass Index (BMI) 27–50 kg/m | PMC10079927 | |
Statistical analyses | SECONDARY | Analyses adhered to the intent-to-treat principle; missing data were accounted for using maximum likelihood estimation. General linear mixed effect models adjusted for sex were used to evaluate changes over time in HbA1c and secondary outcomes (including percent change) at baseline, 12, and 24 weeks. Results are presented as mean±standard errors or overall percentages. Testing of differences employed either | PMC10079927 | |
Power calculation | T2D | The sample size calculation was based on a previous WW study with T2D participants that found a 0.6 ± 1.4% decrease in HbA1c at 6 months [ | PMC10079927 | |
Results | The flow of participants from initial screening through week 24 is shown in Fig. | PMC10079927 | ||
Discussion | weight loss, diabetes distress, diabetes | DIABETES | The WW virtual weight loss and wellness program tailored for diabetes resulted in HbA1c reductions and improvements in diabetes distress similar to in-person trials [ | PMC10079927 |
Limitations | weight loss | REGRESSION | These promising results await replication in a randomized controlled trial. While it is possible that the observed effects were simply a regression to the mean, the baseline A1c of <8 suggest this is less likely. It is also unlikely that a nearly 6% weight loss occurs spontaneously in the absence of a structured weight management program. | PMC10079927 |
Acknowledgements | We are grateful for the PBRC cores including intervention resources (IR), clinical chemistry, and medical records for assisting with the completion of this work. | PMC10079927 | ||
Author contributions | TB | JWA, JGL, SDA, FLG, TB, and GDF contributed to the development of the study concept and design. All authors contributed to data acquisition and interpretation. RAB performed the analysis. JWA and MIC contributed to drafting of the manuscript. All authors contributed to critical revision of the manuscript of important intellectual content. JWA is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10079927 | |
Funding | This work was funded by WW International, Inc. | PMC10079927 | ||
Competing interests | JWA: Grants NIH NIDDK and NIMHD, NSF, and USDA. JGL: Grants NIH NIDDK. FLG: Consultant: Ed Med Resources, NovMeta Pharma, GNC, Basic Research, Scientific Advisory Board: Altimune, Pfizer, Nutraceutical Corporation, Stock/stock options: UR Labs, Plensat, Ketogenic Health Systems, Slim Health Nutrition, Energesis, Rejuvenate Bio, Patents: Melior Discoveries (Tolimidone/menthol). Grants: NovMeta Pharma. GDF: Employee and Shareholder at WW. MIC: Grants: National Institute of Health NHLBI and NIDDK. Stock/Stock Options: WW International, Inc. Employee at WW International, Inc. The authors declare no other competing interests. | PMC10079927 | ||
References | PMC10079927 | |||
Purpose | fractures | Tibial shaft spiral fractures and fractures of the distal third of the tibia (AO:42A/B/C and 43A) frequently occur with non-displaced posterior malleolus fractures (PM). This study investigated the hypothesis that plain X-ray is not sufficient for a reliable diagnosis of associated non-displaced PM fractures in tibial shaft spiral fractures. | PMC10728229 | |
Methods | fractures | 50 X-rays showing 42A/B/C and 43A fractures were evaluated by two groups of physicians, each group was comprised of a resident and a fellowship-trained traumatologist or radiologist. Each group was tasked to make a diagnosis and/or suggest if further imaging was needed. One group was primed with the incidence of PM fractures and asked to explicitly assess the PM. | PMC10728229 | |
Results | fracture, fractures | Overall, 9.13/25 (SD ± 5.77) PM fractures were diagnosed on X-ray. If the posterior malleolus fracture was named or a CT was requested, the fracture was considered “detected”. With this in mind, 14.8 ± 5.95 posterior malleolus fractures were detected.Significantly more fractures were diagnosed/detected (14 vs. 4.25/25; The inner-rater reliability was high with 91.2% agreement. Inter-rater reliability showed fair agreement (Fleiss-Kappa 0.274, | PMC10728229 | |
Conclusion | fractures | Only 17% of PM fractures were identified on plain X-ray and awareness of PM only improved diagnosis by 39%. While experiencing improved accuracy, CT imaging should be included in a comprehensive examination of tibial shaft spiral fractures. | PMC10728229 | |
Level of evidence | II. Diagnostic prospective cohort study. | PMC10728229 | ||
Trail registration number | DRKS00030075. | PMC10728229 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10728229 | ||
Background | fracture, dislocation, postoperative instability, fractures, Fractures | POST-TRAUMATIC OSTEOARTHRITIS, INTRAOPERATIVE COMPLICATIONS, SECONDARY | Concomitant fractures of the posterior malleolus (PM) typically occur in distal tibia fractures (Arbeitsgemeinschaft für Osteosynthesefragen Classification; AO:43A) and especially in spiral fractures of the tibial shaft (AO:42/43A) with a fracture line extending from proximal-lateral to distal-medial in the anterior–posterior (AP) view (type A). The incidence of concomitant PM fractures in tibial shaft fractures type A has been cited to be greater than 50%, and importantly, not all of them were detected preoperatively [Although the occurrence of PM fractures in tibial shaft spiral fractures is now well established, there is no evidence that plain X-ray imaging is sufficient to rule out additional PM fractures. This is clinically relevant—especially for tibial shaft fractures with a high risk of additional PM fractures—to avoid unnecessary radiation, but at the same time not to overlook any PM fractures. Missed PM fractures can lead to intraoperative complications such as secondary dislocation as well as postoperative instability and post-traumatic osteoarthritis. Fractures with an increased risk of PM involvement have already been described several times in the literature [The management of fractures of the PM is currently changing. Several recent publications suggest that surgical fixation—even of small fragments—is important for restoring the articular surface, the fibular notch and trans-syndesmotic stability [This study investigated the hypothesis that plain X-ray is not sufficient for a reliable diagnosis of associated non-displaced PM fractures in tibial shaft spiral fractures. | PMC10728229 |
Material and methods | trauma, fracture, fractures, Trauma, Fractures | SECONDARY, PATHOLOGICAL FRACTURES | 50 plain X-rays of patients from the emergency department (ER) of a Level I Trauma Center with tibial shaft fractures (AO:42A/B/C and 43A) were prospectively evaluated by different physicians. 25 of the 50 patients had an additional fracture of the posterior malleolus. To avoid a selection bias, the last 25 patients admitted to the ER at a Level I Trauma Center meeting the inclusion criteria were used as the study sample for each group (25 tibial shaft fractures with additional PM fractur and 25 tibial shaft fractures without additional fractures; date of data collection: April 1, 2021). Mean age was 47.1 ± 20.0 years old (min. 18, max. 92).All X-rays were initially screened by a specialist in trauma surgery and a specialist in radiology, who independently assessed the images based on the inclusion and exclusion criteria. Tibial shaft fractures were included if there was no direct joint involvement and both plain X-ray and CT imaging of the ankle were available. Fractures without direct joint involvement were defined as all fractures where the main/obvious fracture does not affect a joint. CT imaging was used to confirm the presence of a PM fracture. If both specialists agreed, the diagnosis (PM fracture or no PM fracture) was regarded as certain and used as a basis for the subsequent evaluation of the plain X-ray images. Pathological fractures, open fractures, multiple trauma, imaging of insufficient quality and children under 18 years of age were excluded. The patient data (name, date of birth) were irreversibly anonymized and replaced by numerical codes on all research materials.The selected plain X-rays (at least one AP and one lateral view of sufficient quality) were evaluated by two groups of physicians. Each group consisted of a radiological resident and a senior physician, as well as a trauma surgery resident and a senior physician. All residents had at least three years of professional experience. The assessing physicians did not have access to the CT imaging. All examinations were carried out at the physicians' daily workplaces.The first group (group 1) was unaware of the previous study describing the incidence of concomitant posterior malleolus fractures in type A fractures as the analysis was carried out before the study results were published (January 2022). All physicians were asked to provide a full diagnosis for all patients and to request further imaging if necessary. Only the trauma surgeons were specifically tasked with recommending appropriate treatment options in addition.The second group (group 2) was explicitly informed of the results of the preliminary studies and asked explicitly about a fracture of the posterior malleolus. Again, this group could request additional imaging if necessary and the surgeons could suggest treatment options. In this group, the examination of the same radiographs was repeated in a different order after 4–6 weeks.To avoid bias, all physicians were only asked for additional CT-imaging necessary to make the diagnosis, not for surgical planning.The primary outcome was the correct diagnosis of accompanying PM fractures in plain X-rays and the secondary outcome was the preoperative detection of accompanying PM fractures. A PM fracture was considered as detected if it was diagnosed in plain X-ray or a CT showing the ankle was requested or both (CT requests for surgical planning were not counted).All statistical testing was carried out with Jamovi 2.2.5 (jamovi.org) and for Fleiss’ kappa with SPSS 28 (IBM Germany). Descriptive statistics were presented as mean ± standard deviation. The Fleiss’ kappa and Cohen’s kappa are both statistical measures used to assess the level of agreement between multiple raters. [The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The use of patient data was allowed by the local Ethics Committee. | PMC10728229 |
Results | fracture, fractures | SENSITIVITY | Overall, an average of 9.13 ± 5.77 of the 25 (36.5%) posterior malleolus fractures were correctly diagnosed. In group 1 (no awareness) 4.25 ± 3.77, in group 2 (increased awareness) 14 ± 0 were diagnosed. This was statistically significant (Sensitivity for detecting additional PM fractures in plain X-rays was 0.17 in group 1 and 0.56 in group 2 with a specificity of 0.98 (group 1) and 0.90 (group 2; overall sensitivity 0.365, specificity 0.94) (see Table Summary of PM fractures diagnosed in plain X-rays“Diagnosed PM fractures” refers to the 25 patients with addition PM fracture in the CT imaging. “False positive” refers to the 25 patients without a PM fractur in the CT imaging. **Indicates highly significant values. *Indicates significant valuesPreoperative detection of additional fractures of the posterior malleolus is clinically relevant. In the following, a fracture of the posterior malleolus was considered "detected" if it was either diagnosed by plain X-ray or a CT showing the ankle joint was requested based on the available X-ray (or both). Due to the high sensitivity of CT imaging, it was assumed that all additional fractures of the PM would have been detected on CT.Considering this, an average of 14.8 ± 5.95 of 25 posterior malleolus fractures were detected. Statistically significantly more additional PM fractures were detected in group 2 (increased awareness) (10.5 ± 5.80 in group 1 vs. 19.0 ± 0.82 in group 2; Summary of the additional PM fractures that would have been detected before surgery (diagnosed fractures in plain X-ray or (/and) for diagnostic purpose requested CT imaging showing the ankle joint based on the plain X-ray)**Indicates highly significant valuesSenior physicians recognized slightly more accompanying PM fractures than residents (residents: 13.0 ± 7.79; senior physicians 16.5 ± 3.70; Summary of the additional PM fractures that would have been detected before surgery divided by level of training and specialty* indicates significant valuesTable Overview of patients (#1–25; first column) with additional fractures of the posterior malleolusThe last column indicates whether the fracture of the posterior malleolus was surgically stabilized (screw fixation; Y = Yes; N = No). The remaining columns show the individual physicians results in the first survey. Y = posterior malleolus fracture detected, i.e. the fracture was described or CT imaging showing the ankle was requested. N = the fracture was not named and no CT imaging was requested. R-X-X = resident; S-X-X = senior physician; X-S-X = surgery; X-R-X = radiology; X-X-1 = group 1; X-X-2 = group 2The inner-rater-reliability (the same examiner assesses the same X-ray images a second time) for detection of an additional fracture in group 2 from the first to the second assessment showed a high absolute agreement of 91.2% in average (max. 100%, min. 76%). Cohen’s kappa was calculated for all examiners and showed “moderate” to “almost perfect” agreement (0.534–0.907; The inter-rater-reliability for all physicians (8 examiners) for the first review indicated “fair” agreement for diagnosed (Fleiss’ kappa = 0.292, Divided into groups, group 1 (no previous knowledge) showed a fair agreement (Fleiss’ kappa = 0.234, | PMC10728229 |
Discussion | trauma, fracture, dislocation, fractures, bimalleolar fractures, Fractures | SECONDARY | The results show that based on plain X-rays only it was not possible to rule out accompanying PM fractures in tibial shaft fractures with certainty. Although increased awareness led to a significant improvement in sensitivity (0.17 vs. 0.56), it was still not possible to achieve the required reliability for responsible patient treatment.There are several studies indicating high incidences of additional PM fractures in tibial shaft fractures (25–50%) [The figures show an example of the X-ray and CT images of a patient with a tibial shaft spiral fracture type A with fracture of the posterior malleolus. CT images were not available for the examiners. Additional screw osteosynthesis of the posterior malleolus was performed in this patientNo study has dealt with the reliability of X-ray in identifying these fractures and investigated the impact of previous knowledge, awareness, specialization and level of training on diagnostic accuracy. The present study closes this gap in the literature and shows that plain X-ray imaging is not sufficient to ensure a reliable diagnosis of tibia shaft fractures with a high risk of associated PM fractures—regardless of the examiner. Even with advanced awareness of additional PM fractures, 20% (5/25) of the additional PM fractures in tibial shaft spiral fractures—especially in type A fractures [Fractures with a high risk of PM involvement are primarily spiral fractures and fractures in the distal third of the tibia [Bouche et. al. compared the detection rates of PM fractures in bimalleolar fractures on plain X-ray or CT in a retrospective study. In this study, both, the plain X-rays and the CT scans, were evaluated by 2 surgeons for the presence of a PM fracture twice with an interval of 6 weeks. Similar to the present study, significantly fewer PM fractures were detected on X-rays (35/60 in X-ray vs. 53/60 in CT) and the interrater-reliability on plain X-rays was in a comparable range with a kappa of 0.39 (0.292 in our study). These results support the present results of the current study in that PM fractures cannot be excluded with certainty in the plain X-ray. However, compared to the present study, the study refers to ankle fractures and there were fewer examiners (2 vs. 8) [Furthermore, there is further evidence that the size of the fragments in PM fractures cannot be adequately judged on plain X-rays and that there is poor interrater reliability for these fractures (in plain X-rays) [There are no standardized treatment guidelines for fractures of the PM, however, the size of the PM has been a classic indication of internal fixation. Recent studies suggest that other fracture factors may be more important clinically [In the patient population of the present study, in which preoperative CT imaging was available for all patients, all PM fractures large enough for screw osteosynthesis were fixated internally. Of these fractures, there were 2/17 fractures requiring surgical fixation that would not have been recognized preoperatively by all 8 experienced examiners in their daily routine (see Table In addition, the presence of a fracture of the posterior malleolus is essential for surgical planning as the insertion of an intramedullary nail can result in secondary dislocation of the posterior malleolus. To avoid this, it must either be fixed with screw osteosynthesis beforehand or plate osteosynthesis must be used instead of the intramedullary nailing.Despite the known accumulation of PM fractures in tibial shaft spiral fractures type A and distal tibial fractures, the indication and planning of the surgery are usually carried out without CT imaging on the basis of plain X-rays. Therefore it can be assumed that the PM fractures that are overlooked and not treated in everyday care occur even more frequently here than in ankle fractures, where preoperative CT scans are more common. Due to the ongoing trend towards earlier mobilization and weight bearing in recent years, the reliable detection and surgical fixation of additional PM fractures is becoming increasingly important [The present study has some limitations. There are previous publications demonstrating the coincidence of PM fractures in tibial shaft fractures, so the “no awareness” group maybe had some awareness for PM fractures [However, in our opinion, these limitations do not affect the key statement, that plain X-ray imaging is not sufficient for comprehensive diagnosis of accompanying PM fractures in tibial shaft fractures.The strengths of the study are its prospective design, the inclusion of radiologists and trauma surgeons, and the comparison of different levels of training. In conjunction with the incidences of fractures of the posterior malleolus in tibial shaft fractures described in the literature, we recommend preoperative CT imaging for all tibial shaft spiral fractures—especially with a fracture path in the AP X-ray extending from proximal-lateral to distal-medial (type A)—and all tibial fractures in the distal third. | PMC10728229 |
Conclusion | fracture, fractures | Concomitant fractures of the posterior malleolus in tibial shaft fractures were not reliably detected in plain X-rays, regardless of physicians’ specialty or level of training. Awareness of the frequency of these additional fractures in tibial shaft spiral fractures with a course from proximal-lateral to distal-medial in the AP X-ray (type A) leads to a significantly higher detection rate, but also to a more frequent misdiagnosis in the absence of a fracture of the posterior malleolus. None of the investigators could reach a satisfactory level of certainty in the detection of concomitant posterior malleolus injuries in plain X-rays. Consequently, plain X-ray imaging is not sufficient for the diagnosis of tibial shaft spiral fractures.
| PMC10728229 | |
Abbreviations | ANTERIOR | Anterior–posterior X-rayComputed tomographyEmergency roomMaximumMinimumPosterior MalleolusVersus | PMC10728229 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10728229 | ||
Data availability | The datasets used and analysed during the study are available from the corresponding author on reasonable request. | PMC10728229 | ||
Declarations | PMC10728229 | |||
Ethics Committee approval | LUDWIG | Ethics Committee of the Ludwig Maximilians University in Munich. (Project Nr.: 21-0301). | PMC10728229 | |
References | PMC10728229 | |||
Background | The adoption of digital health technologies can improve the quality of care for polypharmacy patients, if the underlying complex implementation mechanisms are better understood. Context effects play a critical role in relation to implementation mechanisms. In primary care research, evidence on the effects of context in the adoption of digital innovation for polypharmacy management is lacking. | PMC10294464 | ||
Study aim | This study aims to identify contextual factors relevant to physician behavior and how they might mediate the adoption process. | PMC10294464 | ||
Methods | The physicians who participated in this formative evaluation study ( | PMC10294464 | ||
Results | The key dimensions of a (1) context-mechanism-outcome model were mapped and refined. A (2) latent construct of the physicians’ innovation beliefs related to the effectiveness of polypharmacy management practices was identified. Innovation beliefs play a (3) mediating role between the organizational readiness to implement change ( | PMC10294464 | ||
Conclusion | Physician adoption is directly affected by the readiness of primary care organizations for the implementation of change. In addition, the mediation analysis revealed that this relationship is indirectly influenced by primary care physicians’ beliefs regarding the effectiveness of digital innovation. Both individual physician beliefs and practice organizational capacity could be equally prioritized in developing implementation strategies. The methodological approach used is suitable for the evaluation of complex implementation mechanisms. It has been proven to be an advantageous approach for formative evaluation. | PMC10294464 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12875-023-02081-x. | PMC10294464 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10294464 | ||
Background | The implementation of digital health technologies is expected to improve the quality of care and simplify clinical actions [Research has already been conducted on a number of technology-related factors, including the interoperability of new technologies with existing practice systems [As part of the digital transformation of the German healthcare system, we sought to understand the complex implementation mechanisms that lead to the adoption of a digital innovation for polypharmacy management. Therefore, this formative evaluation study within the cluster-randomized controlled trial (cRCT) project “Application of a Digitally Assisted Pharmacotherapy Management System” (AdAM project—original German acronym for the project), was designed to analyze individual and organizational contextual factors related to implementation mechanisms [Our research questions were the following:
What are the possible implementation mechanisms by which digital innovation for polypharmacy management results in intended outcomes?How and in what context does the digital innovation work for primary care physicians? | PMC10294464 | ||
Theoretical framework | Although it is important to identify influential technology-related factors to analyze the complex implementation mechanisms of a digital innovation, these factors were not sufficient as explanatory variables for our theoretical framework. In our study design, we define complexity in terms of both the different levels of the social system in which an innovation is implemented and the influences of the context itself. In particular, the interaction of these factors in implementation mechanisms can be considered complex and the results unpredictable.Therefore, disaggregating the different levels of the social system of primary care organizations was an important prerequisite to make the study of the complexity of implementation mechanisms more manageable for data analysis. In a subsequent step, the disaggregation enabled us to analyze how the inhibiting or facilitating contextual factors at the different levels influence adoption [ | PMC10294464 | ||
Barriers and facilitators to adoption | Empirically studied implementation barriers and facilitators found in the initial literature search were categorized as follows:
Meso level: Research on organizational determinants that affect adoption include numerous topics, such as organizational culture; organizational readiness for change; networks and communication (collaboration and teamwork); resources (financial, education, and training); and leadership [Micro level: The technology acceptance model (TAM) has been widely used as a research model since the 1980s to study the behavior-related micro-level determinants of adoption during the IT implementation process [ | PMC10294464 | ||
Context in implementation research: a new approach | In addition to the empirically observed organizational and behavioral determinants, we examined the current state of research on context in implementation research [Context is defined as “the relational and dynamic features that shape the mechanisms through which the intervention operates; context is assumed to be dynamic and emerge over time at several different levels of the social system” [Advanced empirical research is needed to understand the unresolved causal relationships between the contextual characteristics of implementation and the adoption of new and complex practices [For this purpose, already confirmed general concepts from implementation and complexity research, health services research, and technology acceptance research can be integrated to generate empirically testable research models [ | PMC10294464 | ||
Methods | CMO | Thus, the paradigm of context in (1) realist approaches is situated scientifically and analytically between positivist and constructivist approaches. The goal is to discover semi-predictable patterns related to contexts, underlying generative mechanisms, and outcomes (CMO), and to develop middle-range theories related to the object of study [We then used the (2) belief elicitation approach to develop a contextualized latent scale. This data-driven approach allows the contextualization of behavior-related assumptions for a particular setting, population, or new behavior of interest [Regarding our research questions, we assumed that the (3) structural relations between meso and micro levels in participating primary care organizations should be differentiated in the structural equation model. Two objectives were pursued for empirical investigation: (a) to explain the influence of an organization-related variable on the implementation mechanism and the outcome of implementation (adoption) and (b) to examine the mediating effect of physicians’ contextualized innovation beliefs. Relevant constructs were operationalized for different levels of the organization to enable the mediation model to explain the complex implementation pathways. Testable hypotheses were generated based on the different methodological and analytical steps applied. | PMC10294464 | |
Data collection and research design | CMO | MAY | We collected qualitative data (from May to September 2018) and quantitative data (from November 2019 to January 2020) from primary care physicians who participated in the formative evaluation study of the AdAM project. This formative evaluation study was conducted alongside the stepped-wedge, cRCT in AdAM. In the cRCT study protocol, we described the study design of our formative evaluation study, in which we aimed to examine physician-side barriers and facilitators to the implementation process using a mixed methods approach (see Additional File Interviews with physicians from the intervention group were conducted to determine their experiences with digital innovation (see Additional File Data from the cross-sectional survey of physicians were used for structural equation modeling. The sample for the survey included all the physicians in the intervention group, who had enrolled at least one patient in the study. To increase the response rate, we used the tailored design approach by Dillman, which means that the physicians were reminded three times to respond to a questionnaire administered by post [We used a sequential and exploratory design. Qualitative data analysis was conducted in an exploratory manner in the first phase of the study to identify categories related to the range of physician expectations and experiences, which were then used in the second phase of the study to develop a quantitative measurement instrument and build a model. In addition, we triangulated the data at the modeling level as the qualitatively developed model was transformed into a quantitative model. The results of the first phase of the study were confirmed in the second phase of the study in an attempt to reduce bias in the interpretation of the results. A meta-inference was generated by merging the inferences from the CMO and the mediation model to provide the final description of the mechanism [ | PMC10294464 |
Description of the innovation | The digital innovation was implemented in 688 recruited general practices in North Rhine-Westphalia. It was expected to improve prescription quality and safety for adult patients with polypharmacy compared to patients receiving standard care. The innovation included several design components (e.g., a digitalized clinical decision support system for polypharmacy, patient medication history and diagnosis, information about other specialists, training on system use and management, technical support for physicians, and recommendations for prescribing in polypharmacy). | PMC10294464 | ||
Data analysis | CMO | Qualitative data analysis was conducted for two purposes: (1) summarizing content-deductive mapping of the data material with the aim of describing the categories of context, resources, reasoning, and outcome (CMO) and (2) application of the belief elicitation approach through deductive-inductive qualitative content analysis to develop the latent measurement tool of contextual innovation beliefs for the structural equation model (SEM). A content analysis approach was adopted, which incorporated elements of conventional and directed content analysis [The quantitative items were operationalized based on categories identified by the content analysis and inserted into the structural equation model as latent variables with their measurable indicators (A two-stage approach to quantitative data analysis was implemented. In this approach, the measurement model and the structural model were analyzed separately [We evaluated model fit using the comparative fit index (CFI) and the Tucker–Lewis index (TLI). The values of CFI and TLI range from 0 to 1, with values from ≥ 0.90 to ≥ 0.95 representing acceptable to good fit [ | PMC10294464 | |
Hypothesis development: structural equation model | M)Based | Because structural equation modeling focuses on testing of models of hypothesized theoretical relationships, we synthesized the results of our literature review to select theory-based latent constructs with the findings related to the qualitative configurational model (see Fig. Context-mechanism-outcome model for physician delivery of digital innovationWe chose the construct of organizational readiness for change as an organizational variable at the meso level [At the meso level, we hypothesized that organizational readiness for change is an important prerequisite to enable physicians to evaluate the effectiveness of innovation (mechanism [reasoning]; meso- and micro-level relations; a-path). This assumption was based on what our previous qualitative analyses demonstrated. For example, the process of patient registration and the groundwork for transferring additional patient data into digital innovation depend on the readiness of the primary care employees. They have to adapt to these changes brought about by the implementation of innovation. Both these tasks are related to organizational readiness and are important prerequisites for activating the part of the mechanism that corresponds to physician reasoning. The primary role of the physician is to make appropriate clinical decisions regarding the prescription of medications for patients with polypharmacy. Contextualized beliefs regarding the effectiveness of innovation consist of several components. These components are important from the pragmatic perspective of physicians in the management of polypharmacy patients in ambiguous clinical decision situations (context → mechanism [reasoning]). We hypothesized that physicians would only perceive the innovation as being effective if it addressed components relevant to the care of polypharmacy patients on a practical level.Moreover, physicians’ strong contextual beliefs increase a positive effect on the intention to use the innovation (b-path). Finally, we assessed whether the hypothesized direct relationship between the organization’s readiness to implement innovation and the physician’s intention to adopt (c-path) is mediated by the physicians’ belief in the effectiveness of innovation.Our empirical research questions for the mediation analysis are as follows: Do physicians’ contextualized beliefs regarding the effectiveness of innovation (micro level) mediate the relationship between primary care organizations’ readiness for change (meso level) and physicians’ adoption behavior (micro level) during the change process of implementing digital innovation for polypharmacy management? How strong are the direct and indirect effects?
Mediation modelNote: X = independent variable, M = mediator, and Y = outcome. The indirect effect is estimated as the product of the a- and b-paths (i.e., a*b). The c-path represents the direct effect of X on Y (i.e., the effect of X on Y that is not transmitted through the mediator, M)Based on the previous discussion, the following hypotheses are proposed:H1: Organizational readiness for change has a positive direct effect on behavioral intention to use digital innovation (c-path).H2: Organizational readiness for change has a positive direct effect on physicians’ contextualized innovation effectiveness beliefs (a-path).H3: Physicians’ contextualized innovation effectiveness beliefs have a positive direct effect on behavioral intention to use digital innovation (b-path).H4: Physicians’ contextualized innovation effectiveness beliefs mediate the relations between organizational readiness for change and behavioral intention to use digital innovation.H5: Physician and structural characteristics have direct and indirect effects on contextualized innovation beliefs and intention to use digital innovation. | PMC10294464 | |
Measurement instrument | ’ | The data collected in our survey were used to develop the SEM model. The questionnaire was pre-tested in two stages: in think-aloud interviews (Accordingly, the survey included measurement items for each of the models’ latent constructs: ORIC (organizational readiness for implementing change) [Physicians answered the organization-related aspects of our questionnaire as key persons of the participating practice. Measurement based on individuals’ assessments of collective capabilities is preferable when collective outcomes depend on skillful teamwork [ | PMC10294464 | |
Measurements: organizational readiness for implementing change (ORIC) (X) | The nine items used to measure ORIC are adapted from Shea et al. and the validated German version [ | PMC10294464 | ||
Measurements: contextualized innovation effectiveness beliefs (mediator) | Following the realist research approach, the items of the CB construct were developed to measure different components of beliefs regarding the effectiveness of innovation. The empirically observed influence of the context on the reasoning process from the qualitative analyses was included in the scale. The construct includes six items related to three components of physicians’ contextualized beliefs related to polypharmacy management practices: (1) | PMC10294464 | ||
Measurements: behavioral intention to use (BI) (Y) | Three items are used to measure the behavioral intention to use technology for routinely performed and future work tasks (“I routinely use digital innovation for my work with polypharmacy patients,” “I would like to continue to use digital innovation for my work,” “I have performed many of the routine tasks for my polypharmacy patients with the help of digital innovation”). In particular, we used a BI scale, which was validated, translated into German, and checked for reliability [ | PMC10294464 | ||
Measurements: covariates | Physician characteristics and structural factors were included as covariates. Physician characteristics included age, gender, and work experience in ambulatory care in full years. Age was categorized into three groups (< 50 years, > 50 years, and > 60 years). Gender was dichotomized into male and female (because no answer was provided in the “diverse” category). Structural factors included the position within the primary care organization (i.e., practice owner or employee) and the regional location of the primary care organization (located in a rural or urban area). | PMC10294464 | ||
Results | PMC10294464 | |||
Qualitative data | The initial qualitative data collection of the evaluation study was conducted with 27 physicians, of whom 15 were in the intervention group and 12 were in the waitlist control group. A brief summary of the qualitative findings is provided as an overview; details of the qualitative data collection and the COREQ checklist used have been published elsewhere [Different behavior-related outcomes were identified: sensitization to risks related to polypharmacy; perceived changes of interdisciplinary and doctor–patient cooperation and communication; and learning effects through using the digital tool. The findings from the two RCT arms were similar in terms of physicians’ awareness of high-risk prescription scenarios with polypharmacy and reflections on changes in professional responsibilities when using digital support for decision making. Qualitative findings were synthesized to describe three different scenarios of simple and complex pathways, which have been differentiated paradigmatically with increasing complexity. The main findings of the qualitative study were captured in the qualitative model, and three relevant themes (prescription safety, information quality, and communication) were selected to operationalize the construct of contextual beliefs, which we predicted would have a significant impact on the main mechanism in the mediation model. | PMC10294464 | ||
Psychometric properties of the measurement analysis | MM | To test for unidimensionality, exploratory factor analyses of the individual construct items and their Cronbach alpha reliabilities were first examined. The results of these analyses revealed that all scale items associated with a given construct or subconstruct loaded highly (> 0.70) on a single factor. One item from the behavioral intention to use construct violated this threshold slightly (0.56), and it also demonstrated loadings on a subconstruct of the contextualized beliefs, although these were weak (0.27). As a result, the final items were analyzed in the measurement model (MM) using CFA. Validation of the MM was performed by examining discriminant and convergent validity and reliability. The results indicated that the values for factor loadings and average variance extracted (AVE) were above recommended thresholds (> 0.5), with the value of the context-specific construct lying slightly below the cutoff. The composite reliability of each factor was above the threshold of 0.7, as were the internal reliability values (Cronbach’s alpha > 0.7). Discriminant validity was assessed by calculating squared correlations of latent variables with any other latent constructs. Discriminant validity was assumed only if all AVE values were greater than square correlations of latent variables. Recommended cutoff values for fit indices supporting MM used in SEM are presented in Additional File | PMC10294464 | |
Discussion | MINOR | Our overarching research objective was to examine complex implementation mechanisms that may explain variations in behavior-related outcomes, such as the adoption of innovation. To this end, we examined the relations between the three meso- and micro-level factors, organizational readiness for change, contextualized innovation effectiveness beliefs, and adoption. The findings indicate that an organizationally triggered mechanism lead to the adoption of innovation. The study further demonstrates how contextualized innovation beliefs function within the mechanism, which contributes to a broader understanding of the mechanism.The empirical findings of this study contribute to the literature on realist evaluation research, organizational change, and the study of implementation mechanisms [Regarding the last hypothesis, the control factors had no direct or indirect effects and only the regional variable exhibited minor effects. The results indicate that the implementation of digital innovation in urban or rural physician practices is significant. We can derive one possible explanation for this from our qualitative data collection; compared to physicians from rural areas, physicians from urban areas report that they are less knowledgeable about the medical histories and medications of some of their patients, because they see some patients only briefly. Therefore, it is more likely that they will expect additional benefit from using a digital innovation that provides patient-relevant information.In this paper, we presented a novel approach to SEM mediation analysis that integrates qualitative findings from a context-mechanism-outcome configuration (realist inquiry) and a data-driven latent construct. In addition, the synergistic effects of the two analytic approaches of realist evaluation and SEM were explored. To the best of our knowledge and compared to previous studies in the field of polypharmacy management research [The current state of research on polypharmacy indicates that there is an urgent worldwide need to simplify the complex clinical practice of polypharmacy management, because an increasing number of elderly and multimorbid patients will be affected by polypharmacy, and the workload of primary care physicians who care for these patients with complex medication regimens will increase [ | PMC10294464 | |
Practical implications | At the time of data collection, the physicians were using digital innovation for approximately 60% of the patients who could potentially derive benefit from it. This indicates that the application was not yet fully implemented. This observation may have practical implications for developing implementation strategies for respondents who have not used digital innovation actively, have only used it infrequently, or have not even begun implementing it. Insights into the specific beliefs about the effectiveness of the innovation allow inferences to refine the initial qualitative model of the configuration of context, mechanism, and outcome (see Fig. The employees of primary health care organizations should be encouraged to develop a high readiness for change and to be prepared to perform new tasks. Innovation developers must understand which topics are relevant from the physicians’ perspective, so that the physicians will perceive innovation as effective and adopt it (mechanism [reasoning] → outcome). Physicians need digital innovation that sensitizes them to the risks of polypharmacy, creates a learning effect, and provides valuable and helpful information for practice (mechanism [resources]). Beyond that, digital innovation must serve to reassure and support clinicians in ambiguous decision and communication situations with polypharmacy patients, when (de-) prescribing medications (context → mechanism [reasoning]). Organizations or researchers can use these findings to adapt primary care digital innovation and implementation strategies to improve digital health technology adoption (context → mechanism [reasoning + resources] → outcome) for polypharmacy management [ | PMC10294464 | ||
Strengths and limitations | CMO | The sample consisted of primary care physicians who implemented digital innovation for polypharmacy management. Only physicians who had participated in the study between 2018 and 2020 and were part of the intervention group during that period were included in the data analyses. It is likely that physicians recruited for the study at a later date had different initial conditions, because technical problems had been resolved and better communication strategies had been developed. Non-participation in the survey could be ascribed to physicians not using digital innovation regularly at the time of data collection and, therefore, being unable to provide responses.The inferences drawn from the two strands of qualitative and quantitative data analysis were merged to create a comprehensive understanding of the digital innovation implementation process. The application of the modified methodological approach in this study enabled us to integrate the interdisciplinary evidence on the topic of contextual influences on change processes through realist evaluation. We then explored the intersection with a quantitative analysis method that uses a theory-based confirmatory approach to examine statistical relationships (SEM) [The methodological synergy effects are particularly reflected in the development of the contextual measurement instrument, in which the findings of the qualitative content analysis and CMO were integrated. Furthermore, the directions of the effects and relationships of the micro and meso levels and the corresponding measurement instruments were determined on this basis and confirmed in the mediation model. As explained in the previous section, our analyses indicate reasonable reliability as well as the convergent and discriminant validity of the measurement instruments used in this study. In addition, the requirements for mediation analysis were met. Therefore, we argue that our study provides a robust methodological basis to confirm semi-predictable patterns between contexts, underlying generative mechanisms, and outcomes in primary care settings. Future studies should plan their study design accordingly to conduct more advanced, strictly quantitative mediation analyses. In the present study design, the focus was on the triangulation of the different models in the two study phases. To minimize bias, we sequentially analyzed qualitative and quantitative data and confirmed the assumptions made in the first study phase with the findings of the second phase [ | PMC10294464 | |
Conclusion | Implementation research indicates inconsistent implementation effectiveness, possibly related to the proximal outcomes of the actual implementation behavior during the change processes. This study explored the underlying mechanisms. Empirical confirmation of contextual mechanisms expands the theories regarding the functioning of mechanisms triggered by the implementation of digital health technology. In addition, this study confirms that organizational readiness for change has a direct effect on physician adoption behavior. However, this relationship is indirectly affected by individual beliefs regarding the effectiveness of the innovation.The adoption behavior of primary care physicians correlates strongly with the degree of meso-level readiness to implement change, as well as with the extent to which physicians view the digital innovation as beneficial to their work. Innovation beliefs are related to three subdimensions that pertain to the extent to which the use of digital innovations is perceived as effective: (1) to improve patient safety, (2) to improve clinical decision-making during the course of risk and interaction analysis, and (3) to improve communication regarding the management of polypharmacy for patients in the context of ambiguous decision situations.To the best of our knowledge, this is the first study to provide new insights into in-depth local needs assessment. The adoption of digital innovations for polypharmacy management in primary care organizations can be improved by tailoring implementation strategies accordingly. Our findings contribute to the understanding of the underlying mechanisms and complex adaptive processes of social systems that operate in a primary care setting. Therefore, our approach provides methodological insights into realist evaluation and contributes to current research that seeks to illustrate the complex contextual pathways and their effect on implementation outcomes [ | PMC10294464 | ||
Acknowledgements | We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 491454339). | PMC10294464 | ||
AdAM Study Group | See Supplementary Information (Additional File | PMC10294464 | ||
Authors’ contributions | SS drafted the manuscript and developed interview guides and questionnaires, supported by UK's knowledge. KIH contributed to the formal analysis. JKN provided conceptual input. BSM critically commented on the manuscript. SS performed the qualitative and quantitative data collection and analyses, developed structural equation models and interpreted data with methodical input from ID. UK and HP revised the first version of the manuscript and contributed to the initial planning and discussion. All authors read and approved the final manuscript. | PMC10294464 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. This study was funded by the Innovation Fund of the German Federal Joint Committee (grant no 01NVF16006). The funder had no role in the design of the study, collection, analysis or interpretation of data, or in the writing of the manuscript. | PMC10294464 | ||
Availability of data and materials | The datasets generated and analyzed during the current study are not publicly available due to participant consent restricting data use to the research team but are available from the corresponding author on reasonable request. | PMC10294464 | ||
Declarations | PMC10294464 | |||
Ethics approval and consent to participate | Study design and evaluation protocol were approved by the North Rhine Medical Association’s ethics committee (application no. 2017184). No objections were raised to any part of the study. This study processed anonymized data. Participants gave informed consent to participate in the study. All methods were carried out in accordance with relevant guidelines and regulations. | PMC10294464 | ||
Consent for publication | Not applicable. | PMC10294464 | ||
Competing interests | The authors declare no competing interests. | PMC10294464 | ||
References | PMC10294464 | |||
Purpose | hemorrhoids, postoperative pain, Pain | HEMORRHOIDS | Pain and reduced quality of life (QoL) are major subjects of interest after surgery for hemorrhoids. The aim of this study was to find predictive parameters for postoperative pain and QoL after hemorrhoidectomy. | PMC10622377 |
Methods | NRS, tamponade, pain | This is a follow-up analysis of data derived from a multicenter randomized controlled trial including 770 patients, which examines the usefulness of tamponade after hemorrhoidectomy. Different pre-, intra-, and postoperative parameters were correlated with pain level assessed by NRS and QoL by the EuroQuol. | PMC10622377 | |
Results | NRS, pain | At univariate analysis, relevant (NRS > 5/10 pts.) early pain within 48 h after surgery was associated with young age (≤ 40 years, | PMC10622377 | |
Conclusion | pain | Early relevant pain affects younger patients but can be prevented by avoiding tamponades and using a pudendal block. Relevant pain after 1 week is associated only with early pain. Relief in preexisting pain and opioids improve QoL. | PMC10622377 | |
Trial registration | DRKS00011590 12 April 2017. | PMC10622377 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10622377 |
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