Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with novel coronavirus disease 2019 (COVID-19) recently. In addition, microvesicles (MVs) that contain membrane TM (MV-TM) have been found to be released from activated cells which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and MV-TM have been reported, including enzymatic, chemical, and TM mutation mechanisms. Measurements of sTM and MV-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories as follows: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease. THBD) located on the chromosome 20p12-cen.N-terminus, these domains are the lectin-like domain (TMD1), epidermal growth factor (EGF)-like domain (TMD2), serine/threonine-rich domain (TMD3), transmembrane domain (TMD4), and a cytosolic tail  is a type-I transmembrane glycoprotein that was first discovered by Esmon and Owen in 1981 on endothelial cells as a cofactor for thrombin-catalyzed activation of protein C.il TMD5;.6TM hIn addition to expression as a membrane protein on the cell surface, fragments of TM are also found circulating in the blood,Measurement of the levels of circulating TM has great potential as a biomarker for diagnosis and tracking of different diseases. In this review, we summarize all these advances in three categories: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases.THBDc.1611C > A (p.Cys537X) mutation in a heterozygous state was identified.In healthy humans, the levels of sTM are low (<10 ng/mL),Previous research focused primarily on the proteolytic release of soluble TM from cells, which exists in biological fluids such as plasma, urine, and synovial fluid.sTM can also be generated by chemical cleavage of the membrane bound TM . It hasProteolytic and chemical release are the main contributors of sTM in the blood. However, physical force from the blood flow also causes sTM release from endothelial cells. It is known that blood flow–associated hemodynamic forces, such as cyclic strain (stretch) and shear stress, affect endothelial-dependent regulation of vessel homeostasis.MVs, a population of extracellular vesicles ranging in size from 0.1 to 1 μm, are released from the surface of cells by the process of outward membrane budding through a loss of calcium-dependent membrane phospholipid asymmetry and cytoskeletal rearrangement.THBDCys537Stop is the first identified TM mutation that arises from a premature stop codon at Cys537, resulting in truncation of TM within the transmembrane domainTHBDpPro496Argfs*10) that results in a stop gain that causes synthesis of a TM variant truncated at the membrane-proximal C-terminal region of the extracellular domainTM mutations impair its function and are related to diseases development.Circulating TM exists either as sTM cleaved from membrane TM or MV-TM that is membrane TM released from cell membrane. Therefore, different methods are used to quantify their concentrations in biological samples. The level of sTM has been examined as a parameter of disease severity and progression. However, determination of whether sTM levels change between healthy and patients may have mixed results in certain diseases. Alternatively, TM indexes, which compares sTM and albumin levels in serum or other biofluid, have been used.The most common techniques used to measure the protein levels of sTM are enzyme immunoassays (EIA) and enzyme-linked immunosorbent assays (ELISA). In addition, western blot and high-performance liquid chromatography (HPLC) methods are also used to quantify sTM concentration in biological samples. This section summarizes common methods for detecting and measuring sTM concentrations in biological samples .EIA and ELISA methods are the most common ways to measure the concentration of sTM . The deWestern blot is another antibody-based assay that is used to identify the presence of sTM in samples. In general, the initial gel electrophoresis step separates proteins based on their molecular weights. Transferring the separated protein to a membrane and probing with antibodies against sTM allows for the identification of sTM subspecies. The major advantage of using western blot is the ability to determine different molecular weight species of sTM if they all contain a fragment that can be recognized by an antibody. While the ability to see the different sTM subspecies of TM is helpful, western blot is not the best for gaining quantitative information. In addition to pictorial data, western blot data are represented as a ratio of the protein of interest to a loading control. Thus, western blot offers semiquantitative and most importantly qualitative information.HPLC offers the benefit of obtaining both quantitative and qualitative data at once. Detection limits of HPLC analysis with a UV-Vis detector can be similar to those of EIA/ELISA and reach the low ng/mL range.Flow cytometry is a conventional analytical technique for measuring physical and chemical characteristics of a population of cells or particles. In general, cell or particle surfaces are often labeled with fluorescent markers with defined excitation and emission wavelengths. Cells or particles are then quickly examined, and the data gathered are processed by a computer software. TM-presenting endothelial MVs were found in sepsis-induced DIC.Membrane TM has many biological activities which depend on its different domains and expression by different types of cells.Measurement of the level of circulating sTM by immunological assays can be used to indicate endothelial-cell damage; however, it is not enough to fully evaluate certain diseases.As mentioned above, shedding of sTM and subsequent increased levels of sTM is mainly associated with endothelial injury or damage. Therefore, many diseases show high level of sTM in serum, urine, and other biofluids. Measurement of levels of sTM in serum, urine, and other biofluids are often taken for disease diagnostic and development monitoring, as well as therapeutic monitoring. Circulating sTM levels have been measured in many diseases and medical procedures, such as infectious disease, cardiovascular disease, diabetes, hypertension, obesity, immune diseases, surgical operation, transplantation, and hemodialysis (HD). Most diseases show high levels of circulating sTM, while some diseases show lower than base levels of circulating sTM. The majority of sTM levels are measured in either serum or plasma. The levels of sTM in plasma and in serum often cannot be compared directly often. If the detection method uses an enzyme, then ethylenediaminetetraacetic acid (EDTA) might not be the best choice, since it can inhibit enzyme activity. It should also be pointed out that sTM level alone cannot be used for clinical decision. Other biomarkers are often monitored with sTM as well. This section discusses the correlation of the circulating TM and (1) diseases, (2) surgical operation and intervention, and (3) HD in detail. The sTM levels and major diseases are summarized inAcute lung injury and acute respiratory distress syndrome: the pathogenesis of acute respiratory distress syndrome (ARDS) is linked to a series of inflammation reactions that lead to the accumulation of neutrophils in the lungsNovel coronavirus disease 2019: The novel coronavirus disease 2019 (COVID-19) is a new infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which has been producing devastating effects not only on human health but also on the global economy. Clinical studies showed that endothelial vascular injury plays a key pathogenetic role in the development of COVID-19-associated coagulopathy, especially among intensive care unit (ICU)-hospitalized patients.A report by Goshua et al from Yale University examined blood samples of COVID-19 patients  and others receiving care but in a non-ICU unit) and disease-free volunteers.Pneumonia, community-acquired pneumonia: in the pathogenesis of community-acquired pneumonia (CAP), there is a high inflammatory response which causes damage to the endothelium leading to coagulation activation and the release of inflammatory mediators.Severe acute respiratory syndrome: SARS is a viral respiratory illness caused by a coronavirus called SARS-associated coronavirus (SARS-CoV). Liu et al evaluated classic plasma markers of endothelial injury tissue-type plasminogen activator (t-PA) and sTM in patients with SARS.Sepsis: a key role of the pathogenesis of sepsis are uncontrolled inflammatory responses which causes damage to endothelial cells.There is increasing experimental evidence that endothelial dysfunction represents an important component of cardiovascular disease (CVD) and stroke. In many cases, TM shedding from endothelial cells of arteries and veins contribute to certain amount of circulating sTM. Therefore, the levels of circulating sTM are highly related with CVD and stroke.Abdominal aortic aneurysm: abdominal aortic aneurysm (AAA) is a vascular disease in which endothelial dysfunction plays an important role.Acute myocardial infarction: several studies have indicated an association between hemostatic markers and acute myocardial infarction. Öhlin et al reported that sTM antigen in plasma is increased in patients with acute myocardial infarction treated with thrombolytic therapy.Atherosclerosis: TM is expressed in a variety of cells associated with atherosclerotic lesions. These include endothelial cells, foamy macrophages, spindle cells, intimal smooth muscle cells, and medial smooth muscle cells.Coronary heart disease: the relationship between plasma sTM and the relative risk of coronary heart disease (CHD) has been evaluated, and levels of sTM were seen to be inversely associated with the risk of CHD.Disseminated intravascular coagulation: biomarkers of endothelial damage have been previously seen to increase in DIC patients, including sTM, tissue type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1).Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS): the plasma sTM levels were measured in patients with thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) and in healthy volunteers to examine the relationship between the occurrence of hemostatic abnormality or vascular endothelial cell injury and patient outcome.With both endothelial damage and dysfunction at play in diabetes mellitus (DM), a significant amount of research has been performed on how sTM levels change in DM. The overall trend is that sTM levels are increased in the biological fluids of diabetic patients.Earlier studies on pulmonary hypertension found that the pulmonary vascular endothelium is deficient in anticoagulant proteins like TM. A later study with patients with chronic thromboembolic pulmonary hypertension (CTEPH) showed significantly lower sTM levels than that in the control group.The excretion of sTM from kidney will affect the concentration of the plasma sTM and urinary sTM. Therefore, kidney disease will affect the concentration of the plasma sTM and urinary sTM accordingly. In patients experiencing renal failure caused issues where endothelial cell damage does not occur, plasma sTM is raised. There is also a positive correlation with serum creatinine, a staple biomarker of renal function, and a negative correlation with creatinine clearance.The liver regulates the most chemical levels in the blood by breaking down or converting certain substances. There are considerations on liver function as predictors of sTM levels. Therefore, there is a correlation between sTM levels and liver diseases as well. Plasma sTM levels were often evaluated in patients with liver diseases.Common pathologic features that accompany systemic lupus erythematosus (SLE) are endothelial cell apoptosis, endothelial dysfunction, and inflammation.Determination of whether sTM levels change between healthy and multiple Sclerosis (MS) patients has had mixed results. Some research groups have seen no change in serum sTM levels or sTM levels in cerebral spinal fluid (CSF).Obesity is a complex disease and has high risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure and certain cancers. The plasma concentration of sTM is associated with obesity as well. A previous study investigated the plasma concentration of sTM in children and adolescents with obesity.TM is present on syncytiotrophoblasts and the endothelium of the vasculature that covers the trophoblastic surface.Plasma sTM levels and vWF were often measured to check the risk of ischemic and hemorrhagic stroke.The emergency management of acute severe bleeding in trauma patients has been paid more attention in recent years. In particular, a prompt assessment of coagulation alterations is necessary and allows for immediate hemostatic resuscitation procedures.TM expression has been described in multiple cancer types on the endothelium and tumor cells.Surgical operation and intervention can cause endothelial damages and thus lead to sTM release from the cells and tissues of the injured sites. Therefore, sTM levels were often measured related to the disease treatment and recovery. This section summarizes the sTM levels related to variety of surgical operations and interventions. The sTM levels in surgical procedures are summarized insTM levels were assessed during cardiac catheterization procedure. Vielhaber et al conducted a prospective study in children by measuring sTM concentrations, along with thrombin generation before, at the end of and 24 hours after cardiac catheterization.TM has been hypothesized to play a role in graft rejection as increase in TM expression has been shown to lower the risk of xenotransplantation failureLiver transplantation can cause endothelial damage allowing sTM to serve as a marker during liver transplantation.Renal transplantation can cause endothelial damage and dysfunction that may contribute to the hypercoagulable and inflammation states presents in renal transplant. A recent study assessed sTM, vWF, and IL-6 in renal transplant recipients (RTRs) and associated their plasma levels with primary cause of end-stage renal disease (ESRD) and allograft function.There have been clinical studies suggesting a correlation between increased sTM levels and vascular endothelial damage in patients undergoing HD. Very high plasma levels of sTM were considered to be associated with endothelial cell damage in addition to the presence of uremia.THBDgene. In normal physiologic conditions, sTM circulates at a low concentration (<10 ng/mL) in plasmaTM is a type-1 transmembrane glycoprotein expressed mainly on vascular endothelial cells which plays many biological functions. TM also circulates as sTM and MV-TM in biological fluids ranging from serum and urine to synovial fluid. sTM can be generated by physical stress, enzymatic cleavage, or chemical cleavage of the intact protein,N-terminal sequencing revealed that one form encompasses the EGF repeats and retained the ability to bind thrombin. In contrast, the second fragment corresponded to the equivalent molecular weight for theN-terminal CTLD and failed to bind thrombin. Overall, the precise functional relevance and activity of sTM fragments and the mechanisms for sTM release are not fully understood, mechanistic and proteomic study about sTM fragments merit further investigation. Finally, the physiological and pathological relevance of different sTM fragments require further investigation.It is still unclear how sTM levels contribute to physiology and pathophysiology. It will totally depend on what fragments of the sTMs are as each domain of TM has distinct activity which may be generated under specific conditions. However, it is unknown if the release of sTM is a tightly regulated process in which specific domains are cleaved and released. There have been four,Different methods are used to quantify sTM concentration in biological samples. EIA and ELISA methods are the most common ways to measure sTM in which an anti-TM antibody is used. The main question is if a single antibody can capture all fragments of sTM when multiple forms of sTM exist in the biofluids. However, it is an unanswered question. In addition, TM activity, like protein-C activation, is also measured in biological samples for various diseases, which is often used in conjunction with sTM concentration measurements. Again, since different domains of TM have different activities and many fragments of sTM exist, a single activity assay may not be adequate to evaluate sTM in different diseases. On the other hand, MV-TM activity has not been investigated. It is known that MVs have different membrane assembly from cell membraneOverall, sTM levels are widely investigated in disease monitoring and diagnosis. However, preexisting/coexisting conditions such as liver or kidney disease or both will affect plasma sTM levels after release from vascular endothelial injury.


The artificial intelligence was found to be a useful metric of foot posture but was less useful in developing and obese individuals. Care should be taken when using the foot posture index to associate pronation with injury risk, and the Achilles tendon and longitudinal arch angles are required to elucidate the risk. The statistical shape modeling (SSM) may derive learnt information from population-based inference and fill in missing data from personalized information. Bone shapes and tissue morphology have been associated with pathology, gender, age, and height and may develop rapid population-specific foot classifiers. Based on this review, future studies are suggested for 1) tracking the internal multi-segmental foot motion and mapping the biplanar 2D motion to 3D shape motion using the SSM; 2) implementing multivariate machine learning or convolutional neural network to address nonlinear correlations in foot mechanics with shape or posture; 3) standardizing wearable data for rapid prediction of instant mechanics, load accumulation, injury risks and adaptation in foot tissue and bones, and correlation with shapes; 4) analyzing dynamic shape and posture  However, care must be taken to associate pronation with injury risk, and factors of the Achilles tendon and longitudinal arch angles may be required for elucidating the risks.• Dynamic tracking of foot shape, posture, and internal multi-segmental motion should consider current fluoroscopy, machine learning, statistical shape modeling, wearable, and marker-less techniques.Changes of shape and posture in the human foot have been informed through the evolutionary process . Foot shvia anatomical palpation and structural observation , also known as the “subtalar joint neutral theory” . This moervation . In termervation .In the current literature, several excellent studies have reviewed the relationship of foot shape, foot posture, and foot biomechanical function. Shoe-wearing habits, pathology, or external factors have also played contributing roles in foot shape, posture, muscle and tendon morphology, and bone alignment . SpecifiIn particular, the foot type and foot disorders are strongly associated with the foot arch difference, classified as pes cavus (high arch), pes rectus , and pes planus (flat arch) . Pes plaDuring walking (dynamic conditions), cavus (high arch) feet presented increased frontal and transverse motion in the rearfoot, while planus (flat arch) feet showed a reduced frontal range of motion in the midfoot . The fooAlteration of shape or posture in the foot, functioning as the primary interface with the external surroundings, may lead to the realignment of the kinetic chain. Foot pronation often showed an everted rearfoot and arch drop in the foot–ankle complex, further inducing internally rotated tibia, proven with a continuous vector coding analysis technique , and mobin vivo, a longer first metatarsal size, rounder first metatarsal head, and greater first metatarsophalangeal joint angle were associated with hallux valgus deformity  and population-based modeling using large data sets and statistical shape methods . In thisversus adducted hallux)  , foot po hallux)  have bee hallux)  can also hallux)  and post hallux)  with hig hallux) . The SSM hallux) .The current measurement of foot morphology, shape, and posture using 2D footprints, anthropometric measurements, anatomical palpation, 3D surface scanning, ultrasound imaging, computed tomography (CT), or magnetic resonance imaging (MRI) are mainly under static (non-weight or weight-bearing) conditions . HoweverLong-distance running, or endurance running, is a key evolutionary skill presented by bipeds in addition to walking . Long-diThe arch (either high arch or flat foot) in the midfoot region is commonly used to classify and categorize the foot posture in foot biomechanics. Specifically, it has been quantified using the 2D footprint artificial intelligence (AI) and classified as high arch (AI < 0.21), normal arch (0.21 < AI < 0.26), and low arch (AI > 0.26) . This meRunning biomechanics influences the foot structure. Following long-distance running, foot arch and dorsal height reduce over a week and may take more than a week to return to pre-run profiles and has been linked with increased plantar loadings in the medial foot  . These cFoot types  and postures  have been reported to be associated with running-related injuries , particuThis subsection is focused on foot pronation and potential contribution to running-related injuries, taking distance running as a typical example. Overpronated feet have been implicated in developing overuse injuries, despite there being no scientific evidence that overpronated feet are associated with the diagnosis of injuries or diseases. This misconception exists possibly because altered foot postures have often been observed in people who have musculoskeletal injuries, dysfunctions of the lower limb, and lower back pain .Pronation/supination are important biomechanical functions in gait, and a certain extent of natural pronation/supinations is required as a shock absorber during the early stance phase and as a rigid lever to push forward during the terminal stance phase . During Overpronated feet, specifically at the subtalar joint, have been proposed to develop deterioration of the lower limb joint by disrupting normal alignment with external rotation of the tibia and calcaneal inversion which are not in the normal direction . A previHowever, while numerous studies have observed pronation/supination of the foot in people who have lower limb diseases, there is no scientific evidence supporting the causal relationship between the alteration of foot posture and diagnosis of injuries or diseases. A recent study on knee osteoarthritis with foot posture also put forward the question of foot postural changes leading to injuries or injuries resulting in posture changes . A comprThe idea of our understanding of the association between pronation/supination and running-related injuries is still not clear and no consensus has been reached on the foot posture with injuries . Thus, tvia shape which include the 3D plantar surface  is a reduction technique that can be used to identify independent  geometrical features of a set of similar shapes and rank them . The prihttps://pypi.org/project/gias2/) being developed at the Auckland Bioengineering Institute as an example. To introduce one of the SSM technique, we took musculoskeletal modeling software GIAS2   regression models were first developed to correlate key shape metrics  with walking  and running  plantar pressures using habitually barefoot and shod populations , showingThis review has explored known associations between foot shape, posture, and foot conditions. The foot artificial intelligence was found to be a useful metric of foot posture, which can be measured quickly and associated with motion and joint pain in adults; however, it may be less useful in special population groups, such as developing and obese individuals. The foot posture index to classify feet as pronated, neutral, and supinated is a useful approach under both static and dynamic conditions, but care must be taken when using it to associate pronation with injury risk. While recent studies have associated foot posture with joint loading, more information, such as factors of Achilles tendon angle and longitudinal arch angle, is needed to elucidate risk from normal function. With increasing imaging technology and database sharing, there is an opportunity to apply statistical shape modeling methods to derive learnt information from ‘big data’ and use this to make a population-based inference and fill in missing data from personalized information. Foot bone shapes and tissue morphology have been associated with pathology, gender, age, and height and may help develop rapid population-specific foot classifiers. A popular topic, barefoot running, was investigated, and it was shown that the forefoot toe shape influenced forefoot plantar pressure in habitually barefoot runners only, while the arch shape influenced plantar pressure in any population. This may play a role in footwear design.via 1) tracking the internal foot motion during dynamic activities via biplanar fluoroscopy and multi-segmental models. With reported increased measuring accuracy, mapping the biplanar 2D motion to 3D shape motion and statistical shape modeling in vivo would assist the validation of finite element modeling and reveal the tissue variation, ligament strain, and cartilage loadings; 2) implementing different multivariate (support-vector) machine learning or convolutional neural network (CNN) algorithm to address potential nonlinear correlation scenarios in foot mechanics with shape or posture metrics; 3) standardizing data sets with synchronized IMU data for rapid prediction of instant mechanics, load accumulation, injury risks, and adaptation in the tissues and bones of the foot and correlating with foot shape; 4) analyzing the dynamic foot shape and posture via marker-less depth camera and real-time processing techniques under real-life scenarios for precise evaluation of clinical foot conditions and performance-fit footwear development.Based on findings from the current review and potential gaps in the literature, future studies may consider the following topics


A growing number of Americans are enrolled in high-deductible health plans (HDHPs). Enrollees in HDHPs, particularly those with chronic conditions, face high out-of-pocket costs and often delay or forgo needed care owing to cost. These challenges could be mitigated by the use of cost-conscious strategies when seeking health care, such as discussing costs with providers, saving for medical expenses, and using web-based tools to compare prices, but few HDHP enrollees engage in such cost-conscious strategies. A novel behavioral intervention could enable HDHP enrollees with chronic conditions to adopt these strategies, but it is unknown which intervention features would be most valued and used by this patient population.This study aimed to assess preferences among HDHP enrollees with chronic conditions for a novel behavioral intervention that supports the use of cost-conscious strategies when planning for and seeking health care.In an exploratory sequential mixed methods study among HDHP enrollees with chronic conditions, we conducted 20 semistructured telephone interviews and then surveyed 432 participants using a national internet survey panel. Participants were adult HDHP enrollees with diabetes, hypertension, coronary artery disease, chronic obstructive pulmonary disease, or asthma. The interviews and survey assessed participants’ health care experiences when using HDHPs and their preferences for the content, modality, and frequency of use of a novel intervention that would support their use of cost-conscious strategies when seeking health care.Approximately half  of the interview participants reported barriers to using cost-conscious strategies. These included not knowing where to find information and worrying that the use of cost-conscious strategies would be very time consuming. Most  interviewees who had discussed costs with providers, saved for medical expenses, or used web-based price comparison tools found these strategies to be helpful for managing their health care costs. Most  interviewees expressed interest in an intervention delivered through a website or phone app that would help them compare prices for services at different locations. Survey participants were most interested in learning to compare prices and quality, followed by discussing costs with their providers and putting aside money for care, through a website-based or email-based intervention that they would use a few times a year.Regular use of cost-conscious strategies could mitigate financial barriers faced by HDHP enrollees with chronic conditions. Interventions to encourage the use of cost-conscious strategies should be delivered through a web-based modality and focus on helping these patients in navigating their HDHPs to better manage their out-of-pocket spending. Approximately half of Americans with private health insurance face the risk of high out-of-pocket (OOP) health care spending because they are enrolled in a high-deductible health plan (HDHP), a private health insurance plan with a deductible of at least US $1400 for an individual or US $2800 for a family that can often be combined with a health savings account (HSA) [The increase in HDHP enrollment has created financial and access challenges for many patients. The complicated benefit design of HDHPs often leaves enrollees with misunderstandings about covered services and confusion about OOP costs, especially for urgent services . High coAn approach to mitigate these challenges is to help HDHP enrollees with chronic conditions better understand and use their health plans. Use of beneficial cost-conscious strategies can help HDHP enrollees with chronic conditions pay less for health care and have better access to necessary services . Such stNo behavioral intervention has attempted to encourage HDHP enrollees to engage in cost-conscious strategies to reduce needed health care costs, and there are no previous studies on enrollee preferences to guide the design of effective interventions.The objective of this study was to assess the preferences for the content, modality, and frequency of interaction with an intervention to encourage the use of cost-conscious strategies among patients in HDHPs with chronic conditions to inform the development of future novel behavioral interventions.This study was reviewed and approved by the University of Michigan (U-M) Medical School’s institutional review board (HUM00180179). Informed consent was obtained from all participants. To protect participants’ privacy and confidentiality, all study data were deidentified before analysis. Interview participants were compensated with a gift card worth US $25, and survey participants were compensated in accordance with the policies by Dynata for internet survey panel participants.We conducted an exploratory sequential mixed methods study among HDHP enrollees with chronic conditions. As defined by Creswell and Plano Clark , exploraOur semistructured interview guide and survey items were grounded in the conceptualization of cost-conscious strategies as teachable health behaviors. To identify constructs that could facilitate or impede engagement in cost-conscious strategies, we adapted the Health Belief Model . Key conFrom October 2020 to December 2020, we used the U-M Health Research website  to recruTelephone interviews were conducted by a study team member using a semistructured interview guide  interviews were audio-recorded, deidentified, transcribed, and analyzed for qualitative themes. A deductive codebook was compiled using the interview guide and systematically applied to all  interviews to elicit major themes. Codes and their respective definitions were revised when needed to capture participant’s experiences and preferences. For qualitative analysis, the codebook was uploaded to Dedoose, a cloud-based software platform for qualitative coding. Codes were divided into 4 categories: care for chronic conditions, choice and use of current health plan, cost-conscious strategies in health care, and intervention preferences. Qualitative coding was primarily completed by 2 authors, who consulted with the principal investigator for reconciliation and revisions to the coding system. After revising the codebook to reflect new thematic content, the transcripts were recoded to ensure accuracy. After all the transcripts were double-coded and codes were reconciled, the 2 primary coders conducted thematic analysis to identify overarching themes.On the basis of themes that emerged from interviews, we developed a survey instrument  and different potential modalities for delivering this content . Level of interest for both content and modality was measured using a 3-point scale . The 3-point scale for these self-created questions was adopted from Kullgren et al  because In addition, the survey assessed participants’ use of cost-conscious strategies in the past 12 months, confidence in using these strategies, delayed and forgone care owing to cost, health service utilization, health insurance literacy, health literacy, technological access, and sociodemographic variables. Survey measures on participants’ previous use of and confidence in using cost-conscious strategies were derived from a nationally representative survey of HDHP enrollees conducted by Kullgren et al . We alsoDescriptive statistics were used to assess the characteristics of the interview and survey participants. Survey data captured the frequencies of interest in each type of potential educational content and potential delivery modalities. Quantitative data analysis was conducted using Stata (version 16.0).The median age of survey respondents was 47 (IQR 19) years. Survey participants were also mostly White , and most had graduated from college . Approximately half  of them reported an annual household income of >US $100,000. Less than one-fifth  of the participants had an exchange health insurance plan.The median health insurance literacy scores were 60.5 (IQR 13.5) in the interview sample and 68 (IQR 21) in the survey sample. Interview participants reported low levels of confidence in their ability to engage in cost-conscious strategies  compared with survey participants .Interviews yielded four main themes related to health care experiences and intervention preferences: (1) financial and access challenges, (2) promising cost-conscious strategies, (3) barriers to engaging in cost-conscious strategies, and 4) key intervention preferences for an intervention to support engagement in cost-conscious strategies.  key intefinancial and access challenges theme, participants reported difficulties they faced in accessing needed care for their chronic conditions in their HDHPs  interviewees had saved for health care expenses, 10 (50%) had discussed costs with their provider, and 7 (35%) had compared prices using the web. Most  of those who used these strategies found them helpful for managing their health care costs. As illustrated in More than half  of the interviewees faced barriers to engaging in cost-conscious strategies, including low confidence in using these strategies; difficulty in finding cost information; loyalty to providers with whom they had an established relationship; and limited knowledge of how to navigate HSAs, FSAs, and price comparison tools.Interviewees were most interested in a website or app-based intervention that would allow them to easily search for information when they needed to plan for or seek health care. Many participants expressed interest in an intervention that would help them better understand health insurance terms and find transparent OOP cost estimates to manage spending in their HDHPs . When asMost  survey participants had been enrolled in their HDHP for at least 2 years, and most  had met their deductible in 2020. In the past 12 months, approximately one-third  of them reported having been hospitalized at least once, and a similar percentage  reported having at least one emergency room visit. More than one-third  of the participants reported delayed or forgone care owing to cost in the past 12 months.In the past 12 months, most  participants had put aside money for anticipated health care costs, approximately half had engaged in conversations about cost with a clinician  and compared quality of care at different locations , and less than half of them had compared prices for health services . Most  of them had used technological devices to search for health information, and most  had used devices to track health care costs.As displayed in More than half  of HDHP enrollees with chronic conditions who participated in this mixed methods study had saved for health care costs and talked to their providers about cost, but few of them had experience with comparing prices for, and quality of, services at different locations. On the basis of interview responses, comparing prices and discussing costs with providers were the most challenging strategies because of the difficulty in finding transparent information about health care costs and knowing whom to ask for cost information. Half  of the interviewees had had positive experiences when discussing costs with providers because they were able to obtain coupons, postpone elective services, and consider alternative treatment options or low-cost facilities. However, some interviewees were skeptical about the benefit of discussions with their providers, citing experiences in which a provider had given them limited or incorrect information about their OOP costs. Many interview participants also expressed interest in comparing prices for services such as procedures, laboratory tests, imaging, and prescription drugs but were deterred by loyalty to the providers and health systems with whom they had established care. Most of the interviewed  and surveyed  participants were interested in a web-based informational intervention that they would use a few times in a year to help them find and use web-based price and quality comparison tools, learn to discuss costs with providers, and save for medical expenses.This study has several limitations. Our samples included few racial and ethnic minorities, and most  participants had at least a college degree. Although individuals in our samples had relatively high incomes, education, and health literacy, they still faced considerable financial challenges when seeking health care . This suggests an even more pressing need for interventions to support individuals with lower income, health literacy, and formal education. The preferences among our highly educated participants may also differ from those of HDHP enrollees with low levels of education and health insurance literacy, who may benefit more from such an intervention. Our survey sample was not nationally representative because it was corroborated by qualitative interview data, and we felt that a nonrepresentative sample would be sufficient to gather a nationwide range of experiences and perspectives across this patient population. Relatively few individuals with coronary artery disease participated in the study. Many survey items were newly created for this study and have not undergone formal reliability testing; however, they were created based on qualitative themes that emerged during interviews. The use of a 3-point scale to assess interest in intervention components may have limited our precision in measuring intervention preferences. While analyzing the survey results, our focus was on quantifying participants’ preferences, and thus, we used bivariate analyses rather than multivariable analyses. Future studies could more closely examine the variation in perspectives across different subgroups and also include patients with other relatively common chronic conditions such as mental health conditions, which can also lead to high OOP spending in HDHPs.The demographic data we collected from participants did not include household size, and thus, we were unable to calculate household income as a percentage of the federal poverty level. Finally, interview participants were recruited through U-M Health Research  after coOwing to high cost sharing in HDHPs, many enrollees delay and forgo necessary care , experiePrevious interventions have focused on promoting conversations between patients and physicians , helpingshoppable services [A recent rule by the Centers for Medicare and Medicaid Services requires hospitals, as of January 2, 2021, to publish consumer-friendly lists of negotiated rates for 300 services ,34. Begiservices . Hospitaservices . Our finservices . Patientservices  and are services .Survey and interview participants also expressed interest in learning how to effectively discuss costs with their providers. In addition to patient-facing interventions to help patients initiate cost conversations with their providers, future studies and operational initiatives could examine provider-facing technological solutions that integrate cost information into electronic health records, so that providers have information at the point of care to facilitate high-value conversations and decision-making . SchiavoThese results suggest that some of the cost-related challenges that HDHP enrollees with chronic conditions face in their health plans could be mitigated by an intervention that supports their use of cost-conscious strategies when planning for and seeking health care. On the basis of these findings, we are in the process of developing and pilot-testing a website-based and email-based intervention to teach HDHP enrollees with chronic conditions to better understand and use their health plans.Our results suggest that future interventions should be delivered through an accessible, web-based modality with effective cues to use cost-conscious strategies. To improve affordability for this patient population, future interventions should also ensure high utility for those with multiple chronic conditions and low health insurance literacy, who may face great risks of high OOP spending in HDHPs. As many participants reported inaccessibility of transparent price information to be the biggest barrier, interventions and policies should focus on improving the accessibility of price transparency tools to mitigate this challenge. As enrollment in HDHPs continues to increase, health systems, health plans, and employers should explore these short-term strategies and advocate for long-term policy changes to better support the growing number of Americans who are facing high cost sharing in these plans.


Despite recent rises in fatal overdoses involving multiple substances, there is a paucity of knowledge about stimulant co-use patterns among people who use opioids (PWUO) or people being treated with medications for opioid use disorder (PTMOUD). A better understanding of the timing and patterns in stimulant co-use among PWUO based on mentions of these substances on social media can help inform prevention programs, policy, and future research directions. This study examines stimulant co-mention trends among PWUO/PTMOUD on social media over multiple years.We collected publicly available data from 14 forums on Reddit (subreddits) that focused on prescription and illicit opioids, and medications for opioid use disorder (MOUD). Collected data ranged from 2011 to 2020, and we also collected timelines comprising past posts from a sample of Reddit users (Redditors) on these forums. We applied natural language processing to generate lexical variants of all included prescription and illicit opioids and stimulants and detect mentions of them on the chosen subreddits. Finally, we analyzed and described trends and patterns in co-mentions.Posts collected for 13,812 Redditors showed that 12,306 (89.1%) mentioned at least 1 opioid, opioid-related medication, or stimulant. Analyses revealed that the number and proportion of Redditors mentioning both opioids and/or opioid-related medications and stimulants steadily increased over time. Relative rates of co-mentions by the same Redditor of heroin and methamphetamine, the substances most commonly co-mentioned, decreased in recent years, while co-mentions of both fentanyl and MOUD with methamphetamine increased.Our analyses reflect increasing mentions of stimulants, particularly methamphetamine, among PWUO/PTMOUD, which closely resembles the growth in overdose deaths involving both opioids and stimulants. These findings are consistent with recent reports suggesting increasing stimulant use among people receiving treatment for opioid use disorder. These data offer insights on emerging trends in the overdose epidemic and underscore the importance of scaling efforts to address co-occurring opioid and stimulant use including harm reduction and comprehensive healthcare access spanning mental-health services and substance use disorder treatment.The online version contains supplementary material available at 10.1186/s12954-022-00628-2. Stimulant co-use –4, speciRecent findings also suggest that reasons for co-use, particularly with methamphetamine, are multifaceted—such as ease of access, helping boost the “high,” improving daily function , and helping manage withdrawal symptoms . HoweverEstimate the volumes and short- and long-term trends of opioid-stimulant co-mentionsQuantify estimated co-use rates between pairs of specific opioids and stimulants based on these discussionsIdentify when stimulants are initiated evidenced by mentions among PWUO at an individual level based on timelines of postsThe insights we derive in this study are purely data-driven through natural language processing (NLP) methods, as opposed to hypothesis-driven, and our methods account for growth in the number of Reddit users over time. Being data-driven, we did not start our analyses with any underlying assumptions or hypothesis. Our intuition was that the growing number of overdose deaths due to co-use of opioids and stimulants would be reflected on the Reddit data, but this intuition did not affect our approach. A better understanding of the timing and patterns in stimulant co-use among PWUO as evidenced by mentions of these substances on social media can help inform prevention efforts including harm reduction, as well as future research directions. In the remainder of the article, we refer to people who post on specific subreddits of interest as Redditors, people who use or used prescription and/or illicit opioids, people who used an opioid reversal agent , and people with OUD who are being treated with medications for opioid use disorder (MOUD) as PWUO/PTMOUD, people who use stimulants as PWUS, people who use drugs more broadly as PWUD, and people who co-use opioids and stimulants as PWCU.The overarching objectives of this study are to utilize social media conversation data on Reddit to:subreddits and the moderation of forum-specific content by forum users. Reddit communities have also been found to serve as a means of social support for PWUD [Reddit is particularly popular among PWUO and the broader community of PWUD as it can offer anonymity . Reddit for PWUD , 15, 19.for PWUD , Blueligfor PWUD , and Disfor PWUD  for sevefor PWUD –25. ReddTo find potential PWUO on Reddit, we identified 14 opioid-related subreddits spanning discussions on prescription and illicit opioids and MOUD . We focused the study on a set of common opioids, opioid-related medications, and stimulants, including both prescription and illicit types . Thus, we next included additional filters for the terms stimulant, meth, and oxy  of the substances. Since drug names and related expressions are often misspelled on social media, we generated commonly used lexical variants of the terms using the LexExp tool . We founn = 5 following the mention of a negation trigger. Any opioid, opioid-related medication or stimulant term was considered negated if it appeared in the context window following a detected negation expression and if an end of sentence marker  did not occur between the negation term and the drug term. Negated terms were excluded from the final count of mentions. We also manually reviewed samples of posts detected by our searches to identify keywords with a large amount of noise  and excluded those from our counts and further analysis. Of the 13,812 Redditors sampled, a subset who posted in these subreddits had no mention of either an opioid, opioid-related medication or a stimulant (N = 1506) and was excluded from the analyses. All analyses except for those examining the total numbers of Redditors (including PWCU) over time were based on subsets of the remaining 12,306 Redditors who posted about at least one opioid, opioid-related medication, or stimulant.The third NLP task involved implementing a negation detection strategy, customized for Reddit data, to exclude negated drug mentions. Specifically, we used a subset of negation terms from the NegEx algorithm   over the same time frame; and the annual ratio of PWCU to PWUO/PTMOUD. Due to the growing user base of Reddit over time, we expected numbers of PWUO/PTMOUD and PWCU to both increase annually. Hence, the ratio of PWCU to PWUO/PTMOUD likely serves as the best indicator of social media trends in opioid and stimulant co-use within this population.We first studied trends in opioid and stimulant co-use between 2011 and 2020 through multiple metrics, including, the number of Redditors posting each year; the number of Redditors who mentioned at least one opioid or opioid-related medication and one stimulant  frequency of co-use of specific types of opioid-stimulant pairs among PWUO/PTMOUD aggregated over the entire study period; (2) proportion of specific opioids co-used with any stimulant in a given year among the total number of PWCU in that year, to study how mentions of specific opioids or opioid-related medications co-used with any stimulant changed over time; and (3) proportion of specific stimulants co-used with any opioid or opioid-related medication in a given year among the total number of PWCU in that year, to study how mentions of specific stimulants co-used with any opioid changed over time. Redditors with mentions of more than one type of opioid or opioid-related medication or stimulant within a given year were separately considered for each specific opioid-stimulant pair.We combined the opioids and opioid-related medications listed in our analytic sample into 5 categories: 1) heroin, (2) fentanyl & analogs (including carfentanil), (3) Medications for Opioid Use Disorder , (4) opioid overdose reversal agents , and (5) prescription opioid pain relievers . We combined stimulants into 4 categories: (1) methamphetamine, (2) amphetamine-type stimulants , (3) methylphenidate-type stimulants , and (4) a combination of methamphetamine and heroin . Categories included generic names, trade names, and common misspellings or lexical variants  versus those who mentioned a stimulant first .We collected 13,812 Redditor timelines from the 14 subreddits, 12,306 of whom mentioned at least one of our selected opioid, opioid-related medication, or stimulant keywords. Redditors mentioning any opioid or opioid-related medication, or any stimulant in their timelines were approximately evenly distributed—9329 Redditors mentioned opioids or opioid-related medication at some point in their timeline; 9151 mentioned stimulants  and prescription opioids were most frequently mentioned with prescription amphetamine-type stimulants . This suggests possibly distinct populations within the social media substance use forums we studied with preferences for particular types of substances. Further understanding the distinction between populations focused primarily on prescription drug misuse and those focused on illicit substance use, and the transitions between these preferences, is a future area for exploration of online data that may yield insights for better targeting prevention and harm reduction efforts. Indeed, while there is research on prescription stimulant misuse , less isWe found noticeable increases in the proportion of stimulant mentions among individuals also discussing MOUD over time, consistent with recent reports indicating that stimulant use among people receiving treatment for OUD may be increasing , 3. Co-uWhile relative rates of stimulant co-use among individuals using fentanyl appear to be on the rise, the relative rate for co-use among individuals using heroin showed a gradual decrease. This is perhaps a result of changes in the illicit opioid supply over recent years, as heroin has experienced supply shortages , 35 and Future work can also focus on further utilizing NLP and machine learning methodology to conduct more fine-grained characterization of the data, such as annotation of posts to filter out posts that do not self-report consumption of a substance mentioned –43. AdvaOur study has several limitations. Absent contextual information, the primary limitation is the assumption that an individual mentioning an opioid, opioid-related medication, or stimulant is currently using that substance, which may result in overestimation of the number of PWUO/PTMOUD, PWUS, and PWCU, particularly in analyses where these mentions spanned multiple years. Nonetheless, the number of mentions could be a proxy for use and at minimum, mentions of a substance represent some degree of interest or consideration of a particular substance. Also, since the forums from which the Redditors were initially identified are topic-specific, most posts explicitly or implicitly refer to personal experiences.Second, individuals who post on Reddit may not necessarily be representative of all PWUD and caution when generalizing from these findings is warranted. According to a 2019 PEW Research Center report, Reddit has an overrepresentation of males and younger people . Since tThird, not all PWUO, PWUS, and PWCU necessarily mention all the substances they may use. Additionally, we excluded cocaine from our analyses due to concerns around data quality given challenges associated with accurately identifying mentions. Further, our analyses were limited to opioid-related subreddits and excluded any stimulant-related subreddits given our focus on PWUO/PTMOUDs. These limitations may both lead to an underestimation of stimulant and opioid-stimulant co-use. Fourth, we were only able to conduct our analyses on a sample of Redditors due to the time required for retrieving longitudinal Redditor data. Our concerns about this limitation are mitigated by the finding that statistics derived from smaller samples of Redditors early on in our study remained almost identical to those obtained when larger numbers of individuals were included. The exponentially rising number of Reddit subscribers over time also posed a challenge for us, since we could not quantify how much of the increasing opioid or opioid-related medications and stimulant mentions could be attributed to increases in their use in the community versus the growing Redditor numbers. To address this, we examined the ratio of PWCUs to Redditors, which revealed that the growth rate in substance mentions was higher than the growth rate of Redditors. It is possible that other factors contributed to the rising substance mention rates, but we were unable to include such confounding factors in this analysis. Lastly, methodological limitations inherent to all analyses of unstructured text data apply as not all mentions/expressions are detectable by NLP methods , 47. HowOur study included only publicly available data that were retrievable via the Reddit API. No private information was obtained. Subreddits that require membership before viewing content were not included. Since our study falls under the category of observational studies conducted on publicly available data, the Emory University Institutional Review Board (IRB) deemed the study to be exempt (category 4). It was determined that no additional harm to individuals was introduced by the use of the publicly available data. In clinical settings, when protected clinical data of patients are used for research, the standard practice is to seek informed consent prior to inclusion. With social media based observational studies such as ours, obtaining consent requires contacting the subscribers directly, and this action requires a higher level of IRB approval as the direct communication with the subscriber may be considered to be intervention. Such contact also presents bigger challenges in determining if the study presents any additional risk or unanticipated harms to the individual. The ethical considerations that need to be taken into account when conducting research using social media data are evolving through discussions and collaborations among active researchers in this space. Currently, there is some consensus that it is appropriate, and perhaps necessary, to utilize all available public data for addressing serious public health crises, such as the ongoing opioid overdose epidemic . ExcludiWe examined real-world, longitudinal social media data from online opioid-related forums to explore patterns in opioid and stimulant discussions and found large increases in co-mentions of opioids or opioid-related medications and stimulants. These findings are consistent with those from other health data sources suggesting growing co-use of these substances and resultant harms. Although a multitude of factors may influence substance use trends, many are difficult to elucidate and explore using traditional data sources such as survey records or health care data. The social media data we explored offer important exploratory insights into which opioids or opioid-related medications and stimulants are most frequently co-mentioned and how these patterns have changed over time. These data derived from real-world conversations may help in hypothesis generation and yield early insights to shape prevention activities addressing health harms associated with opioid and stimulant co-use.Additional file 1: Appendix.


A greater understanding of the county-level differences in human papillomavirus (HPV) vaccination rates could aid targeting of interventions to reduce HPV-related cancer disparities.n = 68) through purposeful and snowball sampling to identify potential participants who were most knowledgeable about the HPV vaccination activities within their county and would represent a variety of viewpoints to create a diverse picture of each county, and completed semi-structured interviews. County-level HPV vaccine initiation rates for 2018 were estimated from the Florida Department of Health’s immunization registry and population counts. Implementation strategies were categorized by level of importance and feasibility using the Expert Recommendations for Implementing Change (ERIC) taxonomy. We compared the barriers and implementation strategies for HPV vaccination between tercile groups of counties by HPV vaccine initiation rates: highest (18 stakeholders), middle (27 stakeholders), and lowest (23 stakeholders).We conducted a mixed-methods study to compare the stakeholder-reported barriers and efforts to increase HPV vaccination rates between counties within the highest, middle, and lowest HPV vaccine initiation (receipt of the first dose) rates among 22 northern Florida counties. Between August 2018 and April 2019, we recruited stakeholders , non-Hispanic white (73.5%), and represented a variety of clinical and non-clinical occupations. The mentioned barriers represented five themes: healthcare access, clinician practices, community partnerships, targeted populations, and cultural barriers. Within themes, differences emerged between county terciles. Within healthcare access, the highest rate county stakeholders focused on transportation, lowest rate county stakeholders focused on lack of clinicians, and middle county stakeholders mentioned both. The number of ERIC quadrant I strategies, higher feasibility, and importance described decreased with the tercile for HPV vaccination: highest = 6, middle = 5, and lowest =3 strategies.The differing barriers and strategies between the highest, middle, and lowest vaccination rate counties suggest that a tailored and targeted effort within the lowest and middle counties to adopt strategies of the highest rate counties may reduce disparities. Contributions to the literatureHuman papillomavirus (HPV) vaccination rates remain below national objectives in the USA with wide variations in the rates by geography; however, little is known about the local barriers and implementation strategies that attribute to these differences.The results of this study suggest that the Expert Recommendations for Implementing Change (ERIC) taxonomy was a useful tool to compare the implementation strategies on the importance and feasibility between the groups of high, middle, and low performers.Stakeholders reported a decreased number of high-importance implementation strategies ERIC quadrant I, by decreasing HPV vaccination rate tercile; shifting resources to higher-importance strategies may reduce vaccination disparities.In the USA, human papillomavirus (HPV) vaccine initiation i.e., ≥ 1 dose) and up-to-date  rates among 13- to 17-year-olds remain well below the national objectives (75% initiation and 59% up to date)  dose and. SimilarSocial determinants of health, including rurality, race/ethnicity, poverty, and healthcare access, are associated with county-level differences in HPV vaccination rates , 9–11. IHPV vaccine stakeholders  have identified a variety of barriers to HPV vaccination –16. The Across the USA, local vaccine stakeholders are enacting implementation strategies to increase HPV vaccination , 17, 18.To better understand the reasons for the county-level variation of HPV vaccination rates among 13- to 17-year-olds, we conducted a mixed-methods study examining the differences in stakeholders’ reports of county-level barriers to HPV vaccination and local implementation strategies between the highest, middle, and lowest HPV vaccine initiation rate counties. An increased understanding of the reasons behind these differences may identify promising implementation strategies for counties with lower HPV vaccination rates, thus aiding all counties in reaching the American Cancer Society’s goal of achieving 80% of 13-year-olds up to date for HPV vaccination by 2026 [In 2018 and 2019, we conducted a mixed-methods environmental scan of the University of Florida Health Cancer Center (UFHCC) catchment area using the PRECEDE-PROCEED model as a structure for assessing the communities’ needs in order to develop tailored HPV vaccine initiatives [We estimated county-level vaccinations with records of HPV vaccinations from the statewide Florida immunization information system, Florida State Health Online Tracking System (Florida SHOTS™), obtained from the Florida Department of Health. Florida SHOTS™ includes the immunization records from Florida county health departments and participating clinicians . Using FCounties in the UFHCC catchment areas are mostly rural based on Florida Statutes Section 288.0650 16/22 counties), a majority (74%) of the population is White, and 16% of the population lives beneath the national poverty line  counties. Among 2We aimed to complete three stakeholder interviews for each county within the catchment area. We considered stakeholders to be anyone invested in increasing HPV vaccination including healthcare professionals, county extension agents from the UF Institute of Food and Agricultural Science Extension, community leaders, or parents. We used a purposive sampling approach to identify potential participants who were most knowledgeable about the HPV vaccination activities within their county and would represent a variety of viewpoints to create a diverse picture of each county . SpecifiBetween August 2018 and April 2019, we attempted to contact potential participants up to four times, alternating between email and telephone calls. When a stakeholder expressed interest, a study staff member established a time to complete the interview via telephone. Before beginning the interview, the study staff consented participants under a Health Insurance Portability and Accountability Act waiver of documentation of consent. The study staff members that completed the interviews were masters-level trained in public health or related disciplines, were trained to the specific semi-structured interview script by a communication and qualitative expert (CLB), and had no prior relationships with the stakeholders. The first two interviews by each interviewer were reviewed by two authors (CLB and SAS), and feedback was provided to enhance the interviewers’ skills and study-specific probing. In total, 67 interviews of 68 stakeholders were conducted over the phone and audio-recorded with handheld devices. Upon completion of the interviews, participants were offered a $25 gift card. Recordings were immediately transferred to a secure server and uploaded via a Health Insurance Portability and Accountability secure site for transcription. Transcripts were created verbatim and deidentified by a third party. Coders received anonymized transcripts. All procedures were approved by the University of Florida Institutional Review Board.Following the PRECEDE portion of the PRECEDE-PROCEED model , our semFor qualitative analysis, we started by identifying two major categories based on the interview script:  barriersAfter the coding process was complete, one author (SAS), an expert in HPV vaccination strategies and implementation science, and a trainee categorized the implementation strategies described by stakeholders into the 73 discrete implementation strategies as categorized by the Expert Recommendations for Implementing Change (ERIC) taxonomy , 32. Then = 9) were grouped accordingly: three stakeholders in the highest tercile (2 representing two high counties and 1 representing two high counties and one middle county), five in the middle tercile (3 representing two middle counties and one high county and 2 representing one middle and one lowest where one spoke mainly of the middle county), and one in the lowest tercile representing 2 lowest counties. Due to the small number of stakeholders per county (n = 1 to 5) and our recruitment of diverse stakeholders, we did not assess the saturation within counties.After conducting the interviews, we decided to compare the stakeholder responses by county-level HPV vaccination rates. Thus, we divided the counties into terciles based on the 2018 HPV vaccine initiation rates. Dividing the 68 stakeholders interviewed into the highest, middle, and lowest terciles for HPV vaccination rates yielded 18 stakeholders from counties within the highest tercile , 27 stakeholders from counties from the middle tercile , and 23 stakeholders were from counties in the lowest tercile . Stakeholders representing multiple counties , non-Hispanic white (73.5%), and represented a variety of clinical and non-clinical occupations Table . OverallStakeholders from all settings, highest, middle, and lowest HPV vaccine initiation rate counties, mentioned barriers within five saturated themes . Differences emerged within themes between the highest, middle, and lowest counties Table . The numStakeholders from all types of counties mentioned clinician practices as a barrier. Yet, the highest rate county stakeholders focused on the quality and strengths of clinician recommendations, and the middle and lowest rate county stakeholders focused on clinicians referring patients to the health department for vaccinations instead of offering the vaccine on site. Similarly, stakeholders from all county terciles mentioned difficulties with community partnerships: highest and middle rate county stakeholders focused on difficulties partnering with schools and the lowest rate county stakeholders discussed difficulties partnering with churches. All groups discussed limited knowledge as a barrier to HPV vaccine; however, the highest rate county stakeholders focused the discussion on healthcare providers, and the middle and lowest rate county stakeholders focused on parents in the community. Finally, cultural barriers were a focus of all groups with the highest and middle rate county stakeholders focusing on vaccine exemptions and the lowest rate county stakeholders focusing on religious beliefs.Overall, the number of implementation strategies described by stakeholders decreased by HPV vaccination tercile: 20 in the highest, 19 in the middle, and 13 in the lowest rate counties Table . SimilarWe have done several trainings with providers in teaching them about the ‘Same Day, Same Way,’ helping them to dispel myths, providing them with education about different cancers associated with HPV.In contrast, a representative stakeholder from the lowest vaccination rate counties mentioned training focused on using school nurses to educate students about the vaccine, stating:education provided, again, by the health department for the school nurse liaison as well as the school nurses.Similarly, within quadrant IV strategies, considered lower feasibility and higher importance, stakeholders from the highest and middle rate counties mentioned the most strategies (11 strategies) and stakeholders from the lowest rate counties mentioned the fewest (7 strategies). While stakeholders from all three tercile rate counties mentioned using schools to deliver information to parents, only the highest rate county stakeholders mentioned incorporating HPV in public school sex education. Stakeholders from middle and lower rate counties mentioned that school nurses focus on cancer prevention when discussing the HPV vaccine.Stakeholders from all tercile vaccination rate counties mentioned strategies that directly intervened with parents including participating at health fairs, offering incentives, and dentists discussing the links between HPV and oral cancer. Stakeholders from higher and middle rate counties mentioned using strategies to directly address barriers including sending reminder text messages to parents, offering vaccines at schools or family planning clinics, and offering bus passes. For example, one healthcare provider from a county with a higher vaccination rate described a strategy at schools that provided education and administered the vaccine:There is a school kind of firmly planted in that area where, you know, most of those particular children actually attend, and we did partner with them and offer vaccines at their site.In contrast, a stakeholder from the lowest vaccine rate county described a strategy at schools teaching students about the vaccine:So, you know, again, it’s not like a scared straight type of deal, but it’s kind of similar. You have to show those graphics, so they can actually see that there is a potential for them to get that if they don’t get vaccinated. So, they can actually become their own advocates and tell their parents they do want that.Finally, while some stakeholders from middle tercile counties were able to offer vaccines at schools, most mentioned that schools in their area were resistant to the idea. For example, one stakeholder said:There are some counties we’ve heard where they’re actually doing the vaccines in school. … We haven’t had a whole lot of success in communicating with schools to do that.Stakeholders from all tercile vaccination rate counties did not mention quadrant II strategies, higher feasibility, and lower importance and described a similar number and type of quadrant III strategies considered lower feasibility and lower importance.Important differences in barriers and implementation strategies emerged between northern Florida counties with the highest, middle, and lowest HPV vaccine initiation rates, while stakeholders reported barriers focused on similar themes to each other and prior literature –17, 34, Consistent with previous research –17, 34, Differences between higher, middle, and lower vaccination rate counties add evidence to the possibility of local implementation strategies influencing community vaccination rates , 36. ForOur application of the ERIC framework to the qualitative interviews from stakeholders strengthens and expands the use of the ERIC framework as a strategy to evaluate the differences in implementation strategies between the high- and low-performing groups. The ERIC strategy has been used to quantitively divide the strategies reported in the focus groups . One stuImportantly for the promotion of HPV vaccination, the identified differences in ERIC framework implementation strategy importance between high, middle, and low tercile vaccination counties suggests that implementing higher importance strategies in lower tercile counties may help resolve HPV vaccination disparities. In particular, only stakeholders from the highest and middle tercile HPV vaccine initiation counties described using well-established, evidence-based implementation strategies classified as higher feasibility and higher importance, including reminder-recall messages for parents and training clinicians to strengthen their HPV vaccine recommendations –47. StakOur study includes three important limitations. First, the collected data is a cross-sectional snapshot of practices and vaccination rates in the counties. Thus, we cannot evaluate the cause-and-effect relationship between implementation strategies and vaccination rates. Second, all data were collected at the county level, and important differences in HPV vaccination, barriers, and implementation strategies within counties may have been overlooked. Third, there are important demographic differences  between county terciles that likely affect HPV vaccination rates in conjunction with their implementation practices. For example, it may be more difficult to counteract HPV vaccine misconceptions in the more rural areas typical of the middle and lowest tercile due to the limited healthcare providers, greater parent vaccine hesitancy, and transportation difficulties –54. AddiOur study includes three important strengths. First, expanding other stakeholder studies of HPV vaccination –16, we cComparing stakeholder opinions about barriers and implementation strategies between the highest, middle, and lowest tercile counties for HPV vaccine initiation revealed important differences. The ERIC implementation taxonomy was particularly useful in classifying the importance and feasibility of strategies used by the higher, middle, and lower tercile counties. The study provides an example of how the ERIC implementation taxonomy can be used to compare implementation strategies between the groups. Taking the unique barriers of limited healthcare professionals and religious concerns into account, lower and some middle tercile counties could be encouraged to adopt implementation strategies of higher importance such as reminder/recall, providing alternative locations for vaccinations, training clinicians in recommendation strategies, and addressing barriers to clinician participation in Vaccines for Children. Achieving equity for HPV vaccination across Florida will require tailored and targeted efforts within lower vaccination rate counties.


In atrial and ventricular tachyarrhythmias, reduced time for ventricular filling and loss of atrial contribution lead to a significant reduction in cardiac output, resulting in cardiogenic shock. This may also occur during catheter ablation in 11% of overall procedures and is associated with increased mortality. Managing cardiogenic shock and (supra) ventricular arrhythmias is particularly challenging. Inotropic support may exacerbate tachyarrhythmias or accelerate heart rate; antiarrhythmic drugs often come with negative inotropic effects, and electrical reconversions may risk worsening circulatory failure or even cardiac arrest. The drop in native cardiac output during an arrhythmic storm can be partly covered by the insertion of percutaneous mechanical circulatory support (MCS) devices guaranteeing end-organ perfusion. This provides physicians a time window of stability to investigate the underlying cause of arrhythmia and allow proper therapeutic interventions . Temporary MCS can be used in the case of overt hemodynamic decompensation or as a “preemptive strategy” to avoid circulatory instability during interventional cardiology procedures in high-risk patients. Despite the increasing use of MCS in cardiogenic shock and during catheter ablation procedures, the recommendation level is still low, considering the lack of large observational studies and randomized clinical trials. Therefore, the evidence on the timing and the kinds of MCS devices has also scarcely been investigated. In the current review, we discuss the available evidence in the literature and gaps in knowledge on the use of MCS devices in the setting of ventricular arrhythmias and arrhythmic storms, including a specific focus on pathophysiology and related therapies. Ventricular arrhythmias are responsible for a significant number of sudden cardiac deaths (SCD) . ImplantHeart failure with reduced ejection fraction is burdened with a higher risk of SCD and poor prognosis. Left ventricular ejection fraction (LVEF) has been recognized as the strongest predictor of ventricular arrhythmias and mortality in patients with cardiomyopathies , and it Catheter ablation (CA) of ventricular tachycardia (VT) represents a percutaneous technique that can permanently treat VT and prevent its recurrence. Current expert consensus recommends using CA for recurrent VT refractory to antiarrhythmic therapy or in those who tolerate antiarrhythmic drugs poorly . PreprocPatients requiring CA for ventricular arrhythmias may present with structural heart disease, commonly ischemic heart disease. In such a clinical scenario, acute hemodynamic decompensation during the CA procedure is not uncommon, affecting 11% of patients and is associated with an increased mortality rate . In addiMechanical circulatory support (MCS) devices, such as Impella and venoarterial extracorporeal membrane oxygenation (VA ECMO), may represent an appealing tool to support blood pressure and guarantee adequate end-organ perfusion during the CA of VT. However, MCS implantation carries its own costs and intrinsic risk of complications, mainly related to bleeding and vascular complications , 14. Foret al. analyzed the available evidence regarding the use of temporary MCS in life-threatening arrhythmias with interesting conclusions about the application of the PAINESD risk score, as further discussed, and the prophylactic use of VA ECMO for an electrical storms  is determined by the heart rate (HR) and by the stroke volume (SV) of the left ventricle (LV). The latter is the difference between end-diastolic (EDV) and end-systolic volume (ESV).* SVCO = HR SV = EDV – ESVFrom the first equation, it is easy to understand that (extreme) bradycardia will lead to decreased cardiac output and eventual low-output cardiogenic shock (CS) . In paraAcute sustained bradycardia is most frequently related to hypoxia , conductThe most frequent malignant tachyarrhythmia is ischemia-induced sustained VT, which can result in ventricular fibrillation (VF), SCD, or CS. VT can be related to a new onset acute myocardial infarction or rising from scar tissue from a previous insult . Lethal In a normal cardiac cycle, the LV overcomes the diastolic blood pressure during the isovolumetric contraction phase until the aortic valve opens and the intraventricular blood gets ejected .This drop in the native cardiac output during an arrhythmic storm can be partly covered by the insertion of a percutaneous mechanical circulatory support device , which offers a continuous forward flow of blood from the LV into the aorta. This flow is both afterload sensitive, with end-organ perfusion increasing with lower systemic vascular resistance, and preload dependent, requiring sufficient volume from the right ventricle to operate effectively. If the failing LV can no longer overcome afterload in the new equilibrium of increased mean arterial pressure and reduced preload created by the continuous flow of the percutaneous MCS device, the arterial trace will flatten. This process is called ventriculoarterial uncoupling  28)..28).Bradycardia-induced CS can often be reversed by positive chronotropic agents or urgent temporary (ventricular) pacing, which leaves physicians a time window for diagnosing and resolving the underlying cause.Management of patients with CS shock and (supra) ventricular arrhythmias is particularly difficult. Inotropic treatment, such as dobutamine, is recommended for CS but may exacerbate supraventricular tachycardia or accelerate the heart rate in these patients. Antiarrhythmic drugs  often have negative inotropic effects and may exacerbate the CS state. Electrical reconversions often risk worsening circulatory failure or cardiac arrest in these critically ill CS patients. Therefore, urgent implementation of MCS devices can be an effective way of stabilizing CS patients and allowing physicians a time window of stability to investigate the underlying cause of the arrhythmia and allow therapeutic interventions  . The fieLeft ventricular assist devices (LVADs) are used to support a failing heart as a temporary means (bridge to recovery and bridge to transplant) or as destination therapy. The interaction between reduced native cardiac function and continuous flow generated by LVAD creates a complex interplay, which may impact the restoration of LV performance.in vitro study by Viola et al. confirmed how LVAD flow affects intraventricular hemodynamics and pressure. Indeed, the unloading of LV generated by LVAD causes a reduction in ventricular peak systolic pressure, which is related to LVAD output  in patients who received pre-emptive insertion of percutaneous LVAD (Impella) compared to patients undergoing rescue insertion of MCS .Although the evidence is still scant, the clinical rationale for preemptive implantation of temporary MCS during high-risk CA of VT is strong. The adequate timing of temporary MCS implantation for high-risk patients  undergoing CA of VT is still under debate. However, it is evident that this aspect is of pivotal importance given the high mortality rate of patients requiring emergent implantation of MCS during CA procedures. For this reason, it is crucial to identify, before the procedure, those patients who may experience acute hemodynamic deterioration during the CA of VT.In 2015, Santangeli et al. studied the prevalence and predictors of periprocedural acute hemodynamic decompensation in patients undergoing radiofrequency CA for scar-related VT. In this study, almost one out of 10 patients experienced hemodynamic instability, impacting mortality. The authors identified eight clinical factors predicting periprocedural acute hemodynamic decompensation (PAINESD risk score): advanced age, chronic obstructive pulmonary disease, use of general anesthesia, ischemic cardiomyopathy, heart failure (NYHA classes III and IV), lower LV ejection fraction, presentation with VT storm, and diabetes mellitus .p-value = 0.02]. Conversely, patients with a predicted low risk of acute hemodynamic decompensation did not experience any benefit   0.43; 95% confidence interval (CI) 0.21–0.87;  = 0.35) .robust tool to identify high-risk patients who might benefit from temporary prophylactic MCS during electrophysiological studies.” They suggested a PAINESD cut-off score of 15 for considering preemptive implantation of temporary MCS, particularly if prolonged VT mapping is required or long phases of unstable VT are expected  or no mechanical support .One year later, Bunch et al. analyzed a cohort of high-risk patients with hemodynamically unstable VT undergoing CA guided by activation and entrainment mapping and assisted by Tandem Heart. Despite longer procedure times, the outcomes of acute complications (including death and stroke) and freedom from ICD or therapies for sustained VT were comparable to a matched cohort undergoing substrate mapping without temporary MCS .In a retrospective study, Aryana et al. demonstrated a shorter total radiofrequency ablation time for patients receiving percutaneous LVAD for CA of unstable VT compared to procedures without MCS. That was accompanied by a reduced length of hospital stay . The subDespite the differences found in diverse case series, the long-term follow-up did not reveal any statistically significant difference in rates of VT recurrence between patients undergoing CA with and without temporary MCS , 40. TheIn the context of hemodynamically tolerated ventricular arrhythmias, the substrate-based CA strategy has proven to have similar acute procedural efficacy and VT recurrence compared with activation and entrainment mapping, with a comparable rate of complications and mortality . For thoDifferent devices, from IABP to VA ECMO, have been proposed as hemodynamic support during CA procedures, thus further increasing the variability between the studies. Each MCS device can guarantee a different level of cardiovascular assistance. Unfortunately, only a few studies have addressed the specific issue of direct comparison between MCS devices.IABP was proven less effective in providing hemodynamic support than percutaneous LVAD (Impella 2.5) during CA for VT. In a multicentre study, Reddy et al. found that implantation of Impella or Tandem Heart facilitated activation and entrainment mapping of several unstable VTs with fewer rescue shocks compared to patients supported with IABP . A retroImpella and Tandem Heart have specific contraindications to their implantation: LV thrombosis, mechanical aortic valve replacement, and ventricular septal defect. These contraindications must be considered when choosing a temporary MCS device. Furthermore, these two devices are burdened with technical limitations related to the requirement of transeptal puncture for Tandem Heart and electromagnetic interference during mapping for Impella .VA ECMO can provide both biventricular and respiratory support, thus allowing its use in extreme conditions of hemodynamic instability, such as cardiac arrest, and as a bridge to recovery or heart transplantation , 43. ComGiven its unparalleled capacity to provide end-organ perfusion, VA ECMO represents a useful solution for hemodynamic support in adult patients presenting with electrical storm, VT refractory to antiarrhythmic therapy, and recurrent VF. The combination of hypotension due to refractory VT/VF, cardiac stunning related to repeated shocks, and the frequent requirement for sedation/anesthesia during CA for VT/VF arrhythmic storms may precipitate acute hemodynamic decompensation . In the VA ECMO is the most commonly used temporary MCS device as a rescue strategy for cardiovascular support in children requiring radiofrequency ablation for tachycardia-induced cardiomyopathy , 46, forPermanent ventricular assist devices (VADs) represent a therapeutic option for end-stage heart failure as a bridge to heart transplantation or even as “destination therapy” . The repLin et al. have addressed the role of ventricular arrhythmias in patients with biventricular assist devices (BIVAD) in a retrospective cohort study . The prePatients with CS refractory to inotropic agents and vasopressors have a poor prognosis, and the VA ECMO offers the ability to restore hemodynamics and prevent end-organ damage. Time to decision and time to initiate VA ECMO is crucial. A narrow “window of opportunity” for rescue VA ECMO intervention exists, beyond which a patient may develop hypoperfusion brain damage, multiorgan failure, reperfusion sepsis, and is too ill to benefit from a temporary MCS .cor pulmonale.The applications of the VA ECMO in life-threatening arrhythmias encompass arrhythmogenic storm triggered by cardiac ischemia, fulminant myocarditis with ventricular arrhythmias, periprocedural in the cath-lab, accidental hypothermia, and some poisonings  . Right vIn a patient younger than 70 years with cardiac arrest, an ideal therapeutic window for a VA ECMO start  is within 40 min from the witnessed collapse. The maximum associated delay with acceptable rates of cerebral performance score (CPS) 1–2 is up to 60 min. Crucial is decision-making at 10–15 min of refractory cardiac arrest. That also relates to the expected transfer to the facility or the ECMO to the scene and percutaneous cannulation times of ~14–20 min  trial. The investigators reported rates of survival to hospital discharge up to 60% among recipients of ECMO after in-hospital cardiac arrest (IHCA), especially when related to cardiac etiology (p < 0.0001) (ECMO has demonstrated its impact on outcomes of cardiac arrest and CS . The suretiology . Acute m 0.0001) . ECMO yiThe use of VA ECMO during periprocedural arrhythmia is increasing. A substantial mortality benefit was observed among high-risk patients identified with a PAINESD risk score or suffering from electrical storm and treated with preemptive temporary MCS . The patSevere accidental hypothermia is associated with ventricular arrhythmias –69, and 2 production  with decreasing blood flow and lower sweep gas flow. These are related to an early afterload effect on the heart recovering from hypothermia and hypothermia-related low COoduction .The cannulation should not interfere with the CA techniques if inserted as periprocedural support with a femoro-femoral approach, representing the desirable configuration for periprocedural support or during ECLS.In all the settings, the return arterial cannula may frequently block the distal leg perfusion, which is, in most centers, solved by routine cannulation of the prograde 6–7F vascular sheath into the superficial femoral artery. The insertion should be as close to the ECMO return cannula as possible because the no-flow segment between them soon becomes a site of thrombus formation.A minimum cardiac output of 1–2 l/min should be maintained even in circulatory failure supported by the VA ECMO, which would secure LV unloading and prevent intracardiac thrombus formation. If this is not possible, the available methods of unloading are Impella, a surgical vent of the LV either through the mitral valve and left atrial auricle or transseptal approach, or to a certain degree, also with the IABP , 73.Details regarding VA ECMO configuration, hemodynamics, and complications are beyond the scope of the current review and are detailed elsewhere.As detailed above, MCS is an effective strategy to rest the heart and support the circulation when it is compromised by ineffective cardiac contraction during an arrhythmic storm. Although sinus rhythm may be restored after the initiation of VA ECMO in the ECLS setting, intractable ventricular arrhythmias may persist despite full circulatory support. In a recent publication of patients treated with MCS during arrhythmic storm, no differences between survivors and non-survivors were noted according to the use of antiarrhythmic drugs  .The percutaneous blockade of the stellate ganglion has been described in different populations, including in patients with electrical storm on MCS. It is a minimally invasive (either blind or ultrasound-guided) technique that has been demonstrated to relieve ventricular arrhythmic burden in a remarkable rate of patients when all other pharmacological therapies failed without serious complications –77.Large studies have reported an overall prevalence of arrhythmias after SARS-CoV-2 infection that ranges from 10 to 20%, although the incidence is greatly increased in individuals with severe disease. Arrhythmias are supraventricular in most of the critically ill patients with COVID-19. However, 40% of the overall arrhythmias are ventricular tachyarrhythmias, bradyarrhythmias, and conduction defects, which are associated with remarkably high mortality .via several mechanisms, including complex modulatory activities on the expression and function of specific ion channels and gap junction-forming connexins, cytochrome system inhibition, and structural remodeling by activating the myofibroblast-driven synthesis of extracellular matrix responsible for cardiac fibrosis , from which the publication fees have been provided.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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