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STUDY DESIGN.: Telephone survey and longitudinal analysis of judicial database for cohort of worker's compensation (WC) claimants in Missouri. OBJECTIVE.: To compare legal difficulties experienced by African American and white WC claimants presettlement versus postsettlement. SUMMARY OF BACKGROUND DATA.: Retrospective studies suggest that workers with occupational back injuries experience financial and personal duress after claim settlement. This study examined these issues by comparing financial and domestic court actions for the 5-year presettlement against 5-year postsettlement. Sociodemographic differences also were examined. METHODS.: Missouri judicial records were reviewed for African American (n = 580) and non-Hispanic white (n = 892) WC claimants to determine the frequency with which four types of cases occurred: general financial, domestic financial, residence financial, and domestic behavior. Average annual level of judicial activity during the 5 years before claim settlement was compared to activity for each of five postsettlement years; significance of change was evaluated with univariate and multivariate repeated measures analyses. RESULTS.: Statistically significant (P < 0.001) postsettlement increases in legal cases were noted for each of the four categories of cases. There were significant interactions between race and time for general financial and domestic financial cases. A significant interaction between age and time occurred for general financial cases. Significant three-way interactions (race x income change x time) emerged for general and domestic financial cases. CONCLUSION.: The results confirm that workers with occupational back injuries, especially African American and younger adults, encounter long-term financial and domestic duress that appears to escalate with each passing year after claim settlement. This pattern suggests that short-term studies underestimate postsettlement difficulties, particularly among selected demographic cohorts. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the factor structure of a telephone-administered Pain Disability Index (PDI) and the effects of race and sex on the PDI. DESIGN: Computer-assisted telephone interviews of a cohort with occupational low back injuries. SETTING: General community. PARTICIPANTS: Missouri workers compensation claimants (N=1329) with low back injuries. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PDI, levels of pain severity, Social Security Disability Insurance status, and the Fear-Avoidance Behavior Questionnaire. RESULTS: Results for the total sample and by race/sex group indicated support for a 2-factor model of the PDI corresponding to voluntary activities (eg, social, occupational, recreational) and obligatory activities (eg, activities of daily living, eating, sleeping). Additional psychometric analyses of the voluntary and obligatory subscales indicated adequate reliability and construct validity overall and in each of the race/sex groups. African Americans reported more pain-related disability on both subscales than whites. Women reported more disability on the voluntary subscale than men. CONCLUSIONS: The results support use of the PDI as a bidimensional measure of pain-related disability, with strong psychometric properties. They also support its administration by telephone. Copyright © 2005 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation [ABSTRACT FROM AUTHOR]

CONTEXT: Pain has significant socioeconomic, health, and quality-of-life implications. Racial- and ethnic-based differences in the pain care experience have been described. Racial and ethnic minorities tend to be undertreated for pain when compared with non-Hispanic Whites. OBJECTIVES: To provide health care providers, researchers, health care policy analysts, government officials, patients, and the general public with pertinent evidence regarding differences in pain perception, assessment, and treatment for racial and ethnic minorities. Evidence is provided for racial- and ethnic-based differences in pain care across different types of pain (i.e., experimental pain, acute postoperative pain, cancer pain, chronic non-malignant pain) and settings (i.e., emergency department). Pertinent literature on patient, health care provider, and health care system factors that contribute to racial and ethnic disparities in pain treatment are provided. EVIDENCE: A selective literature review was performed by experts in pain. The experts developed abstracts with relevant citations on racial and ethnic disparities within their specific areas of expertise. Scientific evidence was given precedence over anecdotal experience. The abstracts were compiled for this manuscript. The draft manuscript was made available to the experts for comment and review prior to submission for publication. CONCLUSIONS: Consistent with the Institute of Medicine's report on health care disparities, racial and ethnic disparities in pain perception, assessment, and treatment were found in all settings (i.e., postoperative, emergency room) and across all types of pain (i.e., acute, cancer, chronic nonmalignant, and experimental). The literature suggests that the sources of pain disparities among racial and ethnic minorities are complex, involving patient (e.g., patient/health care provider communication, attitudes), health care provider (e.g., decision making), and health care system (e.g., access to pain medication) factors. There is a need for improved training for health care providers and educational interventions for patients. A comprehensive pain research agenda is necessary to address pain disparities among racial and ethnic minorities. [ABSTRACT FROM AUTHOR]

Recent evidence has indicated that physician judgments of patients can be influenced by contextual factors. This study examined three contextual factors relevant to hypothetical patients with low back pain, using vignettes that were varied in a 2 x 2 x 2 factorial design: level of reported pain (high vs low), level of supporting medical evidence (high vs low), and the valence of the physician-patient interaction (positive vs negative). Perceived levels of pain, disability, emotional distress, and somatic preoccupation were rated by internists after reading a vignette. Ratings of pain and disability were lower for patients without supporting medical evidence; ratings of distress, somatic preoccupation, and disability were greater for patients who exhibited negative rather than positive affect; internist ratings of pain were lower than patient ratings among patients reporting high levels of pain, while ratings were inflated for patients with low levels of pain. The results suggest that characteristics of both the patient and the situation may influence medical judgments. [ABSTRACT FROM AUTHOR]

Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data., Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling., Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01)., Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: This study examined factors influencing lay perceptions of a provider's clinical burden in providing care to a person with chronic pain., Design: In a between-subjects design that varied three levels of pain severity (4, 6, or 8 out of 10) with two levels of medical evidence (low/high), participants rated the credibility of pain reported by a hypothetical patient and the psychosocial factors expected to mediate the effects of evidence and severity on a provider's burden of care., Setting: A randomized vignette study in which community participants were recruited via Amazon Mechanical Turk., Subjects: 337 community participants., Methods: Using a Qualtrics platform, participants read one of six vignettes describing a hypothetical patient with varying levels of medical evidence and pain severity and then rated perceived pain severity, pain credibility, psychosocial variables, and burden., Results: Serial mediation models accounted for all effects of medical evidence and pain severity on burden. Low medical evidence was associated with increased burden, as mediated through lower pain credibility and greater concerns about patient depression, opioid abuse, and learning pain management. Higher levels of reported pain severity were associated with increased burden, as mediated through greater pain discounting and concerns about opioid abuse., Conclusions: The lay public is skeptical of chronic pain that is not supported by medical evidence or is reported at high levels of severity, raising concerns about psychosocial complications and drug seeking and expectations of higher burden of care. Such negative stereotypes can pose obstacles to people seeking necessary care if they or others develop a chronic pain condition., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Measures are lacking that assess the clinical burden that healthcare providers perceive in treating chronic conditions. This study presents a preliminary psychometric evaluation of a novel self-report measure of provider burden in the treatment of chronic pain. Data for eight burden items were available from vignette studies examining the effects of patient pain severity and medical evidence on clinical burden and judgments for chronic pain. Participants (N = 922) were 109 physicians and 813 non-physicians, all acting in the role of physician (232 community members without chronic pain, 105 community members with chronic pain, and 476 American Chronic Pain Association members with chronic pain). Factor analyses of burden items yielded one-factor solutions in all samples, with high factor loadings and adequate explained variance. Internal consistency reliability was uniformly high (≥ 0.87). Burden scores were significantly higher among physicians compared to nonphysicians; nonphysician groups did not differ on any burden score. Significant correlations of burden score with indicators of psychosocial complications in patient care supported scale validity. Burden score was not associated with gender, age, or education. Results provide initial support for the psychometric properties of a Healthcare Provider Burden Scale (HPBS). Research utilizing larger and representative healthcare provider groups is needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hemophilia is a congenital bleeding disorder caused by low levels of clotting factor VIII or IX. The life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased; in retrospective studies, there are conflicting data regarding if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH vs the predicted incidence. This prospective, multicenter, observational study included adult PWH (aged >30 years) from The Netherlands and United Kingdom. They were followed up for a 5-year period, and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary end point was the observed fatal and nonfatal CVD incidence after 5 years compared with the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years' follow-up or reached an end point. For 108 patients, the QRISK score could not be calculated at inclusion. For the remaining 579, fewer CVD events were observed than predicted: 9 vs 24 (relative risk, 0.38; 95% confidence interval, 0.18-0.80; P = .01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistically significant relation between severity of hemophilia and incidence of CVD. In hemophilia, a lower-than-predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov as #NCT01303900., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This study compared perceptions of the burden of patient care and associated clinical judgments between physicians and people with chronic pain (PWCP) in a 2 × 3 × 2 between-subjects design that varied participant type, patient-reported pain severity (4/6-8/10), and supporting medical evidence (low/high). One hundred and nine physicians and 476 American Chronic Pain Association members were randomly assigned to 1 of 6 conditions. Respondents estimated the clinical burden they would assume as the treating physician of a hypothetical patient with chronic low back pain, and made clinical judgments regarding that patient. Physician burden ratings were significantly higher than PWCP ratings, and clinical impressions (eg, trust in pain report, medical attribution) and management concerns (eg, opioid abuse risk) were relatively less favorable. Neither pain severity nor medical evidence affected burden ratings significantly. High medical evidence was associated with more favorable clinical impressions; higher pain severity led to more discounting of patient pain reports. Burden was significantly correlated with a range of clinical judgments. Results indicate that physicians and PWCP differ in their perceptions of provider burden and related clinical judgments in ways that could impact treatment collaboration. Further research is needed that examines provider burden in actual clinical practice. PERSPECTIVE: Physicians and people with chronic pain (PWCP) estimated the clinical burden of patient care and made judgments about a hypothetical patient with chronic pain. Physician burden ratings were higher and clinical judgments less favorable, relative to PWCP respondents. These differences could impact treatment collaboration and merit study in clinical practice., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

While patient perceptions of burden to caregivers is of recognized clinical significance among people with chronic pain, perceived burden to treating physicians has not been studied. This study examined how people with chronic pain perceived levels of medical evidence (low vs high) and pain severity (4,6,8/10) to influence physician burden and how burden then mediated expected clinical judgments. 476 people with chronic pain read vignettes describing a hypothetical patient with varying levels of medical evidence and pain severity from the perspective of a treating physician, rated the burden that patient care would pose, and made a range of clinical judgments. The effect of pain severity on clinical judgments was expected to interact with medical evidence and be conditionally mediated by burden. Although no associations with burden were found for the pain severity x medical evidence interaction or for pain severity alone, low levels of supporting medical evidence yielded higher burden ratings. Burden significantly mediated medical evidence effects on judgments of symptom credibility, clinical improvement, and psychosocial dysfunction. Results indicate that perceived physician burden negatively influenced judgments of patients with chronic pain, beyond the direct effects of medical evidence. Implications are discussed for clinical practice, as well as future research. PERSPECTIVE: : People with chronic pain expect physicians to view the care of patients without supporting medical evidence as burdensome. Higher burden is associated with less symptom credibility, more psychosocial dysfunction, and less treatment benefit. Perceived physician burden appears to impact how patients approach treatment, with potentially adverse implications for clinical practice., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Persistently impaired culprit artery flow (

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease., (© 2020 by The American Society of Hematology.)

Background: Thrombomodulin-associated coagulopathy (TM-AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis., Objectives: To report the characteristics of pedigree with a novel THBD variant causing TM-AC, and co-inherited deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI)., Patients/methods: Identification of pathogenic variants in hemostasis genes by next-generation sequencing and case recall for deep phenotyping., Results: Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs*10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM&#95;AC cases with THBD p.Cys537*. Coincidentally, some pedigree members also harbored a stop-gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM-AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation., Conclusions: These data extend the reported genetic repertoire of TM-AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra-cellular domain. The data further confirm that the delay in fibrinolysis associated with TM-AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin-TM system and its regulation of TAFI., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background:  The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required., Methods:  Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM)., Results:  A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI: -9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children., Conclusion:  We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years., Competing Interests: J.M.H. has received a grant from CSL Behring outside the submitted work. M.M. has received consultancy fees from Takeda, Bayer, Roche Novo Nordisk, Sobi and Freeline and gave advisory board input to Takeda, Travel support form Takeda, CSL, Novo Nordisk and Roche. P.W.C. has received research support from CSL Behring and consultancy fees from Sobi, Roche and Bayer. R.C. Tait has received consultancy fees from Bayer Healthcare, Pfizer, Shire, NovoNordisk, Sanofi, Sobi and Daiichi-Sankyo, and travel grants from Bayer Healthcare, NovoNordisk and CSL Behring. S.M. has received consultancies from Novonordisk, Roche, Pfizer and Takeda, and funding for travel/conference registration from Octapharma and Sobi. B.M. has received financial support to attend meetings by SOBI and Amgen and gave lectures for Pfizer over the last year. F.W.G.L. has received unrestricted research grants from CSL Behring and Shireoutside the submitted work, and is consultant for Shire, uniQureand Novo Nordisk, for which the fees go to the institution. He is a DSMB member for a study supported by Roche. The institution of K.F. has received unrestricted research grants from CSL Behring, Bayer and Novo Nordisk and her institution received consultancy fees from Shire, Roche, Novo Nordisk and B.K.M. has received research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, BoehringerIngelheim, BMS and Aspen; and consulting fees from uniQure. P.C. has received grants and/or personal fees from Bayer, Baxalta, Biogen, Bioverativ, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Shire, Spark and Sobi. M.H.C. has received grants from governmental research institutes such as Dutch Research Institute (NWO), ZonMW, Innovation fund, and unrestricted investigator initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/ Baxalta/ Shire, Bayer Schering Pharma, CSL Behring, SobiBiogen, Novo Nordisk, Novartis and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer. All grants, awards and fees go to the institution. R.M. has received travel grants from Shire and Bayer. The UK Enhanced Half-Life registry was funded by a grant from Sobi. The remaining authors declare no competing financial interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST-segment-elevation myocardial infarction. In the T-TIME (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low-dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T-TIME trial. From 2016 to 2017, patients with ST-segment-elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double-blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2-4, and ≥4 hours) were prespecified. One hundred forty-four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0-55.0), coronary flow reserve(1.4 [1.1-2.0]), and resistive reserve ratio (1.7 [1.3-2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve ( P =0.013), resistive reserve ratio ( P =0.026), and microvascular obstruction ( P =0.022), but not index of microcirculatory resistance. Conclusions In ST-segment-elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension FH+), 75 had hypertension and a negative family history of hypertension (hypertension FH-), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension FH+, both in the univariate (OR = 1.84 [1.17-2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03-3.16], P = .04). Macroscopic hematuria was not associated with hypertension FH-. Moreover, in a multivariate logistic regression the odds of hypertension FH+ were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.

Introduction: Macroscopic hematuria is considered a significant risk factor for urologic disease, and it is highly prevalent in people with hemophilia., Aim: To determine whether prophylactic factor replacement therapy is associated with reduced occurrence of macroscopic hematuria in people with hemophilia in a post hoc analysis using data from a cross-sectional study conducted by the Age-Related Developments and Comobordities in Hemophilia (ADVANCE) Working Group that included males with hemophilia ≥40 years of age., Methods: Data from 16 contributing centers, in 13 European countries and Israel, were analyzed using logistic regression. Of 532 recruited individuals, this analysis included 370 patients with moderate or severe hemophilia who received on-demand or prophylactic therapy., Results: For patients with a history of macroscopic hematuria, we analyzed the association between prophylaxis and reoccurrence of macroscopic hematuria within the past 5 years (n = 235 patients). Frequent (≥3 times/wk) prophylaxis was negatively associated with a recent episode of macroscopic hematuria (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.76). We also analyzed whether prophylaxis corresponded to a lower lifetime number of macroscopic hematuria episodes (n = 285 patients). Frequent prophylaxis for >15 years was associated with a lower number of episodes compared to on-demand treatment (OR, 0.29; 95% CI, 0.16-0.54), whereas nonsteroidal anti-inflammatory drugs (NSAIDs) and severe hemophilia were associated with a higher number. There was no association of prophylaxis <3 times/wk with hematuria., Conclusion: Frequent prophylaxis was negatively associated with the number of episodes of macroscopic hematuria in people with hemophilia. Prevalence of macroscopic hematuria was higher among individuals with severe hemophilia and those regularly using NSAIDs., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes., Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction., Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018., Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant., Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis., Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group., Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Vitamin K antagonists, such as warfarin, have a narrow therapeutic window; patients on these therapies therefore require regular international normalized ratio (INR) monitoring to maintain optimal dosing. This involves periodic checks and laboratory testing using venepuncture, which are often perceived as a burden. This study aimed to determine the accuracy and precision of the LumiraDx INR Test, a new point-of-care in vitro diagnostic platform, in an anticoagulation clinic setting. In this observational, cross-sectional study, precision of the LumiraDx INR Test was assessed using paired replicate samples (n = 366) and 3 test strip lots. Accuracy was determined by comparing capillary blood INR, ascertained by the LumiraDx INR Test, with venous plasma INR, measured by the laboratory reference instrument, the IL ACL ELITE Pro. Furthermore, INR was assessed across a range of hematocrit (25%-55%). In addition, feedback was collected from health-care professionals via a self-completed questionnaire. This trial was registered at ClinicalTrials.gov (NCT03682419). The precision (% coefficient of variation) of the LumiraDx INR Test was <4 when samples were applied by direct application or via a capillary transfer pipette, as well as between test strip lots. Accuracy of the LumiraDx INR Test, across the INR range of 0.8 to 7.5, was confirmed by a strong correlation of 0.965 (95% confidence interval: 0.959-0.970) when compared with the IL ACL ELITE Pro, which was maintained across the hematocrit range. Feedback from health-care professionals indicated that the instructions given by the system were easy to follow. In conclusion, the strong agreement between the LumiraDx Platform INR point-of-care test and the IL ACL ELITE Pro laboratory reference system, as well as between the different application methods and test lots, indicates that it can provide a rapid, accurate, and reliable INR analysis.

Persistent Post-Mastectomy Pain (PPMP) is a common condition that can follow surgeries for breast cancer, the most common cancer in women. Because of the frequency of PPMP and its potential severity, it has received increasing research attention. This manuscript reviews the recent research literature, beginning with a brief history and then relevant medical, surgical, demographic, and psychosocial risk factors. Subsequently, social, psychological, and functional sequelae that have been linked to PPMPS are considered, as is research on current pharmacological, psychological, and rehabilitative approaches to treatment. The review concludes with a discussion of directions for future research and treatment that might reduce the incidence and impact of PPMP on breast cancer survivors. PERSPECTIVE: This article describes current research literature involving mechanisms, risks, and treatments related to persistent post-mastectomy pain. Implications of research findings also are discussed for pre- and post-surgical approaches to pain management, current treatments, and promising research directions., (Copyright © 2018 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: In a moderated mediation model, this study examined the interaction effect of pain severity and medical evidence on physician judgments of chronic pain. The effects of higher pain severity on physician judgments were expected to be mediated through anticipated clinical burden, but only when medical evidence was low., Design: Participants were randomly assigned to one of six case descriptions of a chronic pain patient in a 3 × 2 design that varied by reported pain severity (4, 6, 8/10) and medical evidence (low vs high)., Setting: An academic training program for medical residents/fellows., Subjects: Residents/fellows in clinical departments at postgraduate year 2 or higher (N = 109)., Methods: Participants read case descriptions and then made judgments about the patient and rated the level of burden they expected to assume in treating the patient., Results: Higher pain severity occasioned greater pain discounting and higher likelihood of prescribing opioid medication. When medical evidence was low, participants had less trust in the patient's pain report, attributed pain more to psychosocial than medical factors, and were less likely to refer for possible surgery. Analyses yielded no support for moderated mediation as expected burden was high across all conditions. Significant associations were found between expected burden and multiple clinical judgments., Conclusions: Results did not support the proposed moderated mediation model as all patients were expected to be burdensome across clinical presentations, reflecting negative expectations of patients with chronic pain. Such expectations can have adverse implications for patient-provider communication, shared decision-making, and the delivery of personalized care.

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care.Data from 13 European countries were collected at a single time-point (2011-2013). Univariate and multivariate logistic regression (MLR) analyses were performed.A total of 532 PWH were included with either hemophilia A (n = 467) or hemophilia B (n = 65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR = 17.6, P < .001), diabetes (OR = 3.0, P = .02), and HIV (OR = 1.9, P = .049) were positively associated with CLD. Total cholesterol (OR = 0.6, P = .002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR.The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted.

Background: Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation., Methods: Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1-5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration-time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM ® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model., Results: One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data., Conclusion: The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

Chronic orofacial pain is a symptom associated with a wide range of neuropathic, neurovascular, idiopathic, and myofascial conditions that affect a significant proportion of the population. While the collective impact of the subset of the orofacial pain disorders involving neurogenic and idiopathic mechanisms is substantial, some of these are relatively uncommon. Hence, patients with these disorders can be vulnerable to misdiagnosis, sometimes for years, increasing the symptom burden and delaying effective treatment. This manuscript first reviews the decision tree to be followed in diagnosing any neuropathic pain condition, as well as the levels of evidence needed to make a diagnosis with each of several levels of confidence: definite, probable, or possible. It then examines the clinical literature related to the idiopathic and neurogenic conditions that can occasion chronic orofacial pain, including burning mouth syndrome, trigeminal neuralgia, glossopharyngeal neuralgia, post-herpetic neuralgia, and atypical odontalgia. Temporomandibular disorders also are examined as are other headache conditions, even though they are not neurologic conditions, because they are common and can mimic symptoms of the latter disorders. For each of these conditions, the paper reviews literature regarding incidence and prevalence, physiologic and other contributing factors, diagnostic signs and symptoms, and empirical evidence regarding treatments. Finally, in order to improve the quality and accuracy of clinical diagnosis, as well as the efficiency with which effective treatment is initiated and delivered, criteria are offered that can be instrumental in making a differential diagnosis.

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB., (© 2017 by The American Society of Hematology.)

Background: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions., Methods: The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values., Results: The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations., Conclusions: Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.

Thrombosis is a well-recognized complication of asparaginase therapy for acute lymphoblastic leukemia (ALL), associated with the depletion of antithrombin (AT). Following a high incidence of thrombotic episodes during induction therapy for ALL in our tertiary referral center, we prospectively instituted a protocol of AT replacement. Forty-five consecutive adolescents and adults with ALL treated with asparaginase-containing phase I induction protocols were included in this observational study. Fifteen received standard therapy with no replacement; the subsequent 30 were managed with the protocol described. One or more low AT levels (<70 iu/dl) were recorded in 76% of patients in the cohort managed using the protocol, resulting them in receiving an AT replacement. There was a significant reduction in the incidence of thrombosis with this strategy (0/30 vs. 5/15, p < 0.001). We suggest that such a strategy should be studied in a prospective randomized sub-study within the context of a national ALL trial.