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Jay M Margolis,1 Nicole Princic,2 David M Smith,2 Lucy Abraham,3 Joseph C Cappelleri,4 Sonali N Shah,5 Peter W Park5 1Truven Health Analytics, Bethesda, MD, 2Truven Health Analytics, Cambridge, MA, USA; 3Pfizer Ltd, Tadworth, UK; 4Pfizer Inc, Groton, CT, 5Pfizer Inc, New York, NY, USA Objective: To develop a claims-based algorithm for identifying patients who are adherent versus nonadherent to published guidelines for chronic pain management. Methods: Using medical and pharmacy health care claims from the MarketScan® Commercial and Medicare Supplemental Databases, patients were selected during July 1, 2010, to June 30, 2012, with the following chronic pain conditions: osteoarthritis (OA), gout (GT), painful diabetic peripheral neuropathy (pDPN), post-herpetic neuralgia (PHN), and fibromyalgia (FM). Patients newly diagnosed with 12 months of continuous medical and pharmacy benefits both before and after initial diagnosis (index date) were categorized as adherent, nonadherent, or unsure according to the guidelines-based algorithm using disease-specific pain medication classes grouped as first-line, later-line, or not recommended. Descriptive and multivariate analyses compared patient outcomes with algorithm-derived categorization endpoints. Results: A total of 441,465 OA patients, 76,361 GT patients, 10,645 pDPN, 4,010 PHN patients, and 150,321 FM patients were included in the development of the algorithm. Patients found adherent to guidelines included 51.1% for OA, 25% for GT, 59.5% for pDPN, 54.9% for PHN, and 33.5% for FM. The majority (~90%) of patients adherent to the guidelines initiated therapy with prescriptions for first-line pain medications written for a minimum of 30 days. Patients found nonadherent to guidelines included 30.7% for OA, 6.8% for GT, 34.9% for pDPN, 23.1% for PHN, and 34.7% for FM. Conclusion: This novel algorithm used real-world pharmacotherapy treatment patterns to evaluate adherence to pain management guidelines in five chronic pain conditions. Findings suggest that one-third to one-half of patients are managed according to guidelines. This method may have valuable applications for health care payers and providers analyzing treatment guideline adherence. Keywords: chronic pain, drug therapy, practice guidelines, adherence, algorithm

Background: Staphylococcus aureus alpha-toxin is a major virulence factor, but its mechanism of action in vivo is incompletely understood.Methods: We examined the role of alpha-toxin in S. aureus pneumonia using the mouse model of intranasal lung infection with S. aureus strain 8325-4 (hla(+) S. aureus) and an alpha-toxin-deficient mutant strain made on the 8325-4 background (hla(-) S. aureus).Results: Intranasal infection of mice with hla(-) S. aureus resulted in substantially less lung injury and inflammation, pulmonary edema, and tissue bacterial burden than did infection with hla(+) S. aureus. Furthermore, fewer mice infected with hla(-) S. aureus died of the infection, compared with those infected with hla(+) S. aureus. Levels of the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2 were significantly lower in the airways of mice infected with hla(-) S. aureus, and this difference was the result of reduced secretion of newly synthesized chemokines into the airway. Consistent with these data, significantly fewer neutrophils were present in the airways and lungs of mice infected with hla(-) S. aureus, compared with those infected with hla(+) S. aureus.Conclusions: These data suggest that alpha-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia. [ABSTRACT FROM AUTHOR]

The authors evaluated the effect of high-dose aspirin at a therapeutic dose, using chlorzoxazone as a probe for CYP2E1 enzyme activity. In a randomized, open-label, 2-way crossover study, 10 healthy men were treated 3 times daily for 6 days with 1 g aspirin or placebo. On day 7, 1 dose of 400 mg chlorzoxazone was administered orally. Plasma concentrations of chlorzoxazone and its metabolite, 6-hydroxychlorzoxazone, were measured. During the aspirin phase, the area under the time-concentration curve (AUC) and peak plasma concentration of chlorzoxazone were 95% (90% confidence interval [CI], 87%-103%) and 90% (90% CI, 80%-101%) of the values during the placebo phase, respectively. High-dose aspirin did not affect the oral clearance of chlorzoxazone significantly (90% CI, 98%-120%; P = .24). The AUC ratio and plasma concentration ratios of 6-hydroxychlorzoxazone/chlorzoxazone were not changed significantly by high-dose aspirin. High-dose aspirin at a therapeutic dose does not affect CYP2E1 activity in humans. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the impact of the grade and jet direction of residual aortic regurgitation (rAR) after valve-sparing root replacement (VSRR)., Methods: The study enrolled 248 adult patients who underwent VSRR between 1995 and 2021. The patients were divided into groups based on the postoperative rAR. Patients with rAR were further categorized according to rAR grade and jet direction. The primary endpoint was the development of aortic regurgitation of moderate or greater (≥moderate) severity and/or the need for valve replacement during the follow-up, analyzed by a multivariable competing risk analysis. The secondary endpoints included the occurrence of rAR and overall survival., Results: The median age of the patients was 36.5 years, and 79.8% had been diagnosed with connective tissue disease. After VSRR, 146 patients did not present with rAR; however, 102 had rAR (77 with minimal central, 18 with minimal eccentric, and 7 with mild rAR). The 5-year and 8-year incidence rates of the primary endpoint were 14.6% and 17.9%, respectively. rAR was a significant risk factor (P = .001), and eccentricity and mild rAR seemed to have important roles. The risk factors for rAR included dilated root, preoperative moderate regurgitation, and redo sternotomy. Overall survival was influenced only by age., Conclusions: rAR after VSRR operation could be a risk factor for AR progression. Minimal central rAR generally has a tolerable clinical course; however, patients with even minimal eccentric AR may develop AR progression, so active surveillance and timely management might be required. Furthermore, early VSRR can help reduce the rAR., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to investigate the influence of early diagnosis (ED) on surgical outcomes in patients definitively diagnosed with Loeys-Dietz syndrome (LDS)., Methods: A retrospective review was conducted on 38 patients with LDS who underwent aortic surgery at our institution between January 1995 and June 2022. The primary endpoint was freedom from aortic reoperation., Results: Among the patients, the median age at the initial surgery was 33 (range: 39-44) years, and 23 (60.5%) patients were male. Twenty-one (55.3%; aortic dissection or rupture ( n  = 2) and aneurysm ( n  = 19)) patients were diagnosed with LDS before the initial surgery (ED group). Meanwhile, the remaining 17 (44.7%; aortic dissection or rupture ( n  = 13) and aneurysm ( n  = 4)) patients were after surgery [delayed diagnosis (DD) group]. The ED group had significantly lower rates of emergency surgery and concomitant arch procedure ( P  < .001, respectively) but a higher rate of valve-sparing root surgery ( P  = .018) compared to the DD group. No in-hospital mortality was observed in either group. Nevertheless, the ED group had a shorter postoperative hospital stay (median difference: 3 days, P  = .032) and a lower rate of aortic reoperation ( P  = .013)., Conclusion: Early detection of LDS may help in preventing acute aortic syndrome, reducing the risk of aortic reoperation, and potentially shortening hospital stay. Careful medical management before surgery could contribute to better clinical outcomes and an improved quality of life for patients with LDS., Competing Interests: 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., (© 2024 Kim, Lee, Chung, Park, Park, Kang, Huh, Kim, Cho and Sung.)

Background: Cardiovascular involvement in pediatric patients with connective tissue disease (CTD) is life-threatening, with aortic root dilatation being the most prevalent cardiovascular abnormality. We attempted to determine long-term outcomes of valve-sparing root replacement (VSRR) in this group, including cardiovascular reoperations for aortic aneurysm and dissection., Methods: We conducted a retrospective analysis of pediatric patients with CTD who received VSRR in a single center from 2002 to 2021. The primary end point was a composite event of all-cause death and cardiovascular reoperations. The median follow-up duration was 8.3 years, with a maximum of 20.7 years., Results: The median age of 24 pediatric patients who had VSRR was 14.4 years. Marfan syndrome and Loeys-Dietz syndrome affected 19 (79.2%) and 5 (20.8%) patients, respectively. There was no early death. The 15-year survival rate was 91.7%. At 10 years after VSRR, the cumulative incidence of reoperation for aortic regurgitation was 15.6%, and for aortic aneurysm or dissection, it was 29.1%. The 10-year rate of freedom from the primary end point was 53.1%. The Cox multivariable analysis revealed younger age at surgery (hazard ratio, 1.279; 95% confidence interval, 1.086-1.505; P = .003) and VSRR before 13 years of age (hazard ratio, 5.005; 95% confidence interval, 1.146-21.850; P = .032) as independent prognostic factors for the primary endpoint., Conclusions: VSRR for aortic root dilatation in pediatric patients with CTD demonstrated good long-term survival and low reoperation rates for aortic regurgitation. However, several patients developed later aortic aneurysm or dissection, and careful surveillance may be required, particularly in those who received VSRR at younger age., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to analyze the impact of concomitant Maze procedure on the clinical and rhythm outcomes, and echocardiographic parameters in tricuspid repair for patients with severe tricuspid regurgitation (TR) and persistent atrial fibrillation (AF)., Methods: Patients who had severe TR and persistent AF and underwent tricuspid valve (TV) repair were included in the study. Both primary TR and secondary TR were included in the current study. The study population was stratified according to Maze procedure. The primary outcome was major adverse cardiovascular and cerebrovascular event (MACCE) at 15 years post-surgery. Propensity-score matching analyses was performed to adjust baseline differences., Results: Three hundred seventy-one patients who underwent tricuspid repair for severe TR and persistent AF from 1994 to 2021 were included, and 198 patients (53.4%) underwent concomitant Maze procedure. The maze group showed 10-year sinus rhythm (SR) restoration rate of 55%. In the matched cohort, the maze group showed a lower cumulative incidence of cardiac death (4.6% vs. 14.4%, P = 0.131), readmission for heart failure (8.1% vs. 22.2%, P = 0.073), and MACCE (21.1% vs. 42.1%, P = 0.029) at 15 years compared to the non-maze group. Left atrial (LA) diameter significantly decreased in the maze group at 5 years (53.3 vs. 59.6 mm, P < 0.001) after surgery compared to preoperative level, and there was a significant difference in the change of LA diameter over time between the two groups ( P = 0.013)., Conclusion: The Maze procedure during TV repair in patients with severe TR and persistent AF showed acceptable SR rates and lower MACCE rates compared to those without the procedure, while also promoting LA reverse remodeling., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

The increasing use of sodium glucose transporter 2 inhibitors (SGLT2i) for treating cardiovascular (CV) diseases and type 2 diabetes (T2D) is accompanied by a rise in euglycemic diabetic ketoacidosis occurrences in cardiac surgery patients. Patients undergoing cardiac surgery, due to their pre-existing CV disease which often requires SGLT2i prescriptions, face an increased risk of postoperative metabolic acidosis (MA) or ketoacidosis (KA) associated with SGLT2i, compounded by fasting and surgical stress. The primary aim of this study is to quantify the incidence of SGLT2i-related postoperative MA or KA and to identify related risk factors. We analyzed data retrospectively of 823 cardiac surgery patients, including 46 treated with SGLT2i from November 2019 to October 2022. Among 46 final cohorts treated preoperatively with SGLT2i, 29 (63%) developed postoperative metabolic complications. Of these 46 patients, stratified into two categories based on postoperative laboratory findings, risk factor analysis were conducted and compared. Analysis indicated a prescription duration over one week significantly elevated the risk of complications (Unadjusted OR, 11.7; p = 0.032*; Adjusted OR, 31.58; p = 0.014*). A subgroup analysis showed that a cardiopulmonary bypass duration of 60 min or less significantly raises the risk of SGLT2i-related postoperative MA in patients with a sufficient prescription duration. We omitted the term "diabetes" in describing complications related to SGLT2i, as these issues are not exclusive to T2D patients. Awareness of SGLT2i-related postoperative MA or KA can help clinicians distinguish between non-life-threatening conditions and severe causes, thereby preventing unnecessary tests and ensuring best practice., (© 2024. The Author(s).)

Objective: To create a data-driven definition of post-COVID conditions (PCC) by directly measure changes in symptomatology before and after a first COVID episode., Materials and Methods: Retrospective cohort study using Optum® de-identified Electronic Health Record (EHR) dataset from the United States of persons of any age April 2020-September 2021. For each person with COVID (ICD-10-CM U07.1 "COVID-19" or positive test result), we selected up to 3 comparators. The final COVID symptom score was computed as the sum of new diagnoses weighted by each diagnosis' ratio of incidence in COVID group relative to comparator group. For the subset of COVID cases diagnosed in September 2021, we compared the incidence of PCC using our data-driven definition with ICD-10-CM code U09.9 "Post-COVID Conditions", first available in the US October 2021., Results: The final cohort contained 588,611 people with COVID, with mean age of 48 years and 38% male. Our definition identified 20% of persons developed PCC in follow-up. PCC incidence increased with age: (7.8% of persons aged 0-17, 17.3% aged 18-64, and 33.3% aged 65+) and did not change over time (20.0% among persons diagnosed with COVID in 2020 versus 20.3% in 2021). For cases diagnosed in September 2021, our definition identified 19.0% with PCC in follow-up as compared to 2.9% with U09.9 code in follow-up., Conclusion: Symptom and U09.9 code-based definitions alone captured different populations. Maximal capture may consider a combined approach, particularly before the availability and routine utilization of specific ICD-10 codes and with the lack consensus-based definitions on the syndrome., Competing Interests: Dr Andersen, Mr Khan, Dr Park, Dr Wiemken, Dr Emir, Ms Malhotra, and Dr McGrath are employees of Pfizer Inc and may hold stock or stock options. Dr Alhanai and Dr Ghassemi are co-founders of Ghamut Corporation which has received consulting fees from Pfizer Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Andersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Patients with severe tricuspid regurgitation and persistent atrial fibrillation may not be good candidates for maze procedure due to preoperative atrial remodeling and various comorbidities. We attempted to evaluate the rhythm and clinical outcomes of maze procedure in these patients., Methods: Patients with severe tricuspid regurgitation and persistent atrial fibrillation who underwent tricuspid valve surgery between January 1994 and December 2017 at a single tertiary center were analyzed. The primary end point was sinus rhythm restoration. The key secondary end point was major adverse cardiovascular and cerebrovascular event rate, which is the composite event of stroke, cardiac death, major bleeding, and readmission for heart failure. Propensity score matching analysis was used., Results: A total of 388 patients underwent tricuspid valve surgery, and among them 172 patients (44%) underwent concomitant maze procedure. The maze group had sinus rhythm restoration rate of 56% in 9 years. Further, in the matched cohort, the maze group had higher freedom from major adverse cardiovascular and cerebrovascular event rate at 10 years than the nonmaze group (55.6% vs 36.2%; P = .047). Preoperative left atrial diameter (hazard ratio, 1.022; 95% CI, 1.012-1.033; P < .001) and right atrial diameter (hazard ratio, 1.012; 95% CI, 1.003-1.022; P = .013) were independent risk factors for failure of sinus rhythm., Conclusions: Maze procedure in severe tricuspid regurgitation and persistent atrial fibrillation had acceptable rates of sinus rhythm restoration and reduced major adverse cardiovascular and cerebrovascular events in the long-term. Careful patient selection considering preoperative atrial diameters is needed to enhance maze success rate and long-term clinical outcomes., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

A large number of bacterial pathogens bind to host extracellular matrix (ECM) components. For example, many Gram-negative and Gram-positive pathogens express binding proteins for fibronectin (FN) on their cell surface. Mutagenesis studies of bacterial FN-binding proteins have demonstrated their importance in pathogenesis in preclinical animal models. However, means to draw on these findings to design therapeutic approaches that specifically target FN-bacteria interactions have not been successful because bacterial pathogens can elaborate several FN-binding proteins and also because FN is an essential protein and likely a nondruggable target. Here we report that select heparan compounds potently inhibit Streptococcus pneumoniae infection of injured corneas in mice. Using intact heparan sulfate (HS) and heparin (HP), heparinase-digested fragments of HS, HP oligosaccharides, and chemically or chemoenzymatically modified heparan compounds, we found that inhibition of S. pneumoniae corneal infection by heparan compounds is not mediated by simple charge effects but by a selective sulfate group. Removal of 2- O -sulfates significantly inhibited the ability of HP to inhibit S. pneumoniae corneal infection, whereas the addition of 2- O -sulfates to heparosan (H) significantly increased H's ability to inhibit bacterial corneal infection. Proximity ligation assays indicated that S. pneumoniae attaches directly to FN fibrils in the corneal epithelial ECM and that HS and HP specifically inhibit this binding interaction in a 2- O -sulfate-dependent manner. These data suggest that heparan compounds containing 2- O -sulfate groups protect against S. pneumoniae corneal infection by inhibiting bacterial attachment to FN fibrils in the subepithelial ECM of injured corneas. Moreover, 2- O -sulfated heparan compounds significantly inhibited corneal infection in immunocompromised hosts, by a clinical keratitis isolate of S. pneumoniae , and also when topically administered in a therapeutic manner. These findings suggest that the administration of nonanticoagulant 2- O -sulfated heparan compounds may represent a plausible approach to the treatment of S. pneumoniae keratitis., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest.

Objective: The Electronic Chronic Pain Questions (eCPQ) has been developed to help healthcare providers systematically capture chronic pain data. This study evaluated the impact of using the eCPQ on patient-reported outcomes (PROs) and healthcare resource utilization (HCRU) in a primary care setting, and patient and physician perceptions regarding use of, and satisfaction with, the eCPQ., Methods: This was a prospective pragmatic study conducted at the Internal Medicine clinic within the Henry Ford Health (HFH) Detroit campus between June 2017 and April 2020. Patients (aged ≥18 years) attending the clinic for chronic pain were allocated to an Intervention Group to complete the eCPQ in addition to regular care, or a control group to receive regular care only. The Patient Health Questionnaire-2 and a Patient Global Assessment were assessed at baseline, 6-months, and 12-months study visits. HCRU data were extracted from the HFH database. Telephone qualitative interviews were conducted with randomly selected patients and physicians who used the eCPQ., Results: Two hundred patients were enrolled, 79 in each treatment group completed all 3 study visits. No significant differences ( p  > 0.05) were found in PROs and HCRU between the 2 groups. In qualitative interviews, physicians and patients reported the eCPQ as useful, and using the eCPQ improved patient-clinician interactions., Conclusion: Adding the eCPQ to regular care for patients with chronic pain did not significantly impact the PROs assessed in this study. However, qualitative interviews suggested that the eCPQ was a well-accepted and potentially useful tool from a patient and physician perspective. By using the eCPQ, patients were better prepared when they attended a primary care visit for their chronic pain and the quality of patient-physician communication was increased., Competing Interests: LL, VS, and SE are employees of the Henry Ford Health, which received funding from Pfizer for this study. LA, JC, BD, RH-D, and PP are employees of Pfizer with stock and/or stock options., (Copyright © 2023 Lamerato, Shah, Abraham, Cappelleri, DeLor, Ellsworth, Hegeman-Dingle and Park.)

Background: Cryoablation is effective for not only ablating the myocardium, but also maintaining the structure of the ablated tissue. However, data comparing nitrous oxide (N 2 O)-based and argon gas-based cryoprobes are limited., Methods: This study was a follow-up study of a single-center, prospective, randomized controlled trial in which 60 patients were randomly allocated to either the N 2 O group or the argon group. The primary endpoint of this study was sinus rhythm maintenance, and the key secondary endpoint was a composite of major adverse cardiovascular and cerebrovascular events (MACCEs) (ie, cardiac death, stroke, major bleeding, and readmission for heart failure)., Results: The baseline and operative characteristics of the patients in the N 2 O and argon groups were comparable. At the 5-year follow-up, the rate of sinus rhythm maintenance was 81.8% in the N 2 O group, whereas it was 78.5% in the argon group (P > .999). No significant differences in the rate of freedom from MACCEs (80.6% in the N 2 O group vs 81.9% in the argon group; P = .978) were observed at the 5-year follow-up. The left atrial volume index decreased over time from 114.65 mL/m 2 to 65.74 mL/m 2 (P < .0001) and reached similar values in the 2 groups (P = .279) at the 5-year follow-up., Conclusions: Both N 2 O- and argon gas-based cryoprobes showed similar rates of sinus rhythm maintenance and freedom from MACCEs at the 5-year follow-up. Both cryoprobes might have similar efficacy and safety in the arrested heart in the long term., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Receptor-ligand interactions play an important role in many biological processes by triggering specific cellular responses. These interactions are frequently regulated by coreceptors that facilitate, alter, or inhibit signaling. Coreceptors work in parallel with other specific and accessory molecules to coordinate receptor-ligand interactions. Cell surface heparan sulfate proteoglycans (HSPGs) function as unique coreceptors because they can bind to many ligands and receptors through their HS and core protein motifs. Cell surface HSPGs are typically expressed in abundance of the signaling receptors and, thus, are capable of mediating the initial binding of ligands to the cell surface. HSPG coreceptors do not possess kinase domains or intrinsic enzyme activities and, for the most part, binding to cell surface HSPGs does not directly stimulate intracellular signaling. Because of these features, cell surface HSPGs primarily function as coreceptors for many receptor-ligand interactions. Given that cell surface HSPGs are widely conserved, they likely serve fundamental functions to preserve basic physiological processes. Indeed, cell surface HSPGs can support specific cellular interactions with growth factors, morphogens, chemokines, extracellular matrix (ECM) components, and microbial pathogens and their secreted virulence factors. Through these interactions, HSPG coreceptors regulate cell adhesion, proliferation, migration, and differentiation, and impact the onset, progression, and outcome of pathophysiological processes, such as development, tissue repair, inflammation, infection, and tumorigenesis. This review seeks to provide an overview of the various mechanisms of how cell surface HSPGs function as coreceptors.

Heparan sulfate proteoglycans (HSPGs) are at the forefront of host-microbe interactions. Cell surface HSPGs are thought to promote infection as attachment and internalization receptors for many bacterial pathogens and as soluble inhibitors of host immunity when released from the cell surface by ectodomain shedding. However, the importance of HSPG-pathogen interactions in vivo has yet to be clearly established. Here we describe several representative methods to study the role of HSPGs in systemic bacterial infections, such as bacteremia and sepsis. The overall experimental strategy is to use mouse models to establish the physiological significance of HSPGs, to determine the identity of HSPGs that specifically promote infection, and to define key structural features of HSPGs that enhance bacterial virulence in systemic infections., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

What Is Known and Objective: Age and gender have been reported to play a crucial role in modulating the disposition of pharmacological agents, and to influence the activities of cytochrome P450 (CYP) 2D6, a drug-metabolizing enzyme involved in the disposition of clinically used drugs. In the present study, the effects of age and gender on the CYP2D6 activity were evaluated using dextromethorphan as a probe drug in humans., Methods: Healthy young (20 < age < 30 years, n = 60) and old age (age >60 years, n = 60) subjects were enrolled and were given 15 mg dextromethorphan orally. Blood samples were collected before and 3 h after medication. Dextromethorphan and its metabolite dextrorphan were measured using HPLC-fluorescence, and dextromethorphan metabolic ratio (MR, log [dextromethorphan/dextrorphan]) was used to evaluate the CYP2D6 activity., Results and Discussion: Mean (±SD) dextromethorphan MR was -2.42 ± 0.46 for the young male group, -2.28 ± 0.56 for the young female group, -2.46 ± 0.55 for the older male group and -2.34 ± 0.65 for the old female group. Based on our findings, the effects of age and gender on CYP2D6 activity were not statistically significant., What Is New and Conclusion: The results of the present study indicate that age and gender play a minor role in the modulation of CYP2D6 activity in the Korean population., (© 2021 John Wiley & Sons Ltd.)

Invariant NKT (iNKT) cells are potent immunomodulatory cells that acquire effector function during their development in the thymus. IL-17-producing iNKT cells are commonly referred to as NKT17 cells, and they are unique among iNKT cells to express the heparan sulfate proteoglycan CD138 and the transcription factor RORγt. Whether and how CD138 and RORγt contribute to NKT17 cell differentiation, and whether there is an interplay between RORγt and CD138 expression to control iNKT lineage fate, remain mostly unknown. Here, we showed that CD138 expression was only associated with and not required for the differentiation and IL-17 production of NKT17 cells. Consequently, CD138-deficient mice still generated robust numbers of IL-17-producing RORγt+ NKT17 cells. Moreover, forced expression of RORγt significantly promoted the generation of thymic NKT17 cells, but did not induce CD138 expression on non-NKT17 cells. These results indicated that NKT17 cell generation and IL-17 production were driven by RORγt, employing mechanisms that were independent of CD138. Therefore, our study effectively dissociated CD138 expression from the RORγt-driven molecular pathway of NKT17 cell differentiation.

Background: This study aimed to investigate the early and late outcomes of mechanical tricuspid valve replacement (mTVR)., Methods: We evaluated 113 patients (82 women; median age, 53 years) who underwent mTVR between 1995 and 2017. Based on a history of cardiac surgery, patients were divided into primary (n=42) and reoperative mTVR (n=71) groups. The median follow-up duration was 12.7 years in primary and 9.3 years in reoperative mTVR, respectively (P=0.045)., Results: Patients in the reoperative group were older (54 vs. 46 years; P=0.007) and showed higher central venous pressure (16±6 vs. 13±6 mmHg; P=0.002) than the primary group. Early mortality occurred in 2 patients in the reoperative group (2 vs. 0; P=0.529). There was no significant difference in overall survival between the primary and reoperation groups (15-year survival rate: 86% vs. 78%; P=0.215). The independent risk factors of overall survival were age [P<0.001; hazard ratio (HR), 1.11; 95% confidential interval (CI), 1.05-1.18], left ventricular ejection fraction of less than 40% (P=0.001; HR, 5.1; 95% CI, 2.21-28.2), and central venous pressure over 20 mmHg (P=0.016; HR, 3.7; 95% CI, 1.28-10.7). Overall survival did not differ between the age groups (<60 vs. 60-70 years) in the reoperative group (P=0.772). Tricuspid valve thrombosis occurred in 8 patients (7 primary, 1 reoperative; P=0.004)., Conclusions: The incidence of tricuspid valve thrombosis was significantly higher in the primary mTVR group compared with the reoperative mTVR group. The patients who underwent mTVR at a relatively young age showed good early and late outcomes in both groups., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-3027). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: This study aimed to evaluate the long-term clinical impacts of prophylactic tricuspid annuloplasty (TAP) in patients with mild tricuspid regurgitation (TR) who underwent mitral valve repair., Methods: One hundred fifty-one patients with mild TR who underwent mitral valve repair for degenerative mitral regurgitation between 1997 and 2013 were categorized into the TAP (n = 85) or no TAP (n = 66) groups. The indications for TAP were atrial fibrillation and tricuspid annular dilatation. The mean follow-up duration was 115.5 ± 48.6 months. Inverse probability of treatment weighting analysis and propensity score matching with 53 patients in each group were used to adjust for the baseline differences between the 2 groups., Results: There were no early mortalities in either group, and early morbidities, including heart block, were not different between the groups. Inverse probability of treatment weighting-adjusted survival analysis did not reveal any difference in overall survival (P = .862), freedom from cardiac-related mortality (P = .535), or major adverse valve-related events (P = .972) between the groups. There was no difference in late TR progression (moderate or greater) between the groups (P = .316). These results were consistent in the matched analysis., Conclusions: Prophylactic TAP in mild TR may not have a beneficial effect on TR progress in degenerative mitral regurgitation. Further large studies are necessary to define the role of prophylactic TAP in mild TR., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Several reports described the repair of sinus of Valsalva aneurysms (SVAs); however, there is still debate regarding the optimal method of operation. We investigated the determinants of the development of significant aortic regurgitation (AR) and long-term survival after surgical repair., Methods: Between January 1995 and December 2016, 71 patients (31 females; median age: 33.3 years) underwent surgical SVA repair with ( n  = 60) or without ( n  = 11) rupture. Aortic valvuloplasty (AVP) was performed using Trusler's technique in 28 patients (39.4%), and 11 patients (15.5%) underwent aortic valve replacement during the first operation., Results: There was no early mortality, and three deaths occurred during follow-up (median: 65.4 months). Patients with grade II preoperative AR who underwent AVP tended to develop significant postoperative AR, but freedom from significant AR did not differ statistically ( p  = 0.387). Among patients who underwent AVP, freedom from significant AR did not differ statistically between those with grades I and II and those with grades III and IV ( p  = 0.460)., Conclusion: Surgical repair of SVA with or without rupture can be performed safely using the dual approach technique. Concomitant aortic valve repair can be performed without difficulty and should be recommended not only for patients with moderate or severe preoperative AR (grades III and IV) but also for those with minimal or mild preoperative AR (grades I and II), whose aortic valve geometry needs correction., Competing Interests: The authors declare no conflict of interest., (Thieme. All rights reserved.)

Subversion of heparan sulfate proteoglycans (HSPGs) is thought to be a common virulence mechanism shared by many microbial pathogens. The prevailing assumption is that pathogens co-opt HSPGs as cell surface attachment receptors or as inhibitors of innate host defense. However, there are few data that clearly support this idea in vivo We found that deletion of syndecan-1 (Sdc1), a major cell surface HSPG of epithelial cells, causes a gain of function in a mouse model of scarified corneal infection, where Sdc1 -/- corneas were significantly less susceptible to Streptococcus pneumoniae infection. Administration of excess Sdc1 ectodomains significantly inhibited S. pneumoniae corneal infection, suggesting that Sdc1 promotes infection as a cell surface attachment receptor. However, S. pneumoniae did not interact with Sdc1 and Sdc1 was shed upon S. pneumoniae infection, indicating that Sdc1 does not directly support S. pneumoniae adhesion. Instead, Sdc1 promoted S. pneumoniae adhesion by driving the assembly of fibronectin (FN) fibrils in the corneal basement membrane to which S. pneumoniae attaches when infecting injured corneas. S. pneumoniae specifically bound to corneal FN via PavA, and PavA deletion significantly attenuated S. pneumoniae virulence in the cornea. Excess Sdc1 ectodomains inhibited S. pneumoniae corneal infection by binding to the Hep II domain and interfering with S. pneumoniae PavA binding to FN. These findings reveal a previously unknown virulence mechanism of S. pneumoniae where key extracellular matrix (ECM) interactions and structures that are essential for host cell homeostasis are exploited for bacterial pathogenesis. IMPORTANCE Bacterial pathogens have evolved several ingenious mechanisms to subvert host cell biology for their pathogenesis. Bacterial attachment to the host ECM establishes a niche to grow and is considered one of the critical steps of infection. This pathogenic mechanism entails coordinated assembly of the ECM by the host to form the ECM structure and organization that are specifically recognized by bacteria for their adhesion. We serendipitously discovered that epithelial Sdc1 facilitates the assembly of FN fibrils in the corneal basement membrane and that this normal biological function of Sdc1 has detrimental consequences for the host in S. pneumoniae corneal infection. Our studies suggest that bacterial subversion of the host ECM is more complex than previously appreciated., (Copyright © 2020 Jinno et al.)

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β 7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination.

Heparan sulfate proteoglycans (HSPGs) are at the forefront of host-microbe interactions. Molecular and cell-based studies suggest that HSPG-pathogen interactions promote pathogenesis by facilitating microbial attachment and invasion of host cells. However, the specific identity of HSPGs, precise mechanisms by which HSPGs promote pathogenesis, and the in vivo relevance of HSPG-pathogen interactions remain to be determined. HSPGs also modulate host responses to tissue injury and inflammation, but functions of HSPGs other than facilitating microbial attachment and internalization are understudied in infectious disease. Here we examined the role of syndecan-1 (Sdc1), a major cell surface HSPG of epithelial cells, in mouse models of Listeria monocytogenes (Lm) infection. We show that Sdc1-/- mice are significantly less susceptible to both intragastric and intravenous Lm infection compared to wild type (Wt) mice. This phenotype is not seen in Sdc3-/- or Sdc4-/- mice, indicating that ablation of Sdc1 causes a specific gain of function that enables mice to resist listeriosis. However, Sdc1 does not support Lm attachment or invasion of host cells, indicating that Sdc1 does not promote pathogenesis as a cell surface Lm receptor. Instead, Sdc1 inhibits the clearance of Lm before the bacterium gains access to its intracellular niche. Large intravascular aggregates of neutrophils and neutrophil extracellular traps (NETs) embedded with antimicrobial compounds are formed in Sdc1-/- livers, which trap and kill Lm. Lm infection induces Sdc1 shedding from the surface of hepatocytes in Wt livers, which is directly associated with the decrease in size of intravascular aggregated NETs. Furthermore, administration of purified Sdc1 ectodomains or DNase inhibits the formation of intravascular aggregated neutrophils and NETs and significantly increases the liver bacterial burden in Sdc1-/- mice. These data indicate that Lm induces Sdc1 shedding to subvert the activity of Sdc1 ectodomains to inhibit its clearance by intravascular aggregated NETs., Competing Interests: The authors have declared that no competing interests exist.

Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N -acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N -acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N -acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Rapid and accurate diagnosis of acute myocardial infarction (AMI) is critical for initiating effective treatment and achieving better prognosis. We investigated the performance of copeptin for early diagnosis of AMI, in comparison with creatine kinase myocardial band (CK-MB) and troponin I (TnI)., Methods: We prospectively enrolled 271 patients presenting with chest pain (within six hours of onset), suggestive of acute coronary syndrome, at an emergency department (ED). Serum CK-MB, TnI, and copeptin levels were measured. The diagnostic performance of CK-MB, TnI, and copeptin, alone and in combination, for AMI was assessed by ROC curve analysis by comparing the area under the curve (AUC). Sensitivity, specificity, negative predictive value, and positive predictive value of each marker were obtained, and the characteristics of each marker were analyzed., Results: The patients were diagnosed as having ST elevation myocardial infarction (STEMI; N=43), non-ST elevation myocardial infarction (NSTEMI; N=25), unstable angina (N=78), or other diseases (N=125). AUC comparisons showed copeptin had significantly better diagnostic performance than TnI in patients with chest pain within two hours of onset (AMI: P =0.022, ≤1 hour; STEMI: P =0.017, ≤1 hour and P =0.010, ≤2 hours). In addition, TnI and copeptin in combination exhibited significantly better diagnostic performance than CK-MB plus TnI in AMI and STEMI patients., Conclusions: The combination of TnI and copeptin improves AMI diagnostic performance in patients with early-onset chest pain in an ED setting., Competing Interests: The authors declare that they have no conflict of interests., (© The Korean Society for Laboratory Medicine.)

Background: The present study aimed to compare the long-term clinical and hemodynamic outcomes of aortic valve replacement using Carpentier-Edwards Perimount (Perimount) or Perimount Magna (Magna) valves., Methods: We enrolled 430 patients who underwent aortic valve replacements with Perimount (n=58) or Magna (n=372) valves [1998-2013]. Multivariable and inverse probability of treatment weight (IPTW) analyses were performed., Results: Before IPTW analysis, the overall 8-year survival rate differed significantly between the groups [Perimount 90%±4% vs. Magna 76%±4%; P=0.02; hazard ratio (HR): 0.37 for the Perimount group; 95% confidence interval (CI): 0.17-0.83]. Multivariable analysis of the overall survival identified Perimount valve use as a protective factor (P=0.009; HR: 0.32; 95% CI: 0.14-0.75). Independent risk factors of overall survival were older age, male sex, higher preoperative left ventricular mass index, lower ejection fraction, lower aortic valve pressure gradient, and lower haemoglobin. After applying IPTW, overall survival was again found to be significantly longer in the Perimount group (P=0.04; HR: 0.43; 95% CI: 0.20-0.93). Event-free survival was also better in the Perimount group (P=0.006; HR: 0.38; 95% CI: 0.19-0.75). However, the Magna group had significantly lower aortic valve pressure gradients at one year and five years postoperative., Conclusions: Although Magna use led to decreased aortic valve pressure gradients at follow-up, overall and event-free survival rates were significantly better with use of the Perimount valve. Additional and larger studies are needed to confirm these results., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Objectives: This research compared health care resource use (HCRU) and costs for pharmacotherapy prescribing that was adherent vs nonadherent to published pain management guidelines. Conditions included osteoarthritis (OA) and gout (GT) for nociceptive/inflammatory pain, painful diabetic peripheral neuropathy (pDPN) and post-herpetic neuralgia (PHN) for neuropathic pain, and fibromyalgia (FM) for sensory hypersensitivity pain., Methods: This retrospective cohort study used claims from MarketScan Commercial and Medicare Databases identifying adults newly diagnosed with OA, GT, pDPN, PHN, or FM during July 1, 2006, to June 30, 2013, with 12-month continuous coverage before and after initial (index) diagnosis. Patients were grouped according to their pharmacotherapy pattern as adherent, nonadherent, or "unsure" according to published pain management guidelines using a claims-based algorithm. Adherent and nonadherent populations were compared descriptively and using multivariate statistical analyses for controlling bias., Results: Final cohort sizes were 441,465 OA, 76,361 GT, 10,645 pDPN, 4,010 PHN, and 150,321 FM, with adherence to guidelines found in 51.1% of OA, 25% of GT, 59.5% of pDPN, 54.9% of PHN, and 33.5% of FM. Adherent cohorts had significantly (P < 0.05) fewer emergency department (ED) visits and lower proportions with hospitalizations or ED visits. Mean health care costs increased following diagnosis across all conditions; however, adherent cohorts had significantly lower increases in adjusted costs pre-index to postindex (OA $5,286 vs $9,532; GT $3,631 vs $7,873; pDPN $9,578 vs $16,337; PHN $2,975 vs $5,146; FM $2,911 vs $3,708; all P < 0.001; adherent vs nonadherent, respectively)., Conclusions: Adherence to pain management guidelines was associated with significantly lower HCRU and costs compared with nonadherence to guidelines., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background:  Whether percutaneous coronary intervention (PCI) is superior to coronary artery bypass grafting (CABG) for the right coronary territory is unknown. The aim of this study was to compare the outcomes and patency in the right coronary territory after CABG or PCI., Methods:  We studied 2,467 multivessel coronary artery disease patients from January 2001 to December 2011; 1,672 were off-pump CABG patients and 795 were PCI. The graft patency and the presence of major adverse cardiac and cerebrovascular events (MACCEs) including death, myocardial infarction, target vessel revascularization, and stroke were analyzed., Results:  After propensity score matching, cardiac-related survival was found to be significantly higher in the CABG group than in the PCI group (hazard ratio (HR) for the PCI group: 2.445, p  = 0.006). The PCI group showed higher rates of myocardial infarction (HR: 2.571, p  = 0.011) and target vessel revascularization (HR: 3.337, p  < 0.001). In the right coronary territory, the right internal thoracic artery patency was not different in the PCI group compared with the CABG group ( p  = 0.248). In CABG group, low right coronary artery graft patency was associated with cardiac-related death (HR: 0.17, p  = 0.003) and the occurrence of MACCEs (HR: 0.22, p  < 0.001)., Conclusion:  CABG was superior to PCI in patients with multivessel disease. Low graft patency in the right coronary territory was associated with cardiac-related death and the occurrence of MACCEs., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Currently, two types of cryoprobes are available: nitrous oxide (N 2 O)-based and argon gas-based. However, few studies have compared the outcomes obtained with these two cryoprobe types. The aim of this study was to compare the early outcomes of a concomitant maze procedure using N 2 O-based cryoablation (the N 2 O group) versus argon gas-based cryoablation (the argon group) in patients with persistent atrial fibrillation (AF)., Methods: This study was a single-center, prospective, randomized controlled clinical trial. Sixty patients were randomly assigned to receive a concomitant maze procedure using N 2 O-based cryoablation (n = 30) or argon gas-based cryoablation (n = 30) for persistent AF. Patients were followed up at 3, 6, and 12 months by electrocardiography, 24-hour Holter monitoring, and transthoracic echocardiography., Results: No important intergroup differences were observed in terms of preoperative variables, morbidity, or mortality. During 1 year of follow-up, normal sinus rhythm was maintained in 26 patients in the N 2 O group and 26 patients in the argon group (86.7% versus 86.7%, p = 1.000). Freedom from atrial arrhythmia events at 12 months was observed in 84.5% ± 4.7% without intergroup differences. Early AF episode before discharge was correlated with atrial arrhythmia events during follow-up (hazard ratio 7.89, 95% confidence interval: 1.75 to 35, p = 0.007). The N 2 O group showed earlier recovery of left atrial activity compared with the argon group (p = 0.043); however, this difference disappeared after 6 months., Conclusions: Both procedures have similar 1-year sinus rhythm maintenance rates. Left atrial contractile activity tends to return earlier in the N 2 O group., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Apixaban and rivaroxaban are approved for the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and embolic stroke in atrial fibrillation (AF) patients. The aim of this study was to find appropriate methods of monitoring the anticoagulant effects of are direct oral anticoagulants (DOACs) and establish on-therapy ranges using conventional tests., Methods: A total of 184 samples were collected from 91 patients receiving DOACs. Concentrations of apixaban and rivaroxaban in plasma were accessed by an anti-factor Xa chromogenic assay. PT, APTT, antithrombin, D-dimer, dRVVT screen/confirm, FDP, and fibrinogen levels were measured. On-therapy ranges were calculated by substituting previously reported trough plasma concentrations of DOACs., Results: Anti-factor Xa chromogenic assay-based DOACs levels were 26.0-279.5 (115.9 ± 56.5) ng/mL for apixaban at 2.5 mg BID, 19.9-565.1 (205.3 ± 162.4) ng/mL for apixaban at 5 mg BID, 2.3-395.3 (205.3 ± 162.4) ng/mL for rivaroxaban at 15 mg OD, 3.6-494.8 (119.6 ± 95.1) ng/mL for rivaroxaban at 20 mg OD, and 9.6-431.4 (140.8 ± 113.6) ng/mL for rivaroxaban at 15 mg BID. PT (%), antithrombin, and dRVVT confirm tests showed good correlation with plasma apixaban levels. Plasma rivaroxaban concentrations were correlated well with PT (sec), PT (%),and dRVVT confirm results. On-therapy ranges established for dRVVT confirm test by linear regression were as follows: 1.32-1.52 for apixaban 2.5 mg BID, 1.12-1.75 for apixaban 5 mg BID, 1.11-1.78 for rivaroxaban 15 mg OD, 1.09-1.64 for rivaroxaban 20 mg OD, and 1.22-1.81 for rivaroxaban 20 mg BID., Conclusions: Apixaban concentrations were well correlated with PT (%), antithrombin, and dRVVT confirm test. Rivaroxaban concentrations showed good correlation with PT (sec), PT (%), and dRVVT confirm test., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Bone marrow (BM) study plays an important role as initial investigation specimen of lymphoma as well as staging lymphoma. This study aimed to investigate the utility of BM studies for classification of lymphoma and evaluate features of BM involvement by lymphoma over a period of 11 years., Methods: A total of 1162 cases of BM studies for lymphoma evaluation were reviewed for the incidence of lymphoma subtypes, the percentage of marrow involvement, the pattern of involvement and discordance with histopathologic diagnoses of lymph nodes and other tissues., Results: A total of 255 of 1162 cases underwent BM study without pathologic information, and 108 cases show lymphoma involvement. Lymph node biopsy underwent in 66 cases, and 10 cases show discordant result between BM and lymph node biopsy. Seven discordant cases were due to insufficient further studies. Lymphoma was diagnosed only by BM study in 38 cases. Abnormal lymphocytes were found in BM aspiration in 34 cases. Also, abnormal clonal lymphocytes were detected by flow cytometry in 26 cases. Four cases showed disease-related chromosomal abnormalities. FISH analysis detected abnormal findings in two cases, however, discordant with other additional studies., Conclusions: Discrepancies between the BM study and lymph node biopsy were due to insufficient further study and discordance of immunohistochemical stain result. BM study can be utilized as initial diagnosis of lymphoma by the combination of morphological feature, involvement pattern, and additional tests such as flow cytometry, chromosomal analysis, and FISH analysis. Thus, BM study with further analysis is an essential choice when lymph node biopsies are unavailable., (© 2019 The Authors Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Although flexible-ring annuloplasty is more inclined to increase the transmitral gradient over time, its effect on the tricuspid annulus is unknown. This study was conducted to evaluate serial changes in mean pressure gradient (mPG) across tricuspid and mitral valves after simultaneous dual implantation of flexible bands., Methods: Seventy-one (71) patients (median age, 61.6 years; IQR: 50.8-69.0 years) underwent simultaneous mitral/tricuspid annuloplasties using St. Jude Tailor rings. Serial mPGs across mitral and tricuspid valves were evaluated at three postoperative time points: predischarge, 3 years, and 5 years. To gauge the effects and clinical outcomes of prophylactic intervention, patients were categorised as tricuspid regurgitation (TR)≥moderate or TR

Objective: Opioids with abuse-deterrent properties may reduce widespread abuse, misuse, and diversion of these products. This study aimed to quantify misuse, abuse, dependence, and health resource use of extended-release morphine sulfate with sequestered naltrexone hydrochloride (ER-MSN; EMBEDA®), compared with non-abuse-deterrent extended-release morphine (ERM) products in Medicaid non-cancer patients., Methods: Administrative medical and pharmacy claims data were analyzed for 10 Medicaid states from 1 January 2015, to 30 June 2016. Patients were included if they received a prescription for ER-MSN or any oral, non-abuse-deterrent ERM. Index date was the date of first prescription for an ER-MSN or ERM. Abuse/dependence, non-fatal overdose, emergency department (ED) visits, and ED/inpatient readmissions were determined for each participant. An overall measure of misuse and abuse was also calculated. To account for differences in follow-up, all counts are expressed per 100 patient-years., Results: There were 4,857 patients who received ER-MSN and 10,357 who received an ERM. The average age in the two cohorts was approximately 45 years old. From pre-index to follow-up, the number of patients per 100 patient-years with a diagnosis code indicating abuse or dependence increased by 0.91 (95% confidence interval [CI]: 0.85, 0.97) in the ER-MSN cohort and 2.23 (95% CI: 2.14, 2.32) in the ERM cohort. The number of patients per 100 patient-years with an opioid-related non-fatal overdose increased by 0.05 (95% CI: 0.04, 0.06) in the ER-MSN cohort compared with 0.11 (95% CI: 0.09, 0.13) in the ERM cohort. The opioid abuse overall composite score increased by 1.36 (95% CI: 1.24, 1.48) in the post-index period in the ER-MSN cohort compared to 3.21 (95% CI: 3.10, 3.32) in the ERM cohort., Conclusion: Misuse, abuse, and dependence events were numerically lower in patients receiving ER-MSN compared with those receiving ERM products.

Introduction: Varenicline (VAR) is an effective smoking-cessation therapy compared to the commonly used nicotine-replacement therapy patch (NRT-P). However, comparative real-world evidence on smoking-cessation therapies is limited, especially for economic outcomes., Methods: Using national claims databases (2012-2016) in the United States (US), adults initiating VAR or NRT-P without use of any other smoking-cessation products were followed for up to 1 year on a quarterly basis. Outcomes included smoking-attributable (SA) (cardiovascular, diabetes, pulmonary diseases, and smoking cessation) and all-cause costs (2017 US dollars). Adjusted mean costs were estimated from multivariable regressions, with baseline characteristics and propensity scores as covariates. Annual adjusted costs were calculated from quarterly averages., Results: The VAR cohort (n = 209,284) was younger (mean age 46.7 vs. 49.0 years) and had fewer comorbidities [mean Charlson Comorbidity Index (CCI): 0.8 vs. 1.6] than the NRT-P cohort (n = 34,593). After adjustment, VAR cohort had lower SA and all-cause medical costs than NRT-P cohort in Quarters 1-4 (Q1-Q4) of follow-up, and had lower SA and all-cause total costs in Q2-Q4. Annually, VAR cohort had higher SA total costs ($307) and lower all-cause costs (- $2089) than NRT-P cohort. Annual medical costs were lower in VAR cohort (- $640 for SA and - $2876 for all-cause), and pharmacy costs were higher ($762 for SA and $777 for all-cause). In adherent patients (VAR: n = 38,744; NRT-P: n = 2702), VAR patients had lower annual medical costs (- $794 for SA and - $1636 for all-cause) and higher pharmacy costs ($1175 for SA and $1269 for all-cause); differences in SA and all-cause total costs were not statistically significant between treatment groups., Conclusions: Lower SA and all-cause medical costs associated with the use of VAR versus NRT-P resulted in savings in all-cause total costs and, among adherent patients, potentially offset the high pharmacy costs of VAR., Funding: Pfizer, Inc.

Aim: Group B streptococcus (GBS) is a leading cause of life-threatening bacterial infections among newborns, and neonates born to heavily colonized women may be subject to vertical transmission. We sought to determine an appropriate detection method for genital GBS in pregnant women by comparing culture-based methods and real-time polymerase chain reaction (PCR). In addition, we performed molecular serotyping and multilocus sequence typing (MLST) on isolates., Methods: A total of 150 pregnant women were enrolled and underwent vaginal-rectal swabbing at 16-40 weeks of gestation. GBS was identified by conventional culture and real-time PCR with or without enrichment. Molecular serotyping and MLST were performed on isolates., Results: Overall genital GBS positive rate among the 150 study subjects was 17.3%. Direct culture identified 18 (12.0%) positive specimens, enrichment culture 22 (14.6%), direct PCR 24 (16.0%) and enrichment PCR 25 (16.6%). The sensitivity and specificity by direct and enrichment PCR were as follows: for direct PCR, 90.9% and 96.9%, respectively; and for enrichment PCR, 95.5% and 96.9%, respectively. Resistance rates to clindamycin and erythromycin were 33.3% and 19.1%, respectively. Serotype III-1 was the most common (26.3%), followed by serotype Ib (21.1%), III-3 (15.8%), V (15.8%), II (10.5%), IV (5.3%) and VI (5.3%). Most common sequence types (ST) were ST-1, ST-19 and ST-862 (15.8%), followed by ST-2 and ST-654 (10.5%)., Conclusion: Direct real-time PCR using vaginal-rectal specimen could be used for detecting GBS in emergent conditions. Molecular serotypes III, Ib and V were most common. MLST analysis frequently presented ST-1, ST-19 and ST-862., (© 2018 Japan Society of Obstetrics and Gynecology.)

Objectives: This study assessed diffuse myocardial fibrosis (MF) by cardiac magnetic resonance (CMR) imaging and speckle-tracking echocardiography (STE) in patients with severe aortic stenosis (AS) and validated findings by using histologic confirmation of MF., Background: MF is a concomitant pathologic finding related to hypertrophic response in severe AS. It would be beneficial to have reliable imaging methods to assess MF., Methods: CMR and STE were performed in 71 consecutive patients with severe AS before aortic valve replacement. The extracellular volume (ECV) and native T1 values obtained by CMR and global longitudinal strain (GLS) values by STE were measured. The degree of MF was quantified by using Masson trichrome stain in myocardial biopsy specimens obtained intraoperatively. The study population was divided into 3 groups according to the degree of MF on histology (mild, moderate, and severe MF)., Results: The severe MF group had a higher incidence of heart failure (HF) and diastolic dysfunction than the mild and moderate MF groups. The ECV (r = 0.465; p < 0.0001), GLS (r = 0.421; p = 0.0003), and native T1 (r = 0.429; p = 0.0002) values were significantly correlated with the degree of MF. GLS was moderately correlated with ECV (r = 0.455; p = 0.0001) and less with the native T1 (r = 0.372; p = 0.0014) value. The model using ECV (R 2 = 0.44; Akaike Information Criterion [AIC] = 55.8) was found to predict the degree of MF most accurately than that with GLS (R 2  = 0.35; AIC = 66.84) and the native T1 (R 2  = 0.36; AIC = 66.18) value. The secondary endpoint of interest was clinical outcome of a composite of total mortality, admission for HF, or development of HF symptoms. During follow-up (median: 4.6 years), and there were 16 clinical events. Although statistically insignificant, ECV is more closely related to prediction of the clinical outcome than native T1 or GLS., Conclusions: ECV as assessed by CMR could be an ideal surrogate marker for diffuse MF in patients with severe AS among all 3 models considered., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)