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Direct oral anticoagulants (DOACs; namely, rivaroxaban and apixaban) and warfarin are approved for venous thromboembolism (VTE) treatment. Few direct comparisons exist of DOACs on risk of death among patients with VTE, and for patients with concomitant conditions (eg, kidney disease, liver disease), clinical guidelines are unclear. We evaluated 6-month all-cause mortality by anticoagulant prescribed for primary treatment of VTE. Using data from a 20% sample of Medicare beneficiaries, we created a propensity score-matched analytic data set of 47 860 beneficiaries with noncancer incident VTE. We used Cox regression to estimate adjusted hazard ratios (HRs) of OACs with 6-month mortality, and tested interactions by liver and kidney disease. There were 3422 deaths over 6 months of follow-up. In adjusted models, patients prescribed rivaroxaban (HR = 0.82; 95% CI, 0.76-0.90) had lower mortality rates than those prescribed warfarin. There was no association when comparing apixaban with warfarin (HR = 0.96; 95% CI, 0.87-1.07). In head-to-head comparisons of apixaban and rivaroxaban, the HR was 1.14 (95% CI, 1.01-1.28). Findings were similar among patients with liver and kidney disease. Overall, risk of death was similar by OAC prescribed. Though it is possible residual confounding remained, there was some suggestion of lower risk with rivaroxaban than warfarin. Treatment with DOACs appears safe among patients with VTE who have concomitant kidney or liver disease. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Syphilis is a multistage sexually transmitted disease caused by Treponema pallidum ssp. pallidum (TPA). This study analyzed clinical samples collected from patients with a diagnosed syphilis infection from 2004-2022, isolated in the Czech Republic. Mucocutaneous swab samples (n = 543) from 543 patients were analyzed, and from these samples, 80.11 % (n = 435) were PCR positive, and 19.89 % (n = 108) were PCR negative for TPA DNA. Swabs were more often positive when collected from syphilis patients in the primary and secondary stages, compared to the latent or unknown stage. There was no significant difference in PCR positivity between the primary and secondary stages (p = 0.099). In IgM-positive patients, a statistically significant association with PCR-positivity was found in samples from seropositive (p = 0.033) and serodiscrepant (RPR negative) patients (p = 0.0006). When assessing our laboratory-defined cases of syphilis, the RPR, IgM, and PCR tests were similarly effective (within the range of 80.1-86.1 %). However, parallel testing with these methods was even more effective, i.e., RPR + PCR was 96.1 % effective and RPR + IgM + PCR was 97.8 % effective. A combination of RPR + PCR, or a combination of all three tests (RPR, IgM, and PCR) can therefore be used to reliably detect active syphilis cases, including reinfections. Our findings show that the reverse algorithm for detecting syphilis could be substantially improved by adding IgM and PCR testing., (Copyright © 2025 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Despite improvements in therapy, breast cancer still contributes to high mortality rates. Survival of these patients becomes progressively worse upon diagnosis with cancer-associated thrombosis (CAT). Unfortunately, the mechanism causing CAT has remained unclear., Objective: Set up an acute and non-invasive hypercoagulable mouse model with an aggressive breast cancer and study the mechanism of cancer-associated thrombosis., Methods: Mice were grafted with the aggressive breast cancer cell line MDA-MB-231 or sham-treated. Subsequently, an acute imbalance in coagulation was introduced by injecting a synthetic small interfering (si) RNA targeting hepatic Serpinc1 to knockdown antithrombin - a condition known to predispose to cause a hypercoagulant state in vivo., Results: Silencing Serpinc1 with siRNA decreased plasma antithrombin levels. siRNA treatment had no short-term effects on tumor characteristics, but increased distant metastasis within the timeframe of this study. The systemic pro-inflammatory status, with elevated platelet counts and fibrinogen levels in tumor-bearing mice, was also not affected by antithrombin silencing. While elevated fibrin deposition in the liver upon Serpinc1 targeting was not significantly affected by the presence of breast cancer, knockdown of antithrombin did significantly increase intratumoral fibrin deposition and inflammation. Surprisingly, in the presence of an aggressive tumor, a protective outcome with less clinical features coinciding with venous thrombosis were observed in mice with antithrombin knockdown., Conclusion: We conclude that the presence of a breast tumor protects hypercoagulant mice from severe consumption of coagulation factors after lowering hepatic antithrombin levels, possibly due to elevated platelet counts. However, the consequences on cancer-associated thrombosis remained inconclusive., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hormone therapies, including aromatase inhibitors and tamoxifen, are used with ovarian suppression to improve outcomes in premenopausal patients with breast cancer. Cardiovascular impacts of these treatments among premenopausal women are unknown., Objectives: The aim of this study was to test the hypothesis that the use of aromatase inhibitors in combination with ovarian suppression, relative to tamoxifen, is associated with greater incident cardiovascular disease (CVD) risk in premenopausal breast cancer survivors., Methods: The MarketScan administrative claims databases (2013-2020) were used to identify enrollees younger than 55 years who had incident breast cancer and were treated with either an aromatase inhibitor and ovarian suppression or tamoxifen. Propensity score matching was used to balance treatment groups across confounding variables including age, breast cancer treatments, and comorbidities. The HR for CVD (including atrial fibrillation, myocardial infarction, stroke, heart failure hospitalization, angina, or coronary revascularization) was calculated by treatment group., Results: In the matched cohort, over a median follow-up time of 1.55 years, the incidence rate was 2.3 per 100 person-years among users of aromatase inhibitors plus ovarian suppression (51 CVD events in 2,205 person-years) and 1.0 per 100 person-years for tamoxifen users (102 CVD events in 9,913 person-years). Users of aromatase inhibitors plus ovarian suppression had a 2.20-fold higher hazard of CVD than tamoxifen users (HR: 2.20; 95% CI: 1.57-3.09). In absolute terms, the incidence rate difference was 0.012 (95% CI: 0.006-0.019). Findings were robust to several sensitivity analyses., Conclusions: Premenopausal patients with breast cancer treated with aromatase inhibitors and ovarian suppression may be at elevated risk for CVD and should be monitored for cardiovascular risk., Competing Interests: Dr Lutsey was supported by National Heart, Lung, and Blood Institute grant K24 HL159246. Dr Wang was supported by National Heart, Lung, and Blood Institute grant T32 HL007779. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

GBA2, the non-lysosomal β-glucosylceramidase, is an enzyme involved in glucosylceramide metabolism. Pharmacological inhibition of GBA2 by N -alkyl iminosugars is well tolerated and benefits patients suffering from Sandhoff and Niemann-Pick type C diseases, and GBA2 inhibitors have been proposed as candidate-clinical drugs for the treatment of parkinsonism. With the ultimate goal to unravel the role of GBA2 in (patho)physiology, we sought to develop a GBA2-specific activity-based probe (ABP). A library of probes was tested for activity against GBA2 and the two other cellular retaining β-glucosidases, lysosomal GBA1 and cytosolic GBA3. We show that β-d-arabinofuranosyl cyclitol aziridine (β-d-Araf aziridine) reacts with the GBA2 active site nucleophile to form a covalent and irreversible bond. Fluorescent β-d-Araf aziridine probes potently and selectively label GBA2 both in vitro and in cellulo , allowing for visualization of the localization of overexpressed GBA2 using fluorescence microscopy. Co-staining with an antibody selective for the lysosomal β-glucosylceramidase GBA1, shows distinct subcellular localization of the two enzymes. We proffer our ABP technology for further delineating the role and functioning of GBA2 in disease and propose the β-d-Araf aziridine scaffold as a good starting point for the development of GBA2-specific inhibitors for clinical development., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Syphilis is a multistage sexually transmitted disease caused by Treponema pallidum ssp. pallidum. In the Czech Republic, there are around 700-800 new syphilis cases annually, continuously increasing since 2012. This study analyzed a total of 1228 samples from 2004 to 2022. Of the PCR-positive typeable samples (n = 415), 68.7% were fully-typed (FT), and 31.3% were partially-typed. Most of the identified isolates belonged to the SS14-clade and only 6.3% were the Nichols-like cluster. While in the beginning of sample collection isolates have been macrolide-susceptible, recent isolates are completely resistant to macrolides. Among the FT samples, 34 different allelic profiles (APs) were found. Most of the profiles (n = 27) appeared just once in the Czech population, while seven profiles were detected more than twice. The most frequent APs belonged to two separate groups of SS14-like isolates, including group of 1.3.1 (ST 1) and 1.26.1 (ST 25) profiles, and the second group containing 1.1.8 (ST 3), 1.1.1 (ST 2), and 1.1.3 (ST 11) (representing 57.5%, and 25.3% of all detected APs, respectively). Both groups consistently differed in 6 nucleotide positions in five genes (TP0150, TP0324, TP0515, TP0548, and TP0691) coding amino-acid replacements suggesting that one or more of these differences could be involved in the higher success of the first group., (© 2024. The Author(s).)

Although it is well known that the ancestors of modern humans and Neanderthals admixed, the effects of gene flow on the Neanderthal genome are not well understood. We develop methods to estimate the amount of human-introgressed sequences in Neanderthals and apply it to whole-genome sequence data from 2000 modern humans and three Neanderthals. We estimate that Neanderthals have 2.5 to 3.7% human ancestry, and we leverage human-introgressed sequences in Neanderthals to revise estimates of Neanderthal ancestry in modern humans, show that Neanderthal population sizes were significantly smaller than previously estimated, and identify two distinct waves of modern human gene flow into Neanderthals. Our data provide insights into the genetic legacy of recurrent gene flow between modern humans and Neanderthals.

Background: Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is frequently recommended but underutilized partly due to the absence of studies assessing bleeding risk., Objectives: To determine the rate of severe (hospitalized) bleeding from thromboprophylaxis in patients treated for MM and identify clinical risk factors for bleeding in this population., Methods: Using the MarketScan database, we analyzed 6656 patients treated for MM between 2013 and 2021. Concomitant thromboprophylaxis was defined using prescription claims. Hospitalized bleeding was identified through the Cunningham algorithm. Bleeding rates were compared by thromboprophylaxis status, and Cox regression identified risk factors for bleeding., Results: Anticoagulant thromboprophylaxis was used in 6.6% (436) patients treated for MM. Patients on thromboprophylaxis had a higher rate of immunomodulatory-based therapy (63.8% vs 46.7%; P  < .01) and lower rate of antiplatelet use (2.1% vs 4.7%; P  < .01). Bleeding occurred in 1.4% of them during median follow-up of 1.3 years. Rate of severe bleeding was not different between those on prophylaxis (7.8 per 1000 person-years) and those not on prophylaxis (10.1 per 1000 person-years). No association was identified between thromboprophylaxis and bleeding. Factors associated with increased bleeding included age (hazard ratio [HR], 1.38 per 10 years increase in age), comorbidity index (HR, 1.18 per SD increase), history of bleeding (HR, 1.54), hypertension (HR, 1.87), and renal disease (HR, 1.56)., Conclusion: Risk of serious bleeding from thromboprophylaxis in patients treated for MM was low, and concomitant anticoagulant therapy did not result in increased bleeding risk. Clinical risk factors for bleeding included age, comorbidity index, bleeding history, hypertension, and renal disease., (© 2024 The Author(s).)

Purpose: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA 2 DS 2 -VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death., Methods: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA 2 DS 2 -VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used., Results: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years., Conclusion: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: To evaluate the efficacy and tolerability of a single dose of oral cefixime 800 mg plus oral doxycycline 100 mg twice a day for 7 days, compared with a recommended single dose of ceftriaxone plus single dose of oral azithromycin, for treatment of uncomplicated urogenital, rectal, or pharyngeal gonorrhoea., Methods: A noninferiority, open-label, multicentre randomized controlled trial was conducted in Prague, Czech Republic. Some 161 patients, 18-65 years of age diagnosed with uncomplicated urogenital, rectal, or pharyngeal gonorrhoea by nucleic acid amplification test (NAAT) were randomized to treatment with single dose of cefixime 800 mg plus doxycycline 100 mg twice a day for 1 week or a single dose of ceftriaxone 1 g intramuscularly plus single dose of azithromycin 2 g. The primary outcome was the number of participants with negative culture and NAAT at 1 week and 3 weeks, respectively, after treatment initiation., Results: In all, 161 patients were randomized and 152 were included in per-protocol analyses. All 76 (100%; 95% CI, 0.95-1.00) patients treated with ceftriaxone plus azithromycin achieved negative cultures and NAAT after treatment. In the cefixime plus doxycycline arm at week 1, culture was negative in all 76 (100%) patients; at week 3, culture was negative in 70 of the 76 patients (92%; 95% CI, 0.84-0.97) and NAAT negative in 66 of the 76 patients (87%; 95% CI, 0.77-0.94). At week 3, culture and NAAT were negative in 65 of the 76 patients (86%; 95% CI, 0.76-0.93). Per-protocol risk difference was 14.5%; 95% CI, 6.56-22.38. All treatment failures observed in the cefixime arm were pharyngeal gonorrhoea cases., Discussion: The combination of cefixime and doxycycline did not achieve noninferiority to ceftriaxone and azithromycin for treatment of gonorrhoea when including pharyngeal gonorrhoea. It did, however, show high efficacy for urogenital and rectal gonorrhoea., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Tamoxifen is an effective treatment for primary breast cancer but increases the risk for venous thromboembolism. Tamoxifen decreases anticoagulant proteins, including antithrombin (AT), protein C (PC) and tissue factor (TF) pathway inhibitor, and enhances thrombin generation (TG). However, the relation between plasma concentrations of both tamoxifen and its active metabolite endoxifen and coagulation remains unknown., Methods: Tamoxifen and endoxifen were measured in 141 patients from the prospective open-label intervention TOTAM-study after 3 months (m) and 6 m of tamoxifen treatment. Levels of AT and PC, the procoagulant TF, and TG parameters were determined at both timepoints if samples were available (n = 53-135 per analysis). Levels of coagulation proteins and TG parameters were correlated and compared between: 1) quartiles of tamoxifen and endoxifen levels, and 2) 3 m and 6 m of treatment., Results: At 3 m, levels of AT, PC, TF and TG parameters were not associated with tamoxifen nor endoxifen levels. At 6 m, median TF levels were lower in patients in the 3rd (56.6 [33] pg/mL), and 4th (50.1 [19] pg/mL) endoxifen quartiles compared to the 1st (lowest) quartile (76 [69] pg/mL) (P=0.027 and P=0.018, respectively), but no differences in anticoagulant proteins or TG parameters were observed. An increase in circulating TF levels (3 m: 46.0 [15] versus 6 m: 54.4 [39] pg/mL, P < 0.001) and TG parameters was observed at the 6 m treatment timepoint, while AT and PC levels remained stable., Conclusions: Our results indicate that higher tamoxifen and endoxifen levels are not correlated with an increased procoagulant state, suggesting tamoxifen dose escalation does not further promote hypercoagulability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Parastomal hernias are common and many are never repaired. Emergency parastomal hernia repair (PHR) is a feared complication following ostomy creation, yet the incidence and long-term outcomes of emergency PHR are unknown., Materials and Methods: We performed a retrospective analysis of 100% Medicare claims data (2007-2015) to evaluate complications, readmissions, reoperations, hospitalizations, and mortality after emergency PHR. We used logistic regression and Cox proportional hazard models to determine the association of surgical approach, including repair with ostomy reversal, resiting, mesh, minimally invasive approach, or a myofascial flap. Analysis took place between June 2022 and February 2023., Results: A total of 6658 patients underwent emergency PHR (mean [standard deviation] age, 75.9 [9.8] y; 4031 female individuals [60.5%]). Overall, 3433 (51.2%) patients underwent primary PHR, 1626 (24.4%) underwent PHR with ostomy resiting, and 1599 (24.0%) underwent PHR with ostomy reversal. In the 30 d after surgery, 4151 (62.3%) patients had complications and 55 (0.83%) underwent reoperation. Compared to local repair, the 30-d odds of complications were lower for patients who underwent ostomy resiting (odds ratio 0.82 [95% confidence interval 0.72-0.93]). Five y after surgery, the cumulative incidence of reoperation was 12.0% and was lowest for patients who underwent PHR with ostomy reversal (hazard ratio 0.15 [95% confidence interval 0.11-0.21]) when compared to local repair., Conclusions: Emergency PHR is associated with significant morbidity. However, technique selection may influence outcomes. Understanding the prognosis of emergency PHR may improve decision-making and patient counseling for patients living with this common disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To compare the rates of operative recurrence between male and female patients undergoing groin hernia repair., Background Data: Groin hernia repair is common but understudied in females. Limited prior work demonstrates worse outcomes among females., Methods: Using Medicare claims, we performed a retrospective cohort study of adult patients who underwent elective groin hernia repair between January 1, 2010 and December 31, 2017. We used a Cox proportional hazards model to evaluate the risk of operative recurrence up to 5 years following the index operation. Secondary outcomes included 30-day complications following surgery., Results: Among 118,119 patients, females comprised the minority of patients (n=16,056, 13.6%). Compared with males, female patients were older (74.8 vs. 71.9 y, P <0.01), more often white (89.5% vs. 86.7%, P <0.01), and had a higher prevalence of nearly all measured comorbidities. In the multivariable Cox proportional hazards model, we found that female patients had a significantly lower risk of operative recurrence at 5-year follow-up compared with males (aHR 0.70, 95% CI 0.60-0.82). The estimated cumulative incidence of recurrence was lower among females at all time points: 1 year [0.68% (0.67-0.68) vs. 0.88% (0.88-0.89)], 3 years [1.91% (1.89-1.92) vs. 2.49% (2.47-2.5)], and 5 years [2.85% (2.82-2.88) vs. 3.7% (3.68-3.75)]. We found no significant difference in the 30-day risk of complications., Conclusions: We found that female patients experienced a lower risk of operative hernia recurrence following elective groin hernia repair, which is contrary to what is often reported in the literature. However, the risk of operative recurrence was low overall, indicating excellent surgical outcomes among older adults for this common surgical condition., Competing Interests: A.P.E. receives related funding from SAGES, and unrelated funding from the Blue Cross Blue Shield of Michigan Foundation and the Association for Academic Surgery. R.H. receives unrelated funding from the Blue Cross Blue Shield of Michigan Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK108740-05). D.A.T. receives unrelated funding from the National Institute of Diabetes and Digestive and Kidney Diseases and receives consulting fees from Medtronic. J.B.D. receives unrelated grant funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, Blue Cross Blue Shield of Michigan Foundation, and is a cofounder of ArborMetrix, Inc. The remaining authors do not have any disclosures. No funder had any part in the design or execution of this study. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011-2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0-3.2) at 30 days and 19.6% (95% CI 19.2-20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16-0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management., (© 2023 Wiley Periodicals LLC.)

Objective: To assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and other second-line diabetes therapies with risk of cardiovascular disease (CVD), as well as conduct head-to-head comparisons between SGLT2 inhibitors., Patients and Methods: Using data from the MarketScan databases (January 1, 2013, through December 31, 2019), SGLT2 inhibitor users were matched with up to five other second-line therapy users by age, sex, date of enrollment, and date of second-line therapy initiation. The primary composite outcome included stroke, atrial fibrillation, myocardial infarction, and heart failure. Hazard ratios were estimated, adjusting for demographics and a propensity score reflecting comorbidities and medications., Results: In this study population of 313,396 patients (mean age 53±10 years; 47% female), 9787 incident CVD events occurred over a median follow-up of 1.36 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than other second-line therapy users (HR, 0.66; 95% CI, 0.62 to 0.71). Significant associations were also observed when each CVD outcome was assessed separately. No differences were noted when comparing individual SGLT2 inhibitors., Conclusion: SGLT2 inhibitors were associated with a clinically meaningfully lower CVD risk in the real-world setting. In head-to-head comparisons, the different SGLT2 inhibitors were consistent in their protective associations with CVD. This suggests that as a class, SGLT2 inhibitors may have widespread benefit in preventing CVD among patients with type 2 diabetes., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: Low-cost low-field point-of-care MRI systems are used in many different applications. System design has correspondingly different requirements in terms of imaging field-of-view, spatial resolution and magnetic field strength. In this work an iterative framework has been created to design a cylindrical Halbach-based magnet along with integrated gradient and RF coils that most efficiently fulfil a set of user-specified imaging requirements., Methods: For efficient integration, target field methods are used for each of the main hardware components. These have not been used previously in magnet design, and a new mathematical model was derived accordingly. These methods result in a framework which can design an entire low-field MRI system within minutes using standard computing hardware., Results: Two distinct point-of-care systems are designed using the described framework, one for neuroimaging and the other for extremity imaging. Input parameters are taken from literature and the resulting systems are discussed in detail., Discussion: The framework allows the designer to optimize the different hardware components with respect to the desired imaging parameters taking into account the interdependencies between these components and thus give insight into the influence of the design choices., (© 2023. The Author(s).)

Background: Tumor necrosis factor-alpha (TNF- α ) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation., Methods: We analyzed the power of serum biomarkers to predict the failure of anti-TNF- α . We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF- α , CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor- β 1 (TGF- β 1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1)., Results: We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF- β 1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF- β 1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment., Conclusions: The TGF- β 1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF- β ) are not markedly influenced by the treatment and that anti-TNF- α therapy decreases MMP-9 without influencing the treatment outcome., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Stepan Coufal et al.)

Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumor-expressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liver-derived FVII have opposing effects on EMT and metastasis., (© 2023 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.)

MicroRNAs (miRNAs) are short-length non-protein-coding RNA sequences that post-transcriptionally regulate gene expression in a broad range of cellular processes including neuro- development and have previously been implicated in fetal alcohol spectrum disorders (FASD). In this study, we use our vervet monkey model of FASD to follow up on a prior multivariate (developmental age × ethanol exposure) mRNA analysis (GSE173516) to explore the possibility that the global mRNA downregulation we observed in that study could be related to miRNA expression and function. We report here a predominance of upregulated and differentially expressed miRNAs. Further, the 24 most upregulated miRNAs were significantly correlated with their predicted targets (Target Scan 7.2). We then explored the relationship between these 24 miRNAs and the fold changes observed in their paired mRNA targets using two prediction platforms (Target Scan 7.2 and miRwalk 3.0). Compared to a list of non-differentially expressed miRNAs from our dataset, the 24 upregulated and differentially expressed miRNAs had a greater impact on the fold changes of their corresponding mRNA targets across both platforms. Taken together, this evidence raises the possibility that ethanol-induced upregulation of specific miRNAs might contribute functionally to the general downregulation of mRNAs observed by multiple investigators in response to prenatal alcohol exposure.

Purpose: High permittivity dielectric pads are known to be effective for tailoring the RF field and improving image quality in high field MRI. Despite a number of studies reporting benign specific absorption rate (SAR) effects, their "universal" safety remains an open concern. In this work, we evaluate the impact of the insulation material in between the pad and the body, using both RF simulations as well as phantom experiments., Methods: A 3T configuration with high permittivity material was simulated and characterized experimentally in terms of B 1 + fields and RF power absorption, both with and without electrical insulation in between the high permittivity material and the sample. Different insulation conditions were compared, and electromagnetic analyses on the induced current density were performed to elucidate the effect., Results: Increases in RF heating of up to 49% were observed experimentally in a tissue-mimicking phantom after removing the material insulation. The B 1 + magnitude and RF transceive phase were not affected. Simulations indicated that an insulation thickness of 0.5-2 mm should be accounted for in numerical models in order to ensure reliable results., Conclusion: A reliable RF safety assessment of high permittivity dielectric pads requires accounting for the insulating properties of the plastic encasing. Ignoring the electrical insulation can lead to erroneous results with substantial increases in local SAR at the interface. Conversely, the material insulation does not need to be modeled to predict the B 1 + effects during the design of the pad geometry., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Glioblastoma (GBM) patients have one of the highest risks of venous thromboembolism (VTE), which is even further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. In this study, we aimed to examine the effect of routinely used chemotherapeutic agents Temozolomide (TMZ) and Lomustine (LOM) on TF procoagulant activity and expression in GBM cells in vitro. Three human GBM cell lines (U-251, U-87, U-118) were exposed to 100 µM TMZ or 30 µM LOM for 72 h. TF procoagulant activity was assessed via an FXa generation assay and TF gene and protein expression through qPCR and Western blotting. The externalization of phosphatidylserine (PS) was studied using Annexin V flow cytometry. Treatment with TMZ and LOM resulted in increased procoagulant activity in all cell lines. Furthermore, both agents induced procoagulant activity in the supernatant and tumor-cell-secreted extracellular vesicles. In line, TF gene and protein expression were increased upon TMZ and LOM treatment. Additionally, PS externalization and induction of inflammatory-associated genes were observed. Overall, the chemotherapeutic modalities TMZ and LOM induced procoagulant activity and increased TF gene and protein expression in all GBM cell lines tested, which may contribute to the increased VTE risk observed in GBM patients undergoing chemotherapy.

Psoriasis is a chronic, immune-mediated, inflammatory disease primarily affecting the skin. It is currently coming to light that patients with psoriasis have disrupted intestinal barrier and often suffer from comorbidities associated with the gastrointestinal tract. Moreover, there is growing evidence of both cutaneous and intestinal paradoxical reactions during biologic treatment in patients with psoriasis. This review focuses on barrier defects and changes in immune responses in patients with psoriasis, which play an important role in the development of the disease but are also influenced by modern biological treatments targeting IL-17 and TNFα cytokines. Here, we highlight the relationship between the gut-skin axis, microbiota, psoriasis treatment, and the incidence of paradoxical reactions, such as inflammatory bowel disease in patients with psoriasis. A better understanding of the interconnection of these mechanisms could lead to a more personalized therapy and lower the incidence of treatment side effects, thereby improving the quality of life of the affected patients., (© 2023. The Author(s).)

Importance: Parastomal hernia is a challenging complication following ostomy creation; however, the incidence and long-term outcomes after elective parastomal hernia repair are poorly characterized., Objective: To describe the incidence and long-term outcomes after elective parastomal hernia repair., Design, Setting, and Participants: Using 100% Medicare claims, a retrospective cohort study of adult patients who underwent elective parastomal hernia repair between January 1, 2007, and December 31, 2015, was performed. Logistic regression and Cox proportional hazards models were used to evaluate mortality, complications, readmission, and reoperation after surgery. Analysis took place between February and May 2022., Exposures: Parastomal hernia repair without ostomy resiting, parastomal hernia repair with ostomy resiting, and parastomal hernia repair with ostomy reversal., Main Outcomes and Measures: Mortality, complications, and readmission within 30 days of surgery and reoperation for recurrence (parastomal or incisional hernia repair) up to 5 years after surgery., Results: A total of 17 625 patients underwent elective parastomal hernia repair (mean [SD] age, 73.3 [9.1] years; 10 059 female individuals [57.1%]). Overall, 7315 patients (41.5%) underwent parastomal hernia repair without ostomy resiting, 2744 (15.6%) underwent parastomal hernia repair with ostomy resiting, and 7566 (42.9%) underwent parastomal hernia repair with ostomy reversal. In the 30 days after surgery, 676 patients (3.8%) died, 7088 (40.2%) had a complication, and 1740 (9.9%) were readmitted. The overall adjusted 5-year cumulative incidence of reoperation was 21.1% and was highest for patients who underwent parastomal hernia repair with ostomy resiting (25.3% [95% CI, 25.2%-25.4%]) compared with patients who underwent parastomal hernia repair with ostomy reversal (18.8% [95% CI, 18.7%-18.8%]). Among patients whose ostomy was not reversed, the hazard of repeat parastomal hernia repair was the same for patients whose ostomy was resited vs those whose ostomy was not resited (adjusted hazard ratio, 0.93 [95% CI, 0.81-1.06])., Conclusions and Relevance: In this study, more than 1 in 5 patients underwent another parastomal or incisional hernia repair within 5 years of surgery. Although this was lowest for patients who underwent ostomy reversal at their index operation, ostomy resiting was not superior to local repair. Understanding the long-term outcomes of this common elective operation may help inform decision-making between patients and surgeons regarding appropriate operative approach and timing of surgery.

Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription. The primary end point was a composite of all-cause mortality or heart failure (HF) hospitalization. Secondary end points included all-cause mortality, HF hospitalization, and transplant-free survival. Multivariable Cox proportional hazards analyses determined the hazard ratios (HR) and 95% CIs for the primary and secondary end points. Among 205 patients with PAH in the repository, 32.7% (n=67) were on digoxin. Digoxin was more often prescribed to patients with severe PAH and right ventricular failure. After propensity score-matching, 49 patients were digoxin users, and 70 patients were nonusers; of these 31 (63.3%) in the digoxin group and 41 (58.6%) in nondigoxin group met the primary end point during a median follow-up time of 2.1 (0.6-5.0) years. Digoxin users had a higher combined all-cause mortality or HF hospitalization (HR, 1.82 [95% CI, 1.11-2.99]), all-cause mortality (HR, 1.92 [95% CI, 1.06-3.49]), HF hospitalization (HR, 1.89 [95% CI, 1.07-3.35]), and worse transplant-free survival (HR, 2.00 [95% CI, 1.12-3.58]) even after adjusting for patient characteristics and severity of PAH and right ventricular failure. Conclusions In this retrospective, nonrandomized cohort, digoxin treatment was associated with greater all-cause mortality and HF hospitalization, even after multivariate correction. Future randomized controlled trials should assess the safety and efficacy of chronic digoxin use in PAH.

Methylation silencing of certain cellular genes is a sign of carcinogenesis progression and therefore tests that detect methylation could be used in the diagnosis or staging of malignant diseases. In the diagnosis of squamous cell carcinomas of the cervix which are almost 100% caused by long-term infection with highrisk human papillomavirus (HR-HPV), methylation silencing of certain cellular genes is a highly specific marker of advanced dysplastic lesions and appears to result from aberrant activation of the methyltransferase DNMT1 by viral oncoproteins E6 and E7. A methylation test performed on a cervicovaginal cytology specimen allows to increase the diagnostic value of this non-invasive test and to select patients with severe squamous cell lesions for follow-up. Other less frequent anogenital malignancies that are induced by HR-HPV to a lesser extent can also be detected by cytological examination - glandular lesions of various origins, most commonly cervical and endometrial adenocarcinomas and anal carcinoma. The aim of our pilot study was to evaluate the utility of a methylation test for the diagnosis of these malignancies in a cohort of 50 liquid-based cervicovaginal cytologies with glandular lesion and 74 liquid-based anal cytologies from HIV-positive men having sex with men who are at high risk for anal cancer development.

Background: The risk of pregnancy-related mortality in the United States has nearly doubled since 1990, with venous thromboembolism (VTE) accounting for approximately 10% of these deaths., Objectives: The objective of this study was to assess whether preexisting autoimmune disease is a risk factor for postpartum VTE., Methods: Using the MarketScan Commercial and Medicare Supplemental administrative databases, a retrospective cohort study analyzed whether postpartum persons with autoimmune disease had a higher risk of postpartum VTE incidence than postpartum persons without autoimmune disease. Using International Classification of Diseases codes, we identified 757,303 individuals of childbearing age who had a valid delivery date with at least 12 weeks of follow-up., Results: Individuals were, on average, 30.7 years old (SD, 5.4), and 3.7% ( N  = 27,997 of 757,303) of them had evidence of preexisting autoimmune disease. In covariate-adjusted models, postpartum persons with preexisting autoimmune disease had higher rates of postpartum VTE than postpartum persons without autoimmune disease (hazard ratio [HR], 1.33; 95% CI, 1.07-1.64). When analyzed by individual autoimmune disease, those with systemic lupus erythematosus (HR, 2.49; 95% CI, 1.47-4.21) and Crohn's disease (HR, 2.49; 95% CI, 1.34-4.64) were at an elevated risk of postpartum VTE compared with those without autoimmune disease., Conclusion: Autoimmune disease was associated with a higher rate of postpartum VTE, with evidence that the association was most pronounced among individuals with systemic lupus erythematosus and Crohn's disease. These findings suggest that postpartum persons of childbearing age with autoimmune disease may require more monitoring and prophylactic care after delivery to prevent potentially fatal VTE events., (© 2023 The Authors.)

Objectives: Percutaneous radiofrequency ablation (RFA) is stated as a treatment option for renal cell carcinoma (RCC) smaller than 4 cm (T1a). Microwave ablation (MWA) is a newer technique and is still considered experimental in some guidelines. The objective of this study was to compare the safety and efficacy of RFA and MWA for the treatment of RCC., Methods: Patients with T1a RCC treated by RFA or MWA in two referral centers were retrospectively analyzed. Patient records were evaluated to generate mRENAL nephrometry scores. Local tumor progression (LTP) was considered when new (recurrence) or residual tumor enhancement within/adjacent to the ablation zone was objectified. Differences in LTP-free interval (residual + recurrence) between ablation techniques were assessed with Cox proportional hazards models and propensity score (PS) methods., Results: In 164 patients, 87 RFAs and 101 MWAs were performed for 188 RCCs. The primary efficacy rate was 92% (80/87) for RFA and 91% (92/101) for MWA. Sixteen patients had residual disease (RFA (n = 7), MWA (n = 9)) and 9 patients developed recurrence (RFA (n = 7), MWA (n = 2)). LTP-free interval was significantly worse for higher mRENAL nephrometry scores. No difference in LTP-free interval was found between RFA and MWA in a model with inverse probability weighting using PS (HR = 0.99, 95% CI 0.35-2.81, p = 0.98) and in a PS-matched dataset with 110 observations (HR = 0.82, 95% CI 0.16-4.31, p = 0.82). Twenty-eight (14.9%) complications (Clavien-Dindo grade I-IVa) occurred (RFA n = 14, MWA n = 14)., Conclusion: Primary efficacy for ablation of RCC is high for both RFA and MWA. No differences in efficacy and safety were observed between RFA and MWA., Key Points: • Both RFA and MWA are safe and effective ablation techniques in the treatment of T1a renal cell carcinomas. • High modified RENAL nephrometry scores are associated with shorter local tumor progression-free interval. • MWA can be used as heat-based ablation technique comparable to RFA for the treatment of T1a renal cell carcinomas., (© 2022. The Author(s).)

Crohn's disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD), where the role of gut but not skin dysbiosis is well recognized. Inhibitors of TNF have been successful in IBD treatment, but up to a quarter of patients suffer from unpredictable skin adverse events (SkAE). For this purpose, we analyzed temporal dynamics of skin microbiota and serum markers of inflammation and epithelial barrier integrity during anti-TNF therapy and SkAE manifestation in IBD patients. We observed that the skin microbiota signature of IBD patients differs markedly from healthy subjects. In particular, the skin microbiota of CD patients differs significantly from that of UC patients and healthy subjects, mainly in the retroauricular crease. In addition, we showed that anti-TNF-related SkAE are associated with specific shifts in skin microbiota profile and with a decrease in serum levels of L-FABP and I-FABP in IBD patients. For the first time, we showed that shifts in microbial composition in IBD patients are not limited to the gut and that skin microbiota and serum markers of the epithelium barrier may be suitable markers of SkAE during anti-TNF therapy., 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., (Copyright © 2023 Reiss, Rob, Kolar, Schierova, Kreisinger, Jackova, Roubalova, Coufal, Mihula, Thon, Bajer, Novakova, Vasatko, Kostovcikova, Galanova, Lukas, Kverka, Tresnak Hercogova, Tlaskalova-Hogenova and Jiraskova Zakostelska.)

Background: Ustekinumab, is a new therapy for patients with IBD, especially for patients suffering from Crohn's disease (CD) who did not respond to anti-TNF treatment. To shed light on the longitudinal effect of ustekinumab on the immune system, we investigated the effect on skin and gut microbiota composition, specific immune response to commensals, and various serum biomarkers., Methodology/principal Findings: We recruited 11 patients with IBD who were monitored over 40 weeks of ustekinumab therapy and 39 healthy controls (HC). We found differences in the concentrations of serum levels of osteoprotegerin, TGF-β1, IL-33, and serum IgM antibodies against Lactobacillus plantarum between patients with IBD and HC. The levels of these biomarkers did not change in response to ustekinumab treatment or with disease improvement during the 40 weeks of observation. Additionally, we identified differences in stool abundance of uncultured Subdoligranulum, Faecalibacterium, and Bacteroides between patients with IBD and HC., Conclusion/significance: In this preliminary study, we provide a unique overview of the longitudinal monitoring of fecal and skin microbial profiles as well as various serum biomarkers and humoral and cellular response to gut commensals in a small cohort of patients with IBD on ustekinumab therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Rob 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.)

Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with β1-integrin leading to inactivation of β1-integrin. Inhibition of TF signaling induces a shift in TF-binding from α3β1-integrin to α6β4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin β1 and β4-dependent reduction in metastasic dissemination., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Mucocutaneous mycotic infections are common complications in patients on IL-17 inhibitor therapy. We report a case of a 33-year-old male with severe psoriasis and psoriatic arthritis on secukinumab combined with methotrexate and prednisone with swelling, otorrhea, and pain of the right ear and external auditory canal. Due to progressive hypacusis, a surgical solution was chosen. Tissue samples taken during surgery revealed the presence of Aspergillus fumigatus . Aspergillosis should be suspected in prolonged otorrhea, especially in immunocompromised patients. Without intervention, the disease could be fatal.

Background: HIV-positive men who have sex with men (MSM) are more likely to experience human papillomavirus (HPV) infection. The persistent HPV infection is the major factor in the development of anal and oropharyngeal neoplasms. Data on the prevalence of anal and oral HPV in MSM are almost absent from the countries of Central and Eastern Europe. We conducted a cross-sectional study focused on the prevalence of oral and anal HPV infections and the relationship between current anal and oral HPV intrapersonal infection in a Czech population of predominantly HIV-positive MSM., Methods: Oral gargle and anal swab samples from 205 predominantly HIV-positive MSM from the Czech Republic were analysed for HPV infection using PCR. Selected sociodemographic and clinical data were correlated with HPV detection using generalized linear models and multivariate analysis., Results: HPV infection was detected in 183 (96.8%) anal and 48 (23.6%) oral samples. The most common type of HR-HPV was HPV16 in both anal (25.4%) and oral (2.5%) samples. Multiple anal HPV infections and the presence of vaccine-targeted HR-HPV types were significantly correlated with abnormal anal cytology and HIV status., Conclusion: The prevalence of anal HPV infection in Czech predominantly HIV-positive MSM ranks among the highest reported, while oral HPV prevalence is consistent with MSM populations. Minimal overlap of oral and anal HPV types within a patient was observed.

Current knowledge about human papillomavirus (HPV) infection in psoriasis patients treated with biologics is limited. In this study we evaluated the prevalence of oral and genital HPV infection in psoriasis patients treated with biologics or topical therapy for at least 6 months. The presence of HPV DNA in oral rinse and genital smears was evaluated. In total, 267 patients who met the inclusion criteria and agreed to participate were enrolled: 110 (41.2%) on topical therapy, 84 (31.5%) on anti-TNF-alpha therapy, 31 (11.6%) on anti-IL-12/23 therapy and 42 (15.7%) on anti-IL-17 therapy. The presence of genital HPV infection was detected in 34.6% of men receiving anti-TNF-α treatment, in 25.0% of patients on anti-IL-12/23 and 18.8% of patients on anti-IL-17 therapy. The difference in prevalence was not statistically different from men on topical treatment (26.3%). Prevalence of oral HPV infection was higher across all of the biologic groups (11.9% for anti-TNF-α, 12.9% for anti-IL-12/23 and 19.0% for anti-IL-17) compared to patients on topical therapy (7.3%), but statistically significant only for anti-IL-17 (p < 0.05). The presence of oral HPV infection in patients treated with biologics was significantly higher (44.0%) in patients on long-term biologic treatment (>8 years) compared to patients taking biologics for a shorter period (9.1%; p < 0.01). Our results suggest that patients on biologics for psoriasis have a higher prevalence of oral HPV infection compared to patients on topical treatment. Long-term treatment with biologics seems to be associated with a higher prevalence of oral HPV infection, independent of previous conventional immunosuppressive therapy., (© 2022 Wiley Periodicals LLC.)

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases ( ICD ) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170 021 VTE cases included in the analysis were on average (±SD) 57.5±15.8 years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94 years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2 years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

Purpose: Parallel RF transmission (PTx) is one of the key technologies enabling high quality imaging at ultra-high fields (≥7T). Compliance with regulatory limits on the local specific absorption rate (SAR) typically involves over-conservative safety margins to account for intersubject variability, which negatively affect the utilization of ultra-high field MR. In this work, we present a method to generate a subject-specific body model from a single T1-weighted dataset for personalized local SAR prediction in PTx neuroimaging at 7T., Methods: Multi-contrast data were acquired at 7T (N = 10) to establish ground truth segmentations in eight tissue types. A 2.5D convolutional neural network was trained using the T1-weighted data as input in a leave-one-out cross-validation study. The segmentation accuracy was evaluated through local SAR simulations in a quadrature birdcage as well as a PTx coil model., Results: The network-generated segmentations reached Dice coefficients of 86.7% ± 6.7% (mean ± SD) and showed to successfully address the severe intensity bias and contrast variations typical to 7T. Errors in peak local SAR obtained were below 3.0% in the quadrature birdcage. Results obtained in the PTx configuration indicated that a safety margin of 6.3% ensures conservative local SAR estimates in 95% of the random RF shims, compared to an average overestimation of 34% in the generic "one-size-fits-all" approach., Conclusion: A subject-specific body model can be automatically generated from a single T1-weighted dataset by means of deep learning, providing the necessary inputs for accurate and personalized local SAR predictions in PTx neuroimaging at 7T., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Fetal alcohol spectrum disorders (FASD) are common, yet preventable developmental disorders that stem from prenatal exposure to alcohol. This exposure leads to a wide array of behavioural and physical problems with a complex and poorly defined biological basis. Molecular investigations to date predominantly use rodent animal models, but because of genetic, developmental and social behavioral similarity, primate models are more relevant. We previously reported reduced cortical and hippocampal neuron levels in an Old World monkey (Chlorocebus sabaeus) model with ethanol exposure targeted to the period of rapid synaptogenesis and report here an initial molecular study of this model. The goal of this study was to evaluate mRNA expression of the hippocampus at two different behavioural stages (5 months, 2 years) corresponding to human infancy and early childhood., Methods: Offspring of alcohol-preferring or control dams drank a maximum of 3.5 g ethanol per kg body weight or calorically matched sucrose solution 4 days per week during the last 2 months of gestation. Total mRNA expression was measured with the Affymetrix GeneChip Rhesus Macaque Genome Array in a 2 × 2 study design that interrogated two independent variables, age at sacrifice, and alcohol consumption during gestation., Results and Discussion: Statistical analysis identified a preferential downregulation of expression when interrogating the factor 'alcohol' with a balanced effect of upregulation vs. downregulation for the independent variable 'age'. Functional exploration of both independent variables shows that the alcohol consumption factor generates broad functional annotation clusters that likely implicate a role for epigenetics in the observed differential expression, while the variable age reliably produced functional annotation clusters predominantly related to development. Furthermore, our data reveals a novel connection between EFNB1 and the FASDs; this is highly plausible both due to the role of EFNB1 in neuronal development as well as its central role in craniofrontal nasal syndrome (CFNS). Fold changes for key genes were subsequently confirmed via qRT-PCR., Conclusion: Prenatal alcohol exposure leads to global downregulation in mRNA expression. The cellular interference model of EFNB1 provides a potential clue regarding how genetically susceptible individuals may develop the phenotypic triad generally associated with classic fetal alcohol syndrome., (© 2022. The Author(s).)

Background: Data are needed on the use of oral anticoagulation in patients with atrial fibrillation (AF) in rural versus urban areas, including the initiation of direct oral anticoagulants (DOACs)., Objective: We used Medicare data to examine rural/urban differences in anticoagulation use in patients with AF., Methods: We identified incident AF in a 20% sample of fee-for-service Medicare beneficiaries (aged ≥ 65 years) from 2011 to 2016 and collected ZIP code and covariates at the time of AF. We identified the first anticoagulant prescription filled, if any, following AF diagnosis. We categorized beneficiaries into four rural/urban areas using rural-urban commuting area codes and used Poisson regression models to compare anticoagulant use., Results: We included 447,252 patients with AF (mean age 79 ± 8 years), of which 82% were urban, 9% large rural, 5% small rural, and 4% isolated. The percentage who initiated an anticoagulant rose from 34% in 2011 to 53% in 2016, paralleling the uptake of DOACs. In a multivariable-adjusted analysis, those in rural areas (vs. urban) were more likely to initiate an anticoagulant. However, rural beneficiaries (vs. urban) were less likely to initiate a DOAC; those in isolated areas were 17% less likely (95% confidence interval [CI] 13-20), those in small rural areas were 12% less likely (95% CI 9-15), and those in large rural areas were 10% less likely (95% CI 8-12)., Conclusion: Among Medicare beneficiaries with AF, anticoagulation use was low but increased over time with the introduction of DOACs. Rural beneficiaries were less likely to receive a DOAC., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: Initiation of injection drug use may be more frequent among people dispensed prescription opioid therapy for noncancer pain, potentially increasing the risk of hepatitis C virus (HCV) acquisition., Objective: To assess the association between medically dispensed long-term prescription opioid therapy for noncancer pain and HCV seroconversion among individuals who were initially injection drug use-naive., Design, Setting, and Participants: A population-based, retrospective cohort study of individuals tested for HCV in British Columbia, Canada, with linkage to outpatient pharmacy dispensations, was conducted. Individuals with an initial HCV-negative test result followed by 1 additional test between January 1, 2000, and December 31, 2017, and who had no history of substance use at baseline (first HCV-negative test), were included. Participants were followed up from baseline to the last HCV-negative test or estimated date of seroconversion (midpoint between HCV-positive and the preceding HCV-negative test)., Exposures: Episodes of prescription opioid use for noncancer pain were defined as acute (<90 days) or long-term (≥90 days). Prescription opioid exposure status (long-term vs prescription opioid-naive/acute) was treated as time-varying in survival analyses. In secondary analyses, long-term exposure was stratified by intensity of use (chronic vs. episodic) and by average daily dose in morphine equivalents (MEQ)., Main Outcomes and Measures: Multivariable Cox regression models were used to assess the association between time-varying prescription opioid status and HCV seroconversion., Results: A total of 382 478 individuals who had more than 1 HCV test were included, of whom more than half were female (224 373 [58.7%]), born before 1974 (201 944 [52.8%]), and younger than 35 years at baseline (196 298 [53.9%]). Participants were followed up for 2 057 668 person-years and 1947 HCV seroconversions occurred. Of the participants, 41 755 people (10.9%) were exposed to long-term prescription opioid therapy at baseline or during follow-up. The HCV seroconversion rate per 1000 person-years was 0.8 among the individuals who were prescription opioid-naive/acute (1489 of 1947 [76.5%] seroconversions; 0.4% seroconverted within 5 years) and 2.1 with long-term prescription opioid therapy (458 of 1947 [23.5%] seroconversions; 1.1% seroconverted within 5 years). In multivariable analysis, exposure to long-term prescription opioid therapy was associated with a 3.2-fold (95% CI, 2.9-3.6) higher risk of HCV seroconversion (vs prescription opioid-naive/acute). In separate Cox models, long-term chronic use was associated with a 4.7-fold higher risk of HCV seroconversion (vs naive/acute use 95% CI, 3.9-5.8), and long-term higher-dose use (≥90 MEQ) was associated with a 5.1-fold higher risk (vs naive/acute use 95% CI, 3.7-7.1)., Conclusions and Relevance: In this cohort study of people with more than 1 HCV test, long-term prescription opioid therapy for noncancer pain was associated with a higher risk of HCV seroconversion among individuals who were injection drug use-naive at baseline or at prescription opioid initiation. These results suggest injection drug use initiation risk is higher among people dispensed long-term therapy and may be useful for informing approaches to identify and prevent HCV infection. These findings should not be used to justify abrupt discontinuation of long-term therapy, which could increase risk of harms.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn's disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).

Introduction: Due to the variation in shape and curvature of the clavicle, plates often have to be adjusted during surgery to acquire a good fit. Poorly fitted plates can cause discomfort, eventually requiring implant removal. 3D-printed replicas of the fractured clavicle can assist in planning of the surgical approach, plate selection and, if necessary, adjustment of the plate prior to surgery. We hypothesized this method of preoperative preparation would reduce implant-related discomfort resulting in a reduced reoperation rate MATERIALS AND METHODS: In a prospective cohort study, perioperative plate handling and clavicle fixation were timed and follow-up data were collected from participants undergoing operative treatment for a midshaft clavicle fracture. The control group (n = 7) received conventional surgery with standard precontoured plates. For the intervention group (n = 7), 3D-printed replicas of the fractured clavicle and a mirrored version of the healthy contralateral clavicle were available prior to surgery for planning of the surgical approach, and for plate selection and contouring. Primary outcome was reoperation rate due to implant-related discomfort. Secondary outcomes were complications and time differences in the different surgical phases (reduction, fixation and overall operation time) RESULTS: More participants in the control group had the plate removed due to discomfort compared to the intervention group (5/7 vs. 0/6; P = 0.012). One participant was excluded from the intervention group due to a postoperative complication; an infection occurred at the implant site. No relevant time difference in surgical plate handling was found between both groups., Conclusions: Preoperative preparation using 3D-printed replicas of the clavicle fracture may reduce implant removal caused by plated-related discomfort. No relevant effect on surgery time was found., Trial Registration: Registered with 'toetsingonline.nl', trial number NL51269.075/14, 17-02-2015., (© 2020. The Author(s).)

The hexanucleotide (G4C2)-repeat expansion in the C9ORF72 gene is the most common pathogenic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This repeat expansion can be translated into dipeptide repeat proteins (DPRs), and distribution of the poly-GR DPR correlates with neurodegeneration in postmortem C9FTD/ALS brains. Here, we assessed poly-GR toxicity in zebrafish embryos, using an annexin A5-based fluorescent transgenic line (secA5) that allows for detection and quantification of apoptosis in vivo. Microinjection of RNA encoding poly-GR into fertilized oocytes evoked apoptosis in the brain and abnormal motor neuron morphology in the trunk of 1-4-days postfertilization embryos. Poly-GR can be specifically detected in protein homogenates from injected zebrafish and in the frontal cortexes of C9FTD/ALS cases. Poly-GR expression further elevated MitoSOX levels in zebrafish embryos, indicating oxidative stress. Inhibition of reactive oxygen species using Trolox showed full suppression of poly-GR toxicity. Our study indicates that poly-GR can exert its toxicity via oxidative stress. This zebrafish model can be used to find suppressors of poly-GR toxicity and identify its molecular targets underlying neurodegeneration observed in C9FTD/ALS., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background: Anal cancer (AC) screening is justified in high-risk populations, particularly HIV-positive men having sex with men (MSM). HR-HPV testing could improve the efficiency of cytologically based screening of AC, as in the screening of biologically analogical cervical cancer. The specificity of HR-HPV testing is influenced by the prevalence of HR-HPV infection in the screened population. Reported anal HR-HPV DNA prevalence in MSM is high, but HR-HPV mRNA reflects rather long-term infections and is more specific for high-grade lesions. However, no data were published about HR-HPV DNA and mRNA prevalence in the Czech AC screening population., Method: Results of liquid-based anal cytology of 203 predominantly HIV-positive MSM from the Czech AC screening cohort were correlated with results of DNA and E6/E7 mRNA testing of 14 HR-HPV types, and HPV16 genotyping. Eighty-one MSM underwent a standard anoscopy., Results: A total of 109 (53.7%) samples had abnormal cytology, with 12 (5.9%) ASC-H/HSIL, 67 (33.0%) samples cytologically negative, and 27 (13.3%) unsatisfactory. HR-HPV DNA was detected in 134 (66.0%) and HR-HPV RNA in 72 (35.5%) anal smears. HR-HPV mRNA and HPV16 mRNA positivity were associated with abnormal cytology (p = .0037, p = .0021). No significant association was found between HR-HPV DNA or HPV16 DNA positivity and abnormal cytology. No high-grade lesions were revealed by anoscopy., Conclusion: Prevalence of anal HR-HPV DNA among Czech MSM is high, however, the prevalence of HR-HPV mRNA is half and associated with abnormal cytology. Our results indicate an increased efficiency of cytological screening when combined with HR-HPV mRNA testing., (© 2021 Wiley Periodicals LLC.)

Background Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases ( ICD ) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.

Background Current scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data. Methods and Results We selected patients with incident VTE initiating oral anticoagulation in the 2011 to 2017 MarketScan databases. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use before oral anticoagulation initiation as potential predictors of bleeding using stepwise selection of variables in Cox models run on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165 434 patients with VTE and initiating oral anticoagulation, of whom 2294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% CI, 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95% CI, 0.67-0.69). For comparison, the c-statistic of the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly (>65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score in this population was 0.62 (95% CI, 0.61-0.63). Conclusions We have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.