bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations
Authors: Aherrahrou Rédouane , Baig Ferheen , Theofilatos Konstantinos , Lue Dillon , Beele Alicia , Örd Tiit , Kaikkonen Minna U. , Aherrahrou Zouhair , Cheng Qi , Ghosh Saikat Kumar B. , Karnewar Santosh , Karnewar Vaishnavi , Finn Aloke V. , Owens Gary K. , Joner Michael , Mayr Manuel , Civelek Mete 
Published: February 2024

BACKGROUND:
Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular disease, the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a contractile to a synthetic phenotype characterized by an increased proliferation, migration, production of ECM (extracellular matrix) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of cardiovascular disease, including coronary artery disease, stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease–related loci identified in genome-wide association studies.

METHODS:
Using human aortic SMCs from 123 multiancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted liquid chromatography–tandem mass spectrometry-based proteomic analysis of the conditioned media.

RESULTS:
We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 (latent-transforming growth factor beta-binding protein 1) in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions.

CONCLUSIONS:
Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
Sex-Based Disparities in Acute Myocardial Infarction Treatment Patterns and Outcomes in Older Adults Hospitalized Across 6 High-Income Countries: An Analysis From the International Health Systems Research Collaborative
Authors: Lu Hannah , Hatfield Laura A. , Al-Azazi Saeed , Bakx Pieter , Banerjee Amitava , Burrack Nitzan , Chen Yu-Chin , Fu Christina , Gordon Michal , Heine Renaud , Huang Nicole , Ko Dennis T. , Lix Lisa M. , Novack Victor , Pasea Laura , Qiu Feng , Stukel Therese A. , Uyl-de Groot Carin A. , Weinreb Gabe , Landon Bruce E. , Cram Peter 
Published: February 2024

BACKGROUND:
Sex differences in acute myocardial infarction treatment and outcomes are well documented, but it is unclear whether differences are consistent across countries. The objective of this study was to investigate the epidemiology, use of interventional procedures, and outcomes for older females and males hospitalized with ST-segment–elevation myocardial infarction (STEMI) and non–ST-segment–elevation myocardial infarction (NSTEMI) in 6 diverse countries.

METHODS:
We conducted a serial cross-sectional cohort study of 1 508 205 adults aged ≥66 years hospitalized with STEMI and NSTEMI between 2011 and 2018 in the United States, Canada, England, the Netherlands, Taiwan, and Israel using administrative data. We compared females and males within each country with respect to age-standardized hospitalization rates, rates of cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery within 90 days of hospitalization, and 30-day age- and comorbidity-adjusted mortality.

RESULTS:
Hospitalization rates for STEMI and NSTEMI decreased between 2011 and 2018 in all countries, although the hospitalization rate ratio (rate in males/rate in females) increased in virtually all countries (eg, US STEMI ratio, 1.58:1 in 2011 and 1.73:1 in 2018; Israel NSTEMI ratio, 1.71:1 in 2011 and 2.11:1 in 2018). Rates of cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery were lower for females than males for STEMI in all countries and years (eg, US cardiac catheterization in 2018, 88.6% for females versus 91.5% for males; Israel percutaneous coronary intervention in 2018, 76.7% for females versus 84.8% for males) with similar findings for NSTEMI. Adjusted mortality for STEMI in 2018 was higher for females than males in 5 countries (the United States, Canada, the Netherlands, Israel, and Taiwan) but lower for females than males in 5 countries for NSTEMI.

CONCLUSIONS:
We observed a larger decline in acute myocardial infarction hospitalizations for females than males between 2011 and 2018. Females were less likely to receive cardiac interventions and had higher mortality after STEMI. Sex disparities seem to transcend borders, raising questions about the underlying causes and remedies.
Impact of Residential Social Deprivation on Prediction of Heart Failure in Patients With Type 2 Diabetes: External Validation and Recalibration of the WATCH-DM Score Using Real World Data
Authors: Deo Salil V. , Al-Kindi Sadeer , Motairek Issam , McAllister David , Shah Anoop S.V. , Elgudin Yakov E. , Gorodeski Eiran Z. , Virani Salim , Petrie Mark C. , Rajagopalan Sanjay , Sattar Naveed 
Published: February 2024

BACKGROUND:
Patients with type 2 diabetes are at risk of heart failure hospitalization. As social determinants of health are rarely included in risk models, we validated and recalibrated the WATCH-DM score in a diverse patient-group using their social deprivation index (SDI).

METHODS:

We identified US Veterans with type 2 diabetes without heart failure that received outpatient care during 2010 at Veterans Affairs medical centers nationwide, linked them to their SDI using residential ZIP codes and grouped them as SDI <20%, 21% to 40%, 41% to 60%, 61% to 80%, and >80% (higher values represent increased deprivation). Accounting for all-cause mortality, we obtained the incidence for heart failure hospitalization at 5 years follow-up; overall and in each SDI group. We evaluated the WATCH-DM score using the C statistic, the Greenwood Nam D’Agostino test χ
2
test and calibration plots and further recalibrated the WATCH-DM score for each SDI group using a statistical correction factor.

RESULTS:

In 1 065 691 studied patients (mean age 67 years, 25% Black and 6% Hispanic patients), the 5-year incidence of heart failure hospitalization was 5.39%. In SDI group 1 (least deprived) and 5 (most deprived), the 5-year heart failure hospitalization was 3.18% and 11%, respectively. The score C statistic was 0.62; WATCH-DM systematically overestimated heart failure risk in SDI groups 1 to 2 (expected/observed ratios, 1.38 and 1.36, respectively) and underestimated the heart failure risk in groups 4 to 5 (expected/observed ratios, 0.95 and 0.80, respectively). Graphical evaluation demonstrated that the recalibration of WATCH-DM using an SDI group-based correction factor improved predictive capabilities as supported by reduction in the χ
2
test results (801–27 in SDI groups I; 623–23 in SDI group V).

CONCLUSIONS:
Including social determinants of health to recalibrate the WATCH-DM score improved risk prediction highlighting the importance of including social determinants in future clinical risk prediction models.
Increased Risk of Recurrent Stroke in Symptomatic Large Vessel Disease With Impaired BOLD Cerebrovascular Reactivity
Authors: van Niftrik Christiaan H.B. , Sebök Martina , Germans Menno R. , Halter Matthias , Pokorny Thomas , Stumpo Vittorio , Bellomo Jacopo , Piccirelli Marco , Pangalu Athina , Katan Mira , Wegener Susanne , Tymianski Michael , Kulcsár Zsolt , Luft Andreas R. , Fisher Joseph A. , Mikulis David J. , Regli Luca , Fierstra Jorn 
Published: February 2024

BACKGROUND:
Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events.

METHODS:

We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO
2
) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate.

RESULTS:

Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5–166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14–27.81;
P
<0.001) for recurrent ischemic stroke.

CONCLUSIONS:
Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR.
High-Intensity Aphasia Therapy Is Cost-Effective in People With Poststroke Aphasia: Evidence From the COMPARE Trial
Authors: Kim Joosup , Rose Miranda L. , Pierce John E. , Nickels Lyndsey , Copland David A. , Togher Leanne , Godecke Erin , Meinzer Marcus , Rai Tapan , Hurley Melanie , Foster Abby , Carragher Marcella , Wilcox Cassie , Cadilhac Dominique A. 
Published: February 2024

BACKGROUND:
Evidence from systematic reviews confirms that speech and language interventions for people with aphasia during the chronic phase after stroke (>6 months) improve word retrieval, functional communication, and communication-related quality of life. However, there is limited evidence of their cost-effectiveness. We aimed to estimate the cost per quality-adjusted life year gained from 2 speech and language therapies compared with usual care in people with aphasia during the chronic phase (median, 2.9 years) after stroke.

METHODS:
A 3-arm, randomized controlled trial compared constraint-induced aphasia therapy plus (CIAT-Plus) and multimodality aphasia therapy (M-MAT) with usual care in 216 people with chronic aphasia. Participants were administered a standardized questionnaire before intervention and at 12 weeks after the 2-week intervention/control period to ascertain health service utilization, employment changes, and informal caregiver burden. Unit prices from Australian sources were used to estimate costs in 2020. Quality-adjusted life years were estimated using responses to the EuroQol-5 Dimension-3 Level questionnaire. To test uncertainty around the differences in costs and outcomes between groups, bootstrapping was used with the cohorts resampled 1000 times.

RESULTS:
Overall 201/216 participants were included (mean age, 63 years, 29% moderate or severe aphasia, 61 usual care, 70 CIAT-Plus, 70 M-MAT). There were no statistically significant differences in mean total costs ($13 797 usual care, $17 478 CIAT-Plus, $11 113 M-MAT) and quality-adjusted life years (0.19 usual care, 0.20 CIAT-Plus, 0.20 M-MAT) between groups. In bootstrapped analysis of CIAT-Plus, 21.5% of iterations were likely to result in better outcomes and be cost saving (dominant) compared with usual care. In contrast, 72.4% of iterations were more favorable for M-MAT than usual care.

CONCLUSIONS:
We observed that both treatments, but especially M-MAT, may result in better outcomes at an acceptable additional cost, or potentially with cost savings. These findings are relevant in advocating for the use of these therapies for chronic aphasia after stroke.
The Three Religious Revivals. Pentecostal, Islamic, and Orthodox Upswings in the Context of Long-Term Secularization
Authors: Stolz Jörg , Novak Maruša 
Published: February 2024

Abstract
Secularization theory is often criticized by pointing to counterexamples where— apparently or really—revivals of religion have coincided with modernization. But secularization theorists have responded to such criticisms by arguing that secularization is compatible with temporary religious upswings. Recently, Stolz and Voas (2023) have proposed a typology, distinguishing 5 mechanisms: “crisis”, “reaction”, “transition”, “state intervention”, and “composition”. This paper puts this typology to the test by examining the three most important religious revivals in the 20th and 21st century: the Pentecostal, the Islamic, and the Orthodox religious revival. We argue that all three revivals have led to strong increases in various indicators of religiosity, each of them built on a different combination of central mechanisms. While the Orthodox revival seems to have come to a standstill, the Pentecostal/Charismatic and Islamic revivals are ongoing.
Perceptions on Use of Opioids in Palliative Care of Dyspnoea in Patients with Fibrotic interstitial lung disease and Chronic Obstructive Pulmonary Disease: A Qualitative Study
Authors: Hvelplund Camilla Yde , Refsgaard Birgit , Bendstrup Elisabeth 
Published: February 2024

Background Many patients with chronic obstructive pulmonary disease and fibrotic interstitial lung disease suffer from severe dyspnea and reduced quality of life, despite receiving optimal disease-modifying treatment for their illness. Studies have suggested that these patients may benefit from treatment with low-dose opioids. However, many patients decline opioid treatment. This has led to patients not receiving proper palliative treatment of their lung disease. Aim To identify potential barriers that prevent patients from receiving adequate palliative care with opioids and enable doctors to address patients’ concerns. Design A qualitative study based on semi-structured interviews. Interviews were transcribed and thematic analysis was done using NVivo. Setting/Participants Patients were recruited when scheduled for out-patient follow-up at Center for Rare Lung Diseases or at the COPD clinic, Aarhus University Hospital. Eligible patients were 18 years of age, did not currently receive opioids or had ever received opioids for dyspnea. Results A total of 28 patients participated. One patient was excluded before final analysis of 27 patients. Four themes were identified: Fear of side-effects, Need for more information, Stigma of opioids association with severe illness and dying, and No discernible barriers. Furthermore, three sub-themes to Fear of side-effects were identified: Fear of addiction, concern for sedative effect, and fear for loss of mobility due to inability to drive a car. The most expressed concern was Fear of side-effects, especially addiction. Conclusions Pre-conceived notions about opioids prevent some patients with chronic obstructive lung disease or interstitial lung disease from receiving palliative care for breathlessness.
Diabetes Mellitus and Total Ankle Arthroplasty Complications
Authors: Helbing Jordan , Farley Benjamin , Gu Alex , Zhao Amy Y. , Siram Gautam , Stein Benjamin , Chodos Marc D. 
Published: February 2024

Background: Postoperative infection, aseptic loosening, and perioperative medical complications after total ankle arthroplasty (TAA) are all devastating problems. While previous studies have shown diabetes as a risk factor predisposing patients to postoperative complications, not all literature supports this association following TAA. The goal of this study is to determine if diabetes influences midterm outcomes following TAA. Methods: An insurance database was utilized to identify patients undergoing TAA for ankle arthritis with a concurrent diagnosis of diabetes based on Current Procedural Terminology ( CPT) and International Classification of Diseases, Ninth Revision ( ICD-9) and Tenth Revision ( ICD-10), diagnosis and procedure codes from 2010 to 2021. The postoperative outcomes of all-cause revision, periprosthetic joint infection (PJI), septic revision, and aseptic revision were compared between patients with and without diabetes with a minimum 2-year follow-up using Kaplan-Meier and multivariate Cox proportional hazards analyses. Patient demographics, comorbidities, and Charlson Comorbidity Index were analyzed via univariate and multivariate analysis. Results: The study population included 8317 patients, 345 (4.1%) of whom had a concurrent diabetes diagnosis, who underwent TAA. After multivariate Cox proportional hazards analysis, the 5-year cumulative incidence of being coded as having PJI was 7.3% in patients with known diabetes compared to 3.9% in patients without known diabetes, with a 95% increased risk (hazard ratio [HR] 1.95, 95% CI 1.15-3.30, P = .01). Patients with diabetes also demonstrated a 5-year cumulative incidence of septic revision of 1.4% compared to 0.4% in those without, with a 363% increased risk (HR 4.63, 95% CI 1.22-17.52, P = .02). However, there was no difference in the 5-year cumulative incidence of all-cause revision TAA with 4.6% in patients with diabetes and 4.3% in those without (HR 1.29, 95% CI 0.69-2.44, P = .42) Conclusion: In this database, the 5-year risk of PJI and septic revision was higher among patients with diabetes compared to those without, but cumulative incidence of all-cause revision TAA was not different between groups. Level of Evidence: Level III, retrospective cohort database study.
Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency
Authors: van Beers Eduard J. , Al-Samkari Hanny , Grace Rachael F. , Barcellini Wilma , Glenthøj Andreas , DiBacco Melissa , Wind-Rotolo Megan , Xu Rengyi , Beynon Vanessa , Patel Parija , Porter John B. , Kuo Kevin H. M. 
Published: February 2024

Abstract
Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat’s impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], −1532.3 to 11 072.3), erythroferrone (mean, −9834.9 ng/L; 95% CI, −14 328.4 to −5341.3), soluble transferrin receptor (mean, −56.0 nmol/L; 95% CI, −84.8 to −27.2), and erythropoietin (mean, −32.85 IU/L; 95% CI, −54.65 to −11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were −2.0 mg Fe/g dry weight (dw; 95% CI, −4.8 to −0.8) and −1.8 mg Fe/g dw (95% CI, −4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).
Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP
Authors: Gil Gonzalez Lazaro , Won Kevin D. , Tawhidi Zoya , Cummins Emma , Cruz-Leal Yoelys , Tundidor Cabado Yaima , Sachs Ulrich J. , Norris Peter A. A. , Shan Yuexin , Bhakta Varsha , Li Janessa , Samudio Ismael , Silva-Moreno Begonia , Cerna-Portillo Liza , Pavon Oro Alequis , Bergqvist Peter , Chan Patrick , Moorehead Amy , Sholzberg Michelle , Sheffield William P. , Lazarus Alan H. 
Published: February 2024

Abstract
Fc gamma receptor (FcγR) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). FcγRIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of FcγRIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of FcγRIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody’s Fc and/or bivalent nature. The blockade of human FcγRIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block FcγRIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human FcγRIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum–sensitized human platelets. In vivo studies using FcγR-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human FcγRIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.