bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Healthcare Expenditures Following Combat-Related Traumatic Brain Injury
Authors: Dalton Michael K , Jarman Molly P , Manful Adoma , Koehlmoos Tracey P , Cooper Zara , Weissman Joel S , Schoenfeld Andrew J
Published: June 2021

Background

Traumatic brain injury (TBI) is one of the most common injuries resulting from U.S. Military engagements since 2001. Long-term consequences in terms of healthcare utilization are unknown. We sought to evaluate healthcare expenditures among U.S. military service members with TBI, as compared to a matched cohort of uninjured individuals.

Methods

We identified service members who were treated for an isolated combat-related TBI between 2007 and 2011. Controls consisted of hospitalized active duty service members, without any history of combat-related injury, matched by age, biologic sex, year of hospitalization, and duration of follow-up. Median total healthcare expenditures over the entire surveillance period represented our primary outcome. Expenditures in the first year (365 days) following injury (hospitalization for controls) and for subsequent years (366th day to last healthcare encounter) were considered secondarily. Negative binomial regression was used to identify the adjusted influence of TBI.

Results

The TBI cohort consisted of 634 individuals, and there were 1,268 controls. Healthcare expenditures among those with moderate/severe TBI (median $154,335; interquartile range [IQR] $88,088-$360,977) were significantly higher as compared to individuals with mild TBI (median $113,951; IQR $66,663-$210,014) and controls (median $43,077; IQR $24,403-$83,590; P < .001). Most expenditures were incurred during the first year following injury.

Conclusion

This investigation represents the first continuous observation of healthcare utilization among individuals with combat-related TBI. Our findings speak to continued consumption of health care well beyond the immediate postinjury period, resulting in total expenditures approximately six to seven times higher than those of service members hospitalized for noncombat-related reasons.
Progenitor mass distribution for 22 historic core-collapse supernovae
Authors: Díaz-Rodríguez Mariangelly , Murphy Jeremiah W , Williams Benjamin F , Dalcanton Julianne J , Dolphin Andrew E
Published: June 2021

We infer the progenitor mass distribution for 22 historic core-collapse supernovae (CCSNe) using a Bayesian hierarchical model. For this inference, we use the local star formation histories to estimate the age for each supernova (SN). These star formation histories often show multiple bursts of star formation; our model assumes that one burst is associated with the SN progenitor and the others are random bursts of star formation. The primary inference is the progenitor age distribution. Due to the limited number of historic SNe and highly uncertain star formation at young ages, we restrict our inference to the slope of the age distribution and the maximum age for CCSNe. Using single-star evolutionary models, we transform the progenitor age distribution into a progenitor mass distribution. Under these assumptions, the minimum mass for CCSNe is $M_\textrm {min}~=~8.60^{+0.37}_{-0.41}\ \mathrm M_\odot$ and the slope of the progenitor mass distribution is $\alpha = -2.61^{+1.05}_{-1.18}$. The power-law slope for the progenitor mass distribution is consistent with the standard Salpeter initial mass function (α = −2.35). These values are consistent with previous estimates using precursor imaging and the age-dating technique, further confirming that using stellar populations around SN and supernova remnants is a reliable way to infer the progenitor masses.
Functional Characterization of the Cnidarian Antiviral Immune Response Reveals Ancestral Complexity
Authors: Lewandowska Magda , Sharoni Ton , Admoni Yael , Aharoni Reuven , Moran Yehu
Published: June 2021

Animals evolved a broad repertoire of innate immune sensors and downstream effector cascades for defense against RNA viruses. Yet, this system varies greatly among different bilaterian animals, masking its ancestral state. In this study, we aimed to characterize the antiviral immune response of the cnidarian Nematostella vectensis and decipher the function of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) known to detect viral double-stranded RNA (dsRNA) in bilaterians but activate different antiviral pathways in vertebrates and nematodes. We show that polyinosinic:polycytidylic acid (poly(I:C)), a mimic of long viral dsRNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), triggers a complex antiviral immune response bearing features distinctive for both vertebrate and invertebrate systems. Importantly, a well-characterized agonist of the vertebrate RIG-I receptor does not induce a significant transcriptomic response that bears signature of the antiviral immune response, which experimentally supports the results of a phylogenetic analysis indicating clustering of the two N. vectensis RLR paralogs (NveRLRa and NveRLRb) with MDA5. Furthermore, the results of affinity assays reveal that NveRLRb binds poly(I:C) and long dsRNA and its knockdown impairs the expression of putative downstream effector genes including RNA interference components. Our study provides for the first time the functional evidence for the conserved role of RLRs in initiating immune response to dsRNA that originated before the cnidarian–bilaterian split and lay a strong foundation for future research on the evolution of the immune responses to RNA viruses.
Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons
Authors: Wen Shuangquan , Wang Li , Zhang Wenhua , Xu Mingchang , Song Ruilong , Zou Hui , Gu Jianhong , Bian Jianchun , Yuan Yan , Liu Zongping
Published: June 2021

Cadmium (Cd) is a toxic metal and an environmental pollutant and can cause neurotoxicity by inducing apoptosis. Fas (CD95/Apo-1) is a cell-surface receptor that triggers apoptosis upon ligand binding, mediated through the mitochondrial apoptotic pathway. However, the role and regulatory mechanism of Fas in Cd-induced neuronal apoptosis remain understudied. Here, we demonstrate that activation of caspase-8 and the c-Jun N-terminal kinase (JNK) pathway are mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway in rat cerebral cortical neurons. In vitro, Cd induced apoptosis in primary cortical neurons by activating caspase-8, JNK, and the mitochondrial apoptotic pathway. Fas knockdown enhanced cell viability in the presence of Cd and inhibited apoptosis by blocking Cd-activated Fas, caspase-8, and JNK. Fas knockdown also inhibited the decrease of mitochondrial membrane potential, cleavage of caspase-9/3 and poly (ADP-ribose) polymerase 1, and impaired nuclear translocation of apoptosis-inducing factor and endonuclease G. In vivo, Fas knockdown alleviated Cd-induced neuronal injury and inhibited apoptosis, activation of caspase-8, JNK, and mitochondrial apoptotic pathways in rat cerebral cortical neurons. In summary, our results demonstrate that Cd-activated Fas relays apoptotic signals from the cell surface to the mitochondria via caspase-8 and JNK activation in rat cerebral cortical neurons, leading to aggravation of the neuronal injury.
Underreporting of mesothelioma, asbestosis and pleural plaques in Brazil
Authors: Santana V S , Salvi L , Cavalcante F , Campos F , Algranti E
Published: June 2021

Background

Brazil has a long history of heavy asbestos consumption. However, the number of asbestos-related diseases (ARDs) falls far below the one expected compared with other asbestos consumer countries.

Aims

To examine underreporting of ARDs, that is mesothelioma, asbestosis and pleural plaques, in Brazil’s Mortality Information System (SIM).

Methods

Health information systems (HIS) were mapped, datasets retrieved and records of ARD deaths extracted. Records were pair-matched using anonymous linkage to create a single database. ARD-reported cases missing in SIM were considered unreported. The study’s period ranged from 2008 to 2014, when every HIS contributed to the ARD records pool.

Results

A total of 1298 registered ARD deaths were found, 996 cases of mesothelioma (77%) and 302 (23%) of asbestosis and pleural plaques. SIM was the major single data source of ARD but 335 mesothelioma deaths were missing, an average underreporting of 33%, with no clear time trend. For asbestosis and pleural plaques, underreporting of ARD oscillated from 55% in 2010 to 25% in 2014, a declining trend. ARD underreporting was not associated with sex or age.

Conclusions

One-third of underreported ARD deaths in the universal SIM is unacceptably high and, apparently, it has not been improving substantially over time. After recoveries from multiple databases, the number of cases is still below, which could be expected based on asbestos consumption. Interoperability of multiple information systems could enhance case detection and improve the precision of mortality estimates, which are crucial for surveillance and for evaluation of remedial policies.
Domestic Servants and Master–Servant Regulations in Colonial Calcutta, 1750s–1810s
Authors: Sinha Nitin
Published: June 2021

In the Indian historiography of law and labour, master–servant regulations are an under-explored subject. Based on English precedents, these regulations acquired a specifically colonial nature when applied to control labour in the growing city of Calcutta. Questioning the assumed associations of domestic servants with privacy and informality, this article shows that in fact they were unambiguously one of the earliest groups to be regulated. It approaches the law from both ends, from its formal promulgation to its actual implementation. It analyses various regulations from 1759 to the 1810s that were passed to control employment relations between masters and servants, while for the first time analysing three different sets of court records to reconstruct the history of justice and the enforcement of law. It argues that domestic servants engaged with the law strategically: they made complaints of the non-payment of wages against their Indian masters but never brought such charges against their European masters. This absence is better understood if we unpack the hidden histories behind the juristic terms of these complaints, such as neglect of duty, running away (with or without advance payment of wages), demand for exorbitant wages, and theft, and see them as interlinked modes of control exercised under the master–servant regulations.
Transporter SlSWEET15 unloads sucrose from phloem and seed coat for fruit and seed development in tomato
Authors: Ko Han-Yu , Ho Li-Hsuan , Neuhaus H Ekkehard , Guo Woei-Jiun
Published: June 2021

Tomato (Solanum lycopersium), an important fruit crop worldwide, requires efficient sugar allocation for fruit development. However, molecular mechanisms for sugar import to fruits remain poorly understood. Expression of sugars will eventually be exported transporters (SWEETs) proteins is closely linked to high fructose/glucose ratios in tomato fruits and may be involved in sugar allocation. Here, we discovered that SlSWEET15 is highly expressed in developing fruits compared to vegetative organs. In situ hybridization and β-glucuronidase fusion analyses revealed SlSWEET15 proteins accumulate in vascular tissues and seed coats, major sites of sucrose unloading in fruits. Localizing SlSWEET15-green fluorescent protein to the plasma membrane supported its putative role in apoplasmic sucrose unloading. The sucrose transport activity of SlSWEET15 was confirmed by complementary growth assays in a yeast (Saccharomyces cerevisiae) mutant. Elimination of SlSWEET15 function by clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPR-associated protein gene editing significantly decreased average sizes and weights of fruits, with severe defects in seed filling and embryo development. Altogether, our studies suggest a role of SlSWEET15 in mediating sucrose efflux from the releasing phloem cells to the fruit apoplasm and subsequent import into storage parenchyma cells during fruit development. Furthermore, SlSWEET15-mediated sucrose efflux is likely required for sucrose unloading from the seed coat to the developing embryo.
Factors Affecting Technological Diffusion Through Social Networks: A Review of the Empirical Evidence
Authors: Cheng Hoi Wai Jackie
Published: June 2021

Network theory-based interventions could be particularly effective for promoting technology adoption when information friction serves as the major obstacle to technology diffusion. To inform policy makers interested in such interventions, this paper systematically reviews empirical evidence on determinants of how social networks shape technology diffusion. It identifies three sets of factors that individually and jointly affect technological diffusion on social networks: Population characteristics, including those describe overall network structures and key economic agents’ network positions and technology sophistication; technology parameters; and information propagation mechanisms. Accurate social network assessment—crucial for the formulation of network interventions—relies on making careful selection out of the many measures of network characteristics and layers of socioeconomic interactions to examine, and on accurately defining the scope and size of network data to collect. Evidence indicates effective network interventions should aim to introduce new technologies first to economic agents with high centrality or clustering, sufficient resemblance to average population, and whom are incentivized to communicate with others.
Triceps Tenotomy as an Alternative Exposure for Fixation of OTA/AO 13-C Fractures: A Technical Trick
Authors: Owen Aaron R. , Ivanov David V. , Barlow Jonathan D. , Torchia Michael E. , Yuan Brandon J.
Published: June 2021

Intra-articular fractures of the distal humerus present challenges to treating physician and patient alike. The olecranon osteotomy is accepted as the standard exposure for intra-articular distal humerus fractures; nevertheless, complications such as nonunion and implant prominence are common. In this article, we describe the clinical outcomes and anatomic features of the triceps tenotomy as an alternative method of exposure for internal fixation of intra-articular distal humerus fractures. The olecranon osteotomy approach affords greater exposure of the distal humerus articular surface; however, there was no difference in quality of fracture reduction, progression to fracture union, posttraumatic arthrosis, or implant failure between approaches in our series. The osteotomy approach resulted in a greater need for reoperation (15% vs. 46%, respectively); largely as a result of olecranon implant-related complications. In summary, the triceps tenotomy offers an alternative exposure for intra-articular distal humerus fracture fixation with comparable clinical outcomes to the olecranon osteotomy technique.
Ten steps to establish a national centre for gestational trophoblastic disease
Authors: Coulter John , van Trommel Nienke , Lok Christianne
Published: June 2021

Purpose of review

Gestational trophoblastic disease (GTD) is a group of heterogeneous disorders characterized by abnormal proliferation of trophoblastic tissue. GTD is a rare disease that is curable in the vast majority of patients when managed appropriately. The aim of the review is to discuss the important steps necessary to establish a center of excellence for GTD.

Recent findings

Care of patients with a rare disease is complicated by lack of strong evidence, scattering of patients across the country and limited expertise of medical professionals. The establishment of a center of excellence requires awareness of its benefit, funding, a solid business case and most of all dedicated clinicians. A multidisciplinary team and formulation of national guidelines are important steps before clinical pathways can be developed and treatment can be evaluated for improvement of care and research purposes. International embedding can facilitate the process and lead to the development of a (inter) national acknowledged sustainable center of excellence.

Centers of excellence could optimize the care of patients with GTD and promote research.
Comparison of neoadjuvant chemotherapy followed by surgery vs. surgery alone for locally advanced gastric cancer: a meta-analysis
Authors: Yu Jian-Hong , Wang Zao-Zao , Fan Ying-Chong , Liu Mao-Xing , Xu Kai , Zhang Nan , Yao Zhen-Dan , Yang Hong , Zhang Cheng-Hai , Xing Jia-Di , Cui Ming , Su Xiang-Qian
Published: June 2021

Background:

The neoadjuvant chemotherapy is increasingly used in advanced gastric cancer, but the effects on safety and survival are still controversial. The objective of this meta-analysis was to compare the overall survival and short-term surgical outcomes between neoadjuvant chemotherapy followed by surgery (NACS) and surgery alone (SA) for locally advanced gastric cancer.

Methods:

Databases (PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar) were explored for relative studies from January 2000 to January 2021. The quality of randomized controlled trials and cohort studies was evaluated using the modified Jadad scoring system and the Newcastle-Ottawa scale, respectively. The Review Manager software (version 5.3) was used to perform this meta-analysis. The overall survival was evaluated as the primary outcome, while perioperative indicators and post-operative complications were evaluated as the secondary outcomes.

Results:

Twenty studies, including 1420 NACS cases and 1942 SA cases, were enrolled. The results showed that there were no significant differences in overall survival (P = 0.240), harvested lymph nodes (P = 0.200), total complications (P = 0.080), and 30-day post-operative mortality (P = 0.490) between the NACS and SA groups. However, the NACS group was associated with a longer operation time (P < 0.0001), a higher R0 resection rate (P = 0.003), less reoperation (P = 0.030), and less anastomotic leakage (P = 0.007) compared with SA group.

Conclusions:

Compared with SA, NACS was considered safe and feasible for improved R0 resection rate as well as decreased reoperation and anastomotic leakage. While unbenefited overall survival indicated a less important effect of NACS on long-term oncological outcomes.
Off-hours admission does not impact outcomes in patients undergoing primary percutaneous coronary intervention and with a first medical contact-to-device time within 90 min
Authors: Ma Wen-Jian , Gao Si-De , Huang Si-Zhuang , Lin Xu-Ze , Yang Yue-Jin , Yu Meng-Yue
Published: June 2021

Background:

It remains unclear whether the outcomes of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI) during off-hours are as favorable as those treated during on-hours, especially those with a first medical contact-to-device (FMC-to-device) time within 90 min. We aimed to determine whether off-hours admission impacted late outcomes in patients undergoing PPCI and with an FMC-to-device time ≤90 min.

Methods:

This multicenter retrospective study included 670 STEMI patients who underwent successful PPCI and had an FMC-to-device time ≤90 min from 19 chest pain centers in Beijing from January 2018 to December 2018. Patients were divided into on-hours group and off-hours group based on their arrival time. Baseline characteristics, clinical data, and key time intervals during treatment were collected from the Quality Control & Improvement Center of Cardiovascular Intervention of Beijing by the “Heart and Brain Green Channel” app.

Results:

Overall, the median age of the patients was 58.8 years and 19.9% (133/670) were female. Of these, 296 (44.2%) patients underwent PPCI during on-hours and 374 (55.8%) patients underwent PPCI during off-hours. Compared with the on-hours group, the off-hours group had a longer FMC-to-device time and fewer patients with FMC-to-device time ≤60 min (P < 0.05). During the mean follow-up period of 24 months, a total of 64 (9.6%) participants experienced a major adverse cardiovascular event (MACE), with 28 (9.1%) in the on-hours group and 36 (9.6%) in the off-hours group (P > 0.05). According to the Cox regression analyses, off-hours admission was not a predictor of 2-year MACEs (P = 0.788). Similarly, the Kaplan-Meier curves showed that the risks of a MACE, all-cause death, reinfarction, and target vessel revascularization were not significantly different between the two groups (P > 0.05).

Conclusions:

This real-world, multicenter retrospective study demonstrated that for STEMI patients who underwent PPCI within 90 min, off-hours admission was safe, with no difference in the risk of 2-year MACEs compared with those with on-hours admission.
Patients and physician satisfaction of Degarelix in androgen deprivation therapy for advanced hormone-dependent prostate cancer in the Netherlands
Authors: Roshani Hossain , Roos Erik P.M. , Elzevier Henk W. , van de Beek Cees , van Winkel Peter , Pelger Rob C.M.
Published: June 2021

Background:

To explore the effectiveness and safety of the gonadotropin-releasing hormone antagonist, Degarelix, for the treatment of advanced hormone-dependent prostate cancer (PCa) in a real-world setting.

Methods:

In this noninterventional study, patients with advanced hormone-dependent PCa were included. Primary endpoints were progression-free survival (PFS) failure defined as either prostate-specific antigen failure, additional therapy related to PCa, or death. Secondary endpoints included patient and physician satisfaction scores, urinary symptoms, and adverse events (AEs).

Results:

Of 274 patients with PCa, 271 received at least 1 dose of Degarelix. At a median follow-up of 12.2 (interquartile range 6.2–22.0) months, 148 patients (60.2%) had PFS failure. Thirty-five patients (13%) withdrew from the study due to AEs, 23 patients (8.4%) died, and 36 patients (13%) completed 3 years’ follow-up. Urinary symptoms significantly decreased over time. In the safety population, 87.8% of patients reported AEs, with injection-site reactions commonly reported. The majority of physicians and patients considered the therapy satisfactory and well tolerated.

Conclusions:

In this observational study, Degarelix treatment was well accepted by men with advanced hormone-dependent PCa. Compared with phase III studies, a higher proportion of patients had PFS failure, possibly due to the inclusion of men with more advanced disease in the current study, and more men reported AEs.
Recent Changes in the Patterns of Breast Cancer as a Proportion of All Deaths According to Race and Ethnicity
Authors: Trentham-Dietz Amy , Chapman Christina Hunter , Bird Jennifer , Gangnon Ronald E.
Published: June 2021

Background:

Recent reports suggest that racial differences in breast cancer incidence rates have decreased. We examined whether these findings apply to breast cancer mortality while considering age, period, and cohort influences on both absolute and relative measures of breast cancer mortality.

Methods:

Using publicly available datasets (CDC WONDER, Human Mortality Database), we developed an age–period–cohort model of breast cancer mortality and breast cancer deaths as a proportion of all deaths during 1968–2019 among all women and by 5 race/ethnicity groups with sufficient numbers for estimation: Hispanic (all races), American Indian/Alaska Native and Asian/Pacific Islanders (regardless of ethnicity), non-Hispanic Black, and non-Hispanic White.

Results:

Initially increasing after 1968, age-adjusted breast cancer mortality rates have decreased among all racial/ethnic groups since 1988. The age-adjusted percent of all deaths due to breast cancer also has been declining for non-Hispanic White women since about 1990 while increasing or holding steady for other race/ethnic groups. In 2019, the age-adjusted percent of deaths due to breast cancer for women was highest for Asian/Pacific Islanders (5.6%) followed by non-Hispanic Black (4.5%), Hispanic (4.4%), non-Hispanic White (4.1%), and American Indian/Alaska Native women (2.6%).

Conclusions:

Breast cancer mortality disparities are now greater on both relative and absolute scales for non-Hispanic Black women, and using the relative scale for Asian/Pacific Islander and Hispanic women, compared with non-Hispanic White women for the first time in 50 years.
Upregulation of Long Noncoding RNA FGD5-AS1 Ameliorates Myocardial Ischemia/Reperfusion Injury via MicroRNA-106a-5p and MicroRNA-106b-5p
Authors: Hao Lin , Wang Juan , Bi Shao-Jie , Cheng Chao
Published: June 2021

Long noncoding RNAs have been known to play key roles in myocardial ischemia/reperfusion injury. This study was conducted to investigate whether upregulation of FGD5-AS1 can improve hypoxia/reoxygenation (H/R) injury of cardiomyocytes and its underlying mechanisms. Pc-FGD5-AS1 was used to overexpress FGD5-AS1 in cardiomyocytes. Cholecystokinin octapeptide and flow cytometry assays were performed to detect the effect of FGD5-AS1 on myocardial cell H/R injury. Quantitative real-time polymerase chain reaction and luciferase reporter assay were performed to assess the relationship between FGD5-AS1 and microRNA-106a-5p (miR-106a-5p) or miR-106b-5p. In patients with acute myocardial infarction and in H/R cardiomyocytes and ischemia/reperfusion myocardium, the expression levels of FGD5-AS1 were reduced, whereas the expression levels of miR-106a-5p and miR-106b-5p were increased. Overexpression of FGD5-AS1 increased the viability of H/R-treated cardiomyocytes and reduced the levels of apoptosis and creatine kinase-MB. In addition, FGD5-AS1 could bind to miR-106a-5p or miR-106b-5p and showed a mutual inhibitory effect between them. Furthermore, overexpression of miR-106a-5p or miR-106b-5p inhibited the expression of SMAD5. FGD5-AS1 upregulated the expression of SMAD5. In conclusion, FGD5-AS1 may be a potential therapeutic target for myocardial H/R injury, and its cardioprotective effect may be realized by reducing inflammatory response and cell apoptosis.
Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study
Authors: Škorňová Ingrid , Samoš Matej , Bolek Tomáš , Kamenišťáková Alena , Stančiaková Lucia , Galajda Peter , Staško Ján , Kubisz Peter , Mokáň Marián
Published: June 2021

Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.
Circ_0084043 Facilitates High Glucose-Induced Retinal Pigment Epithelial Cell Injury by Activating miR-128-3p/TXNIP-Mediated Wnt/β-Catenin Signaling Pathway
Authors: Zhang Yun , Zheng Lifang , Xu Haimin , Ling Liqin
Published: June 2021

Diabetic retinopathy is a frequent complication of diabetes mellitus and one of the common causes of blindness. Circular RNAs (circRNAs) can modulate various biological behaviors of human diseases. Circ_0084043 is a novel circRNA, and its function in diabetic retinopathy progression is unclear. Adult retinal pigment epithelial cells (ARPE-19) were treated with high glucose (HG). RNA levels of circ_0084043, microRNA-128-3p (miR-128-3p), and thioredoxin-interacting protein (TXNIP) were detected by quantitative real-time polymerase chain reaction. 3-(4, 5-dimethylthiazole-2-y1)-2, 5-diphenyl tetrazolium bromide and flow cytometry were, respectively, used to examine cell viability and apoptosis. Apoptotic and TNXIP relative protein levels were measured by Western blot. The combination between targets was analyzed through dual-luciferase reporter assay or RNA immunoprecipitation assay. Results showed that HG induced the upregulation of circ_0084043 and the downregulation of miR-128-3p in ARPE-19 cells. Circ_0084043 knockdown or miR-128-3p overexpression mitigated the HG-mediated cell viability inhibition, apoptosis promotion, and inflammatory response. Circ_0084043 targeted miR-128-3p and miR-128-3p inhibitor returned the regulation of si-circ_0084043 in HG-treated cells. TXNIP was the target gene of miR-128-3p and TXNIP overexpression abolished the miR-128-3p-mediated effects after HG treatment. Circ_0084043 regulated the TXNIP expression to activate Wnt/β-catenin signal pathway by targeting miR-128-3p. Our findings unraveled that circ_0084043 promoted the HG-induced retinal pigment epithelial cell injury through activating the Wnt/β-catenin signal pathway by the miR-128-3p/TXNIP axis. Circ_0084043 might be an available biomarker in diabetic retinopathy diagnosis and therapy.
Dynamic Changes in Plasma Urotensin II and Its Correlation With Plaque Stability
Authors: Yin Chun-Lin , Liu Xue , Wang Hong-Xia , Yan Ming-Cong , Guo Li-Juan , Li Guo-Nan , Xia Jing-Gang , Yuan Hui-hui , Yin Yan
Published: June 2021

Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.
Characteristics of Heart Failure Patients With or Without Hypotension When Transitioning From Nitroprusside to Sacubitril-Valsartan
Authors: Adie Sarah K. , Ketcham Scott W. , Abdul-Aziz Ahmad A. , Thomas Michael P. , Konerman Matthew C.
Published: June 2021

Background:

Sacubitril-valsartan is an angiotensin receptor–neprilysin inhibitor indicated for the treatment of patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Little is known about outcomes of HFrEF patients transitioned from sodium nitroprusside (SNP) to sacubitril-valsartan during an admission for acute decompensated heart failure. We sought to describe characteristics of patients initiated on sacubitril-valsartan while receiving SNP and, in particular, those patients who did and did not experience hypotension requiring interruption or discontinuation of sacubitril-valsartan.

Methods:

We performed a retrospective case series of adult patients (>18 years) with HFrEF (left ventricular ejection fraction ≤40%) admitted to the University of Michigan cardiac intensive care unit between July 2018 to September 2020 who received sacubitril-valsartan while on SNP.

Results:

A total of 15 patients with acute decompensated heart failure were initiated on sacubitril-valsartan while on SNP. The mean age was 57 ± 15.9 years. Seven (46.7%) patients experienced hypotension. The patients in the cohort who experienced hypotension were numerically older (60 ± 17 vs. 55 ± 15.5), and the majority were white (86%). Patients with hypotension had a numerically lower left ventricular ejection fraction (13 ± 4.2 vs. 18 ± 8.2) and higher serum creatinine (1.4 ± 0.54 vs. 0.88 ± 0.25). Seven (100%) patients received a diuretic on the day of sacubitril-valsartan initiation in those who experienced hypotension compared with 2 (25%) in those who did not experience hypotension.

Conclusions:

In almost half of patients admitted to the cardiac intensive care unit with acutely decompensated HFrEF, significant hypotension was seen when initiating sacubitril-valsartan while on SNP. Future studies should evaluate appropriate patients for this transition and delineate appropriate titration parameters.
Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition
Authors: Black Donald M. , Miller Michael , Heinonen Therese M. , Zhang Guili
Published: June 2021

Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.
Carvedilol Protects Against the H2O2-induced Cell Damages in Rat Myoblasts by Regulating the Circ_NFIX/miR-125b-5p/TLR4 Signal Axis
Authors: Wang Xiao , Sun Qi , Hu Wei
Published: June 2021

Circular RNAs (circRNAs) have been involved in the regulation of various kinds of cardiovascular diseases, including acute myocardial infarction. This study was performed to investigate the molecular mechanism associated with circRNA nuclear factor IX (circ_NFIX) in carvedilol-mediated cardioprotection in H2O2-treated H9c2 cells. Flow cytometry was performed for the analysis of cell cycle and apoptosis. Cell proliferation was evaluated using colony formation assay and 3-(4,5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide assay. Lactate dehydrogenase (LDH) activity was measured by LDH assay. The relative levels of circ_NFIX, microRNA-125b-5p (miR-125b-5p), and toll-like receptor 4 (TLR4) were determined by quantitative real-time polymerase chain reaction. Protein levels were examined by Western blot. The target interaction was proved by dual-luciferase reporter assay. H2O2-induced cell cycle arrest, proliferation repression, apoptosis, and LDH promotion in H9c2 cells were inhibited by carvedilol. The circ_NFIX level was reduced after carvedilol treatment in H2O2-treated H9c2 cells, and circ_NFIX overexpression inhibited the protective effects of carvedilol on H2O2-induced cell damages. Furthermore, circ_NFIX was validated to serve as a sponge of miR-125b-5p, and the inhibitory function of circ_NFIX in carvedilol-induced cardioprotection was achieved by sponging miR-125b-5p. Moreover, TLR4 acted as a target gene of miR-125b-5p and miR-125b-5p inhibitor upregulated the TLR4 expression to suppress the protective effects of carvedilol on H2O2-treated H9c2 cells. In addition, circ_NFIX regulated the TLR4 level by exerting the sponge influence on miR-125b-5p. The rat model also indicated that Carv might suppress the progression of acute myocardial infarction by regulating the levels of circ_NFIX, miR-125b-5p, and TLR4. These findings suggested that carvedilol protected H9c2 cells against the H2O2-induced cell dysfunction through depending on the circ_NFIX/miR-125b-5p/TLR4 axis.
Fisetin Prevents Oxidized Low-density Lipoprotein–Induced Macrophage Foam Cell Formation
Authors: Varghese Johnna F. , Patel Rohit , Singh Mohit , Yadav Umesh C. S.
Published: June 2021

Foam cell formation is an important event in atherosclerosis. Fisetin, a bioflavonoid, has been identified to possess anti-inflammatory, antilipidemic, and anticancerous properties; however, its role as a lipid homeostasis regulator in macrophages, specifically in the presence of metabolic stressors such as oxidized low-density lipoprotein (oxLDL) is not well understood. In this study, we have investigated the role of fisetin in preventing oxLDL-induced macrophage foam cell formation. U937-derived macrophages were stimulated with oxLDL with or without fisetin for varied time points, and various parameters were assessed including cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay; reactive oxygen species (ROS) by dichlorofluorescin diacetate assay; lipid accumulation by Oil Red O staining; and expression of NLR family pyrin domain containing 3 (NLRP3), sterol regulatory element-binding protein (SREBP)-1, and associated downstream proteins 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and fatty acid synthase (FAS) by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunoblotting. Functionality of FAS enzyme was determined using enzyme activity assay. Docking studies were performed to determine the in silico interaction between NLRP3 and fisetin. The results showed that fisetin up to the dose of 10 µM did not alter cell viability but at the same dose could decrease the accumulation of lipids in macrophages and prevented foam cell formation. Fisetin could also ameliorate and reduce oxLDL-induced upregulation of SREBP-1 and thereby the expression of its downstream lipid synthesis genes HMGCR and FAS and inhibited ROS-induced NLRP3 inflammasome activation. In conclusion, fisetin could inhibit foam cell formation by blocking oxLDL-induced ROS formation and subsequent NLRP3 activation, thereby inhibiting SREBP-1 and its downstream genes including FAS and HMGCR.
Epidemiology and risk factors for stroke in young individuals: implications for prevention
Authors: Hussain Aliza , Lee Michelle , Rana Jamal , Virani Salim S.
Published: June 2021

Purpose of review

Summarize and examine the epidemiology, etiologies, risk factors, and treatment of stroke among young adults and highlight the importance of early recognition, treatment, and primordial prevention of risk factors that lead to stroke.

Recent findings

Incidence of stroke, predominantly ischemic, among young adults has increased over the past two decades. This parallels an increase in traditional risk factors such as hypertension, diabetes, and use of tobacco, and use of illicit substances among young stroke patients. Compared to older patients, there is a much higher proportion of intracerebral and subarachnoid hemorrhage in young adults. The cause of ischemic stroke in young adults is also more diverse compared to older adults with 1/3rd classified as stroke of undetermined etiology due to inadequate effort or time spent on investigating these diverse and rare etiologies. Young premature Atherosclerotic Cardiovascular Disease patients have suboptimal secondary prevention care compared to older patients with lower use of antiplatelets and statin therapy and lower adherence to statins.

Among young patients, time-critical diagnosis and management remain challenging, due to atypical stroke presentations, vast etiologies, statin hesitancy, and provider clinical inertia. Early recognition and aggressive risk profile modification along with primary and secondary prevention therapy optimization are imperative to reduce the burden of stroke among young adults and save potential disability-adjusted life years.
Association of self-measured home, ambulatory, and strictly measured office blood pressure and their variability with intracranial arterial stenosis
Authors: Hisamatsu Takashi , Ohkubo Takayoshi , Hozawa Atsushi , Fujiyoshi Akira , Torii Sayuki , Segawa Hiroyoshi , Kondo Keiko , Kadota Aya , Takashima Naoyuki , Shitara Satoshi , Arima Hisatomi , Nakagawa Yoshihisa , Watanabe Yoshiyuki , Shiino Akihiko , Nozaki Kazuhiko , Ueshima Hirotsugu , Miura Katsuyuki
Published: June 2021

Objective:

Hypertension and intracranial artery stenosis (ICAS) are closely related; however, few studies have compared the strength of the relationship between strictly measured office and out-of-office blood pressure (BP) measurements. The relationship of day-by-day or short-term variability in BP to asymptomatic ICAS also remains unclear.

Methods:

In apparently healthy 677 men (mean age, 70 years) from a population-based cohort, we examined the association of strictly measured office BP and 7-day home BP with ICAS on magnetic resonance angiography. We conducted 24-h ambulatory BP monitoring in 468 of the men. Variability indices included day-by-day, daytime, and night-time variability, nocturnal decline, and morning pressor surge. Any ICAS was defined as either mild (1–49%) or severe (≥50%) stenosis.

Results:

We observed mild and severe ICAS in 153 (22.6%) and 36 (5.3%) participants, respectively. In multivariable-adjusted Poisson regression with robust error variance, higher SBP in office, home, or ambulatory BP monitoring was associated with the presence of any or severe ICAS. The associations with ICAS were comparable between office, home, and ambulatory SBP (all heterogeneity P values >0.1). Independent of mean SBP, greater nocturnal decline or morning pressor surge, but not day-by-day, daytime, or night-time variability, in SBP was associated with higher burden of any or severe ICAS.

Conclusion:

The magnitude of association of strictly measured office BP for asymptomatic ICAS was comparable with that of BP measured at home or in ambulatory BP monitoring. Circadian BP variation based on ambulatory BP monitoring was positively associated with asymptomatic ICAS burden.
The Association Between Intraocular Pressure and Visual Field Worsening in Treated Glaucoma Patients
Authors: Yohannan Jithin , Boland Michael V. , Ramulu Pradeep
Published: June 2021

Precis:

In treated eyes with mild/suspect glaucoma, intraocular pressure (IOP) increments are associated with worsening mean deviation (MD) once IOP reaches the 20s. In moderate/advanced eyes, IOP increments are associated with worse visual field (VF) performance across the entire IOP range.

Purpose:

The purpose of this study was to describe the relationship between mean treated IOP and VF worsening and understand how this relationship is affected by glaucoma severity and IOP range.

Methods:

A total of 1446 eyes of 869 treated glaucoma patients with at least 5 longitudinal reliable VF tests and IOP measures were included. Mixed-effects linear models were employed to understand the effect of eye-specific mean treated IOP on MD slope. Models included interaction terms to assess the differing relationships between MD slope and mean IOP by glaucoma severity (suspect/mild vs. moderate/advanced) and splines to account for the differing effects of mean IOP on MD slope at different IOP ranges (above or below 21 mm Hg).

Results:

In suspect/mild glaucoma, when treated IOP values were <21 mm Hg, a 1 mm Hg increment in IOP was not associated with an increase in the rate of VF worsening (P>0.05) but when treated IOP values rose >21 mm Hg, a 1 mm Hg increment in IOP was associated with faster VF worsening (−0.09 dB/y per 1 mm Hg increment, P<0.05). In moderate/advanced disease, a 1 mm Hg increment in treated IOP was associated with faster VF worsening both below and above 21 mm Hg, but the effect was much more pronounced in the higher range (−0.02 dB/y per mm Hg increment <21 mm Hg vs. −0.74 dB/y per mm Hg increment >21 mm Hg, P<0.05 for both).

Conclusion:

IOP remained associated with VF worsening in eyes with more advanced glaucoma throughout the IOP range but was only associated with VF worsening in eyes with less severe glaucoma at higher IOP.
Outcomes of cataract surgery with toric intraocular lens implantation after keratoplasty
Authors: Pellegrini Marco , Furiosi Luca , Yu Angeli Christy , Giannaccare Giuseppe , Scuteri Gianfranco , Gardeli Ioanna , Busin Massimo , Bovone Cristina , Spena Rossella
Published: June 2021

Purpose:

To evaluate the efficacy and predictability of cataract extraction with toric intraocular lens (IOL) implantation after deep anterior lamellar keratoplasty (DALK) or mushroom penetrating keratoplasty (PK).

Setting:

Villa Igea Hospital, Forlì, Italy.

Design:

Prospective case series.

Methods:

Toric IOL implantation was offered to patients with cataract, corneal astigmatism >1.5 diopters (D) and regular central corneal topography after complete suture removal. Phacoemulsification was performed through a 2.4 mm scleral tunnel and an enVista monofocal toric MX60T or Eyecryl monofocal toric IOL was inserted in the capsular bag. Main outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, total prediction error, and IOL misalignment.

Results:

37 consecutive patients who had previously undergone either DALK (n = 27, 73%) or 2-piece mushroom PK (n = 10, 27%) were included. All patients completed the 6-month follow-up. The mean toric IOL power was 5.3 ± 1.1 D. Both UDVA and CDVA significantly improved (from 1.02 ± 0.27 to 0.46 ± 0.31 logMAR and from 0.65 ± 0.27 to 0.11 ± 0.12 logMAR, respectively; P < .001). 20 eyes (54%) reached UDVA ≥20/40, whereas 35 eyes (95%) reached a CDVA ≥20/40. Final refractive astigmatism was 0.93 ± 0.87 D, with 35 eyes (95%) within 2 D. Prediction error was ≤1 D in 18 eyes (49%). Absolute IOL misalignment was 3.3 ± 3.5 degrees.

Conclusions:

Toric IOL implantation in postkeratoplasty eyes allowed reduction of refractive astigmatism to predictably low levels with concomitant improved visual outcomes.