bluuebunny/crossref_metadata_2025 huggingface dataset:
Adoption Status and Perception of Farmers on Improved Tef Technology Packages: Evidence from East Gojjam Zone, Ethiopia
Authors: Mihretie Atrsaw Anteneh , Misganaw Girmachew Siraw , Siyum Muluneh Negussie
Published: February 2022

Tef is a major staple crop in Ethiopia and Eritrea. Many improved Tef varieties were released from the Ethiopian research institute in the past three decades. Information on the farmers’ adoption status and perception on released improved Tef technology have paramount importance for launching new and modifying Tef technology packages. However, such information is meager in Ethiopia. Therefore, this study was conducted to assess farmers’ status and perception of improved Tef technologies. A multistage random sampling technique was employed to select sample of 224 Tef grower farmers. The results were interpreted and discussed using descriptive and inferential statistics. The result indicated that farmers in the study area found at the medium level of adoption of Tef production technology (i.e., the average adoption index is 0.43). The findings also confirm that farmers perception towards the relative advantages of improved Tef varieties shows that high grain yield, good germination, early mature, and disease resistance capacity were perceived as the most crucial attributes of improved Tef varieties, whereas straw quality and tolerance to lodging were perceived as the least important attributes of the technology. Therefore, efforts and commitments to be expected from plant breeders and genetic specialists to reduce lodging of Tef through hybridizing semidwarf Tef varieties.
Patent Foramen Ovale Closure for Treating Migraine: A Meta-Analysis
Authors: Zhang Yu , Wang Haijiao , Liu Ling
Published: February 2022

Background. Observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine. Objective. This study evaluated the efficacy and safety of PFO closure in patients with migraine using evidence-based medicine. Methods. The Pubmed (MEDLINE), Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs), cohort studies, and retrospective case series from January 1, 2001, to February 30, 2021. The Jadad scale and R 4.1.0 software were used to assess the quality of the literature and meta-analysis, respectively. Results. In total, three randomized controlled trials, one pooled study, and eight retrospective case series including 1,165 participants were included in the meta-analysis. Compared with control intervention in migraine, PFO closure could significantly reduce headache frequency (OR = 1.5698, 95% CI: 1.0465–2.3548,

p
=
0.0293

) and monthly migraine attacks and monthly migraine days (OR = 0.2594, 95% CI: 0.0790–0.4398,

p
=
0.0048

). Subgroup analysis of patients who all completed PFO surgery showed resolution of migraine headache for migraines with aura (OR = 1.5856, 95% CI: 1.0665–2.3575,

p
=
0.0227

). Conclusions. Treatment with PFO closure could reduce the frequency of headaches and monthly migraine days and is an efficient treatment for migraine attacks with aura.
Applications of Bladder Cancer Data Using a Modified Log-Logistic Model
Authors: Kayid Mohamed
Published: February 2022

In information science, modern and advanced computational methods and tools are often used to build predictive models for time-to-event data analysis. Such predictive models based on previously collected data from patients can support decision-making and prediction of clinical data. Therefore, a new simple and flexible modified log-logistic model is presented in this paper. Then, some basic statistical and reliability properties are discussed. Also, a graphical method for determining the data from the log-logistic or the proposed modified model is presented. Some methods are applied to estimate the parameters of the presented model. A simulation study is conducted to investigate the consistency and behavior of the discussed estimators. Finally, the model is fitted to two data sets and compared with some other candidates.
Research on the Mechanism of Kaempferol for Treating Senile Osteoporosis by Network Pharmacology and Molecular Docking
Authors: Tang Fuyu , Zhang Peng , Zhao Wenhua , Zhu Guangye , Shen Gengyang , Chen Honglin , Yu Xiang , Zhang Zhida , Shang Qi , Liang De , Jiang Xiaobing , Ren Hui
Published: February 2022

Kaempferol (KP), as a natural anti-inflammatory compound, has been reported to have curative effects on alleviating senile osteoporosis (SOP), which is an inflammation-related musculoskeletal disease, but the molecular mechanisms remain unclear due to scanty relevant studies. We predicted the targets of KP and SOP, and the common targets of them were subsequently used to carry out PPI analysis. Moreover, we adopted GO and KEGG enrichment analysis and molecular docking to explore potential mechanisms of KP against SOP. There were totally 152 KP-related targets and 978 SOP-related targets, and their overlapped targets comprised 68 intersection targets. GO enrichment analysis showed 1529 biological processes (

p
<
0.05

), which involved regulation of inflammatory response, oxidative stress, regulation of bone resorption and remodeling, osteoblast and osteoclast differentiation, etc. Moreover, KEGG analysis revealed 146 items including 44 signaling pathways (

p
<
0.05

), which were closely linked to TNF, IL-17, NF-kappa B, PI3K-Akt, MAPK, estrogen, p53, prolactin, VEGF, and HIF-1 signaling pathways. By means of molecular docking, we found that kaempferol is bound with the key targets’ active pockets through some connections such as hydrogen bond, pi-alkyl, pi-sigma, pi-pi Stacked, pi-pi T-shaped, and van der Waals, illustrating that kaempferol has close combination with the key targets. Collectively, various targets and pathways involve in the process of kaempferol treatment against SOP through regulating inflammatory response, oxidative stress, bone homeostasis, etc. Moreover, our study first reported that kaempferol may regulate core targets’ expression with involvement of inflammatory response, oxidative stress, and bone homeostasis, thus treating SOP.
Syringocystadenocarcinoma Papilliferum in a Fifteen-Year-Old Girl: A Case Report and Review of the Literature
Authors: Halsey Jordan N. , Faith Esteban Fernandez , Logan Suzanna J. , Shenoy Archana , Schieffer Kathleen M. , Cottrell Catherine E. , Lillis Anna P. , Aldrink Jennifer H. , Setty Bhuvana A. , Pearson Gregory D.
Published: February 2022

Syringocystadenocarcinoma papilliferum (SCACP) is a rare malignant neoplasm arising from adnexal tissues and is the malignant complement to the benign neoplasm syringocystadenoma papilliferum (SCAP). SCACP lesions appear as raised nodules or inflammatory plaques and can be associated with SCAP or nevus sebaceous. There have been fewer than 100 described cases of this neoplasm in the literature, and all previously published cases have been described in adults, with the majority occurring in the elderly. We present a case of an adolescent female with a syringocystadenocarcinoma papilliferum arising from a large thigh mass harboring an in-frame alteration in MAP2K1 along with a brief review of the literature.
Secrecy Analysis of NOMA-Based Integrated Satellite-Multiple UAV Networks under Nonideal Hardware and Colluding Scheme
Authors: Wang Yuanyuan , Zhou Feng , Wang Rugang , Wang Xueling , Guo Kefeng
Published: February 2022

This paper studies the secrecy outage probability (SOP) of nonorthogonal multiple access (NOMA)-based integrated satellite-multiple unmanned aerial vehicle networks (ISMUAVNs) under nonideal hardware and colluding scheme. Colluding scheme is defined as that the eavesdroppers cooperate with each other to overhear the legitimate users’ signals. On this foundation, we obtain the closed-form expression for the SOP for the considered NOMA-based ISMUAVNs along with the partial unmanned aerial vehicle (UAV) selection scheme. To gain more things in the high signal-to-noise ratio (SNR) regime, we derive the asymptotic expression for the SOP, which gives fast ways to evaluate the benefit of the NOMA scheme and the impact of nonideal hardware impairments on the SOP. Finally, Monte Carlo simulation results are provided to show the correctness of the analytical results. In addition, with the help of representative results, some important and interesting findings are obtained.
Fixed Point Results of Dynamic Process Dˇϒ,μ0 through FIC‐Contractions with Applications
Authors: Ali Amjad , Ameer Eskandar , Arshad Muhammad , Işık Hüseyin , Mudhesh Mustafa
Published: February 2022

This article constitutes the new fixed point results of dynamic process D(ϒ, μ0) through FIC‐integral contractions of the Ciric kind and investigates the said contraction to iterate a fixed point of set‐valued mappings in the module of metric space. To do so, we use the dynamic process instead of the conventional Picard sequence. The main results are examined by tangible nontrivial examples which display the motivation for such investigation. The work is completed by giving an application to Liouville‐Caputo fractional differential equations.
Numerical Analysis of Digital Twin System Modeling Methods Aided by Graph‐Theoretic Combinatorial Optimization
Authors: Zhou Sujing
Published: February 2022

This paper combines the digital twin system modeling method to conduct an in‐depth study and analysis of graph‐theoretic combinatorial optimization. This paper provides new ideas and approaches for optimal numerical analysis work by studying the digital twin modeling method that integrates digital modeling and graph theory combination, provides theoretical support for safe, stable, and economic operation of the system, proposes a solution for digital twin model based on big data platform, focuses on the nearest neighbor propagation (AP) and graph theory combination, solves the digital twin real‐time monitoring data asynchronous, incomplete problem, and applies the algorithm to the digital twin model based on the big data platform for data preprocessing to achieve better results. This paper also presents a web‐based digital twin system based on intelligent practical needs, analysis, and comparison of existing models, combined with digital twin technology, detailing the differences and connections between the various levels of numerical analysis and the implementation of this data in various fields, such as user management, equipment health management, product quality management, and workshop 3D navigation and detailed modeling of the digital twin system based on this numerical analysis to realize remote online monitoring, analysis, and management. In this paper, for the numerical analysis process, firstly, the key technologies of modeling and simulation operation control of production line based on digital twin are studied, and the rapid response manufacturing system based on a digital twin is designed and validated. Secondly, a scheduling technology framework for capacity simulation evaluation and optimization is established, and batching optimization, outsourcing decision, and rolling scheduling techniques are thus proposed to form a batching optimization algorithm based on priority rules, which realizes batching processing, outsourcing decision, and rolling scheduling of production orders to optimize equipment utilization and capacity. Finally, digital twin‐based modeling is designed, and the validation results demonstrate the system’s superior performance in achieving information interaction between physical and virtual production lines, optimization of numerical analysis, and display of results.
Coexistence of Megaconial Congenital Muscular Dystrophy and Cystinuria: Mimicking Hypotonia-Cystinuria Syndrome
Authors: Surucu Kara Ilknur , Oncul Ummuhan , Kose Engin , Turan Husnu Mutlu , Ceylan Ahmet Cevdet , Eminoglu Fatma Tuba
Published: February 2022

Introduction: Hypotonia-cystinuria syndrome is a contiguous gene deletion syndrome that is characterized by hypotonia, developmental delay, and cystinuria type A. We present a male patient who was admitted to our center with clinical findings of hypotonia-cystinuria syndrome and diagnosed with megaconial congenital muscular dystrophy and cystinuria. Case Presentation: A 16-month-old male patient was admitted with complaints of restlessness and body laxity. It was stated that the patient had hypotonia and growth retardation at the age of 2 months. Physical examination revealed mild hypotonia, growth retardation, and development delay, while laboratory examinations identified elevated serum creatine kinase and elevated dibasic amino acid in urine analysis. Because of the findings of hypotonia, growth retardation, developmental delay, and cystinuria, hypotonia-cystinuria syndrome was considered as a differential diagnosis. However, by chromosomal microarray no contiguous deletion in region 2p21 was found, while a novel homozygous c.225-2A>T pathogenic variant in the CHKB gene and a c.1266_1267delGT heterozygous variant in the SLC7A9 gene inherited from the mother were identified with whole-exome sequencing. The co-occurrence of megaconial congenital muscular dystrophy and cystinuria, mimicking hypotonia-cystinuria syndrome, was confirmed. Conclusion: This case suggests that in countries with a high frequency of consanguineous marriage, even if the molecular genetic analysis results are not compatible with the clinical findings, it should be kept in mind that different genetic diseases may coexist.
Sense of Purpose in Life and Markers of Hearing Function: Replicated Associations across Two Longitudinal Cohorts
Authors: Sutin Angelina R. , Luchetti Martina , Aschwanden Damaris , Stephan Yannick , Terracciano Antonio
Published: February 2022

Introduction: A sense of purpose in life is a psychological resource that is associated with healthier outcomes. The present research examines whether a greater sense of purpose in life is associated with subjective and objective markers of hearing health and whether hearing acuity contributes to the association between purpose and episodic memory. We sought to evaluate whether these associations were replicable across 2 independent samples. Methods: Participants in the Health and Retirement Study (N = 14,291) and the English Longitudinal Study of Ageing (N = 8,844) reported on their purpose in life and perceived hearing quality at baseline. Hearing acuity was measured using an audiometer 2–4 years later, and episodic memory was measured at baseline and 6–8 years later. Results: In both samples, higher purpose in life was associated with better hearing quality measured concurrently, lower risk of either subjective or objective hearing impairment, and hearing acuity accounted for some of the longitudinal relation between sense of purpose and better episodic memory. Discussion: Across samples, measures, and analytical approaches, the present research indicates replicable associations between sense of purpose in life and hearing health. It further indicates that hearing may be one factor that associates purpose with better episodic memory.
Three-Corridors Procedure to Operate in the Infralabyrinthine Cervico-Jugulo-Carotico-Tympanic Area
Authors: Altin Gokhan , Bayazit Yıldırım Ahmet
Published: February 2022

Introduction: The aim of the study was to present the results of our experience in three-corridors procedures applied for the tumors and inflammatory lesions of the infralabyrinthine cervico-jugulo-carotico-tympanic area. Methods: The lesions located in the infralabyrinthine cervico-jugulo-carotico-tympanic area were operated in 13 patients using the 3-corridors technique. The anatomical and functional integrity of the external and middle ears and the facial nerve (FN) could be preserved. Results: The diagnoses were glomus jugulare, infralabyrinthine petrous bone cholesteatoma, jugular foramen schwannoma, and giant-cell tumor. The follow-up duration ranged from 2 to 24 months. No tumor recurrence or growth was encountered in the follow-up. The operations were uneventful. Total surgical excision could be achieved in 10 patients. A second-stage retrosigmoid approach was performed for the total removal of the intracranial tumor remnant in two patients. A wait-and-scan policy has been considered in one patient who had partial resection for a glomus jugulare tumor. Conclusion: Three-corridors procedure seems to be a useful technique to operate in the infralabyrinthine, cervico-jugulo-carotico-tympanic area as it takes the advantage of hearing preservation, preservation of the anatomic and functional integrity of the external and middle ear structures as well as the FN.
Glaukombehandlung während Schwangerschaft und Stillzeit
Authors: Rohrschneider Klaus
Published: February 2022

Glaucoma and pregnancy is an uncommon combination, but it constitutes a very challenging situation for the treating doctor. The challenge is not only controlling the intraocular pressure and preventing glaucoma progression in the mother, but also having to deal with her mental stress and anxiety regarding the safety of her child. The situation is further worsened by the lack of definite guidelines as to how to deal with such patients. Relative rarity of glaucoma in this population restricts any large prospective randomized clinical trials or any large systematic studies. Moreover, none of the existing anti-glaucoma medications is absolutely safe in pregnancy. Current practice patterns depend on some case reports, a few observational studies and a few animal studies that attempt at determining the safety and efficacy of the available medicines. These are then prescribed on the basis of their relative safety in any particular stage of pregnancy or lactation. Newer medications that were released recently in 2018, such as Vyzulta and Rhopressa, presently have limited data to support their safety for use during pregnancy. Laser trabeculoplasty, conventional filtration surgery (of course without anti-metabolites), and minimally invasive glaucoma surgery represent a few non-pharmacological management options. Surgical procedures such as trabeculectomy and tube-shunts or collagen matrix implants, and newer minimally invasive glaucoma surgery procedures such as the gelatin stents are currently being explored and may prove to be viable solutions for severe glaucoma during pregnancy, although they too have their own inherent drawbacks. Management of glaucoma during pregnancy and lactation requires careful consideration of the disease status, gestational stage, US Food and Drug Administration classification and guidelines, and potential benefits and limitations of the various therapeutic modalities. This review focuses on the importance of a multidisciplinary team approach, starting with preconception planning and counseling, determining the treatment options depending on the stage of glaucoma and of pregnancy, and emphasizes the involvement of the patients, their obstetrician, and pediatrician through active discussion regarding the various medical, laser, or surgical modalities currently available or under exploration for use during pregnancy and lactation. The ultimate aim is to achieve an optimal balance between the risks and benefits of any type of intervention, and to customize treatment on an individual basis in order to achieve the best outcomes for both mother and fetus.
Uveitis in entzündlich-rheumatischen Erkrankungen
Authors: Pleyer Uwe
Published: February 2022

Background: Uveitis is one of the most frequent ophthalmologic manifestations in rheumatology. Uveal inflammation can underlie a systemic inflammatory rheumatic disease (SIRD) in approximately 30% of cases with a significant burden on the quality of life since it represents a cause of blindness in up to 20% of cases in Western countries. Methods: In this review, we provide a comprehensive overview of the pathophysiology of uveitis associated with SIRDs. According to our literature survey on the epidemiology of uveitis among SIRDs, spondyloarthritides, Behçet’s disease and sarcoidosis get the major impact. Results: In Behçet’s uveitis, the key players are highly polarized Th1 and Th17 lymphocytes, natural killer T cells and γδ T cells. All contribute to a great destructive inflammatory environment with the most serious visual damage resulting from the involvement of the posterior segment of the eye. In contrast, spondyloarthritides-related uveitis derives from a complex interaction between genetic background and extra-ocular inflammatory mediators originating from enthesitis, arthritis, psoriatic lesions and microbiome pro-inflammatory alterations. In such conditions, the immune infiltration of CD4+ T cells, Th17 and natural killer cells along with pro-inflammatory cytokines, TNF-α among all, leads to intraocular inflammation. Lastly, granuloma formation represents the primary hallmark lesion in sarcoid uveitis. This suggests a profound link between the innate system that mainly recruits activated macrophages and adaptive system involving by Th1, Th17 and Th17.1 cells. Conclusions: Awareness among rheumatologists of a potential severe ocular involvement generates new insights into targeted therapeutic approaches and personalized treatments for each patient.
Evaluation of the Autoimmunity and Preexisting Risky Conditions for Hypersensitivity Reactions to COVID-19 Vaccines
Authors: Tuzer Can , Terzioglu Kadriye
Published: February 2022

Introduction: The role of autoimmunity and other preexisting risky conditions in hypersensitivity reactions (HSRs) to COVID-19 vaccines seems unclear. The aim of the study was to investigate the autoimmunity and preexisting risky conditions in HSRs to COVID-19 vaccines. Methods: The patients aged ≥18 years with a history of HSR to CoronaVac or Pfizer-BioNTech COVID-19 vaccines within 24 h in 2 tertiary centers were assessed. The patients were divided according to the type of vaccine which they showed immediate-type (<4 h) HSR to (group A1 for CoronaVac and group B1 for Pfizer-BioNTech). Equal number of subjects who did not show HSR to two doses of either CoronaVac or Pfizer-BioNTech was recruited into the study as control groups (group A2 for CoronaVac and group B2 for Pfizer-BioNTech). The autologous serum skin test (ASST) was performed on patient and control groups. Later, the demographic, clinical, and laboratory features were compared between groups. Results: A total number of 27 patients were included in the study. Subjects with chronic spontaneous urticaria (CSU) were more frequent in group B1 than in group B2 (p:0.041). In addition to CSU, the presence of HSRs to drugs was higher in group A1 than in A2 (both p:0.007). The presence of autoimmunity and autoimmune diseases, positivity of antithyroid peroxidase antibody, and ASST were less in group A2 than in A1 (p:0.015, p:0.048, p:0.048, and p:0.037). Additionally, COVID-19 infection history was less in group A2 than in A1 (p:0.037). Discussion/Conclusion: Type IIb autoimmunity seems to play a role in immediate type HSRs to the CoronaVac vaccine as previously shown in autoimmune CSU and multidrug hypersensitivity.
Mid-Life Physical Activity and Late-Life Cognitive Performance among American Indians
Authors: Carty Cara L. , Noonan Carolyn , Muller Clemma , Suchy-Dicey Astrid , Fretts Amanda M. , Verney Steven P. , Howard Barbara V. , Buchwald Dedra
Published: February 2022

Introduction: Research on factors associated with late-life cognitive performance in diverse racial/ethnic groups is increasingly important due to the growing size and racial diversity of the elder population. Methods: Using data on American Indians (AIs) from the Strong Heart Study, we measured associations between mid-life physical activity (PA), assessed by a questionnaire or pedometer, and performance on tests of general cognitive function, phonemic fluency, verbal learning and memory, and processing speed. Cognitive tests were administered 7–21 years after PA measurements. To estimate associations, we used regression models with and without inverse-probability weights to account for potential attrition bias in the cohort. Results: Questionnaire and pedometer measures of PA were positively associated with cognitive function. Participants in the top quartile of questionnaire-based PA had Modified Mini-Mental State examination scores 3.2 (95% CI: 1.5–4.9) points higher than participants in the lowest quartile. Phonemic fluency scores also trended higher for participants in the top compared to the bottom categories for both PA measures: top questionnaire quartile = 2.7 (95% CI: 0.6–4.8) points higher and top pedometry tertile = 6.7 (95% CI: 2.7–10.7) points higher. We observed no associations between PA and tests assessing verbal learning and memory, or processing speed. Weighted model results were similar, but less precise. Conclusions: In this cohort of AIs with relatively low levels of PA, positive associations between mid-life PA and late-life cognitive performance were dose-dependent and of modest clinical significance.
Primary Nonfunction and Early Allograft Dysfunction after Liver Transplantation
Authors: Masior Łukasz , Grąt Michał
Published: February 2022

Background: Despite continuous progress in the field of liver transplantation, considerable proportion of patients still suffer from the postoperative graft dysfunction. Clinically, it presents as early allograft dysfunction (EAD), and its more severe form defined as primary nonfunction (PNF). Posttransplant liver dysfunction translates into significantly worse treatment outcomes. Summary: Both entities are multifactorial, with donor (graft), recipient, and procedure-related factors playing the key roles. Ischemia-reperfusion injury is a major driver of their development. So far, various noninvasive (pharmacological) and invasive strategies have been tested to mitigate its negative effects. This article pre­sents the current approach to diagnosis, prediction, and management of EAD and PNF. Key Messages: Different pharmacological interventions may be considered to improve graft function after liver transplantation. Machine perfusion seems to be the most effective method at the moment.
Additive Value of a Face-to-Face Visit to Virtual Remote Decision in Patients with Neovascular Age-Related Macular Degeneration
Authors: Zvi Dana , Zur Dinah , Schwartz Shula , Cohen Shai , Saranga Avi , Loewenstein Anat , Goldstein Michaella
Published: February 2022

Introduction: The increasing high prevalence of neovascular age-related macular degeneration (nvAMD) in the aging population combined with the need for frequent monitoring and treatment for many years, especially in the COVID-19 era, raises the need to establish an effective, reliable, and safe follow-up and treatment model. This study evaluates the difference in treatment decisions comparing between the gold standard face-to-face clinical examination and virtual evaluation approach based only on visual acuity (VA) and optical coherence tomography (OCT) scans without clinical fundoscopic examination in nvAMD patients. Methods: A single-center retrospective cohort study was conducted that compared an original “face-to-face” visit treatment decision regarding the need for anti-vascular endothelial growth factor drug, interval, and treatment regimen based on routine VA, spectral domain OCT imaging, and dilated fundus examination to two “virtual” treatment decisions based on evaluation of OCT scans and previous medical records before and after revealing VA data on the same nvAMD patients eyes. Results: About 169 eyes of 114 patients were included in the study. Forty-nine patients (43%) suffered from bilateral nvAMD and had both eyes included in the study. Agreement between the “face-to-face visit treatment decision” and “virtual treatment decision” was noted in 74.6% and 71.6% eyes before and after revealing the patient’s VA in the study visit, respectively. Conclusions: Virtual evaluation results in similar treatment decisions for nvAMD patients compared to standard face-to-face clinical examination.
Risk and Incidence of Infection with Bevacizumab in Non-Small-Cell Lung Cancer Patients: A Meta-Analysis
Authors: Peng Ling , Qin Bao-Dong , Xu Song , Xia Yang , Yang Jin-Song , Xiao Kui , Stebbing Justin
Published: February 2022

Background: A previous meta-analysis suggested that use of bevacizumab is associated with an increased risk of infection in cancer patients. With the continuous accumulation of evidence in non-small-cell lung cancer (NSCLC), we performed a new, focused meta-analysis of randomized controlled trials (RCTs) to quantify the relative risk (RR) and incidence of infectious complications in those individuals treated with bevacizumab. Methods: Electronic databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were prospective randomized clinical trials of NSCLC patients treated with bevacizumab with toxicity data on infectious complications. RR, overall incidence rates, and 95% confidence intervals (CI) were calculated using fixed- or random-effects models, depending on the heterogeneity of the included studies. Results: A total of 4,545 patients from 14 prospective RCTs were included in the meta-analysis. Treatment with bevacizumab was not associated with an increased risk of all-grade (RR 1.12, 95% CI: 0.84–1.49) or high-grade (RR 1.11, 95% CI: 0.86–1.41) infections, respectively. The summary incidences of all-grade and high-grade infections in patients receiving bevacizumab in the treatment group were 16.4% (95% CI: 15.7–17.2%) and 4.3% (95% CI: 3.0–6.1%), respectively. Conclusions: The use of bevacizumab is not associated with a significantly higher risk of infections in NSCLC patients. These data provide reassurance regarding the risk of infection in patients with NSCLC receiving bevacizumab.
The Influence of Modern Neurophysiology on the Previous Definitions of “Segment” and “Interference Field” in Neural Therapy
Authors: Engel Raphaela , Barop Hans , Giebel Jürgen , Ludin Sabina Maria , Fischer Lorenz
Published: February 2022

Background: In neural therapy, local anesthetics are injected for diagnostic and therapeutic purposes. In this process, therapy makes use of the regulatory functions and plastic properties of the nervous system, especially its autonomic part. Up until now, a distinction has been made between “local/segmental neural therapy” and “interference field therapy.” This division dating back to the middle of the last century was based on the assumption that anatomical and clinical segments were identical. However, this is only true for the projection symptoms, which are limited to metamerism. All pathophysiological processes beyond this segment were called “interference field events” (“outside of any segmental order” and “not explainable by neuroanatomical circuitry”). Summary: However, modern neurophysiology no longer recognizes segmental boundaries, taking into account the occurrence of cross-segmental sensitization processes, neuroplastic changes, immune processes, and neurogenic inflammation. In addition, new insights into neuroanatomical circuitry have also contributed to segmental expansion. Thus, in recent years, much of the interference field activity has been assigned to an “extended” segment; however, even there, no segment boundaries can be defined. Thus, the former definition of the interference field effect (considered to be outside any segmental order) is considered obsolete. Nowadays, interference fields are called “neuromodulatory triggers.” They can act anywhere, both locally and fairly distant, and even systemically. Key Messages: Thus, it is no longer tenable to classify interference field therapy as “unscientific” and “not recognized” while local and segmental neural therapy is being scientifically recognized. In the work at hand, the interference fields discovered by the Huneke brothers become scientifically definable as “neuromodulatory triggers” by showing that clinically and pathologically, hardly any segmental boundaries exist.
Staphylococcus aureus
and Neutrophil Extracellular Traps: The Master Manipulator Meets Its Match in Immunothrombosis
Authors: Meyers Severien , Crescente Marilena , Verhamme Peter , Martinod Kimberly
Published: February 2022

Over the past 10 years, neutrophil extracellular traps (NETs) have become widely accepted as an integral player in immunothrombosis, due to their complex interplay with both pathogens and components of the coagulation system. While the release of NETs is an attempt by neutrophils to trap pathogens and constrain infections, NETs can have bystander effects on the host by inducing uncontrolled thrombosis, inflammation, and tissue damage. From an evolutionary perspective, pathogens have adapted to bypass the host innate immune response.
Staphylococcus aureus
(
S. aureus
), in particular, proficiently overcomes NET formation using several virulence factors. Here we review mechanisms of NET formation and how these are intertwined with platelet activation, the release of endothelial von Willebrand factor, and the activation of the coagulation system. We discuss the unique ability of
S. aureus
to modulate NET formation and alter released NETs, which helps
S. aureus
to escape from the host’s defense mechanisms. We then discuss how platelets and the coagulation system could play a role in NET formation in
S. aureus
-induced infective endocarditis, and we explain how targeting these complex cellular interactions could reveal novel therapies to treat this disease and other immunothrombotic disorders.
Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure
Authors: Keceli Gizem , Gupta Ashish , Sourdon Joevin , Gabr Refaat , Schär Michael , Dey Swati , Tocchetti Carlo G. , Stuber Annina , Agrimi Jacopo , Zhang Yi , Leppo Michelle , Steenbergen Charles , Lai Shenghan , Yanek Lisa R. , O’Rourke Brian , Gerstenblith Gary , Bottomley Paul A. , Wang Yibin , Paolocci Nazareno , Weiss Robert G.
Published: February 2022

Background:

Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.

Methods:

First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.

Results:

In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.

Conclusions:

In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00181259.
Macrophages, Metabolism and Heterophagy in the Heart
Authors: Nicolás-Ávila José A. , Pena-Couso Laura , Muñoz-Cánoves Pura , Hidalgo Andrés
Published: February 2022

The heart is a never-stopping engine that relies on a formidable pool of mitochondria to generate energy and propel pumping. Because dying cardiomyocytes cannot be replaced, this high metabolic rate creates the challenge of preserving organelle fitness and cell function for life. Here, we provide an immunologist’s perspective on how the heart solves this challenge, which is in part by incorporating macrophages as an integral component of the myocardium. Cardiac macrophages surround cardiomyocytes and capture dysfunctional mitochondria that these cells eject to the milieu, effectively establishing a client cell–support cell interaction. We refer to this heterologous partnership as heterophagy. Notably, this process shares analogies with other biological systems, is essential for proteostasis and metabolic fitness of cardiomyocytes, and unveils a remarkable degree of dependence of the healthy heart on immune cells for everyday function.
Research Goes Red: Early Experience With a Participant-Centric Registry
Authors: Gilchrist Susan C. , Hall Jennifer L. , Khandelwal Abha , Hidalgo Bertha , Aggarwal Brooke , Kinzy Claire , Mallya Pratheek , Conners Katie , Stevens Laura M. , Alger Heather M. , Mehta Laxmi , Wexler Laura , Mega Jessica L. , Hernandez Adrian , Hayes Sharonne N. , Mieres Jennifer H. , Jessup Mariell , Roger Veronique L.
Published: February 2022

Rationale:

Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention.

Objective:

To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women.

Methods and Results:

The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants’ areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women.

Conclusions:

RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women’s heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women’s health.
Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction
Authors: van Ouwerkerk Antoinette F. , Bosada Fernanda M. , van Duijvenboden Karel , Houweling Arjan C. , Scholman Koen T. , Wakker Vincent , Allaart Cornelis P. , Uhm Jae-Sun , Mathijssen Inge B. , Baartscheer Ton , Postma Alex V. , Barnett Phil , Verkerk Arie O. , Boukens Bastiaan J. , Christoffels Vincent M.
Published: February 2022

Background:

The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental transcription factor modulates cardiac physiology in vivo will provide unique insights into the mechanisms underlying atrial fibrillation in these patients.

Methods:

We analyzed ECGs of an extended family pedigree of Holt–Oram syndrome patients. Next, we introduced the TBX5-p.G125R variant in the mouse genome (
Tbx5

G125R

) and performed electrophysiologic analyses (ECG, optical mapping, patch clamp, intracellular calcium measurements), transcriptomics (single-nuclei and tissue RNA sequencing), and epigenetic profiling (assay for transposase-accessible chromatin using sequencing, H3K27ac [histone H3 lysine 27 acetylation] CUT&RUN [cleavage under targets and release under nuclease sequencing]).

Results:

We discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt–Oram syndrome patients.
Tbx5

G125R/+

mice were morphologically unaffected and displayed variable RR intervals, atrial extra systoles, and susceptibility to atrial fibrillation, reminiscent of TBX5-p.G125R patients. Atrial conduction velocity was not affected but systolic and diastolic intracellular calcium concentrations were decreased and action potentials were prolonged in isolated cardiomyocytes of
Tbx5

G125R/+

mice compared with controls. Transcriptional profiling of atria revealed the most profound transcriptional changes in cardiomyocytes versus other cell types, and identified over a thousand coding and noncoding transcripts that were differentially expressed. Epigenetic profiling uncovered thousands of TBX5-p.G125R-sensitive, putative regulatory elements (including enhancers) that gained accessibility in atrial cardiomyocytes. The majority of sites with increased accessibility were occupied by Tbx5. The small group of sites with reduced accessibility was enriched for DNA-binding motifs of members of the SP (specificity protein) and KLF (Krüppel-like factor) families of transcription factors. These data show that Tbx5-p.G125R induces changes in regulatory element activity, alters transcriptional regulation, and changes cardiomyocyte behavior, possibly caused by altered DNA binding and cooperativity properties.

Conclusions:

Our data reveal that a disease-causing missense variant in TBX5 induces profound changes in the atrial transcriptional regulatory network and epigenetic state in vivo, leading to arrhythmia reminiscent of those seen in human TBX5-p.G125R variant carriers.
Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020
Authors: Wall Susan M.
Published: February 2022

Intercalated cells make up about a third of all cells within the connecting tubule and the collecting duct and are subclassified as type A, type B and non-A, non-B based on the subcellular distribution of the H
+
-ATPase, which dictates whether it secretes H
+
or HCO
3
−
. Type B intercalated cells mediate Cl
−
absorption and HCO
3
−
secretion, which occurs largely through the anion exchanger pendrin. Pendrin is stimulated by angiotensin II via the angiotensin type 1a receptor and by aldosterone through MR (mineralocorticoid receptor). Aldosterone stimulates pendrin expression and function, in part, through the alkalosis it generates. Pendrin-mediated HCO
3
−
secretion increases in models of metabolic alkalosis, which attenuates the alkalosis. However, pendrin-positive intercalated cells also regulate blood pressure, at least partly, through pendrin-mediated Cl
−
absorption and through their indirect effect on the epithelial Na
+
channel, ENaC. This aldosterone-induced increase in pendrin secondarily stimulates ENaC, thereby contributing to the aldosterone pressor response. This review describes the contribution of pendrin-positive intercalated cells to Na
+
, K
+
, Cl
−
and acid-base balance.
Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study
Authors: Manderstedt Eric , Lind‐Halldén Christina , Halldén Christer , Elf Johan , Svensson Peter J. , Dahlbäck Björn , Engström Gunnar , Melander Olle , Baras Aris , Lotta Luca A. , Zöller Bengt , Abecasis Goncalo , Baras Aris , Cantor Michael , Coppola Giovanni , Economides Aris , Lotta Luca A , Overton John D , Reid Jeffrey G , Shuldiner Alan , Beechert Christina , Forsythe Caitlin , Fuller Erin D , Gu Zhenhua , Lattari Michael , Lopez Alexander , Overton John D , Schleicher Thomas D , Padilla Maria Sotiropoulos , Widom Louis , Wolf Sarah E , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H , Bai Xiaodong , Balasubramanian Suganthi , Blumenfeld Andrew , Boutkov Boris , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J , Maxwell Evan K , Nafde Mrunali , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Reid Jeffrey G , Salerno William , Staples Jeffrey C , Jones Marcus B , Mighty Jason , Mitnaul Lyndon J
Published: February 2022

Background

Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle‐aged and older adults.

Methods and Results

Factor V Leiden, prothrombin G20210A and protein‐coding variants in the
PROC
(protein C),
PROS1
(protein S), and
SERPINC1
(antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease‐causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease‐causing mutations in the
PROC
,
PROS1
, and
SERPINC1
genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants.

Conclusions

The 5 classic thrombophilias are associated with a dose‐graded risk of VTE in middle‐aged and older adults. Disease‐causing variants in the
PROC
,
PROS1
, and
SERPINC1
genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.