bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P480: Myeloid YAP Inhibition Improves Cardiac Phenotype During Pressure Overload Stress
Authors: Francisco Jamie J , Zhang Yu , Nakada Yasuki , Zhai Peiyong , Del Re Dominic
Published: November 2021

Inflammation is a component of cardiovascular disease and is thought to contribute to cardiac dysfunction in ischemic and non-ischemic models of heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP), a transcriptional co-factor, in modulating cardiac inflammation and remodeling after myocardial infarction. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition is cardioprotective. PO in mice elicits an immune response characterized by infiltration of myeloid cells that precedes cardiac dysfunction. Myeloid cells isolated from the heart after 7d PO showed evidence of increased YAP activity. Myeloid-specific YAP knockout mice (YAP
F/F
;LysM
Cre
) were subjected to PO stress. After 4 weeks, cardiac hypertrophy was similar between YAP KO mice and controls. However, systolic dysfunction, cardiac fibrosis, and indicators of pathological remodeling were all attenuated in YAP KO mice compared to controls. Additionally, inflammatory gene expression and macrophage infiltration to the myocardium were significantly attenuated in YAP KO mice after PO, indicating reduced inflammation compared to controls. Experiments using RAW264.7 macrophages and primary bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that increased YAP expression enhanced, while YAP suppression attenuated, inflammatory gene expression. The inflammasome is a multiprotein complex and important facilitator of cytokine processing that mediates inflammation in the PO heart. We observed attenuated inflammasome priming and function in YAP deficient BMDMs, as well as in YAP KO hearts following PO, indicating disruption of inflammasome induction. Together these data implicate YAP as an important mediator of inflammasome function and cardiac inflammation during PO stress and suggest that selective inhibition of YAP in the myeloid compartment may prove a novel therapeutic target in non-ischemic heart disease.
Abstract P485: Loss Of Acta2 In Cardiac Fibroblasts Does Not Prevent The Myofibroblast Differentiation Or Affect The Cardiac Repair After Myocardial Infarction
Authors: Li Yuxia , Li Chaoyang , Liu Qianglin , Wang Leshan , Bao Adam X , Jung Jangwook P , Francis Joseph , Molkentin Jeffery , Fu Xing
Published: November 2021

In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair in the infarcted area. One of the most widely accepted markers of myofibroblast differentiation is the expression of
Acta2
which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of
Acta2
/ SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained largely unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific
Acta2
knockout mouse line. Surprisingly, mice that lacked
Acta2
in cardiac fibroblasts had a normal survival rate after MI. Moreover,
Acta2
deletion did not affect the function or overall histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and
Acta2
-null cardiac myofibroblasts. It was identified that
Acta2
-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level.
Acta2
deletion caused a unique compensatory increase in the transcription level of
Actg2
and an increase in the protein level of sarcomeric actin isoform(s). In addition, the specific muscle actin isoforms that were upregulated in
Acta2
-null cardiac myofibroblasts varied between individual cells. Moreover, the formation of stress fibers by cytoplasmic actin isoforms, especially the cytoplasmic gamma-actin, was enhanced in
Acta2
-null cardiac myofibroblasts despite their unchanged RNA and protein expression. In conclusion, the deletion of
Acta2
does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of
Acta2
in cardiac myofibroblasts.
Abstract P488: FAK Inhibition Reduces Hemangioma Proliferation By Blocking YAP Mediated HBEGF Expression
Authors: Rodriguez Rodirguez Yelitza , Murphy James , Jeong Kyuho , Phung Thuy , Ahn Erin , Lim Steve
Published: November 2021

Hemangiomas are vascular tumors that develop from proliferative endothelial cells (EC). While primarily occurring on the skin of the head, neck, back and chest, hemangiomas can occur within any vascular beds including brain, liver and heart, which can lead to life-threatening complications. Non-surgical treatments are limited, and there are few phases I and II trials underway. Therefore, better understanding of what drives hemangioma proliferation and new therapeutic targets are needed. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that acts as a primary nexus of extracellular signals from integrins and growth factor receptors that sustain EC migration, proliferation, and survival. We observed that genetic and pharmacological inhibition of FAK significantly blocked vascular endothelial growth factor (VEGF)/ fibroblast growth factor (FGF)-induced Matrigel plug angiogenesis in vivo. To identify angiogenic factors regulated by FAK catalytic activity, we used an angiogenesis array in human umbilical vein ECs (HUVECs) and found that FAK inhibition reduced major regulators of angiogenesis including heparin-binding epidermal growth factor (HB-EGF). Further, using immunoblotting and RT-qPCR, we confirmed that FAK inhibition significantly reduced HB-EGF protein and mRNA expression in various mouse, human EC lines and human infantile hemangioma cell line, resulting in reduced EC proliferation. Importantly, HB-EGF mRNA expression was also reduced within in vivo Matrigel plugs of FAK inhibitor treated mice. Mechanistically, FAK binds to and phosphorylates YAP, which enhances HB-EGF expression. Loss of YAP tyrosine phosphorylation following FAK inhibition decreased YAP nuclear localization and protein stability. Since FAK inhibitors are undergoing clinical trials to treat cancer, these results suggest that FAK inhibitors could also prove beneficial in blocking EC proliferation associated with hemangioma.
Abstract P495:
Authors: Diaz Magda C. , Flores-Vergara Raúl , Olmedo Ivonne , Pedrozo Zully
Published: November 2021

Background:
Transverse tubules (T-tubules) play a key role in cardiac contractility. The expression of Bridging integrator 1 (BIN1), specifically, the cardiac isoforms BIN1+13 and BIN1+ 13+17 promote the formation and ultrastructure of T-tubules and it has been described that the transcriptional factor c-Myc may be a negative regulator of BIN1 expression. Polycystin-1 (PC1) is a mechanosensor in cardiomyocytes, with a crucial role to maintain cardiac function. Our aim was to determine whether PC1 regulates BIN1-induced T-tubule formation by a c-Myc-regulated mechanism.

Methods:
We used adult C57BL/6 cardiomyocyte-specific knockout mice (PC1 KO). Cardiac function was tested by echocardiography, whereas protein and mRNA content of BIN1, PC1 and c-Myc were measured using western blot and qRT-PCR, respectively. T-tubules were analyzed by transmission electron microscopy (TEM). For statistical analyses, t-test or one-way ANOVA followed by Tukey's test were used. Differences were considered significant at p < 0.05.

Results:
Survival of PC1 KO mice decreased dramatically after 7 months of age, with clear symptoms of dilated cardiomyopathy and heart failure (decreased fractional shortening and ejection fraction). Ventricular cardiac tissue of PC1 KO mice without (< 7-month-old mice) and with symptoms (7-9-month-old mice) of heart failure (HF) was associated with reduced levels of BIN1 protein content. Total BIN1 mRNA in PC1 KO mice without symptoms did not show differences as compared to controls, but it was significantly decreased in mice with symptoms of HF. Moreover, PC1 KO mice with and without symptoms showed decreased BIN1+13 mRNA levels, whereas BIN1+13+17 mRNA was only increased in mice without symptoms. These changes in BIN1 isoforms were related with T-tubules, which showed increased lumen and decreased intra-luminal density in PC1 KO mice with and without symptoms. Furthermore, c-Myc protein content was increased in cardiac tissue of PC1 KO mice.

Conclusion:
PC1 may be a regulator of the differential expression of cardiac isoforms of BIN1 in cardiomyocytes by a mechanism that involves negative regulation of c-Myc, related to loss of T-tubule ultrastructure and heart failure development.
Abstract P498: Polycystin-1 Regulates Excitation-contraction Coupling In Atrial Cardiomyocytes
Authors: Hendrickson Troy , Perez William , Provasek Vincent , Altamirano Francisco J
Published: November 2021

Patients with Autosomal Dominant Polycystic Kidney disease (ADPKD) have multiple cardiovascular manifestations, including increased susceptibility to arrhythmias. Mutations in polycystin-1 (PC1) encoding gene accounts for 85% cases of ADPKD, whereas mutations in polycystin-2 (PC2) only accounts for 15%. In kidney cells, PC1 interacts with PC2 to form a protein complex at the primary cilia to regulate calcium influx via PC2. However, cardiomyocytes are non-ciliated cells and the role of both PC1 and PC2 in atrial cardiomyocytes remains unknown. We have previously demonstrated that PC1 regulates action potentials and calcium handling to fine-tune ventricular cardiomyocyte contraction. Here, we hypothesize that PC1 regulates action potentials and calcium handling in atrial cardiomyocytes independent of PC2 actions. To test this hypothesis, we differentiated human induced pluripotent stem cells (iPSC) into atrial cardiomyocytes (iPSC-aCM) using previously published protocols. To determine the contribution of PC1/PC2 in atrial excitation-contraction coupling, protein expression was knocked down utilizing specific siRNA constructs, for each protein, or a universal control siRNA transfected using lipofectamine RNAiMAX. We measured action potentials using the potentiometric dye FluoVolt and intracellular calcium with Fura-2 AM or Fluo-4. Changes in fluorescence were monitored using a multiwavelength IonOptix system. iPSC-aCM were paced at 2 Hz to synchronize the beating pattern using field electrical stimulation. Our data shows that PC1 ablation significantly decreased action potential duration at 50% and 80% of repolarization, by 24% and 23%, respectively. Moreover, we observed that PC1 knockdown significantly reduced calcium transient amplitude elicited by field electrical stimulation without changes in calcium transient decay. Interestingly, PC2 knockdown did not modify calcium transients in atrial cardiomyocytes (iPSC-aCM). Our data suggest that PC1 regulates atrial excitation-contraction coupling independent of PC2 actions. This study warrants further investigation into atrial dysfunction in ADPKD patients with PC1 mutations.
Abstract P502: Abnormal Myocyte Calcium Dynamics And The Resultant Contraction Band Formation Of The Rat Heart Under Irreversible Injury By Membrane Permeabilization
Authors: Morishita Yuma , Tamura Shoko , Mochizuki Kentaro , Harada Yoshinori , Tanaka Hideo
Published: November 2021

Ca
2+
overload is a cardinal feature of cardiomyocyte injury, and its progression to irreversible state leads to cell death. However, unknowns are the precise spatiotemporal changes in the myocyte Ca
2+
dynamics and the relevant cell morphology of irreversibly injured hearts. On the hypothesis that myocytes exhibit high-frequency Ca
2+
waves and contraction band necrosis in saponin-permeabilized injured heart, we observed changes in the Ca
2+
dynamics and the relevant morphological changes in the subepicardial myocardium of the Fluo4-loaded rat hearts (n = 14) by rapid-scanning confocal microscopy (100 frames/s) under Langendorff perfusion with 0.3 mM Ca
2+
-Tyrode solution including 0.4 % saponin at 30°C. Also performed was confocal imaging of tetramethylrhodamine methyl ester (TMRM) fluorescence of the myocardium. Under quasi-quiescence of the heart after dissection of the SA node, individual myocytes barely exhibited spontaneous Ca
2+
waves, whereas after commencement of saponin perfusion high-frequency (118 ± 9.7 /min/cell, mean ± SEM) Ca
2+
waves (hereafter, “agonal waves”) emerged within 1 min, showing asynchronous, oscillatory contractions in the individual myocytes with a V
prop
of 124 ± 2.5 μm/s (n = 60). Subsequently, the waves gradually decreased in frequency with concomitant slowing of its decay time course, and eventually, disappeared in 6 min; myocytes exhibited high, static Fluo4-fluorescence intensity. Along with the progression of Ca
2+
overload by saponin, the TMRM fluorescence intensity was discretely lost in individual myocytes. The myocytes showing the agonal waves exhibited contraction bands, i.e., band-like aggregations of the actin fibers. Under mechanical arrest of the heart by 2,3-butanedione monoxime (20 mM), saponin still induced the agonal waves with a frequency of 253 ± 10.6 /cell/min and V
prop
of 118 ± 2.1 μm/s (n = 60); however, contraction bands were barely seen.In conclusion, irreversible myocyte injury by saponin provoked agonal Ca
2+
waves and oscillatory contractions indicating progressive Ca
2+
overload and the following mitochondrial damage, which may provide deeper insights into understanding the mechanism of contraction band necrosis.
Abstract P503: Aldehyde Dehydrogenase 2 Activator 1 Potentiates The Effects Of Empagliflozin, A Sodium-glucose Cotransporter 2 Inhibitor, In Diabetes-mediated Heart Failure With Preserved Ejection Fraction
Authors: Pan Guodong , Roy Bipradas , Palaniyandi Suresh
Published: November 2021

4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm
2
), cardiomyocyte cross-section area (CA, 251 ± 32 μm
2
) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm
2
; CA 303 ± 55 μm
2
; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm
2
; CA 288 ± 34 μm
2
; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm
2
; CA 448 ± 65 μm
2
; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.
Abstract P504: Transient Angiotensin Converting Enzyme Inhibition Protects Against Future Fibrogenic Responses Via Sex-specific Mechanisms
Authors: Garvin Alexandra M , Floyd Dana B , Nunez Wendy S , Altaf Amal W , Siegel Matthew M , Hale Taben M
Published: November 2021

Following washout of angiotensin converting enzyme inhibitor (ACEi) treatment in hypertensive rats (SHR), there is an increase in the proportion of homeostatic cardiac fibroblasts (CFs) characterized by a less fibrogenic gene profile. The present study investigated the impact of this shift in CFs on subsequent Ang II-induced oxidative stress and fibrogenic responses in the left ventricle (LV). Male and female SHRs (11 wk old) underwent a 6-week treatment scheme: 2-week ACEi (enalapril, 30mg/kg/day) or vehicle treatment, followed by a 2-week washout period, and then a 2-week Ang II (400ng/kg/min, s.c.) or vehicle infusion (n=5-11/group/sex). RT-qPCR for collagens and immunoblotting for LOX, Postn, OPN, NOX2, SOD2, and catalase was performed. In males, Ang II-induced increases in ColI, III, and IV expression were significantly attenuated by prior ACEi. While in females, Ang II significantly increased the expression of ColI and III similarly, regardless of prior ACEi treatment; highlighting a sex-specific impact of ACEi. After Ang II infusion, both Postn and LOX are reduced in LV of male and female SHR previously treated with an ACEi - suggesting reduced collagen cross-linking. Oxidative stress induced by NOX2 has been linked to OPN in fibrotic tissue. Ang II-induced increases in NOX2 are attenuated in LV of both sexes, while OPN is only reduced in females previously treated with an ACEi. NOX2 is significantly positively correlated with OPN in males only suggesting a sex-specific link between OPN and oxidative stress. Antioxidant (SOD2, catalase) levels were positively correlated to NOX2 in females, but not males. This suggests that females more efficiently neutralize oxidative stress than males - regardless of prior ACEi. Taken together, the persistent genomic and phenotypic changes in CFs following transient ACEi render the heart resistant to future fibrotic and oxidative effects of Ang II, but the mechanisms of protection may differ by sex. Collectively, these data reveal that there are sex-specific processes that govern collagen production vs. cross-linking and oxidative stress. Future studies will elucidate the mechanistic underpinnings of sex-specific cellular memory following transient ACEi with a goal of identifying novel therapeutic targets.
A new species of Nogunius Jałoszyński in Japan (Coleoptera: Staphylinidae: Scydmaeninae)
Authors: JAŁOSZYŃSKI PAWEŁ , NOMURA SHÛHEI
Published: November 2021

The genus Nogunius Jałoszyński was proposed to accommodate four species distributed exclusively in Japan: N. sokani Jałoszyński (Okinawa Island), N. aogashimanus Jałoszyński (Aogashima, Izu Islands), N. kerri Jałoszyński (Ishigaki Island), and N. fukuuzanus Jałoszyński (Okinawa Island). A female of an undescribed species collected in mainland Japan, on Shikoku, was also recorded. In the present paper we provide evidence that this interesting and apparently very rare genus occurs also on Kyushu. Nogunius sagaensis sp. n. is described, based on a single male collected in Saga Prefecture, NW Kyushu. Diagnostic characters of all nominal species are compared, and a distribution of Nogunius is summarized.
Cartap wastewater treatment by a microwave-induced catalytic oxidation procedure over Ce/Co/γ-Al2O3
Authors: Liu Kaixuan , Lian Fang , Wang Guoqi , Dai Jiaru , Tian Xuepeng , Zhang Yufeng
Published: November 2021

Microwave-assisted catalytic technology is potentially promising in the application of water treatment due to its merits of high reaction rates, simple equipment and operations. In case of the cartap wastewater rarely studied, the easy transformation of cartap into metabolites could
induce higher toxicity. This study aimed to develop a novel catalyst Ce/Co/γ-Al2O3 to dispose cartap effectively. The catalyst was prepared by loading Ce and Co on the surface of the support Al2O3, followed by characterization with X-ray
diffraction, scanning and transmission electron microscopies. Based on the treatment results, the microwave-induced catalytic oxidation procedure over Ce/Co/γ-Al2O3 could decompose the contaminants efficiently and fast in the case of a low oxidant dosage
and a wide pH range. Under the conditions of pH of 5, microwave power of 450 W, catalyst dosage of 0.7 g and hydrogen peroxide dosage of 0.2 mL, the activity of Ce/Co/γ-Al2O3 catalyst could reach up to 86.08%. Importantly, the Ce/Co/γ-Al2O3
catalyst displayed excellent stability after using for 6 times in the degradation process. This work paved a new way for the effective catalyst design for efficient microwave-induced oxidative degradation.
Synthesis and fluorescence of novel complexes of tricyano-dihydrofuran and ofloxacin
Authors: Zhang Huizhu , Ming Liang , Zhang Tao , Guo Baohui , Lv Yuguang
Published: November 2021

Quinolones are widely used, but there are few reports on the application of fluorescent probe analysis. In this paper, we synthesized a tricyano-dihydrofuran (DCDHF-2-V) electron acceptor, and a (DCDHF-2-V)-quinolone fluorescent nanoprobe was designed. Its structure was characterized
by infrared spectroscopy (IR), nuclear magnetic resonance (NMR) and ultraviolet (UV). A novel tricyano-dihydrofuran-ofloxacin fluorescent nanoprobe was established for the first time by fluorescence spectrophotometry. A novel fluorescent nanoprobe was obtained and used in the determination
of ofloxacin in vitro. The results showed that tricyano-dihydrofuran can form stable charge transfer complex with ofloxacin, and it can be used for the determination of ofloxacin in drugs as a fluorescent probe. While important experimental steps are for the first time achieved in this
study for future Quinolone fluorescent nanoprobe implementations, this method is simple and sensitive.
Cds nanocrystal enhanced TiO2photoelectrochemical aptasensor for sensitive detection of cytochrome c
Authors: Fan Shanji , Huang Hong , Chen Hong , Xu Jiachi , Hu Zecheng , Cui Ying
Published: November 2021

A CdS nanocrystal enhanced TiO2 nanotubes (CdS@TiO2 NATs) photoelectrode was prepared via successive ionic layer adsorption and reaction (SILAR) of CdS on the surface of TiO2 NATs. A HS-aptamer owing a specific binding toward cytochrome c was modified
onto the CdS@TiO2 NATs, which resulting a decrease in the photoelectrical current intensity. Cytochrome c is therefore quantified based on the decrease in photoelectrical current. High specificity and high sensitivity were obtained with a linear range from 3 pM to 80 nM, and a limit
of detection of 2.53 pM.
Relative salience of chord-type and chord-voicing changes: A two-oddball paradigm
Authors: Jimenez Ivan , Kuusi Tuire , Ojala Juha
Published: November 2021

Our research project investigated the effect of background and stimuli factors on the relative salience of chord-type and chord-voicing changes. Earlier studies have shown that surface features tend to be easier to perceive than deeper features and that musical training attenuates this general tendency. For further studying how deeper-level and surface-level musical features are perceived, we used a two-oddball paradigm. Each item consisted of a succession of five same-root chords: one chord-type oddball (deeper feature), one voicing oddball (surface feature), and three standards. Participants chose the chord that sounded most different to them. All chord-type pairings formed of major, minor, dominant seventh, major seventh, and minor seventh chords were tested. Chord-type oddball and voicing oddball were chosen equally often, together forming the majority of the responses. Musical training and conceptual knowledge of chords affected the chord-type oddball responses, but not the voicing-oddball responses. However, chord-type oddballs were chosen regardless of the musical training. Chord-type responses were easiest for pairs consisting of a major-based and a minor-based chord and for pairs involving two pitch-class changes. Our results suggest that musical training and conceptual knowledge about chords is not the only factor influencing the relative salience of chord-type changes over voicing changes.
Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity
Authors: Xu Zichun , Lin Xiaolei
Published: November 2021

Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.
Appropriateness of Using Vitamin K for the Correction of INR Elevation Secondary to Hepatic Disease in Critically ill Patients: An Observational Study
Authors: Al Sulaiman Khalid , Al Mutairi Mashael , Al Harbi Omar , Al Duraihim Alanoud , Aldosary Sara , Al Khalil Haifa , Al Shaya Abdulrahman , Al Harbi Shmeylan , Alotaibi Nouf , Al Aamer Kholoud , Vishwakarma Ramesh , Al Asiri Mohammed , Aljuhani Ohoud , Al Katheri Abdulmalik , Al Bekairy Abdulkareem M.
Published: November 2021

Background

Using vitamin K for correction of coagulopathy in critically ill patients is controversial with limited evidence. This study aims to evaluate the efficacy and safety of vitamin K in the correction of international normalized ratio (INR) elevation secondary to liver disease in critically ill patients.

Method

A retrospective study of critically ill patients with coagulopathy secondary to liver disease. The primary outcome was to evaluate the association between vitamin K administration and the incidence of new bleeding events in critically ill patients with INR elevation; other outcomes were considered secondary. Patients were categorized into two groups based on vitamin K administration to correct INR elevation. The propensity score was generated based on disease severity scores and the use of pharmacological DVT prophylaxis.

Results

A total of 98 patients were included in the study. Forty-seven patients (48%) received vitamin K during the study period. The odds of the new bleeding event was not statistically different between groups (OR 2.4, 95% CI 0.28-21.67, P = .42). Delta of INR reduction was observed with a median of 0.63 when the first dose is given ( P-value: <.0001). However the INR reduction with other subsequent doses of vitamin K was not statistically significant.

Conclusion

The administration of vitamin K for INR correction in critically ill patients with coagulopathy secondary to liver disease was not associated with a lower odds of new bleeding events. Further studies are needed to assess the value of vitamin K administration in critically ill patients with liver diseases related coagulopathy.
Short report: A quantitative methodological review of participant characteristics in the literature testing mental health interventions for youth with autism spectrum disorder
Authors: Dickson Kelsey S , Galligan Megan Ledoux , Lok Ho
Published: November 2021

There have been significant efforts to develop, adapt, and test interventions targeting the co-occurring mental health conditions common among autistic youth, with several extant narrative and systematic reviews demonstrating the efficacy of these interventions. Yet, a methodological analysis of the literature testing these interventions, particularly the characteristics of the participant samples comprising this evidence base, is needed to contextualize our current understanding of treatment effects and highlight current gaps in the current evidence base to inform future research. This systematic quantitative methodology review characterized participants included in the mental health treatment research for autistic youth. One hundred and thirty-one articles testing mental health interventions for autism spectrum disorder were coded for youth, caregiver, and provider participant demographics. Findings indicated limited representation of females, transition age youth, racial/ethnic minority groups, and youth diverse in cognitive functioning and co-occurring mental health symptoms or conditions. Limited inclusion of providers’ representative of the clinical workforce was also noted. These results illuminate several critical gaps in the current evidence base for mental health interventions for autistic youth and provide recommendations for future research directions.

Lay abstract

Previous research has highlighted the importance of mental health treatment for autistic youth. In that research base, most studies focus on demonstrating the efficacy of a particular intervention with a sample of autistic youth. However, understanding the characteristics of samples used within these studies (i.e. demographics) is an important avenue for expanding this research to a more diverse, representative sample of autistic youth in community settings. As such, the current review examined and characterized participants included within mental health treatment research. We coded studies for various demographics among the youth sample, caregivers, and providers participants. Results indicated that while efforts have been made to increase diversity in research, very few studies including transition-aged youth, those identifying as female, and/or those identifying as non-Caucasian. Clinically, a few studies included youth with lower cognitive abilities and/or those with specific mental health problems (e.g. trauma and depression) or more than one co-occurring mental health conditions. Overall, our results highlight several critical gaps in our current evidence base regarding mental health treatment for autistic youth, including the limited clinical representativeness of both provider and child participants.
Form-fit joining of hybrid busbars using a flexible tool demonstrator
Authors: Reichel A , Sampaio RFV , Pragana JPM , Bragança IMF , Silva CMA , Martins PAF
Published: November 2021

This paper is focused on hybrid busbars made from copper and aluminum strips and presents a flexible tool demonstrator capable of replicating material flow in the lancing, bending and compression stages of a new joining by forming process without auxiliary elements. The flexible tool demonstrator is defined by its modular concept that allows the active tool components to be easily interchanged for testing and exploring different materials and thickness combinations, surface conditions and cross-section areas of the strips under laboratory conditions. Experimental and numerical simulation with a selected hybrid busbar geometry validates the overall concept and fabrication of the demonstrator and shows that the new joining by forming process can produce permanent form-fit joints with smooth upper and lower surfaces containing all the plastically deformed material within the thickness of the two strips. Complete filling of the free volume left in-between the thickness of the two strips allows obtaining an electric resistance lower than that of fastened hybrid busbars.
A Survey to Determine the Capacity Development Needs of Research Ethics Committee Administrators in South Africa
Authors: Mulondo Mutshidzi A. , Tsoka-Gwegweni Joyce M. , LenkaBula Puleng , Chikobvu Perpetual
Published: November 2021

Most capacity development efforts for research ethics committees focus on committee members and little on ethics administrators. Increasing studies mandate the focus on administrators’ capacity development needs to enable adequate and effective committee support. This study investigated current responsibilities, training requirements, and administrator role needs. An online cross-sectional survey was conducted among administrators from 62 National Health Research Ethics Council-registered research ethics committees in South Africa. In total, 36 administrators completed the questionnaire. Results show that, in addition to administration, they perform managerial, review process and guidance-advisory tasks. Nearly 49% indicated only having received informal research ethics-related training, not targeted formal training, with 81% of the informal training being through workshops. Research ethics administrators’ responsibilities have evolved to complex tasks requiring targeted capacity development efforts.
Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma
Authors: Mohan Meera , Kendrick Samantha , Szabo Aniko , Yarlagadda Naveen , Atwal Dinesh , Pandey Yadav , Roy Arya , Parikh Richa , Lopez James , Thanendrarajan Sharmilan , Schinke Carolina , Alapat Daisy , Sawyer Jeffrey , Tian Erming , Tricot Guido , van Rhee Frits , Zangari Maurizio
Published: November 2021

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next-generation flow cytometry (sensitivity of 10−5 cells) at 3- to 6-month intervals. With a median follow-up of 9.9 years from diagnosis (range, 0.4-30.9), 61% of patients maintained MRD negativity, whereas 39% experienced MRD conversion at a median of 6.3 years (range, 1.4-25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95% vs 84%; P = .001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 years (range, 0-4.9). However, 27% of MRD conversion-positive patients had not yet experienced a clinical relapse, with a median follow-up of 9.3 years (range, 2.2-21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared with patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.
Divergence time estimation of Galliformes based on the best gene shopping scheme of ultraconserved elements
Authors: Chen De , Hosner Peter A. , Dittmann Donna L. , O’Neill John P. , Birks Sharon M. , Braun Edward L. , Kimball Rebecca T.
Published: November 2021

Background

Divergence time estimation is fundamental to understanding many aspects of the evolution of organisms, such as character evolution, diversification, and biogeography. With the development of sequence technology, improved analytical methods, and knowledge of fossils for calibration, it is possible to obtain robust molecular dating results. However, while phylogenomic datasets show great promise in phylogenetic estimation, the best ways to leverage the large amounts of data for divergence time estimation has not been well explored. A potential solution is to focus on a subset of data for divergence time estimation, which can significantly reduce the computational burdens and avoid problems with data heterogeneity that may bias results.

Results

In this study, we obtained thousands of ultraconserved elements (UCEs) from 130 extant galliform taxa, including representatives of all genera, to determine the divergence times throughout galliform history. We tested the effects of different “gene shopping” schemes on divergence time estimation using a carefully, and previously validated, set of fossils. Our results found commonly used clock-like schemes may not be suitable for UCE dating (or other data types) where some loci have little information. We suggest use of partitioning (e.g., PartitionFinder) and selection of tree-like partitions may be good strategies to select a subset of data for divergence time estimation from UCEs. Our galliform time tree is largely consistent with other molecular clock studies of mitochondrial and nuclear loci. With our increased taxon sampling, a well-resolved topology, carefully vetted fossil calibrations, and suitable molecular dating methods, we obtained a high quality galliform time tree.

Conclusions

We provide a robust galliform backbone time tree that can be combined with more fossil records to further facilitate our understanding of the evolution of Galliformes and can be used as a resource for comparative and biogeographic studies in this group.
Biogeographic and demographic history of the Mediterranean snakes Malpolon monspessulanus and Hemorrhois hippocrepis across the Strait of Gibraltar
Authors: Machado Luis , Harris D. James , Salvi Daniele
Published: November 2021

Background

The contribution of North Africa to the assembly of biodiversity within the Western Palaearctic is still poorly documented. Since the Miocene, multiple biotic exchanges occurred across the Strait of Gibraltar, underlying the high biogeographic affinity between the western European and African sides of the Mediterranean basin. We investigated the biogeographic and demographic dynamics of two large Mediterranean-adapted snakes across the Strait and assess their relevance to the origin and diversity patterns of current European and North African populations.

Results

We inferred phylogeographic patterns and demographic history ofM. monspessulanusandH. hippocrepis, based on range-wide multilocus data, combined with fossil data and species distribution modelling, under present and past bioclimatic envelopes. For both species we identified endemic lineages in the High Atlas Mountains (Morocco) and in eastern Iberia, suggesting their persistence in Europe during the Pleistocene. One lineage is shared between North Africa and southern Iberia and likely spread from the former to the latter during the sea-level low stand of the last glacial stage. During this periodM. monspessulanusshows a sudden demographic expansion, associated with increased habitat suitability in North Africa. Lower habitat suitability is predicted for both species during interglacial stages, with suitable areas restricted to coastal and mountain ranges of Iberia and Morocco. Compiled fossil data forM. monspessulanusshow a continuous fossil record in Iberia at least since the Pliocene and throughout the Pleistocene.

Conclusions

The previously proposed hypothesis of Pleistocene glacial extinction of both species in Europe is not supported based on genetic data, bioclimatic envelopes models, and the available fossil record. A model of range retraction to mountain refugia during arid periods and of glacial expansion (demographic and spatial) associated to an increase of Mediterranean habitats during glacial epochs emerges as a general pattern for mesic vertebrates in North Africa. Moreover, the phylogeographic pattern ofH. hippocrepisconforms to a well-established biogeographic partition between western and eastern Maghreb.
The whole-genome sequencing in predicting Mycobacterium tuberculosis drug susceptibility and resistance in Papua, Indonesia
Authors: Maladan Yustinus , Krismawati Hana , Wahyuni Tri , Tanjung Ratna , Awaludin Kamla , Audah Kholis Abdurachim , Parikesit Arli Aditya
Published: November 2021

Background

Tuberculosis is one of the deadliest disease caused byMycobacterium tuberculosis. Its treatment still becomes a burden for many countries including Indonesia. Drug resistance is one of the problems in TB treatment. However, a development in the molecular field through Whole-genome sequencing (WGS) can be used as a solution in detecting mutations associated with TB- drugs. This investigation intended to implement this data for supporting the scientific community in deeply understanding any TB epidemiology and evolution in Papua along with detecting any mutations in genes associated with TB-Drugs.

Result

A whole-genome sequencing was performed on the random samples from TB Referral Laboratory in Papua utilizing MiSeq 600 cycle Reagent Kit (V3). Furthermore, TBProfiler was used for genome analysis, RAST Server was employed for annotation, while Gview server was applied for BLAST genome mapping and a Microscope server was implemented for Regions of Genomic Plasticity (RGP). The largest genome ofM. tuberculosisobtained was at the size of 4,396,040 bp with subsystems number at 309 and the number of coding sequences at 4326. One sample (TB751) contained one RGP. The drug resistance analysis revealed that several mutations associated with TB-drug resistance existed. In details, mutations ofrpoBgene which were identified as S450L, D435Y, H445Y, L430P, and Q432K had caused the reduced effectiveness of rifampicin; while the mutases inkatG(S315T),kasA(312S),inhA(I21V), and Rv1482c-fabG1(C-15 T) genes had contributed to the resistance in isoniazid. In streptomycin, the resistance was triggered by the mutations inrpsL(K43R) andrrs(A514C, A514T) genes, and, in Amikacin, its resistance was led by mutations inrrs(A514C) gene. Additionally, in Ethambutol and Pyrazinamide, their reduced effectiveness was provoked byembBgene mutases (M306L, M306V, D1024N) andpncA(W119R).

Conclusions

The results from whole-genome sequencing of TB clinical sample in Papua, Indonesia could contribute to the surveillance of TB-drug resistance. In the drug resistance profile, there were 15 Multi Drugs Resistance (MDR) samples. However, Extensively Drug-resistant (XDR) samples have not been found, but samples were resistant to only Amikacin, a second-line drug.
Correction to: GPC3 affects the prognosis of lung adenocarcinoma and lung squamous cell carcinoma
Authors: Ning Jing , Jiang Shenyi , Li Xiaoxi , Wang Yang , Deng Xuhong , Zhang Zhiqiang , He Lijie , Wang Daqing , Jiang Youhong
Published: November 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A home-based pulmonary rehabilitation mHealth system to enhance the exercise capacity of patients with COPD: development and evaluation
Authors: Deng Ning , Sheng Leiyi , Jiang Wangshu , Hao Yongfa , Wei Shuoshuo , Wang Bei , Duan Huilong , Chen Juan
Published: November 2021

Background

Patients with chronic obstructive pulmonary disease (COPD) experience deficits in exercise capacity and physical activity as their disease progresses. Pulmonary rehabilitation (PR) can enhance exercise capacity of patients and it is crucial for patients to maintain a lifestyle which is long-term physically active. This study aimed to develop a home-based rehabilitation mHealth system incorporating behavior change techniques (BCTs) for COPD patients, and evaluate its technology acceptance and feasibility.

Methods

Guided by the medical research council (MRC) framework the process of this study was divided into four steps. In the first step, the prescription was constructed. The second step was to formulate specific intervention functions based on the behavior change wheel theory. Subsequently, in the third step we conducted iterative system development. And in the last step two pilot studies were performed, the first was for the improvement of system functions and the second was to explore potential clinical benefits and validate the acceptance and usability of the system.

Results

A total of 17 participants were enrolled, among them 12 COPD participants completed the 12-week study. For the clinical outcomes, Six-Minute Walk Test (6MWT) showed significant difference (P = .023) over time with an improvement exceeded the minimal clinically important difference (MCID). Change in respiratory symptom (CAT score) was statistically different (P = .031) with a greater decrease of − 3. The mMRC levels reduced overall and showed significant difference. The overall compliance of this study reached 82.20% (± 1.68%). The results of questionnaire and interviews indicated good technology acceptance and functional usability. The participants were satisfied with the mHealth-based intervention.

Conclusions

This study developed a home-based PR mHealth system for COPD patients. We showed that the home-based PR mHealth system incorporating BCTs is a feasible and acceptable intervention for COPD patients, and COPD patients can benefit from the intervention delivered by the system. The proposed system played an important auxiliary role in offering exercise prescription according to the characteristics of patients. It provided means and tools for further individuation of exercise prescription in the future.
Evaluation of a flexible and integrative psychiatric care model in a department of child and adolescent psychiatry in Tübingen, Germany: study protocol (EVA_TIBAS)
Authors: Neumann Anne , Hense Helene , Baum Fabian , Kliemt Roman , Seifert Martin , Harst Lorenz , Kubat Denise , Maicher Birgit , Schrey Christopher , Schmitt Jochen , Pfennig Andrea , Weinhold Ines , Swart Enno , Soltmann Bettina
Published: November 2021

Background

Model projects for flexible and integrated treatment (FIT) in Germany aim at advancing the quality of care for people with mental disorders. A new FIT model project was established in 2017 at the Department of child and adolescent psychiatry (KJP) of the University Hospital Tübingen (Universitätsklinikum Tübingen, UKT). The study design of EVA_TIBAS presented here describes the evaluation of the FIT model project at the KJP of the UKT. This evaluation aims at quantifying the anticipated FIT model project changes, which are to improve patients’ cross-sectoral care at the same maximum cost as standard care.

Methods

EVA_TIBAS is a controlled cohort study using a mix of quantitative and qualitative methods. The FIT evaluation consists of three modules. In Module A, anonymized claims data of a statutory health insurance fund will be used to compare outcomes (duration of inpatient and day care psychiatric treatment, inpatient and day care psychiatric length of stay, outpatient psychiatric treatment in hospital, inpatient hospital readmission, emergency admission rate, direct medical costs) of patients treated in the model hospital with patients treated in structurally comparable control hospitals (estimated sample size = ca. 600 patients). In Module B, patient-reported outcomes (health related quality of life, symptom burden, return to psychosocial relationships (e.g. school, friends, hobbies), treatment satisfaction, societal costs) will be assessed quantitatively using validated questionnaires for the model and two control hospitals (estimated sample size = ca. 300 patients). A subsequent health economic evaluation will be based on cost-effectiveness analyses from both the insurance fund’s and the societal perspective. In Module C, about 30 semi-structured interviews will examine the quality of offer, effects and benefits of the service offered by the social service of the AOK Baden-Württemberg (for stabilizing the overall situation of care in the family) in the model hospital. A focus group discussion will address the quality of cooperation between employees of the university hospital and the social services.

Discussion

The results of this evaluation will be used to inform policy makers whether this FIT model project or aspects of it should be implemented into standard care.

Trial registration

This study was registered at ClinicalTrials.gov PRS (ID: NCT04727359, date: 27 January 2021).