bluuebunny/crossref_metadata_2025 huggingface dataset:
Bleeding in patients with continuous-flow left ventricular assist devices: acquired von Willebrand disease or antithrombotics?
Authors: Consolo Filippo , Marasi Alessandra , Della Valle Patrizia , Bonora Marta , Pieri Marina , Scandroglio Anna Mara , Redaelli Alberto , Zangrillo Alberto , D’Angelo Armando , Pappalardo Federico
Published: October 2021

OBJECTIVES

To evaluate the competing pro-haemorrhagic contribution of acquired von Willebrand (vW) disease and antithrombotic therapy in patients implanted with continuous-flow left ventricular assist devices (LVADs).

METHODS

We compared the extent of vW factor (vWf) degradation [vWf antigen (vWf:Ag)] and a decrease of functional activity of large vWf multimers [vWf collagen binding (vWf:CB)] in LVAD patients who did and did not suffer from bleeding. Data were measured pre-implant, at short-term (t1: <3 months) and long-term (t2: >12 months) follow-up. The occurrence of primary bleeding events, as well as bleeding recurrence, was correlated with patient-specific vWf profile and antithrombotic regimen. Indeed, patients were discharged on warfarin (international normalized ratio: 2–2.5) and aspirin, with the latter withhold after a first bleeding episode.

RESULTS

Fifty-three patients were enrolled. The median follow-up was 324 (226–468) days. We recorded 25 primary bleeding events (47% of patients). All primary events occurred in patients on warfarin and aspirin. Both vWf:Ag and vWf:CB decreased significantly post-implant (P = 0.0003 and P < 0.0001), and patients showing pathological vWf:CB/vWf:Ag ratio (<0.7) increased progressively over the time of support (pre-implant = 26%, t1 = 58%, t2 = 74%; P < 0.0001). Of note, activity of large vWf multimers of bleeders was significantly lower at t2 with respect to non-bleeders (vWf:CB: 61 (36–115) vs 100 (68–121), P = 0.04; vWf:CB/vWf:Ag ratio: 0.36 (0.26–0.61) vs 0.58 (0.33–0.96), P = 0.04). Despite these marked differences in the vWf profile, following aspirin discontinuation only 3 patients had bleeding recurrence.

CONCLUSIONS

Aspirin contributes significantly to haemorrhagic events in the background of acquired vW disease; its discontinuation significantly reduces bleeding recurrence.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT03255928; ClinicalTrials.gov Identifier: NCT03255928.
The Measurement Error Elephant in the Room: Challenges and Solutions to Measurement Error in Epidemiology
Authors: Innes Gabriel K , Bhondoekhan Fiona , Lau Bryan , Gross Alden L , Ng Derek K , Abraham Alison G
Published: October 2021

Measurement error, although ubiquitous, is uncommonly acknowledged and rarely assessed or corrected in epidemiologic studies. This review offers a straightforward guide to common problems caused by measurement error in research studies and a review of several accessible bias-correction methods for epidemiologists and data analysts. Although most correction methods require criterion validation including a gold standard, there are also ways to evaluate the impact of measurement error and potentially correct for it without such data. Technical difficulty ranges from simple algebra to more complex algorithms that require expertise, fine tuning, and computational power. However, at all skill levels, software packages and methods are available and can be used to understand the threat to inferences that arises from imperfect measurements.
Risk factors for left ventricular thrombus formation on transthoracic echocardiography in a propensity-matched case control study
Authors: Tang G H , Wang A , Markson L J , Manning W J , Strom J B
Published: October 2021

Introduction

The specific risk factors for left ventricular thrombus (LVT) formation on transthoracic echocardiography (TTE) independent of age, sex, and left ventricular ejection fraction (LVEF) remain uncertain.

Purpose

To conduct a propensity-matched case control study of LVT.

Methods

We queried structured TTE report data from 113,673 patients at our institution to identify individuals with LVT on TTE, 2000–2011. Cases were matched 1:1 with controls on age, sex, LVEF, inpatient/outpatient status, image quality, test year, blood pressure, heart rate, height, and weight. using propensity scores. Risk factors for LVT formation were determined using medical chart review.

Results

Over 12 years, we identified 132 patients with LVT and 132 matched controls (mean age 62.0±16.1 years, 73.1% male, mean LVEF 27.0% ± 16.0%). Cases were similar to controls across all matched variables except height (cases vs. controls, mean height 172.2±8.8 vs. 174.8±9.3 cm, p=0.03). Compared with controls, TTEs for cases were more frequently performed for the indications of myocardial infarction (MI; 28.0% vs. 9.9%, p<0.001) and source of embolism (3.8% vs. 0.0%, p=0.008). Despite no differences between cases and controls in rates of hypertension, hyperlipidemia, diabetes, and thrombophilia (Table), a history of peripheral arterial disease was associated with a 3.4-fold increased odds of LVT formation (univariate odds ratio [OR], 3.35, 1.50–7.47, p=0.003). This association persisted despite adjustment for history of MI, stroke, height, history of recent major bleeding, and receipt of percutaneous coronary intervention (PCI) (adjusted OR, 4.33, 1.66–11.29, p=0.003). On presentation, 22.0% of cases were on anticoagulation including 20.5% on warfarin, none on a direct oral anticoagulant (DOAC), and 1.5% on heparin products. Additionally, 48.5% of cases were on antiplatelet medications. Of the 27 patients on warfarin on diagnosis of LVT, 25.9% had an International Normalized Range (INR) value <2.0. All TTE parameters were similar across groups (p>0.05 for all). Of those with LVT, 54 (40.9%) had LVT resolution over a median of 4.4 (0.9 to 13.6) months.

Conclusions

In this single center, propensity-matched case-control study of individuals with LVT on TTE, a history of peripheral arterial disease was associated with a 4.3-fold increased odds of LVT formation independent of age, sex, LVEF, history of MI, stroke, or PCI. Of those with LVT, anticoagulation was used on presentation in 22.0%. Nearly half had LVT resolution within 4.4 months.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The project was funded by a grant from the National, Heart, Lung, and Blood Institute (1K23HL144907 - Strom).
Association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan: a cohort study
Authors: Kato T , Momose M , Uemura Y , Naya M , Matsumoto N , Hida S , Yamauchi T , Nakajima T , Suzuki E , Inoko M , Tamaki N
Published: October 2021

Background

There is an ongoing controversy regarding the necessity of single-photon emission computed tomography (SPECT) for patients with ischemic heart diseases after the publication of the results of the ISCHEMIA trial.

Purpose

We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan.

Methods

From the data of 2780 patients with stable angina who were enrolled prospectively between January 2006 and March 2008 in Japan and had undergone physician-referred non-invasive imaging tests, 1205 patients managed with SPECT were stratified by 10% myocardial ischemia. Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalization for heart failure, and late revascularization, were followed-up for 1 year.

Results

Patients with ≥10% myocardial ischemia (n=173) were older than patients with <10% myocardial ischemia (n=1032) and had a significantly higher 1-year cumulative incidence of MACEs (9.1% vs. 1.2%, P<0.0001). After adjusting for confounders, the risk of ≥10% myocardial ischemia relative to <10% myocardial ischemia for MACEs remained significant (adjusted hazard ratio [95% confidence interval], 2.40 [1.09–5.26], P=0.029).

Conclusion

The presence of ≥10% myocardial ischemia was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease.

Funding Acknowledgement

Type of funding sources: None. Study flowchartOutcomes
The role of left atrial wall thickness and pulmonary vein anatomy in success of pulmonary vein isolation using the CLOSE protocol
Authors: Boussoussou M , Vattay B , Szilveszter B , Kolossvary M , Vecsey-Nagy M , Sallo Z , Geller L , Maurovich-Horvat P , Merkely B , Szegedi N ,   Cardiovascular Imaging Research Group
Published: October 2021

Introduction

The CLOSE protocol is a novel contact-force guided technique for enclosing pulmonary veins in patients with atrial fibrillation (AF). Consistency and lesion contiguity are essential factors for procedural success. We sought to determine whether left atrial (LA) wall thickness (LAWT) and pulmonary vein (PV) dimensions as assessed by coronary CT angiography (CTA) could influence the efficacy of successful first-pass isolation using the CLOSE protocol.

Methods

In a single center, prospective study we enrolled 94 patients with symptomatic, drug-refractory AF who underwent pre-ablation left atrial CTA and initial radiofrequency catheter ablation between 2019.01–2020.09. The LA was divided into 11 regions when assessing LAWT. Additionally, the diameter and area of the PV orifices were obtained. First pass isolation was recorded separately for the right and left PVs. After the first pass ablation circles were ready, additional ablations were applied in those cases where first pass isolation was not achieved, to reach complete PV isolation. Predictors of successful first pass isolation were determined using logistic regression models that included anthropometrical, echocardiographic and CTA derived parameters.

Results

A total of 94 patients were included in the analysis with mean CHA2DS2-VASc score of 2.1±1.5 (mean age 62.4±12.6 years, 39.5% female). 61.7% were paroxysmal, 38.3 were persistent AF patients. Mean procedure times were 81.2±19.3 minutes.

Complete isolation of all four PVs was achieved in 100% of patients. First-pass isolation rate was 76%, 71% and 54%, for the right PVs, left PVs and all four PVs, respectively. No difference was found regarding comorbidities and imaging parameters between those with and without first pass isolation. LAWT (mean of all 11 regions or separately) had no effect on the procedural outcome (all p>0.05). Out of all assessed parameters, only RSPV diameter was associated with right sided successful PVI on first pass isolation (p=0.04, OR 1.01).

Conclusion

The use of CLOSE protocol in AF patients resulted in high periprocedural success rate in terms of first pass isolation, independently from the thickness of the LA wall. RSPV diameter could influence the results of first pass isolation.

Funding Acknowledgement

Type of funding sources: None.
Cytokine storm induced coagulopathy in septic shock and critical Covid-19: head-to-head comparison
Authors: Dechamps M D M , De Poortere J , Laterre P F , Octave M , Ginion A , Robaux V , Bodart J , Gruson D , Van Dievoet M , Douxfils J , Derive M , Campion A , Martin M , Horman S , Beauloye C
Published: October 2021

Background

Septic shock generates an important inflammatory reaction, endothelial activation and a procoagulant state leading to microvascular thrombosis and subsequent organ impairment [1].

Similarly, a severe inflammatory reaction and a coagulopathy with pulmonary micro-thrombosis eventually leading to acute lung injury, is a typical feature of critical form of Coronavirus disease 2019 (Covid-19) [2].

Our aim was to compare coagulation, platelet activation and platelets-neutrophils interplay between control, septic shock and critical Covid-19 patients.

Methods/Materials

A total of 118 patients were included in our prospective, monocentric, observational study between February 2019 and June 2020. Septic shock (n=48) and Covid-19 (n=22) patients were consecutively included at admission in our ICU department. Control patients (n=48) with matched gender and co-morbidities were recruited at central lab consultation.

Results

Septic shock patients had worse severity scores due to multiple organ failure (assessed by APACHE II and SOFA score) whereas Covid-19 patients had more severe respiratory failure and a longer ICU length-of-stay (Table 1).

At the time of inclusion, CRP and lymphocyte count were comparable between septic shock and Covid-19 patients. White cell count ad neutrophil count was higher for septic shock patients.

Analysis of coagulation showed a prolonged INR, TT and aPTT in septic shock although only INR was prolonged in Covid-19. Thrombin antithrombin complex (TATc) formation was similar in both pathologies, whereas consumption of antithrombin III (ATIII) and D-dimers formation was more pronounced in septic shock.

Platelet count was lower in septic shock and platelet activation, assessed via plasmatic levels of soluble P-selectin (sCD62P) and Trem-like transcript 1 (sTLT-1), was more important in septic shock.

Neutrophil activation and NETosis, evaluated by levels of circulating myeloperoxidase (MPO) and citrullinated histone 3 (H3-Cit), was similarly increased in both groups (Figure 1).

Conclusions

This study confirmed an activation of coagulation cascade, platelet activation and NETosis in both septic shock and critical Covid-19, compared with control patients. Importantly, the extent of these changes was similar or less pronounced in critical COVID-19 compared with septic shock.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Fondation Saint Luc Figure 1
MMP-2 gene silencing attenuates age-dependent carotid stiffness via reduction of elastin degradation and increased eNOS activation
Authors: Puspitasari Y M , Diaz-Canestro C , Liberale L , Guzik T J , Flammer A J , Bonetti N R , Constantino S , Paneni F , Akhmedov A , Beer J H , Ruschitzka F , Hermann M , Luscher T F , Sudano I , Camici G G
Published: October 2021

Background and aims

Arterial stiffness is a hallmark of vascular aging. Being characterized by a loss of elasticity of large arterial walls, arterial stiffness is associated with an increased risk of cardiovascular disease (CVD). The age-dependent arterial stiffness is primarily attributed to alterations in the elastic and collagen deposition that is regulated by a number of enzymes, including matrix metalloproteinase-2 (MMP-2). Nevertheless, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear.

In this study, we investigated the effect and efficacy of therapeutic MMP-2 knockdown using small interfering RNA (siRNA) on age-dependent arterial stiffness.

Methods

Pulse wave velocity (PWV) was assessed in the right carotid artery of wild-type (WT) mice of different age groups. MMP-2 levels and activity in the carotid artery and plasma of young (3 months) and aged (20–25 months) WT mice were determined. Old WT mice (18–21 months) were treated for 4 weeks with either MMP-2 or scrambled siRNA, in which carotid PWV was assessed at baseline, 2 and 4 weeks after the start of the treatment. Elastin to collagen ratio, desmosin (DES) level, and endothelial nitric oxide synthase (eNOS) pathways were also evaluated and compared. Lastly, levels of circulating MMP-2 and DES, the breakdown product of elastin, were measured in a human cohort (23–86 years old), in whom carotid-femoral PWV was assessed.

Results

Carotid PWV, as well as both vascular and circulating MMP-2 levels, were elevated with increasing age in WT mice (Figure 1). Therapeutic MMP-2 knockdown in aged WT mice reduced the vascular MMP-2 expression and attenuated age-dependent carotid stiffness. Increased elastin to collagen ratio and a lower plasma DES level were observed on MMP-2 silenced treated animals (Figure 2). Moreover, siMMP-2 treated mice showed enhanced eNOS phosphorylation on Ser1177. A direct interaction between MMP-2 and eNOS was also observed, which, interestingly, is augmented with age. Finally, collected human data showed a higher level of circulating MMP-2 levels on the elderly subjects. In addition, plasma DES level is positively correlated with age and aortic PWV, indicating the involvement of vascular elastin catabolism on arterial stiffness.

Conclusions

Therapeutic MMP-2 gene silencing, specifically targeting vascular MMP-2, attenuates age-dependent carotid stiffness. This effect is mediated by augmenting eNOS activation and reducing elastin degradation. Thus, our findings indicate MMP-2 as a potential therapeutic target to mitigate age-dependent arterial stiffness and CVD.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation,Foundation for Cardiovascular Research–Zurich Heart House Figure 1
Metabolic reprogramming in pulmonary arterial hypertension: is it a cancer-like disease?
Authors: Ferreira C , Abreu M , Castro G , Goncalves L , Baptista R , Girao H
Published: October 2021

Background

Idiopathic pulmonary arterial hypertension (iPAH) is a rare and chronic disease associated with poor outcomes. Previously considered a disease restricted to the pulmonary circulation, PAH is now being recognized as a systemic disorder that is associated with metabolic dysfunction. The aim of this study is to analyze the metabolic reprogramming in the lung and peripheral blood mononuclear cell (PBMCs) of iPAH patients and explore their potential roles in PAH pathophysiology.

Methods

Five independent datasets, containing transcriptomic data of human PBMCs (GSE22356 and GSE33463) and lung (GSE48149 GSE113439 and GSE117261) samples, from 139 iPAH patients and 96 healthy controls, were downloaded at the GEO database. In each dataset, the samples were normalized and a pair-wise comparison between control and iPAH samples was performed using limma package, for the R programming language. Genes with a p-value lower than 0.05 were considered differentially expressed between the two groups. A subset of metabolism related genes was selected, and their expression was compared across the datasets.

Results

Among the 13 genes with differential expression identified, only 10 had a coherent expression across all datasets (Figure 1). Firstly, we report an association with insulin resistance through impairment of PI3K signaling in iPAH patients, by expressing lower levels of the heterodimer PIK3CD and regulatory PIK3IP1 and PIKR1 subunits in PBMCs, and by expressing higher levels of its downstream targets in the lung (TBC1D4). However, more extensive metabolic dysfunction was observed. A significant glycolytic shift in the lung and PBMCs was present, as a consequence of deregulation in genes involved in aerobic glycolysis and decreased fatty acid oxidation, namely increased expression of PD1K and lower levels of expression of LDHB. The findings of decreased SLC25A1 protein in both PBMCs and lung suggest impairment of the tricarboxylic acid (TCA) cycle flux in PAH. Additionally, SLC1A5 highlights the involvement of glutamine metabolism and glutaminolysis derangements in PAH. Conversely, SREBP1 is involved in sterol biosynthesis and lower levels in PMBCs results in impaired resolution of inflammatory responses. Finally, although the role of autophagy in iPAH is complex, higher levels of expression of ATG13 in PBMCs and lower levels in the lung confirm autophagy deregulation in iPAH. Interestingly, all the metabolic pathways identified (Figure 2) are hallmarks of the metabolic reprogramming seen in cancer cells, a finding already suggested by the clonal proliferation of pulmonary artery smooth muscle cells described in plexiform lesions.

Conclusion

Our results provide novel insights into the metabolic regulation in iPAH. Molecularly, these cells exhibit many features common to cancer cells, suggesting the opportunity to exploit therapeutic strategies used in cancer to treat iPAH.

Funding Acknowledgement

Type of funding sources: None.
Fiber-optic laser energy for pulmonary artery denervation: results of an experimental study
Authors: Condori Leandro H I , Vakhrushev A , Goncharova N , Korobchenko L , Koshevaya E , Mitrofanova L , Andreeva E , Moiseeva O , Lebedev D , Mikhaylov E
Published: October 2021

Background/Introduction

Pulmonary artery denervation (PADN) is an interventional procedure aiming to modulate and correct pulmonary artery (PA) pressure. New technologies and energy sources are being tested currently. However, the effects of laser energy on the PA wall are unknown.

Purpose

To assess the acute effects and impact of laser energy for PADN procedure in normotensive sheep by applying different power settings and session times.

Methods

A total of 10 normotensive Katumsky sheep were included in the experiment. Percutaneous vascular access was performed under general anesthesia. A fiberoptic open-irrigated non-steerable catheter was introduced via a femoral vein through a steerable sheath. Laser applications were applied in the PA trunk and the proximal areas of the right and left PA under fluoroscopic guidance with a 5mm distance between points in the anterior, posterior and lateral walls. Applications were delivered with power 10–30W, 10–35s in duration; irrigation flow 40ml/min. After the procedure, experimental animals were euthanized and underwent an autopsy. PA samples were obtained regardless of the absence of visible laser-related lesions for histological analysis (hematoxylin staining) and immunohistochemical labelling (S100).

Results

A total of 108 ablation sessions were performed, 33 in the right PA, 30 in the left PA and 42 in the PA trunk. During macroscopic examination, laser-related lesions described as irregular brown hemorrhage spots and rough defects observed in the PA endothelium were not homogenous in all experimental animals. Thermal injuries either in the left or right lung lobes were identified in 5 (50%) experimental animals when using 30W during 10–20sec. In 5 (50%) sheep no collateral lung injuries were identified when using 10–20W from 20–35s. A total of 64 PA fragments underwent microscopic examination, acute thermal tissue lesions were observed in all experimental animals despite the absence of laser-related lesions in the PA endothelium; dissection, edema, disruption trough tunica layers, hemorrhage and necrosis at different depth walls. The most frequent nerve damage was obtained with 20W ablation: 5/8 PAs vs, 1/6 with 10–15W and 1/14 with 25–30W (P=0.01). At the same time, there was no difference in intima necrosis between the groups (1/6, 2/8 and 4/14 for 10–15, 20 and 25–30W groups, respectively).

Conclusion(s)

Percutaneous PA laser ablation is feasible, reduction of perivascular nerve expression is seen most frequently, when 20W/20–35 s ablation is performed. PA lesions may differ in depth and characteristics, and perivascular nerve damage might be seen in cases with preserved intima.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant of the Ministry of Science and Higher Education of the Russian Federation
Staphylococcus aureus flavohaemoglobin contributes to early stage biofilm development under nitrosative stress
Authors: Carvalho Sandra M , Freitas Cláudia S , Oliveira Ana S , Saraiva Lígia M
Published: October 2021

Staphylococcus aureus is a Gram-positive bacterium with capacity to form biofilms, which constitute an important resistance mechanism and virulence factor. Flavohaemoglobin (Hmp) is a major nitric oxide (NO) detoxifier of several bacteria, including S. aureus. Although Hmp has a well-known physiological role linked to response of planktonic cells to nitrosative stress, its contribution to biofilm formation remains unaddressed. Hence, in this work, we investigated the role of Hmp in biofilm development of a methicillin-resistant S. aureus strain. For this purpose, we exposed the hmp mutant to nitrosative stress and examined its behaviour along biofilm development. We observed that cells inactivated in hmp and grown under nitrosative stress conditions have significantly impaired capacity to develop early stage biofilms. Furthermore, the wild-type biofilm phenotype was fully restored by trans-complementation of hmp in the hmp mutant. Coculture studies of NO-producing macrophages with S. aureus revealed that the hmp mutant has significantly lower capacity to develop biofilm biomass when compared with the wild type. Thus, we concluded that the pathogen S. aureus relies on Hmp to establish viable biofilms in the presence of cells of the host innate immune system.
Temporal filtering and time-lapse inversion of geoelectrical data for long-term monitoring with application to a chlorinated hydrocarbon contaminated site
Authors: Nivorlis Aristeidis , Rossi Matteo , Dahlin Torleif
Published: October 2021

We present a solution for long-term direct current resistivity and time-domain induced polarization (DCIP) monitoring, which consists of a monitoring system and the associated software that automates the data collection and processing. This paper describes the acquisition system that is used for remote data collection and then introduces the routines that have been developed for pre-processing of the monitoring data set. The collected data set is pre-processed using digital signal processing algorithms for outlier detection and removal; the resulting data set is then used for the inversion procedure. The suggested processing workflow is tested against a simulated time-lapse experiment and then applied to field data. The results from the simulation show that the suggested approach is very efficient for detecting changes in the subsurface; however, there are some limitations when no a priori information is used. Furthermore, the mean weekly data sets that are generated from the daily collected data can resolve low-frequency changes, making the approach a good option for monitoring experiments where slow changes occur (i.e. leachates in landfills, internal erosion in dams, bioremediation). The workflow is then used to process a large data set containing 20 months of daily monitoring data from a field site where a pilot test of in situ bioremediation is taking place. Based on the time-series analysis of the inverted data sets, we can detect two portions of the ground that show different geophysical properties and that coincide with the locations where the different fluids were injected. The approach that we used in this paper provides consistency in the data processing and has the possibility to be applied to further real-time geophysical monitoring in the future.
A multiethnic whole genome sequencing study to identify novel loci for bone mineral density
Authors: Greenbaum Jonathan , Su Kuan-Jui , Zhang Xiao , Liu Yong , Liu Anqi , Zhao Lan-Juan , Luo Zhe , Tian Qing , Shen Hui , Deng Hong-Wen
Published: October 2021

At present, there have only been a few DNA sequencing-based studies to explore the genetic determinants of bone mineral density (BMD). We carried out the largest whole genome sequencing analysis to date for femoral neck and spine BMD (n = 4981), with one of the highest average sequencing depths implemented thus far at 22×, in a multiethnic sample (58% Caucasian and 42% African American) from the Louisiana Osteoporosis Study (LOS). The LOS samples were combined with summary statistics from the GEFOS consortium and several independent samples of various ethnicities to perform GWAS meta-analysis (n = 44 506). We identified 31 and 30 genomic risk loci for femoral neck and spine BMD, respectively. The findings substantiate many previously reported susceptibility loci (e.g. WNT16 and ESR1) and reveal several others that are either novel or have not been widely replicated in GWAS for BMD, including two for femoral neck (IGF2 and ZNF423) and one for spine (SIPA1). Although we were not able to uncover ethnicity specific differences in the genetic determinants of BMD, we did identify several loci which demonstrated sex-specific associations, including two for women (PDE4D and PIGN) and three for men (TRAF3IP2, NFIB and LYSMD4). Gene-based rare variant association testing detected MAML2, a regulator of the Notch signaling pathway, which has not previously been suggested, for association with spine BMD. The findings provide novel insights into the pathophysiological mechanisms of osteoporosis.
¿Límites de tratados internacionales al poder constituyente? Análisis del caso chilenoLimits of international treaties to the constituent power? Analysis of the Chilean case
Authors: Salgado Constanza , Lovera Domingo , Contreras Pablo
Published: October 2021

Chile is undergoing a constituent process to replace its Constitution. Within the rules that regulate the process, it is established that the text of the new Constitution must respect the international treaties ratified by Chile. Some authors have pointed out that this rule entails a substantive limit to the process underway. This paper argues that the rule has another constitutional function: to ensure the exclusive dedication of the Constitutional Convention. It does not follow, however, that international treaties —especially human rights treaties— will not serve as a standard or guideline for the process. Such soft approach, which is a way to respect international law, is fully consistent with a democratic version of the constituent power.
Thoracic stent-graft herniation through the aortic wall in a case of lung cancer
Authors: Nishioka Naritomo , Kurimoto Yoshihiko , Abe Masaru , Kato Hiroaki
Published: October 2021

A 67-year-old man had left upper lung cancer with invasion into the descending aorta. He underwent pre-emptive thoracic endovascular aortic repair using a Valiant Navion followed by left lung upper lobectomy with resection of the aortic wall. Because of continuous bleeding, he underwent re-thoracotomy. Since the surgically resected aortic wall was largely cleaved, bleeding around the stent-graft that herniated into the left pleural cavity was observed. Re-thoracic endovascular aortic repair using a GORE TAG was immediately performed to prevent further stent-graft herniation and impending lethal haemorrhage. It may be necessary to consider reinforcement of the resected aortic wall to prevent thoracic endovascular aortic repair-related complications.
Subxiphoid-subcostal thoracoscopic thymectomy for seropositive myasthenia offers equivalent remission rates and potentially faster recovery
Authors: Cao Peng , Hu Shan , Qu Wensheng , Kong Kangle , Han Peng , Yue Jiaqi , Deng Yu , Fu Xiangning , Li Fan , Zhao Bo
Published: October 2021

OBJECTIVES

To compare the perioperative and follow-up outcomes of patients with myasthenia gravis (MG) receiving subxiphoid-subcostal or unilateral thoracoscopic thymectomy and to identify the factors affecting MG prognosis.

METHODS

From January 2013 to December 2019, a total of 137 consecutive MG patients received subxiphoid-subcostal thoracoscopic thymectomy (STT, n = 65) or conventional unilateral thoracoscopic thymectomy (UTT, n = 72). The primary outcomes of this study were perioperative complications, duration and expenses of hospitalization, VAS score and complete stable remission (CSR).

RESULTS

The patients receiving STT had significantly shorter drainage duration and postoperative hospital stay and lower hospitalization expenses (P < 0.01). Pain scores on postoperative Days 1, 3, 7 and 14 were significantly lower in patients undergoing STT (P < 0.01). The average follow-up was 54.3 ± 24.18 months, with a CSR rate of 30.6% and an overall effective rate of 87.3%. Through uni- and multivariable analyses, shorter symptom duration and Myasthenia Gravis Foundation of America (MGFA) class I were independent predictors for CSR in MG patients receiving thymectomy.

CONCLUSIONS

The present study not only showed that STT was a safe and feasible technique for MG, with a potentially faster postoperative recovery, lower hospitalization expenses, less postoperative pain and equivalent remission rate, but also revealed that shorter symptom duration and MGFA class I were favourable prognostic factors for CSR.
Graft flow assessment and early coronary artery bypass graft failure: a computed tomography analysis
Authors: D’Alessio Andrea , Akoumianakis Ioannis , Kelion Andrew , Terentes-Printzios Dimitrios , Lucking Andrew , Thomas Sheena , Verdichizzo Danilo , Keiralla Amar , Antoniades Charalambos , Krasopoulos George
Published: October 2021

OBJECTIVES

We evaluated graft patency by computed tomography and explored the determinants of intraoperative mean graft flow (MGF) and its contribution to predict early graft occlusion.

METHODS

One hundred and forty-eight patients under a single surgeon were prospectively enrolled. Arterial and endoscopically harvested venous conduits were used. Intraoperative graft characteristics and flows were collected. Graft patency was blindly evaluated by a follow-up computed tomography at 11.4 weeks (median).

RESULTS

Graft occlusion rate was 5.2% (n = 22 of 422; 8% venous and 3% arterial). Thirteen were performed on non-significant proximal stenosis while 9 on occluded or >70% stenosed arteries. Arterial and venous graft MGF were lower in females (Parterial = 0.010, Pvenous = 0.009), with median differences of 10 and 13.5 ml/min, respectively. Arterial and venous MGF were associated positively with target vessel diameter ≥1.75 mm (Parterial = 0.025; Pvenous = 0.002) and negatively with pulsatility index (Parterial < 0.001; Pvenous < 0.001). MGF was an independent predictor of graft occlusion, adjusting for EuroSCORE-II, pulsatility index, graft size and graft type (arterial/venous). An MGF cut-off of 26.5 ml/min for arterial (sensitivity 83.3%, specificity 80%) and 36.5 ml/min for venous grafts (sensitivity 75%, specificity 62%) performed well in predicting early graft occlusion.

CONCLUSIONS

We demonstrate that MGF absolute values are influenced by coronary size, gender and graft type. Intraoperative MGF of >26.5 ml/min for arterial and >36.5 ml/min for venous grafts is the most reliable independent predictor of early graft patency. Modern-era coronary artery bypass graft is associated with low early graft failure rates when transit time flow measurement is used to provide effective intraoperative quality assurance.
True thymic hyperplasia causing pure red cell aplasia: a case report
Authors: Mohammad Adam , Dawson Alan G , Bajaj Amrita , Rathinam Sridhar
Published: October 2021

Pure red cell aplasia caused by true thymic hyperplasia is extremely rare. We report the case of a 25-year-old female diagnosed with pure red cell aplasia. Following a thymectomy confirming true thymic hyperplasia and corticosteroid therapy, complete response was achieved. Patients diagnosed with pure red cell aplasia should be investigated with a computerized tomographic scan to assess for thymic pathology and if present, this should be resected. Follow-up is essential to monitor for recurrence.
Paediatric Takayasu’s arteritis complicated by thrombotic occlusion of the distal thoracic aorta
Authors: Nakata Tomohiro , Tachi Maiko , Suehiro Shoichi , Oda Teiji
Published: October 2021

We present the case of a 1-year-old girl with mid-aortic syndrome due to untreated Takayasu’s arteritis who developed cardiogenic shock. Enhanced computed tomography revealed long-segment occlusion of the distal thoracic aorta. We successfully performed graft interpose (10 mm in diameter) under cardiopulmonary bypass through both median sternotomy and left posterolateral thoracotomy. The thrombus was relatively small and the distal thoracic aorta was narrow over a long segment due to severely thickened intima. Follow-up computed tomography showed widely patent graft without a stenotic region in the abdominal aorta or its branches. The patient discharged ambulatory without major complications.
Cell-Associated Human Immunodeficiency Virus (HIV) Ribonucleic Acid Has a Circadian Cycle in Males With HIV on Antiretroviral Therapy
Authors: Stern Jared , Solomon Ajantha , Dantanarayana Ashanti , Pascoe Rachel , Reynaldi Arnold , Davenport Miles P , Milush Jeffrey , Deeks Steven G , Hartogensis Wendy , Hecht Frederick M , Cockerham Leslie , Roche Michael , Lewin Sharon R
Published: October 2021

Background

Circadian transcription factors that regulate cell-autonomous circadian clocks can also increase human immunodeficiency virus (HIV) transcription in vitro. We aimed to determine whether circadian variation in HIV transcription exists in people with HIV (PWH) on antiretroviral therapy (ART).

Methods

We performed a prospective observational study of male PWH on ART, sampling blood every 4 hours for 24 hours. Using quantitative polymerase chain reaction, we quantified expression of circadian-associated genes, HIV deoxyribonucleic acid (DNA), and cell-associated unspliced (CA-US) ribonucleic acid (RNA) in peripheral blood CD4+ T cells. Plasma sex hormones were quantified alongside plasma and salivary cortisol. The primary outcome was to identify temporal variations in CA-US HIV RNA using a linear mixed-effect regression framework and maximum likelihood estimation.

Results

Salivary and plasma cortisol, and circadian genes including Clock, Bmal1, and Per3, varied with a circadian rhythm. Cell-associated unspliced HIV RNA and the ratio of CA-US HIV RNA/DNA in CD4+ T cells also demonstrated circadian variations, with no variation in HIV DNA. Circulating estradiol was highly predictive of CA-US HIV RNA variation in vivo.

Conclusions

Cell-associated unspliced HIV RNA in PWH on ART varies temporally with a circadian rhythm. These findings have implications for the design of clinical trials and biomarkers to assess HIV cure interventions.
Antimicrobial stewardship in Australia: the role of qualitative research in programme development
Authors: Thursky Karin A , Hardefeldt Laura Y , Rajkhowa Arjun , Ierano Courtney , Bishop Jaclyn , Hawes Lesley , Biezen Ruby , Saha Sajal K , Dowson Leslie , Bailey Kirsten E , Scarborough Ri , Little Stephen B , Gotterson Fiona , Hur Brian , Khanina Anna , Urbancic Karen , Crabb Helen K , Richards Suzanna , Sri Anna , James Rodney , Kong David C M , Marshall Caroline , Mazza Danielle , Peel Trisha , Stuart Rhonda L , Manski-Nankervis Jo-Anne , Friedman N Deborah , Bennett Noleen , Schulz Thomas , Billman-Jacobe Helen , Buono Evette , Worth Leon , Bull Ann , Richards Michael , Ayton Darshini , Gilkerson James R , Browning Glenn F , Buising Kirsty L ,   National Centre for Antimicrobial Stewardship, Manias Elizabeth , Trubiano Jason , McMullan Brendan , Douglas Abby , Slavin Monica , Davis Mark , Chen Caroline , Ingram Robyn , Cheah Ron , Fang Xin , Sakthivel Jegadeesh , Koning Sonia
Published: October 2021

Antimicrobial stewardship (AMS) in Australia is supported by a number of factors, including enabling national policies, sectoral clinical governance frameworks and surveillance programmes, clinician-led educational initiatives and health services research. A One Health research programme undertaken by the National Centre for Antimicrobial Stewardship (NCAS) in Australia has combined antimicrobial prescribing surveillance with qualitative research focused on developing antimicrobial use-related situational analyses and scoping AMS implementation options across healthcare settings, including metropolitan hospitals, regional and rural hospitals, aged care homes, general practice clinics and companion animal and agricultural veterinary practices. Qualitative research involving clinicians across these diverse settings in Australia has contributed to improved understanding of contextual factors that influence antimicrobial prescribing, and barriers and facilitators of AMS implementation. This body of research has been underpinned by a commitment to supplementing ‘big data’ on antimicrobial prescribing practices, where available, with knowledge of the sociocultural, technical, environmental and other factors that shape prescribing behaviours. NCAS provided a unique opportunity for exchange and cross-pollination across the human and animal health programme domains. It has facilitated synergistic approaches to AMS research and education, and implementation of resources and stewardship activities. The NCAS programme aimed to synergistically combine quantitative and qualitative approaches to AMS research. In this article, we describe the qualitative findings of the first 5 years.
PSVIII-22 Maternal vitamin and mineral supplementation affect fetal hepatic expression of genes underlying mineral homeostasis and lipid metabolism in early pregnancy
Authors: da Silva Diniz Wellison Jarles , Ward Alison K K , Reynolds Lawrence P P , Borowicz Pawel P P , Sedivec Kevin K K , McCarthy Kacie L L , Kassetas Cierrah J J , Baumgaertner Friederike , Kirsch James D , Dorsam Sheri T T , Neville Tammi L L , Forcherio J Chris , Scott Ronald , Caton Joel , Dahlen Carl R
Published: October 2021

Vitamins and minerals play critical roles in functions such as hormone production, DNA synthesis, regulation of gene expression, and lipid metabolism. However, the impact of vitamin and mineral supplementation on fetal programming and the interplay with gene expression of fetal organs remains unclear. We used a differential gene expression analysis to determine effects of maternal vitamin and mineral supplementation (from pre-breeding to d 83 post-breeding) on fetal hepatic gene expression and the pathways underlying liver function and metabolism at 83 d of gestation. Crossbred Angus beef heifers were supplemented (VTM, n = 7) or not (CON, n = 8) with 113 g•heifer-1•d-1 of mineral premix (Purina® Wind & Rain Storm All-Season 7.5 Complete) from a minimum d 71 before breeding through d 83 of gestation. After breeding, heifers were fed to gain 0.79 kg/d. All heifers were surgically ovariohysterectomized on d 83 and fetal liver collected. Total RNA was isolated from the fetal liver (n = 15) and gene expression measured with RNA-Seq. After library quality control and read mapping, differential expression was performed using edgeR. We identified 53 genes upregulated and 37 downregulated in the VTM group (adj.Pval < 0.1). Genes involved with mineral homeostasis, such as MT1A, MT1E, and MT2A, were among those differentially expressed underlying the mineral absorption pathway. ABCA1 and ABCA6, which are involved in cholesterol and metal ion transport across the plasma membrane, and PPARG and SDR16C5, that act on lipoprotein transport and metabolism, were upregulated in the VTM group. Also upregulated in the VTM group, the CUBN gene plays a role in vitamin and iron metabolism. In summary, maternal vitamin and mineral supplementation from pre-breeding to d 83 of gestation leads to upregulation of fetal hepatic genes acting on mineral homeostasis, lipid transport, and metabolism.
PSVIII-25 Transcriptional reprogramming in rumen epithelium during the developmental transition of pre-ruminant to the ruminant in cattle
Authors: Baldwin Ransom L , Connor Erin E , Ramsay Timothy G , Liu George E , Li Cong-Jun
Published: October 2021

The rumen is a critical organ mediating nutrient uptake and use in cattle. Healthy rumen development is essential to ensure animal feed efficiency. In this work, we present an analysis of transcriptomic dynamics in rumen epithelium during the transition from pre-rumination to rumination in cattle-fed hay or concentrated diets at weaning (eighteen Holstein bull calves, 3 X 6 groups). These two distinct phases of rumen development and function in cattle are tightly regulated by a series of signaling events and clusters of effectors on key pathways. Our analysis identifies putative signaling events and effectors. Gene activity shifts indicated the transcriptomic reprogramming required to induce developmental changes in ruminal epithelium and functional transitions. A principal component analysis distinguished the temporal expression patterns that clustered separately between pre- and post-weaning groups. A GO-term enrichment analysis reflected functional (physical and metabolic) development of ruminal epithelium and revealed the greatest number of DEGs were enriched in biological processes related to energy metabolism. Canonical pathway and upstream regulator analyses revealed transcription reprogramming with clusters of critical pathways and upstream regulators controlling functional and developmental transitions with no significant differences between hay- and concentrate-fed groups at weaning. The most highly activated transcription factors expressed during the weaning transition were PPARGC1A, INSR, NFE2L2, MYC, MYCN, and PPARA. Overall, the dietary shift from liquid to solid feeds prompted transcriptional reprogramming in rumen epithelial tissue reflecting critical nutrient-gene interactions occurring during the developmental progression of ruminant digestion.
PSXV-14 Level of spontaneous oxidative modification of sperm plasma proteins in stallions of different ages
Authors: Atroshchenko Mikhail , Engalycheva Mariya , Shitikova Anna
Published: October 2021

The objective of the study was to assess the level of spontaneous oxidative modification of sperm plasma proteins (OMP) in young and mature stallions as indicators of the severity of oxidative stress. Sperm from 12 stallions aged 14–18 years (average age 15.8±1.9 years) (Group I) and 12 stallions aged 3–5 years (average age 4.3±0.6 years; Group II) was obtained during the breeding season (February-May). Each ejaculate was evaluated by volume, concentration, total number of spermatozoa, as well as by the progressive motility and survival of spermatozoa in diluted sperm during its hypothermic storage at +4°C. For a quantitative assessment of the OMP level, a spectrophotometric analysis of 2,4-dinitrophenylhydrazones formed during the interaction of carbonyl derivatives of proteins with 2,4-dinitrophenylhydrazine was carried out (SF-2000, Russia). The level of aldehyde- and ketone-dinitrophenylhydrazones of neutral (ADNPHn, KDNPHn) and basic (ADNPGb, KDNPGb), and the total level of OMP (S OMP) was measured. Significance of differences was assessed by the Mann-Whitney test, the results were statistically significant at P ≤ 0.05. The total level of spontaneous OMP of sperm plasma in aged stallions is statistically significantly higher than in young stallions (531.7 and 384.3 Uod/g protein, respectively, P < 0.05). This indicates a higher degree of oxidative stress in Group I, a more significant damage to the amino acid residues of sperm plasma proteins. In Group I a shift in the absorption spectrum towards neutral aldehyde derivatives (367.6 and 255.8 Uod/g protein, respectively, P < 0.05) was noted. We assume that the pro-oxidant systems in a stallion body increasingly prevail over the protective ones with the age. This leads to an increase in the level of OMP in the sperm and a decrease in the survival of spermatozoa during the hypothermic storage of diluted sperm. Authors acknowledge financial support from Russian Science Foundation, Grant No: 20-16-00101.