bluuebunny/crossref_metadata_2025 huggingface dataset:
P254 The differential impact of renal resistive index on future cardiovascular event in the hospitalised cardiovascular patients according to left ventricular ejection fraction: J-VAS study
Authors: Kotruchin P , Hoshide S , Ueno H , Komori T , Kario K
Published: January 2020

Introduction

Renal resistive index (RRI) not only reflects renal vascular hemodynamics but also correlates well with systemic arterial stiffness. RRI associated with cardiovascular events in the selected group of cardiovascular patients including heart failure (HF). However, previous study limited only in the preserved ejection fraction (EF) patients.

Purpose

To determine the differential impact of RRI on cardiovascular events among cardiovascular patients according to EF.

Methods

A retrospective analysis of the Jichi Vascular Hemodynamics in Hospitalised Cardiovascular Patients (J-VAS) cohort. EF and RRI were measured in all patients, then categorised into groups of reduced EF (rEF < 40%), mid-range EF (mrEF 41-49%), and preserved EF (pEF≥50%). The latter group was subdivided into RRI≥0.8 and <0.8 to identify the risk of the primary endpoint, which was the composite of cardiac death, HF, acute coronary syndrome (ACS), aortic disease, arterial occlusion, and stroke.

Results

We included 1765 patients (mean age 64.7 years, 76% men). The most common diagnoses were ACS(66%) and HF(25%). During the median follow up of 1.9 years, 252 cardiovascular events occurred, 30.7%, 17.7%, and 10.4% in the rEF, mrEF and pEF group. RRI≥0.8 associated with the primary endpoint in the patients with pEF (Hazard ratio(HR), 1.69; 95%confident interval(CI) 1.11-2.58), but the association was not found in the other EF groups. Multivariate Cox regression analysis putting the pEF with RRI < 0.8 as a reference, pEF with RRI≥0.8 had a comparable risk for the primary endpoint to the mrEF group (HR, 1.55; 95%CI, 1.04-2.30 and HR, 1.92; 95%CI, 1.31-2.80, respectively), while the risk was highest in the rEF group (HR, 3.80; 95%CI, 2.73-5.29).

Conclusions

The risk of cardiovascular events in cardiovascular patients with pEF related to renal vascular hemodynamic alterations justified by RRI. In the patients with pEF, those with high RRI had comparable risk to the mrEF patients.

Risk of RRI≥0.8 for the primary endpoint Preserved EF HR (95%CI); P Mid-range EF HR (95%CI); P Reduced EF HR (95%CI); P Model 1 2.05 (1.39-3.02); P <0.001 1.60 (0.81-3.18); P =0.179 0.94 (0.53-1.67); P =0.838 Model 2 1.86 (1.25-2.78); P =0.002 1.33 (0.65-2.72); P =0.430 0.93 (0.52-1.66); P =0.792 Model 3 1.69 (1.11-2.58); P =0.015 1.10 (0.51-2.36); P =0.810 0.70 (0.38-1.28); P =0.242 Adjusted hazard ratio of RRI≥0.8 for the primary endpoint, RRI≥0.8 associated with a significant risk for the primary endpoint in the pEF group but not in the mrEF and rEF group. Model 1 was adjusted for age, sex and body mass index (BMI). Model 2 was adjusted for age, sex, BMI, smoking, dyslipidemia, and diabetes. Model 3 was adjusted for age, sex, BMI, smoking, dyslipidemia, diabetes, and glomerular filtration rate (GFR).

Abstract P254 Figure. Survival plot of the 4 subgroups
P259 Adherence to optimal medical therapy in Asian patients with acute myocardial infarction treated with PCI
Authors: Koh T , Huang W , Gao F , Allen J C , Liman C , Yap J , Yeo K K
Published: January 2020

On Behalf

SingCLOUD collaborators

Background

 Notable regional differences have been observed worldwide in clinical characteristics and outcomes in patients experiencing acute myocardial infarction (AMI). Asian patients present younger and report higher adverse outcomes rates compared to Western cohorts. The reasons are multifactorial, but adherence to medication prescription guidelines is one of the modifiable factors.

Purpose

 Our aim was to study the effect of physician adherence to Optimal Medical Therapy (OMT) prescription guidelines on a MACE outcome in a high-risk group of Asian AMI patients over 1 year following percutaneous coronary intervention (PCI).

Method

 Data for this retrospective study was from the Singapore Cardiac Longitudinal Outcomes Database (SingCLOUD) pilot study involving AMI patients surviving primary PCI at two tertiary centers from 2012 to 2013. Guideline-directed OMT adherence was defined as concurrent prescription of at least one statin plus dual antiplatelet therapy (DAPT – aspirin plus P2Y12-I). Prescription of β-blockers and ACE-i/ARBs was also recorded. Prescription status and MACE (repeat MI, stroke, death) was recorded at discharge, 3, 6 and 9 months, and 1 year following the index discharge. The cumulative effect of OMT adherence at 3, 6, 9 months and 1 year post-discharge was studied by comparing risk of first MACE among patient groups with complete, partial and non-adherence to OMT prescription guidelines.

Results

 2,478 patients, 80.3% males, mean age 60.3 ± 11.7 years were studied. 1094 (44.1%) underwent primary PCI for STEMI. Single drug prescription at discharge for aspirin, P2Y12-I, and statins was 95, 97 and 95.8%, while prescription of β -blockers and ACE-inhibitors was 86.5 and 75.7%. Prescription of statins and aspirin declined gradually while P2Y12-I fell to 67.9% at 6mo and 47.6% at 1 year. Adherence to OMT declined from 92.3% at discharge to 82.1, 58.5, 56.1 and 40.3% at 3, 6, 9 months and 1 year, respectively. Of 342 (13.8%) occurrences of first MACE, 48.5% occurred within 3mo post-discharge. Complete adherence to OMT upon discharge significantly decreased risk of MACE at 3mo (OR = 0.066; 95% CI: 0.054-0.080; p < 0.001) and 12mo (OR = 0.017; 95% CI: 0.010-0.028; p < 0.001) relative to non-adherence.

Conclusion

 Over the course of a year in this high-risk group of PCI-treated AMI patients, there was a reduction in prescription adherence to the minimally essential OMT. Complete OMT adherence is beneficial in reducing MACE. Interventions targeting reasons for non-adherence are important in improving patient outcomes.

Abstract P259 Figure 1 - Medication over 1 year
P261 The relationship between carotid intime-media thickness and modified gensini score in patients with acute coronary syndrome
Authors: Nguyen Hoang Tai M Y , Huynh Kim PHUONG , Nguyen Thuong NGHIA
Published: January 2020

Introduction

Detection of extent and severity of atherosclerosis using easy, non-invasive methods is of great importance. Coronary atherosclerotic burden may be evaluated with the modified Gensini score (mGSS) while carotid intima media thickness (CIMT) is well known as a surrogate marker of atherosclerosis.

Aim

 To investigate whether CIMT is a predictor of coronary atherosclerosis in Vietnamese patients.

Methods

This is a cross-sectional study of 276 patients who was diagnosed index acute coronary syndrome and underwent coronary angiography. mGSS was used to determine the extent and severity of coronary atherosclerosis. CIMT was estimated by carotid duplex ultrasound.

Results

In 276 patients, there were 192 men and 84 women, with ages ranging from 24 to 90 years.  Median CIMT was 0.76mm (IQT 0.26mm); median mGSS was 140 (IQT 70). CIMT and mGSS were correlated with age (r= 0.269, p< 0.001 and r= 0.134, p< 0.001). CIMT were also correlated with vessels score (r= 0.222, p< 0.001), with stenosis score (r= 0.214, p< 0.001) and with the mGSS (r= 0.216, p< 0.001). This correlation were significantly recognized between groups with or without elevated CIMT.

Conclusion

Our data suggests that CIMT correlates positively with the extent and severity of coronary atherosclerosis. CIMT may be useful as a screening tool for the presence of CAD in Vietnamese population.
P263 Characterisation of patients with acute myocardial infarction complicated by left ventricular thrombus
Authors: Leow A S T , Sia C H , Tan B Y Q , Kaur R , Sim H W , Yeo T C , Chan M Y Y , Richards M A , Tay E L W , Loh J P Y
Published: January 2020

Funding Acknowledgements

None

Background/Introduction

Left ventricular (LV) thrombus is a widely recognized complication of acute myocardial infarction (AMI).  Limited data are available from South East Asian patients with this post-infarction complication nor on whether patients with non-ST segment elevation myocardial infarction (NSTEMI) or STEMI with associated LV thrombosis exhibit differing clinical characteristics and/or outcomes. Left Ventricular Ejection Fraction (LVEF) ≤ 40% is a recognized predictor of LV thrombus formation, but there is limited data on LV thrombus patients with EF > 40% or in NSTEMI patients.

Purpose

This study aims to investigate and compare the clinical characteristics, treatment and outcomes of post-AMI patients with LV thrombus formation, with a particular emphasis on those with EF ≤ 40% and in NSTEMI patients. 

Methods

Among 5829 consecutive echocardiogram results containing the keyword "thrombus" from August 2006 to September 2017, we identified 289 post-AMI patients with acute LV thrombus formation. Demographics, treatment and outcome measures were analysed.

Results

Cardiovascular risk factors such as dyslipidaemia (54.0%) and hypertension (50.5%) were commonly present in post-AMI patients with LV thrombus. Mean LVEF was 33.0 ± 10.4%. The majority (68.0%) of patients received triple therapy and 59.5% achieved thrombus resolution. NSTEMI patients had greater number of co-morbidities including heart failure (p < 0.01), documented history of  ischaemic heart disease preceding the AMI leading to thrombus formation (p < 0.01) and lower LVEF (28.3 ± 9.3% vs. 34.8 ± 10.3% , p < 0.01) compared with STEMI cases. On multivariate analysis, having a lower EF was a significant independent predictor of stroke (HR 0.96, 95% CI 0.93-1.00, p = 0.03) and all-cause mortality (HR 0.95, 95% CI 0.92-0.99, p < 0.01). The categories of STEMI and NSTEMI did not predict thrombus resolution, stroke events or all-cause mortality after adjustment.

Conclusion(s)

  Post-AMI LV thrombus patients with NSTEMI and STEMI differed in terms of their co-morbidities in their demographics and co-morbidities but it was a lower EF that was associated with an increased risk of stroke and all-cause mortality. Further studies on this topic are required.
P275 Uncontrolled post-clinic blood pressure readings can identify nocturnal non-dipping blood pressure pattern
Authors: Shahab H , Khan H , Tufail M , Artani A , Almas A , Khan A H
Published: January 2020

Funding Acknowledgements

Aga Khan University Faculty of Health Sciences Research Committee (#80096)

On Behalf

PC BP (Post Clinic Blood Pressure) Study Group

Background

Nocturnal non-dipping increases cardiovascular morbidity and mortality in both hypertensive and normotensive subjects. Ambulatory blood pressure monitoring(ABPM) can identify nocturnal blood pressure(BP) dipping patterns but clinic BP cannot. We previously showed that 15-minute post-clinic BP correlates well with 24- hour ABPM.

Purpose

We aimed to determine if 15-minute post-clinic BP reading helped to identify patients with nocturnal non-dipping pattern.

Methods

A cross-sectional study involving 150 participants, as part of the Post Clinic-Ambulatory Blood Pressure(PC-ABP) study, was conducted in cardiology clinics. Participants aged ≥18 years, with hypertension or those referred for its assessment, were included. Pregnant females were excluded. Post-clinic BP was taken 15 minutes after the patient-physician encounter in the clinic using an automated, validated BP device by a research assistant. All the participants were then referred for 24-hour ABPM. Patterns of nocturnal dipping were studied amongst groups of controlled(<140 mmHg) and uncontrolled(≥140mmHg) post-clinic systolic BP(SBP). Fischer exact test was used to determine the difference in dipping patterns amongst the two groups.

Results

The mean age of participants was 60.3 ± 11.9 years. Of 150 participants, 49% were male and of all, 76% were hypertensive. Mean nighttime SBP(±SD) was 121.9(±18) mmHg(p-value <0.001). Mean nighttime DBP(±SD) was 68.7(± 8.7) mmHg(p < 0.001). Patterns of nocturnal dipping amongst patients with mean post-clinic SBP <140mmHg versus ≥140mmHg has been shown in Table 1. The difference in nocturnal dipping patterns between the two groups was statistically insignificant(p-value 0.071). Pearson correlation coefficient between post-clinic SBP and nighttime SBP for patients with loss of dip was higher (0.64; p < 0.001) whereas it was 0.56(p-value <0.001) for those with preserved dip. 

Conclusion

Uncontrolled post-clinic BP can help in identifying patients with nocturnal non-dipping. Larger studies can help determine the prognostic value of post-clinic BP amongst patients with nocturnal non-dipping.

Nocturnal Dipping Amongst The Two Groups Controlled PC SBP <140mmHg (n = 80) Uncontrolled PC SBP ≥140mmHg (n = 70) Preserved Nocturnal Dipping (10 to 20% nocturnal drop in SBP) 61.2% (n = 49) 47.1% (n = 33) Loss of Dip (>0% to <10% of nocturnal drop in SBP) 33.8% (n = 27) 48.6% (n = 34) Reversed Dip (≤0% drop in SBP) 5% (n = 4) 1.4%(n = 1) Excessive Dip (>20% drop in SBP) 0 2.9% (n = 2) Table 1 shows the patterns of nocturnal dipping amongst patients with controlled (<140mmHg) and uncontrolled (≥140mmHg) 15-minute post-clinic systolic blood pressure (PC SBP).
P281 Factors influencing apixaban dosing in the middle east gulf region
Authors: Atallah B , Alsolh S , El Nekidy W , Sabbour H , Almahmeed W , Almuti K
Published: January 2020

Background

Approved dose adjustment criteria for apixaban are based on the clinical trial. Adjustments require presence of 2 of 3 criteria. In the ARISTOTLE trial, 4.7% of patients met those criteria. Real world data show much higher utilization of the lower dose. Accurate statistics on the prevalence and predictors of such dosing in the Middle East Gulf region are lacking.

Purpose

We sought to explore the appropriateness of apixaban dosing and to predict the factors influencing physician dosing strategies at a tertiary care center in our United .

Methods

We performed a retrospective chart review of patients receiving apixaban for atrial fibrillation from our hospital-based outpatient pharmacy between April 1, 2015 and October 1, 2018. Patients with missing data or on apixaban for other indications were excluded.

Results

A total of 232 patients were included with a mean follow-up of 400 ± 271 days. The mean age was 66.0 ± 13.2 years, 45.5% female, mean weight 82.4 ± 44.7 kg, mean serum creatinine 1.0 ± 0.4 mg/dL, CHA2DS2VASc 3.7 ± 1.8, and 30.1% were on at least 1 concomitant antiplatelet drug. Seventy three patients (31.3%) received a reduced apixaban dose of 2.5 mg twice daily. Deviation from recommended criteria was seen in a total of 62 patients (26.6%), most being under-dosed (93.5%). The significant predictors of underdosing in our model were older age (risk of under-dosing increases by 7.2% for each additional year of age) and eGFR 30 to 60 mL/min/1.73 m2.

Conclusion

Under-dosing of apixaban is prevalent in the Middle East Gulf region. Advancing age and eGFR are the main predictors of under-dosing. More education is needed to optimize dosing of apixaban for stroke prevention in AF.

Table 1 % Change in Odds Ratio Variables coef. std. error p expected min max Intercept -1.563 0.223 0.000 Age 0.069 0.022 0.002 7.2% 2.5% 12.1% eGFR (30-60 relative to >60) 1.583 0.625 0.011 386.9% 39.6% 1597.8% Table 1. Stepwise logistic regression model for predictors of apixaban underdosing. Adjusted for serum creatinine, weight, BMI, gender, CHADS2-VASc score, concomitant antiplatelets, and eGFR < 30 or > 60 mL/min/m2
Are Advances in Survival Among the Oldest Old Seen Across the Spectrum of Health and Functioning?
Authors: Thinggaard Mikael , Jeune Bernard , Osler Merete , Vaupel James W , McGue Matt , Christensen Kaare
Published: January 2020

Background

Mortality rates have been reduced by half over the last 60 years for nonagenarians, and the progress is continuing. The greater survival might be due to overtreatment of severely physically and cognitively disabled individuals, which is a big concern for societies and individuals.

Methods

The study population comprised two Danish birth cohorts: the 1905 Cohort and the 1915 Cohort. At age 95, all from the two cohorts who were still alive and living in Denmark were invited to participate in a health survey that used the same assessment instrument. A total of 2,670 (56.8%) persons participated in the two surveys and survival was assessed through a 7.3-year follow-up period during which 2,497 (93.5%) had died, and with virtually no loss to follow-up.

Results

Despite the increasing chance of surviving to age 95, the 1915 Cohort had significantly better health and functioning than the 1905 Cohort. The survival advantage in the 1915 Cohort continued in the follow-up period after age 95: Median survival length was 2.4 months longer, p = .011. This advantage was not statistically associated with different levels of activities of daily living, physical performance, cognitive functioning, self-rated health and life satisfaction. However, the advantage tended to be more pronounced among people with better health.

Conclusions

Life span and health increases among the oldest old. The improvement in survival for 95-year olds born in 1915 compared with 1905 was seen across the whole spectrum of health and functioning, with a tendency towards bigger improvement among those in good health.
The Itinerant Library of Lala Lajpat Rai
Authors: Moffat Chris
Published: January 2020

This essay traces the movements of a library from New York to Lahore in the wake of the First World War and then to Shimla and Chandigarh following the partition of the Indian subcontinent in 1947. It explores how this collection of books, assembled by the anti-colonial nationalist Lajpat Rai (1865–1928), intersected with and informed key moments of political struggle in twentieth-century urban America and colonial India. The essay then considers the fate of Lajpat Rai’s library today, its place in twenty-first-century Punjab, and the questions it poses for historians interested in anti-colonial histories, post-colonial presents and the commemorative work (as well as enduring political questions) that bind them.
Photojournalism and the Moss Side Riots of 1981: Narrowly Selective Transparency
Authors: Hirsch Shirin , Swanson David
Published: January 2020

In the summer of 1981 a series of riots broke out across England. Here we look at the contemporary photojournalism of the Moss Side, Manchester, riots in the local newspaper, the Manchester Evening News, in order to better understand the riots and media representation of riots more generally. We begin by exploring the contradictory nature of photography (and news photography in particular) – what Susan Sontag refers to as photography’s narrowly selective transparency. We then outline a brief history of the riots, before turning to examine photographs in the Manchester Evening News at the time. We analyse the images both collectively and individually on the basis of what has been selected to be shown and why, and what has been excluded. This perspective allows us then to see in the photographs themselves what was intended to be excluded, primarily the causes of the riots – poverty, racism and oppressive policing; and the humanity of those who took part.
Descriptive epidemiology of energy expenditure in the UK: findings from the National Diet and Nutrition Survey 2008–15
Authors: Brage Soren , Lindsay Tim , Venables Michelle , Wijndaele Katrien , Westgate Kate , Collins David , Roberts Caireen , Bluck Les , Wareham Nick , Page Polly
Published: January 2020

Background

Little is known about population levels of energy expenditure, as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measured energy expenditure in a 10% subsample by gold-standard doubly labelled water (DLW).

Methods

DLW-subsample participants from the NDNS (383 males, 387 females) aged 4–91 years were recruited between 2008 and 2015 (rolling programme). Height and weight were measured and body-fat percentage estimated by deuterium dilution.

Results

Absolute total energy expenditure (TEE) increased steadily throughout childhood, ranging from 6.2 and 7.2 MJ/day in 4- to 7-year-olds to 9.7 and 11.7 MJ/day for 14- to 16-year-old girls and boys, respectively. TEE peaked in 17- to 27-year-old women (10.7 MJ/day) and 28- to 43-year-old men (14.4 MJ/day), before decreasing gradually in old age. Physical-activity energy expenditure (PAEE) declined steadily with age from childhood (87 kJ/day/kg in 4- to 7-year-olds) through to old age (38 kJ/day/kg in 71- to 91-year-olds). No differences were observed by time, region and macronutrient composition. Body-fat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to body mass or fat-free mass. Compared with females with <30% body fat, females with >40% recorded 29 kJ/day/kg body mass and 18 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region and time of assessment. Similarly, compared with males with <25% body fat, males with >35% recorded 26 kJ/day/kg body mass and 10 kJ/day/kg fat-free mass less PAEE.

Conclusions

This first nationally representative study reports levels of human-energy expenditure as measured by gold-standard methodology; values may serve as a reference for other population studies. Age, sex and body composition are the main determinants of energy expenditure.

Key Messages This is the first nationally representative study of human energy expenditure, covering the UK in the period 2008-2015. Total energy expenditure (MJ/day) increases steadily with age throughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age. Physical activity energy expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males. Body-fat percentage is strongly inversely associated with physical activity energy expenditure. We found little evidence that energy expenditure varied by geographical region, over time, or by dietary macronutrient composition.
Density ofg-Vector Cones From Triangulated Surfaces
Authors: Yurikusa Toshiya
Published: January 2020

We study $g$-vector cones associated with clusters of cluster algebras defined from a marked surface $(S,M)$ of rank $n$. We determine the closure of the union of $g$-vector cones associated with all clusters. It is equal to $\mathbb{R}^n$ except for a closed surface with exactly one puncture, in which case it is equal to the half space of a certain explicit hyperplane in $\mathbb{R}^n$. Our main ingredients are laminations on $(S,M)$, their shear coordinates, and their asymptotic behavior under Dehn twists. As an application, if $(S,M)$ is not a closed surface with exactly one puncture, the exchange graph of cluster tilting objects in the corresponding cluster category is connected. If $(S,M)$ is a closed surface with exactly one puncture, it has precisely two connected components.
Role of ppGpp-regulated efflux genes in Acinetobacter baumannii
Authors: Jung Hye-Won , Kim Kyeongmin , Islam M Maidul , Lee Je Chul , Shin Minsang
Published: January 2020

Objectives

Treatment of infections caused by Acinetobacter baumannii nosocomial strains has become increasingly problematic owing to their resistance to antibiotics. ppGpp is a secondary messenger involved in growth control and various stress responses in bacteria. The mechanism for inhibition of antibiotic resistance via ppGpp is still unidentified in various pathogenic bacteria including A. baumannii. Here, we investigated the effects of ppGpp on efflux pump (EP)-related genes in A. baumannii.

Methods

ppGpp-deficient and -complementary strains were constructed by conjugation and we confirmed (p)ppGpp measurements by thin-layer chromatography. We observed that the ppGpp-deficient strain (ΔA1S_0579) showed abnormal stretching patterns by transmission electron microscopy analysis. The MICs of antimicrobial agents for the WT A. baumannii (ATCC 17978), ppGpp-deficient and complementary strains were determined by the Etest and broth dilution assay methods. The expression levels of EP-related genes were determined by quantitative RT–PCR.

Results

We observed morphological differences between a ppGpp-deficient strain (ΔA1S_0579) and the WT strain. Dramatic reductions of MICs in the ppGpp-deficient strain compared with the WT were observed for gentamicin (2.6-fold), tetracycline (3.9-fold), erythromycin (4-fold) and trimethoprim (>4-fold). Expression of the EP-related genes abeB (2.8-fold), tet(A) (2.3-fold), adeB (10.0-fold), adeI (9.9-fold), adeJ (11.8-fold) and adeK (14.4-fold) was also decreased in the ppGpp-deficient strain.

Conclusions

This study demonstrates that ppGpp regulates EP-related gene expression in A. baumannii, affecting antibiotic susceptibility. To date, treatment for MDR A. baumannii has had no new antimicrobial agents, so the A1S_0579 gene could be a novel therapeutic target for rational drug design by affecting ppGpp production.
Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate and emtricitabine in transgender women receiving feminizing hormone therapy
Authors: Cirrincione Lauren R , Podany Anthony T , Havens Joshua P , Bares Sara H , Dyavar Shetty Ravi , Gwon Yeongjin , Johnson Tanner M , Amoura N Jean , Fletcher Courtney V , Scarsi Kimberly K
Published: January 2020

Background

Transwomen have an increased risk of HIV acquisition compared with other adults. Drug–drug interactions between pre-exposure prophylaxis (PrEP) and gender-affirming therapy are cited as a reason for poor PrEP uptake among transwomen. We evaluated plasma tenofovir and emtricitabine pharmacokinetics and their active intracellular anabolites, tenofovir-diphosphate and emtricitabine-triphosphate, in transwomen receiving feminizing hormones.

Methods

We enrolled HIV-negative transwomen (≥19 years) not receiving PrEP. Participants took oral tenofovir disoproxil fumarate/emtricitabine 300/200 mg daily for 14 days. Plasma was collected at 0 h (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 h on day 14 post-tenofovir disoproxil fumarate/emtricitabine dose. The plasma AUC0–24 was calculated using the trapezoidal rule and compared with historical HIV-negative cisgender adults as geometric mean ratios (GMRs, 90% CI). Secondarily, tenofovir-diphosphate and emtricitabine-triphosphate from PBMCs collected at 0 h and 12 h were reported descriptively as geometric means (90% CI). Clinical trials registration: NCT03270969.

Results

Among 15 transwomen (mean age 32 years), geometric mean tenofovir and emtricitabine plasma AUC0–24 were lower compared with controls: tenofovir, 2.10 versus 2.76 mg·h/L, GMR 0.76 (0.65–0.90), P = 0.01; emtricitabine, 9.15 versus 10.64 mg·h/L, GMR 0.86 (0.75–0.98), P = 0.07. Tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in the literature: 167.1 (146.6–190.5) fmol/106 cells and 15.4 (13.8–17.3) pmol/106 cells, respectively.

Conclusions

We observed lower plasma tenofovir and emtricitabine concentrations in transwomen compared with historical cisgender adults, yet intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in PBMCs. Understanding the differences of PrEP pharmacokinetics in plasma and tissue compartments and the resultant impact on efficacy remains important for transwomen.
Separation and Quantification of Superwarfarin Rodenticide Diastereomers—Bromadiolone, Difenacoum, Flocoumafen, Brodifacoum, and Difethialone—in Human Plasma
Authors: Nosal Daniel G , Feinstein Douglas L , Chen Luying , van Breemen Richard B
Published: January 2020

Background

Superwarfarins, second-generation long-acting anticoagulant rodenticides, are 4-hydroxycoumarin analogues of warfarin that contain a large hydrophobic side chain. These compounds contain two chiral centers and are synthesized for commercial use as two pairs of diastereomer.

Objective

To support studies of superwarfarin pharmacokinetics and other efforts to improve clinical care for poisoning victims, a quantitative assay was developed for the measurement of diastereomer of bromadiolone, difenacoum, flocoumafen, brodifacoum, and difethialone in human plasma.

Method

Based on ultrahigh-pressure liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), this method was validated according to U.S. Food and Drug Administration (FDA) guidelines. Sample preparation involved simple protein precipitation followed by reversed phase UHPLC, which resolved all five pairs of cis/trans diastereomer in less than 10 min. Superwarfarins were measured using negative ion electrospray followed by selected-reaction monitoring on a triple quadrupole mass spectrometer.

Results

Calibration curves covered 3–4 orders of magnitude with linear regression coefficients of >0.999. The lower limits of quantitation were from 0.013 to 2.41 ng/mL, and intra-day and inter-day accuracy and precision coefficients of variation were <12%.

Conclusions

A 10-min UHPLC-MS/MS assay was developed and validated for the separation and quantitative analysis of the pairs of diastereomer of five superwarfarins in human plasma.

Highlights

This method was used to identify and measure superwarfarins and their cis/trans diastereomers in plasma obtained from patients treated for coagulopathy following consumption of contaminated synthetic cannabinoid products.
A malectin domain kinesin functions in pollen and seed development in Arabidopsis
Authors: Galindo-Trigo Sergio , Grand Thomas M , Voigt Christian A , Smith Lisa M
Published: January 2020

The kinesin family is greatly expanded in plants compared with animals and, with more than a third up-regulated in expression during cell division, it has been suggested that this expansion facilitated complex plant-specific cytoskeletal rearrangements. The cell cycle-regulated kinesins include two with an N-terminal malectin domain, a protein domain that has been shown to bind polysaccharides and peptides when found extracellularly in receptor-like kinases. Although malectin domain kinesins are evolutionarily deep rooted, their function in plants remains unclear. Here we show that loss of MALECTIN DOMAIN KINESIN 2 (MDKIN2) results in stochastic developmental defects in pollen, embryo, and endosperm. High rates of seed abnormalities and abortion occur in mdkin2 mutants through a partial maternal effect. No additive effect or additional developmental defects were noted in mdkin1 mdkin2 double mutants. MDKIN2 is expressed in regions of cell division throughout the plant. Subcellular localization of MDKIN2 indicates a role in cell division, with a possible secondary function in the nuclei. Our results reveal a non-essential but important role for a malectin domain kinesin during development in plants.
Ionized gas outflow signatures in SDSS-IV MaNGA active galactic nuclei
Authors: Wylezalek Dominika , Flores Anthony M , Zakamska Nadia L , Greene Jenny E , Riffel Rogemar A
Published: January 2020

The prevalence of outflow and feedback signatures in active galactic nuclei (AGNs is a major unresolved question which large integral field unit (IFU) surveys now allow to address. In this paper, we present a kinematic analysis of the ionized gas in 2778 galaxies at z ∼ 0.05 observed by Sloan Digital Sky Survey-IV (SDSS-IV) Mapping Nearby Galaxies at Apache Point Observatory (MaNGA). Specifically, we measure the kinematics of the [O iii] λ5007 Å emission line in each spatial element and fit multiple Gaussian components to account for possible non-gravitational motions of gas. Comparing the kinematics of the ionized gas between 308 MaNGA-selected AGNs that have been previously identified through emission-line diagnostics and sources not classified as AGN, we find that while 25 per cent of MaNGA-selected AGN show [O iii] components with emission-line widths of >500 km s−1 in more than 10 per cent of their spaxels, only 7 per cent of MaNGA non-AGNs show a similar signature. Even the AGNs that do not show nuclear AGN photoionization signatures and that were only identified as AGN based on their larger scale photoionization signatures show similar kinematic characteristics. In addition to obscuration, another possibility is that outflow and mechanical feedback signatures are longer lived than the AGN itself. Our measurements demonstrate that high velocity gas is more prevalent in AGN compared to non-AGN and that outflow and feedback signatures in low-luminosity, low-redshift AGN may so far have been underestimated. We show that higher luminosity MaNGA-selected AGNs are able to drive larger scale outflows than lower luminosity AGN. But estimates of the kinetic coupling efficiencies are ≪1 per cent and suggest that the feedback signatures probed in this paper are unlikely to have a significant impact on the AGN host galaxies. However, continuous energy injection may still heat a fraction of the cool gas and delay or suppress star formation in individual galaxies even when the AGN is weak.
Trend filtering – II. Denoising astronomical signals with varying degrees of smoothness
Authors: Politsch Collin A , Cisewski-Kehe Jessi , Croft Rupert A C , Wasserman Larry
Published: January 2020

Trend filtering – first introduced into the astronomical literature in Paper I of this series – is a state-of-the-art statistical tool for denoising 1D signals that possess varying degrees of smoothness. In this work, we demonstrate the broad utility of trend filtering to observational astronomy by discussing how it can contribute to a variety of spectroscopic and time-domain studies. The observations we discuss are (1) the Lyman-α (Lyα) forest of quasar spectra; (2) more general spectroscopy of quasars, galaxies, and stars; (3) stellar light curves with planetary transits; (4) eclipsing binary light curves; and (5) supernova light curves. We study the Lyα forest in the greatest detail – using trend filtering to map the large-scale structure of the intergalactic medium along quasar-observer lines of sight. The remaining studies share broad themes of: (1) estimating observable parameters of light curves and spectra; and (2) constructing observational spectral/light-curve templates. We also briefly discuss the utility of trend filtering as a tool for 1D data reduction and compression.
The identity and methylation status of the first transcribed nucleotide in eukaryotic mRNA 5′ cap modulates protein expression in living cells
Authors: Sikorski Pawel J , Warminski Marcin , Kubacka Dorota , Ratajczak Tomasz , Nowis Dominika , Kowalska Joanna , Jemielity Jacek
Published: January 2020

7-Methylguanosine 5′ cap on mRNA is necessary for efficient protein expression in vitro and in vivo. Recent studies revealed structural diversity of endogenous mRNA caps, which carry different 5′-terminal nucleotides and additional methylations (2′-O-methylation and m6A). Currently available 5′-capping methods do not address this diversity. We report trinucleotide 5′ cap analogs (m7GpppN(m)pG), which are utilized by RNA polymerase T7 to initiate transcription from templates carrying Φ6.5 promoter and enable production of mRNAs differing in the identity of the first transcribed nucleotide (N = A, m6A, G, C, U) and its methylation status (±2′-O-methylation). HPLC-purified mRNAs carrying these 5′ caps were used to study protein expression in three mammalian cell lines (3T3-L1, HeLa and JAWS II). The highest expression was observed for mRNAs carrying 5′-terminal A/Am and m6Am, whereas the lowest was observed for G and Gm. The mRNAs carrying 2′-O-methyl at the first transcribed nucleotide (cap 1) had significantly higher expression than unmethylated counterparts (cap 0) only in JAWS II dendritic cells. Further experiments indicated that the mRNA expression characteristic does not correlate with affinity for translation initiation factor 4E or in vitro susceptibility to decapping, but instead depends on mRNA purity and the immune state of the cells.
RNAsamba: neural network-based assessment of the protein-coding potential of RNA sequences
Authors: Camargo Antonio P , Sourkov Vsevolod , Pereira Gonçalo A G , Carazzolle Marcelo F
Published: January 2020

The advent of high-throughput sequencing technologies made it possible to obtain large volumes of genetic information, quickly and inexpensively. Thus, many efforts are devoted to unveiling the biological roles of genomic elements, being the distinction between protein-coding and long non-coding RNAs one of the most important tasks. We describe RNAsamba, a tool to predict the coding potential of RNA molecules from sequence information using a neural network-based that models both the whole sequence and the ORF to identify patterns that distinguish coding from non-coding transcripts. We evaluated RNAsamba’s classification performance using transcripts coming from humans and several other model organisms and show that it recurrently outperforms other state-of-the-art methods. Our results also show that RNAsamba can identify coding signals in partial-length ORFs and UTR sequences, evidencing that its algorithm is not dependent on complete transcript sequences. Furthermore, RNAsamba can also predict small ORFs, traditionally identified with ribosome profiling experiments. We believe that RNAsamba will enable faster and more accurate biological findings from genomic data of species that are being sequenced for the first time. A user-friendly web interface, the documentation containing instructions for local installation and usage, and the source code of RNAsamba can be found at https://rnasamba.lge.ibi.unicamp.br/.
The Effect of Infectious Diseases Consultation on Mortality in Hospitalized Patients With Methicillin-Resistant Staphylococcus aureus, Candida, and Pseudomonas Bloodstream Infections
Authors: Chesdachai Supavit , Kline Susan , Helmin Derrek , Rajasingham Radha
Published: January 2020

We evaluated the association between infectious disease consultation and bloodstream infection outcomes, including methicillin-resistant Staphylococcus aureus, Candida, and Pseudomonas. No infectious diseases consultation was associated with over 4-fold increased hazard of death at 3 months and 6-fold increased hazard of death in hospital.
Impaired Vaccine-Induced Antibody Response Against Clade 6B H1N1 Viruses in Individuals Before Viral Emergence
Authors: Huang Kuan-Ying A , Huang Yhu-Chering , Chiu Cheng-Hsun , Tsao Kuo-Chien , Lin Tzou-Yien
Published: January 2020

Background

Clade 6B H1N1 pdm09 influenza viruses cause substantial morbidity and mortality worldwide. Human antibody profiles elicited upon vaccination against the clade 6B virus are largely unclear before viral emergence.

Methods

Healthy volunteers, including children aged 3–8 years, adolescents aged 9–17 years, and adults, were enrolled before the clade 6B H1N1 outbreak and received the 2013–2014 inactivated influenza vaccine. We determined antibody responses before and after vaccination. Vaccine-induced plasmablast-derived antibodies were tested against H1N1 pdm09 reference and clade 6B viruses.

Results

The majority of the subjects generated robust hemagglutination inhibition and neutralizing antibody responses upon vaccination across the different age groups. Nevertheless, a subset of young adults preferentially produced antibodies that failed to neutralize clade 6B viruses that emerged and circulated in 2014–2016. The hemagglutinin K163Q change at the Sa antigenic site, one of the substitutions that define clade 6B viruses, was responsible for resistance to neutralization by both postvaccination sera and vaccine-induced plasmablast-derived antibodies.

Conclusions

Vaccine-induced antibody immunity is compromised by the antigenic change of H1N1 pdm09 virus in a subset of adults, and this may warrant the incorporation of human serology in the antigenic characterization of virus and vaccine strain selection.
Intermittent Starvation Extends the Functional Lifetime of Primary Human Hepatocyte Cultures
Authors: Davidson Matthew D , Khetani Salman R
Published: January 2020

Primary human hepatocyte (PHH) cultures have become indispensable to mitigate the risk of adverse drug reactions in human patients. In contrast to dedifferentiating monocultures, coculture with nonparenchymal cells maintains PHH functions for 2–4 weeks. However, because the functional lifespan of PHHs in vivo is 200–400 days, it is desirable to further prolong PHH functions in vitro toward modeling chronic drug exposure and disease progression. Fasting has benefits on the longevity of organisms and the health of tissues such as the liver. We hypothesized that a culturing protocol that mimics dynamic fasting/starvation could activate starvation pathways and prolong PHH functional lifetime. To mimic starvation, serum and hormones were intermittently removed from the culture medium of micropatterned cocultures (MPCCs) containing PHHs organized onto collagen domains and surrounded by 3T3-J2 murine fibroblasts. A weekly 2-day starvation optimally prolonged PHH functional lifetime for 6+ weeks in MPCCs versus a decline after 3 weeks in nonstarved controls. The 2-day starvation also enhanced the functions of PHH monocultures for 2 weeks, suggesting direct effects on PHHs. In MPCCs, starvation activated 5' adenosine monophosphate-activated protein kinase (AMPK) and restricted fibroblast overgrowth onto PHH islands, thereby maintaining hepatic polarity. The effects of starvation on MPCCs were partially recapitulated by activating AMPK using metformin or growth arresting fibroblasts via mitomycin-C. Lastly, starved MPCCs demonstrated lower false positives for drug toxicity tests and higher drug-induced cytochrome-P450 activities versus nonstarved controls even after 5 weeks. In conclusion, intermittent serum/hormone starvation extends PHH functional lifetime toward enabling clinically relevant drug screening.
Mild Acute Kidney Injury after Noncardiac Surgery Is Associated with Long-term Renal Dysfunction
Authors: Turan Alparslan , Cohen Barak , Adegboye Janet , Makarova Natalya , Liu Liu , Mascha Edward J. , Qiu Yuwei , Irefin Samuel , Wakefield Brett J. , Ruetzler Kurt , Sessler Daniel I.
Published: January 2020

Background

Perioperative acute kidney injury is common. However, it is unclear whether this merely represents a transient increase in creatinine or has prognostic value. Therefore, the long-term clinical importance of mild postoperative acute kidney injury remains unclear. This study assessed whether adults who do and do not experience mild kidney injury after noncardiac surgery are at similar risk for long-term renal injury.

Methods

This study is a retrospective cohort analysis of adults having noncardiac surgery at the Cleveland Clinic who had preoperative, postoperative, and long-term (1 to 2 yr after surgery) plasma creatinine measurements. The exposure (postoperative kidney injury) and outcome (long-term renal injury) were defined and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) initiative criteria. The primary analysis was for lack of association between postoperative kidney injury (stage I vs. no injury) and long-term renal injury.

Results

Among 15,621 patients analyzed, 3% had postoperative stage I kidney injury. Long-term renal outcomes were not similar in patients with and without postoperative stage I injury. Specifically, about 26% of patients with stage I postoperative kidney injury still had mild injury 1 to 2 yr later, and 11% had even more severe injury. A full third (37%) of patients with stage I kidney injury therefore had renal injury 1 to 2 yr after surgery. Patients with postoperative stage I injury had an estimated 2.4 times higher odds of having long-term renal dysfunction (KDIGO stage I, II, or III) compared with patients without postoperative kidney injury (odds ratio [95% CI] of 2.4 [2.0 to 3.0]) after adjustment for potential confounding factors.

Conclusions

In adults recovering from noncardiac surgery, even small postoperative increases in plasma creatinine, corresponding to stage I kidney injury, are associated with renal dysfunction 1 to 2 yr after surgery. Even mild postoperative renal injury should therefore be considered a clinically important perioperative outcome.

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Expression and subcellular localization of the bromodomain-containing protein 7 is a prognostic biomarker in breast cancer
Authors: Vivenza Daniela , Garrone Ornella , Brizio Rodolfo , Mantovani Fiamma , Del Sal Giannino , Merlano Marco , Crook Tim , Lo Nigro Cristiana
Published: January 2020

Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family. Previous studies suggest that BRD7 is predominantly localized in the nucleus, wherein it functions as a transcriptional regulator. Several lines of evidence imply a tumour suppressor function for BRD7. However, the importance of BRD7 in the pathogenesis of breast cancer is not well understood. We have investigated the expression, CpG island methylation and subcellular localization of BRD7 in breast cancer cell lines and clinical cases and thereby assessed its prognostic significance by correlating with clinical-pathological features and time-dependent clinical outcomes. We show that nuclear exclusion of BRD7 occurs commonly in breast cancer and is strongly associated with cases expressing wild-type p53. Moreover, clinical outcomes are significantly less favourable in cases with nuclear exclusion or loss of expression than those in which there is nuclear expression of BRD7. Methylation of the CpG island of BRD7 increases in breast cancer relative to normal breast tissue, but there is not an obvious correlation between methylation and reduced expression or between methylation and clinical outcomes. Overall, our results suggest that nuclear exclusion, rather than transcriptional silencing, is a common mechanism by which the tumour suppressor function of wild-type p53 is inhibited in breast cancer, and show that BRD7 is a promising candidate biomarker in breast cancer.
Mohs Surgery for SEER Registry-Captured Melanoma In Situ and Rare Cutaneous Tumors: Comparing National Utilization Patterns Before and After Implementation of the Affordable Care Act (2010) and Appropriate Use Criteria (2012)
Authors: Garland Kevin , Condon Sean , Xiong David D. , Crowe David , Knackstedt Thomas J.
Published: January 2020

BACKGROUND

The Affordable Care Act (ACA) and the appropriate use criteria (AUC) for Mohs micrographic surgery (MMS) had the potential to increase utilization rates of MMS for indicated skin cancers, but it is unknown whether this has occurred.

OBJECTIVE

To determine whether rates of MMS utilization for head and neck melanoma in situ (MIS) and rare cutaneous tumors (RCTs) increased after the implementation of the ACA and AUC publication.

MATERIALS AND METHODS

Retrospective review using data from the SEER database. Melanoma in situ and RCT tumor cases from before and after the ACA and AUC publication were compared.

RESULTS

Twenty-four thousand six hundred seventy-eight cases were analyzed. Mohs micrographic surgery utilization for MIS decreased from 13.9% before the ACA to 12.3% after the ACA (odds ratio 0.87; p = .012). There was no significant change in MMS utilization for MIS after publication of the AUC. There was also no significant change in MMS utilization for treatment of RCT after the ACA or AUC publication. Stratification of patients into age groups younger or older than 65 years did not change utilization rates.

CONCLUSION

Rates of MMS for treatment of MIS and RCT have not increased since the advent of the ACA or AUC. This finding highlights the need for continued efforts to improve access to MMS and to increase education of its utility in treating skin cancer.