bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-operative delirium associated with metabolic alterations following hemi-arthroplasty in older patients
Authors: Guo Yong , Li Yingchuan , Zhang Yinan , Fang Shudong , Xu Xiaotao , Zhao Aihua , Zhang Junfeng , Li Jia V , Ma Daqing , Jia Wei , Jiang Wei
Published: October 2019

Background

post-operative delirium (POD) is a common complication in older patients, though a possible link between metabolic changes and POD development has yet to be investigated.

Methods

older patients with hip fracture who underwent hemi-arthroplasty were recruited, and delirious states were assessed for 3 days after surgery using the confusion assessment method-Chinese revision. Simultaneously, fasting blood samples were collected on the morning of surgery and on the first post-operative day. Ultimately, 244 older patients who met the inclusion and exclusion criteria were assessed. Blood samples from 60 patients with POD and 60 matched controls were analysed using metabolomics platforms.

Results

sixty patients (24.6%) developed POD. Principal component analysis scores plot and cross-validated scores plots from orthogonal partial least squares-discriminant analysis were implemented to visualise the differences in metabolites between the two groups before and after surgery (P < 0.05). Our data indicate that levels of ω3 and ω6 fatty acids were lower in the POD group than in the NPOD (non-POD) group both before and after surgery; tricarboxylic cycle intermediate levels were lower in the POD group than in the NPOD group, but glycolysis products were higher in the POD group than in the NPOD group after surgery. Furthermore, the branched-chain amino acid (BCAA)/aromatic amino acid ratio was lower in the POD group than in the NPOD group after surgery.

Conclusions

metabolic abnormalities, including deficiencies in ω3 and ω6 fatty acids, perturbations in tricarboxylic cycle and oxidative stress and metabolic imbalances in BCAA and AAA might contribute to POD development.
Distinguishing Causation from Correlation in the Use of Correlates of Protection to Evaluate and Develop Influenza Vaccines
Authors: Lim Wey Wen , Leung Nancy H L , Sullivan Sheena G , Tchetgen Tchetgen Eric J , Cowling Benjamin J
Published: October 2019

There is increasing attention to the need to identify new immune markers for the evaluation of existing and new influenza vaccines. Immune markers that could predict individual protection against infection and disease, commonly called correlates of protection (CoPs), play an important role in vaccine development and licensing. Here, we discuss the epidemiologic considerations when evaluating immune markers as potential CoPs for influenza vaccines and emphasize the distinction between correlation and causation. While an immune marker that correlates well with protection from infection can be used as a predictor of vaccine efficacy, it should be distinguished from an immune marker that plays a mechanistic role in conferring protection against a clinical endpoint—the latter might be a more reliable predictor of vaccine efficacy and a more appropriate target for rational vaccine design. To clearly distinguish mechanistic and nonmechanistic CoPs, we suggest using the term “correlates of protection” for nonmechanistic CoPs, and ‘‘mediators of protection’’ for mechanistic CoPs. Furthermore, because the interactions among and relative importance of correlates or mediators of protection can vary according to age or prior vaccine experience, the effect sizes and thresholds for protective effects for CoPs could also vary in different segments of the population.
The SAUR41 subfamily of SMALL AUXIN UP RNA genes is abscisic acid inducible to modulate cell expansion and salt tolerance in Arabidopsis thaliana seedlings
Authors: Qiu Ting , Qi Mengyuan , Ding Xiaohui , Zheng Yanyan , Zhou Tianjiao , Chen Yong , Han Ning , Zhu Muyuan , Bian Hongwu , Wang Junhui
Published: October 2019

Background and Aims

Most primary auxin response genes are classified into three families: AUX/IAA, GH3 and SAUR genes. Few studies have been conducted on Arabidopsis thaliana SAUR genes, possibly due to genetic redundancy among different subfamily members. Data mining on arabidopsis transcriptional profiles indicates that the SAUR41 subfamily members of SMALL AUXIN UP RNA genes are, strikingly, induced by an inhibitory phytohormone, abscisic acid (ABA). We aimed to reveal the physiological roles of arabidopsis SAUR41 subfamily genes containing SAUR40, SAUR41, SAUR71 and SAUR72.

Methods

Transcriptional responses of arabidopsis SAUR41 genes to phytohormones were determined by quantitative real-time PCR. Knock out of SAUR41 genes was carried out with the CRISPR/Cas9 (clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9) genome editing technique. The saur41/40/71/72 quadruple mutants, SAUR41 overexpression lines and the wild type were subjected to ultrastructural observation, transcriptome analysis and physiological characterization.

Key Results

Transcription of arabidopsis SAUR41 subfamily genes is activated by ABA but not by gibberellic acids and brassinosteroids. Quadruple mutations in saur41/40/71/72 led to reduced cell expansion/elongation in cotyledons and hypocotyls, opposite to the overexpression of SAUR41; however, an irregular arrangement of cell size and shape was observed in both cases. The quadruple mutants had increased transcription of calcium homeostasis/signalling genes in seedling shoots, and the SAUR41 overexpression lines had decreased transcription of iron homeostasis genes in roots and increased ABA biosynthesis in shoots. Notably, both the quadruple mutants and the SAUR41 overexpression lines were hypersensitive to salt stress during seedling establishment, whereas specific expression of SAUR41 under the ABA-responsive RD29A (Responsive to Desiccation 29A) promoter in the quadruple mutants rescued the inhibitory effect of salt stress.

Conclusions

The SAUR41 subfamily genes of arabidopsis are ABA inducible to modulate cell expansion, ion homeostasis and salt tolerance. Our work may provide new candidate genes for improvement of plant abiotic stress tolerance.
Breaking Down the Pseudo-Pacification Process: Eight Critiques of Ultra-Realist Crime Causation Theory
Authors: Wood Mark A , Anderson Briony , Richards Imogen
Published: October 2019

This paper critically examines ultra-realist criminology’s two central crime causation theories: the breakdown of the pseudo-pacification process and special liberty. We identify a number of shortcomings in these theories pertaining to (1) their explanation of gender-related disparities in criminal offending; (2) their explanation of violence reduction through Freudian notions of drives, libidinal energy, and sublimation; and (3) their explication of crime as an expression of capitalist values. Fundamentally, we suggest that in treating political economy as the underlying source of all causative power in society, both theories engage in what Margaret Archer terms ‘downwards conflationism’. To this end, ultra-realism offers what we term a ‘direct expression theory of crime’, in which crime is a synecdoche and direct unmediated expression of political-economic conditions alone. Drawing on Margaret Archer’s realist social theory, we conclude by sketching out several potential principles of an ‘indirect expression theory’ that avoid the shortcomings of ultra-realism in explaining the complicated relationship between political economy and crime.
Trans Women’s Perceptions of Residential Aged Care in Australia
Authors: Waling Andrea , Lyons Anthony , Alba Beatrice , Minichiello Victor , Barrett Catherine , Hughes Mark , Fredriksen-Goldsen Karen , Edmonds Samantha
Published: October 2019

Many older people in trans communities in Australia and elsewhere have experienced long histories of violence and discrimination in the health and social care sectors, making some of them fearful of interacting with contemporary health and social care providers. This study explored older trans women’s perceptions of these services. It involved a qualitative, thematic analysis of semi-structured, one-on-one audio-recorded interviews with ten trans women aged sixty years and older in Australia. Participants expressed a number of concerns about using residential facilities for older people in Australia, including potential for abuse and discrimination as a result of being trans, and not having access to appropriate treatments. Participants indicated a range of alternatives in using services, such as renovating the home, relocating to areas with greater access to trans-inclusive services and potential euthanasia. Participants perceived that service providers were not adequately trained for trans and gender diverse needs, and highlighted a number of ways aged care services could better support the trans and gender diverse community. The findings provide important information to assist health and social care professionals, including social workers, as well as residential care service providers, in supporting the health and well-being of older trans women.
Phylogeography of Excoecaria acerifolia (Euphorbiaceae) suggests combined effects of historical drainage reorganization events and climatic changes on riparian plants in the Sino–Himalayan region
Authors: Wang Zhi-Wei , Zhang Ti-Cao , Luo Dong , Sun Wen-Guang , Sun Hang
Published: October 2019

It has been hypothesized that geological and climatic changes in the Sino–Himalayan region played a significant role in evolutionary history. In this study, we tested this hypothesis by investigating the phylogeography of Excoecaria acerifolia (Euphorbiaceae), a riparian plant species that is widely distributed in the hot/warm-dry river valleys of the Sino–Himalayan region. Spatial analysis of molecular variance, a median-joining network and a Bayesian phylogenetic tree based on plastid DNA, all suggested three major lineages corresponding to the Jialing-Min-Dadu (JMD lineage), Jinsha-Yalong-Salween (JY lineage) and Yarlung Tsangpo-Mekong-Red-Nanpan (YMRN lineage) drainage basins. This was also generally supported by the results based on nuclear DNA. The divergence times of these three major lineages based on both datasets fell in the early Pleistocene, coinciding with the period of drainage reorganization events in the Sino–Himalayan region. The diversification times in the lineages were, however, dated back to the mid Pleistocene, corresponding to the Naynayxungla glaciation (0.72–0.50 Mya) and the penultimate glaciation (0.30–0.13 Mya), which were the most and second most severe glaciations in this region, respectively. Furthermore, mismatch analyses, neutrality test and ecological niche modelling suggest long-term demographic stability of the JY and JMD populations, with expansion only in the YMRN populations during the period(s) from the late penultimate glaciation (138.12 Kya) to the Last Interglacial (95.79 Kya), probably because of less extensive glaciations since the late Pleistocene and the gradually warming interglacial stage. Our study provides one of the few pieces of evidence indicating that combined historical drainage reorganization and climatic change since the Pleistocene might also have acted as important factors in the evolutionary history of riparian plants in the region.
The structural connectivity of discrete networks underlies impulsivity and gambling in Parkinson’s disease
Authors: Mosley Philip E , Paliwal Saee , Robinson Katherine , Coyne Terry , Silburn Peter , Tittgemeyer Marc , Stephan Klaas E , Breakspear Michael , Perry Alistair
Published: October 2019

See O’Callaghan (doi:10.1093/brain/awz349) for a scientific commentary on this article.

Mosley et al. examine impulsivity and naturalistic gambling behaviours in patients with Parkinson’s disease. They link within-patient differences to the structural connectivity of networks subserving reward evaluation and response inhibition, and reveal pivotal roles for the ventral striatum and subthalamic nucleus within these networks.
Phospho-valproic acid (MDC-1112) reduces pancreatic cancer growth in patient-derived tumor xenografts and KPC mice: enhanced efficacy when combined with gemcitabine
Authors: Luo Dingyuan , Digiovanni Matthew G , Wei Ran , Lacomb Joseph F , Williams Jennie L , Rigas Basil , Mackenzie Gerardo G
Published: October 2019

New chemotherapeutic agents are needed for pancreatic cancer (PC). We have previously shown that phospho-valproic acid (MDC-1112) is effective in cell-line xenografts of PC. Here, we explored whether MDC-1112 is effective in additional clinically relevant animal models of PC and whether MDC-1112 enhances the anticancer effect of clinically used chemotherapeutic agents. MDC-1112 alone strongly reduced patient-derived pancreatic tumor xenograft growth, and extended survival of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mice. In both models, MDC-1112 inhibited STAT3 activation and its downstream signals, including Bcl-xL and cyclin D1. In human PC cell lines, P-V enhanced the growth inhibitory effect of gemcitabine (GEM), Abraxane and 5-FU, but not that of irinotecan. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of MDC-1112/GEM combination. Furthermore, MDC-1112 enhanced GEM’s effect on colony formation, apoptosis, cell migration, and cell invasion. In vivo, MDC-1112 and GEM, given alone, reduced patient-derived pancreatic tumor xenograft growth by 58% and 87%, respectively; whereas MDC-1112/GEM combination reduced tumor growth by 94%, inducing tumor stasis. In conclusion, MDC-1112 should be further explored as a potential agent to be used in combination with GEM for treating PC.
Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion
Authors: B Hughes Rebecca , Whittingham-Dowd Jayde , Simmons Rachel E , Clapcote Steven J , Broughton Susan J , Dawson Neil
Published: October 2019

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/− mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic “rich club” and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic “rich club” regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/− mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.
Multiple Morphological Factors Underlie Experience-Dependent Cross-Modal Plasticity in the Developing Sensory Cortices
Authors: Wang Miao , Yu Zixian , Li Guangying , Yu Xiang
Published: October 2019

Sensory experience regulates the structural and functional wiring of sensory cortices. In previous work, we showed that whisker deprivation (WD) from birth not only reduced excitatory synaptic transmission of layer (L) 2/3 pyramidal neurons of the correspondent barrel cortex in mice, but also cross-modally reduced synaptic transmission of L2/3 pyramidal neurons in other sensory cortices. Here, we used in utero electroporation, in combination with optical clearing, to examine the main morphological components regulating neural circuit wiring, namely presynaptic bouton density, spine density, as well as dendrite and axon arbor lengths. We found that WD from P0 to P14 reduced presynaptic bouton density in both L4 and L2/3 inputs to L2/3 pyramidal neurons, as well as spine density across the dendritic tree of L2/3 pyramidal neurons, in the barrel field of the primary somatosensory cortex. The cross-modal effects in the primary auditory cortex were manifested mostly as reduced dendrite and axon arbor size, as well as reduced bouton density of L2/3 inputs. Increasing sensory experience by rearing mice in an enriched environment rescued the effects of WD. Together, these results demonstrate that multiple morphological factors contribute to experience-dependent structural plasticity during early wiring of the sensory cortices.
Decreases in Antimicrobial Use Associated With Multihospital Implementation of Electronic Antimicrobial Stewardship Tools
Authors: Graber Christopher J , Jones Makoto M , Goetz Matthew Bidwell , Madaras-Kelly Karl , Zhang Yue , Butler Jorie M , Weir Charlene , Chou Ann F , Youn Sarah Y , Samore Matthew H , Glassman Peter A
Published: October 2019

Background

Antimicrobial stewards may benefit from comparative data to inform interventions that promote optimal inpatient antimicrobial use.

Methods

Antimicrobial stewards from 8 geographically dispersed Veterans Affairs (VA) inpatient facilities participated in the development of antimicrobial use visualization tools that allowed for comparison to facilities of similar complexity. The visualization tools consisted of an interactive web-based antimicrobial dashboard and, later, a standardized antimicrobial usage report updated at user-selected intervals. Stewards participated in monthly learning collaboratives. The percent change in average monthly antimicrobial use (all antimicrobial agents, anti-methicillin-resistant Staphylococcus aureus [anti-MRSA] agents, and antipseudomonal agents) was analyzed using a pre–post (January 2014–January 2016 vs July 2016–January 2018) design with segmented regression and external comparison with uninvolved control facilities (n = 118).

Results

Intervention sites demonstrated a 2.1% decrease (95% confidence interval [CI], −5.7% to 1.6%) in total antimicrobial use pre–post intervention vs a 2.5% increase (95% CI, 0.8% to 4.1%) in nonintervention sites (absolute difference, 4.6%; P = .025). Anti-MRSA antimicrobial use decreased 11.3% (95% CI, −16.0% to −6.3%) at intervention sites vs a 6.6% decrease (95% CI, −9.1% to −3.9%) at nonintervention sites (absolute difference, 4.7%; P = .092). Antipseudomonal antimicrobial use decreased 3.4% (95% CI, −8.2% to 1.7%) at intervention sites vs a 3.6% increase (95% CI, 0.8% to 6.5%) at nonintervention sites (absolute difference, 7.0%; P = .018).

Conclusions

Comparative data visualization tool use by stewards at 8 VA facilities was associated with significant reductions in overall antimicrobial and antipseudomonal use relative to uninvolved facilities.
Thirteen-Valent Pneumococcal Conjugate Vaccine in Children With Acute Lymphoblastic Leukemia: Protective Immunity Can Be Achieved on Completion of Treatment
Authors: Bate Jessica , Borrow Ray , Chisholm Julia , Clarke Stuart C , Dixon Elizabeth , Faust Saul N , Galanopoulou Angeliki , Goldblatt David , Heath Paul T , Maishman Tom , Mapstone Susan , Patel Soonie R , Williams Antony P , Gray Juliet C
Published: October 2019

Background

Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy.

Methods

Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months.

Results

One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%–27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%–75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%–57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%–72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%–62.6%) maintained immunity at 12 months.

Conclusions

This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection.

Clinical Trials Registration

EudraCT 2009-011587-11.
Moving Towards Hepatitis C Microelimination Among People Living With Human Immunodeficiency Virus in Australia: The CEASE Study
Authors: Martinello Marianne , Yee Jasmine , Bartlett Sofia R , Read Phillip , Baker David , Post Jeffrey J , Finlayson Robert , Bloch Mark , Doyle Joseph , Shaw David , Hellard Margaret , Petoumenos Kathy , Lin Lanni , Marks Philippa , Applegate Tanya , Dore Gregory J , Matthews Gail V
Published: October 2019

Background

Microelimination of hepatitis C virus (HCV) among people living with human immunodeficiency virus (HIV) may be feasible in Australia, given unrestricted access to direct-acting antiviral (DAA) therapy from 2016. Our aim was to evaluate progress towards elimination goals within HIV/HCV-coinfected adults in Australia following universal DAA access.

Methods

The CEASE prospective cohort study enrolled adults with HIV/HCV, irrespective of viremic status, from 14 primary and tertiary clinics in Australia. Annual and cumulative HCV treatment uptake, outcome, and HCV RNA prevalence were evaluated, with follow-up through May 2018 (median follow-up, 2.63 years). Factors associated with DAA uptake were analyzed.

Results

Between July 2014 and March 2017, 402 participants who were HIV/HCV antibody positive were enrolled (95% male [80% gay and bisexual men,], 13% cirrhosis, 80% history of injecting drug use [39% currently injecting]). Following universal DAA access, annual HCV treatment uptake in those eligible increased from 7% and 11% per year in 2014 and 2015, respectively, to 80% in 2016. By 2018, cumulative HCV treatment uptake in those ever eligible for treatment was 91% (336/371). HCV viremic prevalence declined from 82% (95% CI, 78–86%) in 2014 to 8% (95% CI, 6–12%) in 2018. Reinfection was reported in only 5 participants for a reinfection incidence of 0.81 per 100 person-years (95% CI, 0.34–1.94).

Conclusions

High uptake and effectiveness of unrestricted DAA therapy in Australia have permitted rapid treatment scale-up, with a dramatic reduction in HCV infection burden and low reinfection rate among people living with HIV, suggesting that microelimination is feasible.

Clinical Trials Registration

NCT02102451.
Why Colonialism Is Wrong
Authors: Renzo Massimo
Published: October 2019

Historically, colonial domination has involved subjecting innocent populations to atrocities such as murder, torture, and exploitation. But pointing at these wrongs is not enough to explain the distinctive way in which colonialism is wrong. After all, murder, torture and exploitation are wrong whether or not they occur in the context of colonial occupation. If all we can do to explain the nature of colonialism is point at the fact that it typically involves the perpetration of these crimes, we cannot vindicate the thought that there is something distinctively wrong with it. And yet, intuitively the victims of colonial domination have suffered a distinctive wrong over and above those associated with these crimes. How should we understand the nature of this wrong? I answer this question by arguing that colonial domination undermines the capacity of political communities to exercise their self-determining agency in a particular way.
homeBase: Participation, Engagement, Alliance, and Social Validity of a Motivational Parenting Intervention
Authors: Frey Andy , Small Jason W , Lee Jon , Crosby Shantel D , Seeley John R , Forness Steve , Walker Hill M
Published: October 2019

This article examines the participation, engagement, alliance, and social validity of homeBase—a parent management intervention developed specifically to address parent engagement of elementary-level students. The intervention infuses motivational interviewing (MI) into its implementation procedures and trains behavioral coaches to use this approach as their primary interactive vehicle with parents. Process data from participants (N = 120) assigned to one of the two homeBase intervention conditions were examined to better understand the following dimensions: parental participation and engagement, coach–parent alliance, and the satisfaction of the homeBase intervention. Results indicate that parental participation was challenging in that 21 percent of the parents seemed unable to engage at all in the intervention. However, those who did participate were highly engaged and developed effective relationships with their coach. Parents perceived the homeBase intervention to be socially valid. There were also several interesting correlations among these measures that might potentially guide further research and practice. The authors recommend that school social work preparation programs and school districts consider including MI in curriculum and professional development efforts as a strategy for parental engagement.
Bilateral internal thoracic artery grafting: propensity analysis of the left internal thoracic artery versus the right internal thoracic artery as a bypass graft to the left anterior descending artery
Authors: Ogawa Shinji , Tsunekawa Tomohiro , Hosoba Soh , Goto Yoshihiro , Kato Takayoshi , Kitamura Hideki , Tomita Shinji , Okawa Yasuhide
Published: October 2019

OBJECTIVES

To compare different configurations of the bilateral internal thoracic arteries for the left coronary system and examine early and late outcomes, including mid-term graft patency.

METHODS

We reviewed 877 patients who underwent primary isolated coronary artery bypass grafting using in situ bilateral internal thoracic arteries [in situ right internal thoracic artery (RITA)-to-left anterior descending artery (LAD) grafting, n = 683; in situ left internal thoracic artery (LITA)-to-LAD grafting, n = 194]. We compared mid-term patency between the grafts. Propensity score matching was performed to investigate early and long-term outcomes.

RESULTS

The 2-year patency rate for RITA-to-LAD and LITA-to-LAD grafts were similar. Multivariate analysis revealed that RITA-to-non-LAD anastomosis (P = 0.029), postoperative length of stay (P = 0.003) and chronic obstructive pulmonary disease (P = 0.005) were associated with graft failure. After statistical adjustment, 176 propensity-matched pairs were available for comparison. RITA-to-LAD grafting enabled a more distal anastomosis. Kaplan–Meier analysis revealed that the incidences of death, repeat revascularization and myocardial infarction were significantly higher in the LITA-to-LAD group among both the unmatched and matched samples (P = 0.045 and 0.029, respectively).

CONCLUSIONS

The mid-term patency and outcomes of RITA-to-LAD grafting are good and reduces future cardiac event, in contrast to LITA-to-LAD grafting.
A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor
Authors: Rimbert Antoine , Dalila Nawar , Wolters Justina C , Huijkman Nicolette , Smit Marieke , Kloosterhuis Niels , Riemsma Marijn , van der Veen Ydwine , Singla Amika , van Dijk Freerk ,   Biobank-Based Integrative Omics Studies Consortium, Frikke-Schmidt Ruth , Burstein Ezra , Tybjærg-Hansen Anne , van de Sluis Bart , Kuivenhoven Jan Albert
Published: October 2019

Aims

Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR).

Methods and results

Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10−6 to 8.0 × 10−9), with lower risk of MI (P-trend 0.04–0.002) and lower risk of cardiovascular mortality (P-trend 0.005–0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane.

Conclusion 

This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.
Impact of dual-chamber pacing with closed loop stimulation on quality of life in patients with recurrent reflex vasovagal syncope: results of the SPAIN study
Authors: Barón-Esquivias Gonzalo , Moya-Mitjans Angel , Martinez-Alday Jesús , Ruiz-Granell Ricardo , Lacunza-Ruiz Javier , Garcia-Civera Roberto , Gutiérrez-Carretero Encarnación , Romero-Garrido Rafael , Morillo Carlos A
Published: October 2019

Aims 

Reflex vasovagal syncope (VVS) is the most common cause of syncope and patients with recurrent episodes may severely impair quality of life (QoL). This pre-specified analysis evaluated whether the clinically significant reduction in syncope burden demonstrated by dual-chamber pacing with closed loop stimulation (DDD-CLS) reported in the SPAIN trial translates into improved QoL.

Methods and results

Patients aged ≥40 years with ≥5 VVS episodes and cardioinhibitory response induced by head-up tilt testing were included. Patients were randomized 1:1 to active DDD-CLS pacing algorithm for 12 months followed by sham DDI mode for the remaining 12 months (Group A) or vice versa (Group B). QoL was assessed using the Short Form-36 (SF-36) health survey, Physical Component Score (PCS), and Mental Component Score (MCS) before randomization (baseline) and at 12- and 24-month follow-up. Fifty-four patients were enrolled from 11 participating centres. No significant carryover effect was detected for any variable, and the only period effect was observed in the vitality subdomain (P = 0.033). Mean SF-36 scores were higher in the DDD-CLS group vs. the DDI group for the eight subdomains and significantly different in physical role, bodily pain, and vitality (P < 0.05). The analysis of component summary scores indicated that DDD-CLS benefited both mental and physical components with significant differences in PCS when compared with the DDI group.

Conclusion

Dual-chamber pacing with closed loop stimulation determined a significant and clinically relevant improvement in QoL across both mental and physical components in patients with recurrent VVS.

Registration

Closed Loop Stimulation for Neuromediated Syncope (SPAIN Study); NCT01621464.
Changes in General Practitioners’ consultation frequency over time for patients with hypertension or anxiety/depression symptoms: a 10-year follow-up of the Norwegian HUNT study
Authors: Skarshaug Lena J , Kaspersen Silje L , Bjørngaard Johan H , Pape Kristine
Published: October 2019

Background

General Practitioners’ (GPs’) workload has been suggested to increase in many countries; how does this impact patient follow-up?

Objective

To investigate trends in GP consultation patterns for adults according to baseline hypertension and anxiety/depression symptoms and attribution of the GP to trend differences.

Methods

Prospective cohort study, linking survey data and clinical measurements from the Norwegian HUNT3 study (2006–08) with national administrative data on GP list assignment and consultations with GP services. We grouped participants aged 40–59 years according to sex and their baseline status regarding hypertension and anxiety/depression symptoms. We registered GP consultations in 2007–16 and used general estimation equation models to estimate the level of GP consultations per month per year during follow-up. We used multilevel models with participants nested in their assigned regular GP to calculate GP-level intra-class correlation coefficients, reflecting to what extent patients’ consultation patterns could be attributed to the individual GP.

Results

In total, 47 550 HUNT3 participants were registered with 102 different GPs in Nord-Trøndelag County, Norway, in 2007. Adjusted for age, we observed an overall increase in GP consultations in 2007–16, particularly in those with a better health status at baseline. About 2% of the variance of patient consultations could be attributed to differences between GPs and 10% to the use of lengthy consultations. Out-of-hours consultations did not change much in the study period 2007–16.

Conclusion

Increased use of GP consultations, mainly among the healthiest participants, encourage further research into whether these patients displace patients with heavier and more complex needs.
In vitro assembly and cellulolytic activity of a β-glucosidase-integrated cellulosome complex
Authors: Hirano Katsuaki , Saito Tsubasa , Shinoda Suguru , Haruki Mitsuru , Hirano Nobutaka
Published: October 2019

The cellulosome is a supramolecular multi-enzyme complex formed by protein interactions between the cohesin modules of scaffoldin proteins and the dockerin module of various polysaccharide-degrading enzymes. In general, the cellulosome exhibits no detectable β-glucosidase activity to catalyze the conversion of cellobiose to glucose. Because β-glucosidase prevents product inhibition of cellobiohydrolase by cellobiose, addition of β-glucosidase to the cellulosome greatly enhances the saccharification of crystalline cellulose and plant biomass. Here, we report the in vitro assembly and cellulolytic activity of a β-glucosidase-coupled cellulosome complex comprising the three major cellulosomal cellulases and full-length scaffoldin protein of Clostridium (Ruminiclostridium) thermocellum, and Thermoanaerobacter brockii β-glucosidase fused to the type-I dockerin module of C. thermocellum. We show that the cellulosome complex composed of nearly equal numbers of cellulase and β-glucosidase molecules exhibits maximum activity toward crystalline cellulose, and saccharification activity decreases as the enzymatic ratio of β-glucosidase increases. Moreover, β-glucosidase-coupled and β-glucosidase-supplemented cellulosome complexes similarly exhibit maximum activity toward crystalline cellulose (i.e. 1.7-fold higher than that of the β-glucosidase-free cellulosome complex). These results suggest that the enzymatic ratio of cellulase and β-glucosidase in the assembled complex is crucial for the efficient saccharification of crystalline cellulose by the β-glucosidase-integrated cellulosome complex.
Oenological potential of non-Saccharomycesyeasts to mitigate effects of climate change in winemaking: impact on aroma and sensory profiles of Treixadura wines
Authors: Castrillo David , Rabuñal Eva , Neira Noemi , Blanco Pilar
Published: October 2019

The effects of climate change on wine include high-alcohol content, low acidity and aroma imbalance. The potential of several non-Saccharomyces wine yeasts to mitigate these effects was evaluated by sequential fermentation of Treixadura grape must. Fermentations with only Saccharomyces cerevisiae ScXG3 and a spontaneous process were used as control assays. All yeast strains were obtained from the yeast collection of Estación de Viticultura e Enoloxía de Galicia (EVEGA), Galicia, Spain. Fermentation kinetics as well as yeast dynamics and implantation ability varied depending on inoculated yeasts. In addition, the results showed significant differences in the chemical composition of wine. Starmerella bacillaris 474 reduced the alcohol content (1.1% vol) and increased the total acidity (1.2 g L−1) and glycerol of wines. Fermentation with Lachancea thermotolerans Lt93 and Torulaspora delbrueckii Td315 also decreased the alcohol content, although to a lesser extent (0.3% and 0.7% vol, respectively); however, their effect on wine acidity was less significant. The wines also differed in their concentration of volatile compounds and sensory characteristics. Thus, wines made with Metschnikowia fructicola Mf278 and S. cerevisiae ScXG3 had higher content of esters, acetates and some acids than other wines, and were most appreciated by tasters due to their fruity character and overall impression.
Social Determinants of Health: Underreported Heterogeneity in Systematic Reviews of Caregiver Interventions
Authors: Young Heather M , Bell Janice F , Whitney Robin L , Ridberg Ronit A , Reed Sarah C , Vitaliano Peter P
Published: October 2019

Background and Objectives

Although most people have some experience as caregivers, the nature and context of care are highly variable. Caregiving, socioeconomic factors, and health are all interrelated. For these reasons, caregiver interventions must consider these factors. This review examines the degree to which caregiver intervention research has reported and considered social determinants of health.

Research Design and Methods

We examined published systematic reviews and meta-analyses of interventions for older adults with age-related chronic conditions using the PRISMA and AMSTAR 2 checklists. From 2,707 papers meeting search criteria, we identified 197 potentially relevant systematic reviews, and selected 33 for the final analysis.

Results

We found scant information on the inclusion of social determinants; the papers lacked specificity regarding race/ethnicity, gender, sexual identity, socioeconomic status, and geographic location. The majority of studies focused on dementia, with other conditions common in later life vastly underrepresented.

Discussion and Implications

Significant gaps in evidence persist, particularly for interventions targeting diverse conditions and populations. To advance health equity and improve the effectiveness of interventions, research should address caregiver heterogeneity and improve assessment, support, and instruction for diverse populations. Research must identify aspects of heterogeneity that matter in intervention design, while recognizing opportunities for common elements and strategies.
Moving from 1-D to 3-D velocity model: automated waveform-based earthquake moment tensor inversion in the Los Angeles region
Authors: Wang Xin , Zhan Zhongwen
Published: October 2019

Earthquake focal mechanisms put primary control on the distribution of ground motion, and also bear on the stress state of the crust. Most routine focal mechanism catalogues still use 1-D velocity models in inversions, which may introduce large uncertainties in regions with strong lateral velocity heterogeneities. In this study, we develop an automated waveform-based inversion approach to determine the moment tensors of small-to-medium-sized earthquakes using 3-D velocity models. We apply our approach in the Los Angeles region to produce a new moment tensor catalogue with a completeness of ML ≥ 3.5. The inversions using the Southern California Earthquake Center Community Velocity Model (3D CVM-S4.26) significantly reduces the moment tensor uncertainties, mainly owing to the accuracy of the 3-D velocity model in predicting both the phases and the amplitudes of the observed seismograms. By comparing the full moment tensor solutions obtained using 1-D and 3-D velocity models, we show that the percentages of non-double-couple components decrease dramatically with the usage of 3-D velocity model, suggesting that large fractions of non-double-couple components from 1-D inversions are artifacts caused by unmodelled 3-D velocity structures. The new catalogue also features more accurate focal depths and moment magnitudes. Our highly accurate, efficient and automatic inversion approach can be expanded in other regions, and can be easily implemented in near real-time system.
Mitigating temporal aliasing effects of high-frequency geophysical fluid dynamics in satellite gravimetry
Authors: Poropat Lea , Kvas Andreas , Mayer-Gürr Torsten , Dobslaw Henryk
Published: October 2019

Temporal aliasing errors induced by high-frequency tidal and non-tidal mass variability in the Earth system are among the three most important error sources that limit the accuracy of present-day surface mass estimates from satellite gravimetry. By means of end-to-end simulations, we demonstrate that the Kalman Smoother approach developed by Kurtenbach et al. effectively captures non-tidal submonthly variability, and thereby reduces temporal aliasing errors way beyond the level of simply subtracting the standard dealiasing model AOD1B. Validation against in situ ocean bottom pressure observations confirms that the Kalman Smoother solutions published together with the ITSG-Grace2016 monthly gravity fields contain high-frequency signal over the oceans not predicted by AOD1B. The daily gravity fields therefore reduce aliasing artefacts in the monthly gravity fields, and at the same time provide observational evidence on submonthly bottom pressure variability presently not reflected in state-of-the-art numerical ocean circulation models. It is thus recommended to include a Kalman Smoother approach into any standard GRACE processing scheme. For a hypothetical double-pair configuration currently under consideration as a future mass change mission, we find that the benefit of the Kalman Smoother is much smaller thanks to the increased number of observations taken at different inclinations, which lead to generally reduced aliasing errors and much more isotropic spatial error correlations. We also reassess the idea of pre-eliminating low-resolution daily gravity fields and find large distortions in the monthly mean gravity solution at spatial wavelengths around the cut-off-degree of the daily fields. We thus recommend further study for any satellite gravity mission concept that critically relies on such pre-elimination schemes for reaching its science objectives.
Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity
Authors: Valdez Clarissa , Ysselstein Daniel , Young Tiffany J , Zheng Jianbin , Krainc Dimitri
Published: October 2019

Frontotemporal dementia (FTD) is a common neurogenerative disorder characterized by progressive degeneration in the frontal and temporal lobes. Heterozygous mutations in the gene encoding progranulin (PGRN) are a common genetic cause of FTD. Recently, PGRN has emerged as an important regulator of lysosomal function. Here, we examine the impact of PGRN mutations on the processing of full-length prosaposin to individual saposins, which are critical regulators of lysosomal sphingolipid metabolism. Using FTD-PGRN patient-derived cortical neurons differentiated from induced pluripotent stem cells, as well as post-mortem tissue from patients with FTLD-PGRN, we show that PGRN haploinsufficiency results in impaired processing of prosaposin to saposin C, a critical activator of the lysosomal enzyme glucocerebrosidase (GCase). Additionally, we found that PGRN mutant neurons had reduced lysosomal GCase activity, lipid accumulation and increased insoluble α-synuclein relative to isogenic controls. Importantly, reduced GCase activity in PGRN mutant neurons is rescued by treatment with saposin C. Together, these findings suggest that reduced GCase activity due to impaired processing of prosaposin may contribute to pathogenesis of FTD resulting from PGRN mutations.
Intraspecific demography of the silky shark (Carcharhinus falciformis): implications for fisheries management
Authors: Grant Michael I , Smart Jonathan J , Rigby Cassandra L , White William T , Chin Andrew , Baje Leontine , Simpfendorfer Colin A
Published: October 2019

The silky shark (Carcharhinus falciformis) is one of the most heavily fished tropical shark species globally, and currently there is increasing concern for its conservation status. However, large differences and ambiguity in life history parameter estimates among regions complicates its conservation and fisheries management. Using a Leslie matrix model that incorporated stochastic effects, we analysed the intraspecific demography of C. falciformis using available life history data from seven regions. Among regions, large differences were observed in generation time and age-specific reproductive contributions. Carcharhinus falciformis generally had low resilience to fishing mortality (F) throughout its distribution. Age-at-first-capture and age-at-last-capture management approaches resulted in substantial differences among regions. This was largely influenced by age-at-maturity. However, in scrutinizing some regional life history studies, it is likely that sampling design and methodological differences among regions have resulted in inaccuracies in life history parameter estimates and subsequent demographic attributes. This implies that age and life-stage-dependent management approaches using these possibly inaccurate life history parameters may be inappropriate. We suggest that a greater emphasis needs to be placed on eliminating human sources of error in elasmobranch life history studies to ensure management for wide-ranging species, such as C. falciformis, is most effective.
Tim-3 Promotes Listeria monocytogenes Immune Evasion by Suppressing Major Histocompatibility Complex Class I
Authors: Wang Zhiding , Li Ge , Dou Shuaijie , Zhang Yanling , Liu Yiqiong , Zhang Jiacheng , Li Guoxian , Hou Chunmei , Wang Renxi , Shen Beifen , Han Gencheng
Published: October 2019

Background

T-cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint inhibitor that has therapeutic implications for many tumors and infectious diseases. However, the mechanisms by which Tim-3 promotes immune evasion remain unclear.

Methods

In this study, we demonstrated that Tim-3 inhibits the expression of major histocompatibility complex class I (MHC-I) in macrophages at both the messenger ribonucleic acid and protein levels by inhibiting the STAT1-NLRC5 signaling pathway.

Results

As a result, MHC-I-restricted antigen presentation by macrophages was inhibited by Tim-3 both in vitro and in a Listeria monocytogenes infection model in vivo. Systemic overexpression of Tim-3 or specific knockout of Tim-3 in macrophages significantly attenuated or enhanced CD8+ T-cell activation and infection damage in L monocytogenes-infected mice, respectively.

Conclusions

Thus, we identified a new mechanism by which Tim-3 promotes L monocytogenes immune evasion. Further studies on this pathway might shed new light on the physio-pathological roles of Tim-3 and suggest new approaches for intervention.